Transcript for:
Overview of Nervous System Development

Title: URL Source: blob://pdf/3421481d-34be-4f80-bb40-de2e489a7069 Markdown Content: 2nd Lesson Neuroanatomy Development of the nervous system 1 Development of the Nervous system The central nervous system originates from the neural plate and from the neural tube ; the peripheral nervous system originates from the neural crest cells ; the Dura Mater , the thickest meninges, originates from the mesoderm , while the Pia mater and the Arachnoid originate from the neural crest cells . (Revision of gastrulation and neurulation from 3 rd week lesson of BB) Some neural crest cells remain close to the neural tube, forming the sensory ganglia . While the neural tube is forming, somitogenesis is also taking place and, therefore, the future spinal cord is starting to establish connections with the derivatives of the somites. Importance of folic acid (B9 vitamin) As part of the preconception care, primary care clinicians should advise all women of reproductive age to take a vitamin that contains folic acid 400 to 800 mcg one/day (0.5 0.8 mg per day). Folate reduces risk of neural tube defects . If women have had a fetus or infant with a neural tube defect, the recommended daily dose is 4000 mcg (4 mg). Taking folate before and after conception may also reduce the risk of other birth defects. The most distal portion of the neural tube forms by a secondary neurulation from the tail bud or caudal eminence (remnant of the primitive streak). This process is formed by condensation of mesenchymal cells in the tail bud, formation of a cord, canalization and junction with the rest of the neural tube. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 2 Defects of the neural tube and spine due to perturbation of neurulation Defects of the neural tube are called dysraphisms (incomplete fusion). They originate during the 3 rd and 4 th week. They can be open or closed ; they are closed when covered by the skin. There are 3 main subdivisions: Craniorachischisis (complete dysraphism ) (1): the neural tube is completely open all throughout its length. The neural tube does not form and, associated to this, also the bones that cover the neural tube do not form. Cranioschisis or anencephaly (2): the neural tube is open in the cephalic region and the spinal cord is normal. The brain is not functional and most babies die a few hours after birth. It is usually due to the fact that the anterior neural pore does not close. Also, the cranium is not developed: the development of the cranium is usually driven by the correct formation of the brain, if it is not formed, we will have also problems in the formation of the cranium. The spinal cord is normal, but the skull is open and the brain is absent. Myeloschisis (3): dysraphism of the neural tube at the level of the spinal cord. Usually affects the lumbosacral region (only the most caudal portion of the neural tube is open). In this case we can notice a Spina Bifida Aperta due to the fact that the vertebral arches of the last part do not fuse together. Spina bifida Usually, a baby that is born with a spina bifida is the most likely to survive. Depending on the gravity of the spina bifida we can judge how long and how well it will survive. Most defects of the spinal cord are caused by a problem in the closure of the neural tube during the 4 th week . These defects are called spinal dysraphism . They are most commonly associated to defects of the vertebral arches , which cause an opening of the vertebral canal (spina bifida). We have different types of spina bifida, with a different clinical outcome that have in common the lack of fusion of the vertebral arches. The main types are spina bifida occulta (not evident at observation); spina bifida aperta (visible at observation); spina bifida cystica , which can be associated to meningocele, meningomyelocele or myeloschisis. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 3 The spina bifida occulta is characterized by the growth of some strange hair on the skin that overlay the affected region of the back. In the spina bifida with meningocele , the spinal cord is in place, but there is a cyst that grows from the meninges, which protrudes outside the vertebral canal, below the skin. In the spina bifida with meningomyelocele , we have the protrusion of the meninges again, but, in this case, we also have a portion of the spinal cord that is protruding in the cyst. In this condition, usually, the roots are stretched and damaged . The spina bifida with myeloschisis is characterized by the lack of spinal cord in that region. Its severity is established according on how stretched are the roots. It can cause paralysis of the lower limbs, impossibility to control the lower sphincters (which causes formation of infections at the level of the urinary system). Spina bifida is more common among whites and Hispanics . Girls are more affected than males. A woman who was born with a neural tube defect, or who has a close relative with one, has a greater chance of giving birth to a child with spina bifida. Folate (vitamin B9) is important to the healthy development of a baby. Anti-seizures medications, such as valproic acid (Depakene) can be the cause of the development of the spina bifida. Diabetes, especially if not controlled can cause the woman to have a higher chance of having a baby with spina bifida. Pre-pregnancy obesity is associated with an increased risk of neural tube birth defects, including spina bifida. Moreover, some evidences suggest that increased body temperature (hyperthermia) in the early weeks of pregnancy may increase the risk of spina bifida. Elevating the core body temperature, due to fever or due to the use of saunas or hot tubes, has been associated with the risk of spina bifida. Cranium bifidum Defects of ossification of the skull, mostly of the occipital bone may lead to Encephaloceles or cranium bifidum , which has an incidence of 1:2,000. This defect of ossification of the skull can probably be caused by a defect in communication between the mesoderm and the forming neural tube. In a meningocele , we have the protrusion of the meninge; with the meningoencephalocele , we have the herniation of the external part of the brain as well; while in the meningohydroencephalocele , which is the worst condition, we have, besides the herniation of the external cortex of the brain, we also have the herniation of the ventricular spaces that are inside the CNS. The problem in this condition is how much brain is herniated and how much of it is still functional. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 4 Midline defects: problems in the separation of structures because of the lack of expression of some genes In the rostral portion of the neural plate there is the eye field , where the eye vesicles are going to form. At the beginning there is only 1 eye field, which at some point will be divided into 2. In that area, we will have also the developing of the 2 brain hemispheres . If Sonic hedgehog is not expressed correctly on the midline, it can lead to holoprosencephaly and cyclopia . It is seen in trisomy 13 (Patau syndrome) and it may result from alcohol abuse (especially in the first 4 weeks). It is the most severe manifestation of fetal alcohol syndrome. Most cases of holoprosencephaly seem to be multifactorial. Nevertheless, maternal drinking alcohol during the first month of pregnancy appears to be one of the most important causative factors. In case of maternal diabetes, 1-2% of new-borns may develop a degree of holoprosencephaly. The fetal alcohol syndrome can cause growth retardation, low nasal bridge, congenital heart abnormalities, microcephaly, intellectual disabilities, learning disorders, hyperactivity, poor attention span, moodiness. Histogenesis of the neural tube When the neural plate forms, we can start to appreciate, the region of the neural tube to become a columnar epithelium. If we look more carefully, in reality it becomes a sort of pseudostratified epithelium, where we can observe some neuroepithelial cells that are mitotically active. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 5 If we look at the nuclei of the cells, many of them are in the process of dividing, which means that the neural tube is starting to increase the number of precursor cells. The process of increasing the number of cells take place through a process called interkinetic nuclear migration. To proliferate, the precursor cells, they extend 2 cytoplasmic processes, one remains in contact with the ventricular side (V) and the other that attaches to the external side (Pial side). Then the nucleus is pushed to the pial side and in the meanwhile, the cells enter into the S phase. When the cells are pushed back to the ventricular side, they first enter into the G2 stage and then they undergo mitotic division. This is a symmetric cell division, which generates 2 morphologically similar daughter cells that are both likely to be stem cells, increases the population of precursors cells. This mechanism of symmetric division also takes place in the skin. At some point (from day 33), some of the cells, rather than undergoing a symmetric division, they undergo an asymmetric division (perpendicular to the plane of the epithelium) and one of them is going to remain a precursor cell, while the other one stops the cycle and starts to differentiate either in a neuron or in a glial cell. The differentiated cells start to move to their final position in the nervous system. They move through radial glia, through a process called neural terminal translocation. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 6 CDC42 is an adhesion molecule, which helps the cell to attach to the radial glial. The radial glia, besides serving as a sort of framework to move neurons, is a sort of stem cell itself, finally they are also going to form neurons themselves. Through the process of interkinetic nuclear migration, there is the formation of neurons, glial cells and the organization of the neural tube into 3 zones: the ventricular layer or ependymal layer; the mantle layer or presumptive grey matter and the marginal layer or presumptive white matter. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 7 This organization is very similar to the adult organization of the spinal cord, while in the rest of the nervous system, it is going to undergo to major changes. This organization will be initially the same for all the neural tube, except for the zone where the cortex is going to form. Differentiation of nerve cells and neural circuits is a long process. It begins with neurulation; it proceeds all throughout pregnancy and then it continues for many years after birth. Before birth we have the production of neurons and glial cells, then we have the cell migration and then the molecular specification and initial connectivity. In the meanwhile, we have a lot of cell death. After birth, the cytoarchitecture of the of the different areas of the nervous system starts to acquire a more definite shape; we reach a neurochemical maturation and we have dendritic arborization and synapses formation. After 2 years, we have a pruning of the neurons. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 8 While the nerve cells and the synapsis are forming, we also have the formation of myelination. It is very important that the relationship between the axon the myeline takes place correctly. The diet of the baby can affect very much the myelination of the baby, in fact, most of the myelination takes place after birth: Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 9 Babinski reflex or plantar reflex Babinski reflex is one of the normal reflexes in infants. Reflexes are responses that occur when the body receives a certain stimulus. The Babinski reflex occurs after the sole of the foot has been firmly stroked. The big toe then moves upward or toward the top surface of the foot. The other toes fan out. This reflex is normal in children up to 2 years old. It disappears as the child gets older. It may disappear as early as 12 months. When the Babinski reflex is present in a child older than 2 years or in an adult, it is often a sign of a brain or nervous system disorder. Disorders may include: amyotrophic lateral sclerosis; brain tumour or injury; meningitis; multiple sclerosis; spinal cord injury, defect or tumour; stroke. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 10 Other reflexes: Palmar (lost over the first 3 months) and plantar grasp reflex (lost over the first 10-15 months) Moro reflex (lost over the first 5 months) Asymmetric tonic neck reflex (lost over the first 6 months) Parachute reaction (develops from the 6th month) Balance test (forward develops from the 6th month; sideward develops from the 7 th month; backward develops from the 11 th month) Many of these reflexes disappear because the descending pathways are maturing and therefore the simple reflex activities are under the control of the descending pathways. Derivatives of the neural crest The neural crest is at the origin of the peripheral nervous system. Some cells that are close to the neural tube remain there and they are going to form the neural tube ganglia, while some others migrate, forming several parts of the body (review neurulation from BB) . The neural crest cells can be divided into a cranial portion and a trunk portion. Cranial neural crest cells contribute to the formation of Pharyngeal arches: skeletal and connective tissue Bones of the neurocranium Pia and arachnoid Parafollicular (C cells) of the thyroid Aorticopulmonary septum Odontoblasts Sensory ganglia of cranial nerves (V, VII, IX, X) together with placodes Parasympathetic ganglia (ciliary CNIII; Pterygopalatine, CNVII; submandibular, CNVII, Otic, CN X) Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 11 Trunk neural crest cells give rise to Melanocytes Schwann cells Chromaffin cells of adrenal medulla Dorsal root ganglia Sympathetic ganglia Enteric nervous system ganglia Abdominopelvic parasympathetic ganglia Placodes If we look at the head of the embryo early (around day 32), where the pharyngeal apparatus is forming, we can see that the ectoderm, in some region, is thickening, forming some placodes, such as the crystalline placode (eye); the acoustic placode (ear); and the olfactory placode (nose). For the formation of cranial nerves sensory ganglia, we need the contribution of the neural crest cells and the placodes. Neurocristopathies Neurocristopathies (NCP) are a class of pathologies occurring in vertebrates, especially in humans that result from the abnormal specification, migration, differentiation or death of neural crest cells during embryonic development. Various pigment, skin, thyroid and hearing disorders, craniofacial and heart abnormalities, malfunctions of the digestive tract and tumours can also be considered as neurocristopathies. Some examples of neurocristopathies can be: Medullary carcinoma of thyroid (C cells): can be associated with MEN (multiple endocrine neoplasia) autosomal genetic disorder Schwannoma: benign tumour, most common acoustic neurinoma Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 12 Neurofibromatosis type I (von Recklinghausen disease): dominant genetic disorder, protein neurofibromin (tumour-suppressor gene). Multiple neural tumours (neurofibromas) dispersed in the body originating from peripheral nerves cells (neurites, fibroblasts, Schwann cells), pigmented skin lesions. CHARGE association Coloboma of the iris Pheochromocytoma: generally, in the adrenal medulla. Contains both epinephrine and norepinephrine. 40-60 years old. Persistent or paroxysmal hypertension, anxiety, tremor, profuse sweating, pallor, chest pain and abdominal pain. Signs due to the excessive production of epinephrine and norepinephrine. Neuroblastoma: common extracranial neoplasm. Contains primitive neuroblasts (Homer Wright pseudo rosette). Mainly in children (up to 15 years) in sympathetic chain ganglia or in the adrenal medulla. Metastasis to bones and bone marrow and lymph nodes very easily. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 13 Cleft palate DiGeorge Syndrome Hirschsprung Disease or Megacolon Development of the spinal cord The development of the spinal cord is a useful prototype for studying the overall structural and functional features of the CNS. In the spinal cord, we find the simplest organization of the neural tube. When we observe the neural tube at the spinal cord level, we find the typical arrangement into 3 layers: the ventricle, the mantle and the marginal layer. When we look at the future spinal cord, we see a ventricular cavity (the future central canal), limited by a ventricular zone; surrounding them we can notice the mantellar zone, where we find all the neurons (cell bodies). Soon after development, the mantellar zone is going to be divided into 2 territories: one dorsal, called alar plate, and the other ventral, called basal plate. If we look from the inside of the ventricular cavity, we can notice a sort of sulcus that delimits the territories that are going to form the alar plate dorsal and the basal plate ventral, which is called limiting sulcus. The alar plate is going to become the sensory region and the basal plate the motor region. The alar plate will form the dorsal cord (posterior, sensory territory), while the basal plate will form the ventral cord (anterior, motor territory). We can also appreciate that, between the right and left side, ventrally and dorsally, we have the formation of the roof plate and of the floor plate. The roof plate is called a non-permissive territory, while the floor plate is a permissive territory. Permissive refers to axons that are able to cross on the other side. The lumen is going to be progressively reduced in size, up to becoming the spinal canal or ependymal canal. The alar plate and basal plate are going to change their shape, becoming the dorsal and ventral horns (in some region, we can even find the lateral horn). Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 14 Surrounding the alar and basal plate, we have the formation of white matter, made of axons coming from the grey matter. Morphogens and transcription factors specify the dorso-ventral patterning of progenitors in the neural tube. Ventral to the neural tube there is the notochord, which starts to produce a lot of Shh together with the floor plate, thus creating a gradient from ventral to dorsal of concentration of Shh. This gradient of concentration, helps to specify the progenitor domain of the mantellar zone of the neural tube. On the other hand, the epidermis that is located above the neural tube produces BMPs (bone morphogenetic proteins), creating an opposite gradient respect to Shh. These 2 gradients determine the dorsal-ventral cell fates. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 15 This is why we can graft an additional notochord close to the neural tube and create 2 floor plates. The notochord ha an influence on the development of the floor plat and exit sites of nerves from the spinal cord. Development of the spinal nerves While the alar and basal plate are forming, on the side of the neural tube, we have the neural crest cells that did not migrate. They are going to form the sensory ganglia, where progressively we start to see the formation of the pseudo-unipolar sensory neurons, those neurons that collect information from the periphery and bring them to the CNS. This sensory neurons have 2 branches, one toward the periphery and the other toward the sensory territory of the spinal cord, starting to form the dorsal roots (which contain the centripetal branches of the sensory neurons). At the same time, in the basal plate, which is becoming the motor territory, we have the formation of motor neurons, which will innervate and control muscle fibers. Some of them are somatic motor neurons and are going to innervate the skeletal muscle; some other are visceral motor neurons and are going to innervate the smooth muscle fibers (the same is for sensory neurons). The axons of these motor neurons are going to form the ventral roots of the spinal cord. Each dorsal root and each ventral root come together to form spinal nerves. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 16 When we consider a dorsal root, in it we can find a somatic sensory component and a visceral sensory component; in the ventral root, we can find, instead, a somatomotor component and a visceromotor component. Since the 2 roots come together to form a spinal nerve, each of them has 4 components: a somatosensory component, a visceral sensory component, a somatomotor component and a visceromotor component. That is why the spinal nerves are also called mixed nerves. In the spinal cord, we must have neurons to process each of the type of information carried in the spinal nerves, so we can divide the grey matter of the spinal cord into regions corresponding to each type of neuron of the spinal nerve. Autonomic and somatic motor systems The innervation of skeletal muscle is formed by the muscle itself, by the motor control, so the motor neuron either in the spinal cord or in the brain stem, which leaves them by the spinal root and finally forms a motor end plate with the skeletal muscle. When we consider the innervation of smooth muscle and glands, the chain of events involves at least 2 synapses: we have a visceromotor neuron (or preganglionic neuron) in the CNS that has an axon linked outside the CNS via the ventral root and then it reaches on other neurons, located on autonomic ganglia, which then innervates smooth muscle or glands in visceral organs. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 17 Pattern of autonomic innervation During development, some of the axons of neurons in the motor portion of the spinal cord will have to decide if they will be synapses on skeletal muscle fibers or ganglion, which belongs to the autonomic nervous system. The spinal cord is divided into segments, also called neuromeres. Each segment is defined by the presence of 2 dorsal, 2 ventral roots, and 2 spinal nerves, one on the right and one on the left. The dorsal root and the ventral root come together at the level of the intervertebral foramina, where we find the dorsal root ganglia, to form the spinal nerve. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 18 We have segmentation of the spinal cord due to the formation of the somites, which are innervated by nerves coming from the neural tube. (Review of somitogenesis from BB) The spinal cord acquires a segmental organization because each segments innervate the cutaneous territory (dermatome), the bony territory (sclerotome) and the muscular territory (myotome) originating from the adjacent somite. This connection is maintained also when the somites disappear, forming the dermatomeric map: A dermatomeric map is the representation of stretches of skin whose sensory innervation depends mostly from a single segment of the spinal cord. There is a partial overlapping in the innervation of the dermatomeres, that is why it is very difficult to lose completely the sensation of the skin in a particular zone if only one segment of the spinal cord is damaged (we would have a hypoesthesia, which is a reduction of sensation in a territory of the skin). Close to the spinal cord we have the formation of the dorsal root ganglia, and each of them, sends its centripetal branches to a segment of the spinal cord; while its centrifugal branches to the derivatives of a somite. We can understand at which level of the spinal cord something is going wrong touching the correspondent part of the skin. If we consider the innervation of muscles, the division isnt very clear: if the innervation of a territory of the skin originates from only one somites; to control one muscles, we need more than one segment because one muscle originates from more than one myotome and one myotome gives rise to more than one muscle. That is why when we study the innervation of the muscles, we cant say exactly which segment innervates a muscle and, therefore, the motoneurons that innervates one muscle are localized in more than one segment of the spinal cord. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 19 A neuromere usually innervates more than one muscle and a muscle is usually innervated by more than one neuromere, which causes the formation of anastomosis between nerves that originate from different neuromeres (neural plexuses). Most of the spinal nerves, with the exception of the thoracic spinal nerve, have to form plexuses, which means that they exchange fibers to one another. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 20 In this drawing we have 3 segments of the spinal cord which innervates different muscles. If we consider muscle C, it needs to receive motor fibers from 3 different segments of the spinal cord; but these 3 segments, they do not innervate only muscle C, but for example red segment also innervates muscle A and D The plexuses form because of the embryological origin of muscles, which causes the fact that different spinal nerves have to exchange fibers thus to allow each muscle to receive the correct innervation. Due to the fact that the myotome is going to be divided into 2 portions, the spinal nerve has to be divided into a dorsal ramus and a ventral ramus or branch. That is why they have to reach the ventral and dorsal division of the myotome. Ascent of the spinal cord The vertebral column grows relatively more compared to the spinal cord, which causes the apparent ascending of the spinal cord. In fact, the spinal cord ends at the level of L2, but at the beginning of development, the spinal cord has the exact same length of the vertebral column. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 21 The roots of the spinal nerves acquire progressively a more oblique course inside the vertebral canal. At the beginning, the motoneurons and the sensory ganglia have already been making the connections with the periphery and in the first portion of the spinal cord, the roots of the spinal nerves exit at the same level of the vertebra with the corresponding number; but, when the disparity between the length of the vertebral column and the spinal cord becomes evident, still the roots continue to exit from the same intervertebral foramina, starting to become slightly more oblique. When this happens, the segment of the spinal cord is not anymore at the same level of the correspondent vertebra. This obliqueness of the roots is very evident for the caudal most root: when we consider the cervical segment of the spinal cord the root exit horizontally since they remain at the same level, but going down through the spinal cord, they become progressively more oblique until finally the last portion of the vertebral canal is filled with the roots of the last segments of the spinal cord, forming the cauda equina. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 22 Development of the brain In the rostral portion of the neural tube, we find 3 subdivision. In the first subdivision we have the forebrain (prosencephalon), the midbrain (mesencephalon) and the hindbrain (rhombencephalon). These 3 subdivision are not straight, but curved due to the fact that in the 4 th week of development we have the rostral folding of the embryo. Because of this bending we can recognize some flexures: the cephalic flexure, at the level of the midbrain and a cervical flexure, between the rhombencephalon and the spinal cord. Then we have a second subdivision, with the formation of the telencephalon and diencephalon from the prosencephalon; and the formation of the metencephalon and myelencephalon from the rhombencephalon. Ventricular system At the beginning, when it is still a simple tube, the lumen of the tubular nervous system is quite roundish, but then, because of the growth of the wall of the neural tube and because of the formation of the vesicles, also the cavity that are inside the neural tube change their shape, forming the ventricles. The lumen of the neural tube, at the level of the area where the spinal cord will be formed, will shrink always more, as to form the central canal. At the level of the rhombencephalon, we find a large cavity, which will form the 4 th ventricle; if we move to the mesencephalon or midbrain, the cavity inside progressively becomes very thin, as to form the Aqueduct of Silvius. Inside the diencephalon, the cavity will form the 3 rd ventricle; while the telencephalon will divides into 2 subdivisions that will form the cerebral hemispheres, we have 2 lateral ventricles, one on the right and one on the left. In conclusion we will have 4 ventricles: the 2 lateral ventricles (from the telencephalon), the 3 rd ventricle (from the diencephalon) and the 4 th ventricle (from the rhombencephalon). These cavities, even after all the development of the nervous system, will continue to be in communication with one another. In the telencephalon and diencephalon, we can notice the choroid plexuses, which are specific regions of the wall of the neural tube where we have the formation of the cerebrospinal fluid, which will fill the different cavities of the brain. The fluid is a filtrate from blood, which is produced at the level of the ventricle cavities. We find choroid plexuses at the level of the lateral ventricles, in the roof of the 3 rd ventricle and at the level of the roof of the 4 th ventricle. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 23 The cerebrospinal fluid is found inside the neural cavities, but it can also be found in the subarachnoid space, between the meninges, which means that at some point, the ventricular cavities communicate with the subarachnoid space that surrounds the brain and the spinal cord so that the fluid can flow from the ventricles to the subarachnoid spaces. The brainstem The brainstem is deriving from the vesicles of the myelencephalon, metencephalon and mesencephalon. These 3 vesicles are going to give rise to the 3 components of the brain stem, which are the medulla oblongata or medulla; the pons or pons of Varolii and the midbrain or mesencephalon. In the adult, the brainstem does not look segmented like the spinal cord. Dorsal to the brain stem, we can find the cerebellum. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 24 In humans, the cranial nerves are 12, from the brain stem we have the origin of 10 cranial nerves, from the 3 rd to the 12 th . Looking at the organization of the nerve cells, we can notice how in the cranial nerves we have no segmental organization in their exit. The cranial nerves are not part of the CNS, they constitute a communication between the central nervous system and the periphery. In the brain stem we do not find the same segmented structure of the spinal cord because, in a spinal nerve, we have 4 components of the spinal nerves (visceromotor and somatomotor, viscerosensory and somatosensory), in the cranial nerves we have an heterogenous composition: for example, the 4 th cranial nerve (the trochlear nerve) innervates just one muscle and therefore this nerve is only somatomotor; if we consider the hypoglossal nerve (12 th nerve), we have only muscular territory innervation, so only somatomotor innervation; if we take the 8 th nerve, it has only somatosensory component. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 25 The first 2 cranial nerves, the olfactory and optic nerves do not originate from the brin stem and they are not considered peripheral nerves. If we look at the wall of the vesicles that will form the brain stem, at the beginning, we have the formation of the alar, basal, roof and floor plate as we saw in the spinal cord. This organization, in the brain vesicles, though, does not remain like that: at the level of the rhombencephalon there is a change in the structure of it, which undergoes to a book-like opening and the territories of the alar plate start to move very lateral. This causes a change in the relative position between the alar plate and the basal plate: now the basal plate can be considered medial and the alar plate is lateral and at the same time, the roof plate, at the top, is very stretched. It happens only in the rhombencephalon, with the formation of the 4 th ventricle. Besides this, we have a fragmentation of the alar and basal plates that leads to the migration and clustering of neurons into nuclei, which are divided into nuclei of the cranial nerves and specific nuclei. Some of the nuclei of the cranial nerves are going to form the motor roots of the cranial nerves, some are going to form the sensory nuclei that receives the information from the ganglia; the specific nuclei are intercalated into ascending and descending pathways. At the level of the rhombencephalon, because of the book-like opening, the cavity that was inside the rhombencephalon becomes quite large and gives rise to the 4 th ventricle. At the level of the roof of the 4 th ventricle we have the formation of the choroid plexuses. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 26 In the spinal cord we could recognize 4 territories; in the brain stem, the organization of the territories is, initially, medial to lateral. When the brain stem will be completely developed, we will have 7 different territories. The skeletal muscles innervated from the cranial nerves are divided into 2 categories: those that originate from the somites and those that originate from the pharyngeal arches. Therefore, instead of having 1 somatomotor regions, in the brain stem there are 2 somatomotor regions, one innervating the muscles of somatic origin and one that innervates muscles of branchial origin. Then we have the visceromotor component (cranial nerves that innervate viscera), like the vagus nerve; the viscerosensory territory; then we have the special viscerosensory, which collects special visceral sensation from the region of the tongue; the somatosensory territory; and the special somatosensory, which collects special information from the ear. In the image we can read somatic efferent column, where efferent means motoneurons (from the brain to the periphery); branchial efferent column that innervates the muscles of pharyngeal origin; visceral efferent column, which means innervation of internal organs; visceral afferent column that brings information from the viscera to the CNS; special visceral afferent column, which innervates the tastebud; general (somatic) afferent column, which innervates skin and muscles of the head; and special somatic afferent column, which collects specific information by the inner ear. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 27 Cranial nerves differ in composition and each of the 7 territories is not always present along the longitudinal axis of the brainstem. The differences can be noted along the longitudinal axes. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 28 When we look at the mesencephalic vesicle, we do not have a book-like opening, we have the normal proliferation of the wall of the neural tube, but we still find the process of fragmentation of the basal and alar plates. The cavity of this vesicles shrinks quite a lot, to give rise to the aqueduct of Silvius. At the level of the midbrain, we find a special structure called lamina quadrigemina or tectum, which is visible only in the most rostral portion of the brainstem. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 29 In the cavity of the 4 th ventricle, we can recognize a floor and a roof, which is very thin and does not contains functional neural cells, but derives from the original roof plate that has been stretched during the opening. The 4 th ventricle is important because it is the only place where the cavities that are inside the CNS communicate with the spaces that surrounds the CNS and which also contain cerebrospinal fluid. In particular, the cerebrospinal fluid will be stored in the subarachnoid spaces of the meninges. This fluid is produced by the choroid plexuses and then at the level of the posterior and lateral walls of the 4 th ventricle, it exits by 3 openings in the subarachnoid spaces. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 30 The thin roof of the 4 th ventricle (ependymal lamina) becomes covered by the innermost of the meninges (pia mater) and becomes the tela choroidea. Wherever in the CNS we have a region that is very thin, that is an ependymal lamina, and the pia mater adheres to it, we have the formation of the tela choroidea. At its level, we have the formation of choroid plexuses: some vessels start to push in front of them the tela choroidea, which protrudes inside the lumen, forming the choroid plexuses. These tele choroidea and choroid plexuses will also be formed at the level of the 3 rd ventricle and of the medial wall of the telencephalic vesicle. The choroid plexuses of the lateral ventricle are in continuity with the ones of the third ventricle. At the level of the 4 th ventricle, the cerebrospinal fluid both continues to flow below, as to fill the spinal canal and it exits and then flow into the subarachnoid spaces. Then it is reabsorbed mostly at the level of the venus sinuses that we find inside the skull. The only communication between the ventricles and the subarachnoid spaces is at the level of the 4 th ventricle, so if, for any reasons, we have an obstruction of that opening (inflammation of meninges that leads to fibrosis, cerebellum tumour that compresses that region, herniation of the cerebellum, etc.), it will cause an accumulation of fluids inside the ventricular cavity that is called hydrocephalus (it will start to compress from the inside to the outside the CNS). Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 31 Development of the cerebellum The cerebellum lies above the roof of the 4 th ventricle and, together with the brain stem, it lies in a region of the skull that is called the posterior cranial fossa. The cerebellum is connected to the brain stem through 3 pairs of cerebellum peduncles, which are divided into superior (connect the cerebellum with the midbrain), middle (the largest, called the brachium pontes since they connect the cerebellum with the pons) and inferior (connect the cerebellum with the medulla oblungata and they are also called the corpus restiformis) peduncles. The origin of the cerebellum is mostly from the alar plate of the metencephalic vesicle (pons), which grows to cover the roof of the 4 th ventricle. The metencephalic vesicle, through the neurons of the alar plate, gives rise to the cerebellum. The cerebellum, which is a proliferation of the alar plate on the right and left side, starts to grow, up to cover the roof of the 4 th ventricle. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 32 While the cerebellum is developing, very early, we start to appreciate that we can recognize in it a central region, called vermis of the cerebellum and on the 2 side we start to see the formation of the 2 cerebellar hemispheres. We start to distinguish, very early again, that the cerebellum can be divided into 3 main lobes: the anterior and posterior, separated by the primary fissure; moreover, we have the flocculonodular lobe, which is the oldest form the phylogenetic point of view. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 33 The organization of the grey and white matter in the cerebellum is quite peculiar: we have the cortex at the surface, which is organized into 3 layers, below it, we find white matter and deep to the white matter, we find grey matter, organized into 4 nuclei, called deep nuclei. Another thing that happens is, because the cerebellum cortex has to host a huge number of neurons, the cerebellar cortex starts to fold on itself, which causes the organization of the cerebellum in folia or lamellae, which are parallel to one another. Medulloblastoma is the most common malignant brain tumour in children accounting for 10-20% of primary CNS neoplasm and approximately 40% of all posterior fossa tumours. It is a highly invasive embryonal neuroepithelial tumour that arises in the cerebellum (mostly vermis) and has a tendency to disseminate throughout the CNS early in its course. The tumour can grow as to compress the roof of the 4 th ventricle, causing hydrocephalus. There are at least 4 types of neuroblastoma. The one we know better is the one originating from the population of cells of neuroepithelial cells, which is called the external granular layer. Most neurons of the cerebellar cortex originate from the ventricular zone (Purkinje cells, basket cells, stellate cells, Golgi cells, deep nuclei cells), but some of them originates in a different way and form a layer in the primordial cerebellar cortex, called external granular layer, which then starts to migrate deep into the cerebellar cortex as to form the internal granular layer. This external layer starts to be present from the 8th week and it is still visible up to the 2 nd year of age. What it can happens is that some of the cells of this layer start to proliferate in an anomalous way, giving rise to a neuroblastoma. At the beginning the signs are intermittent and subtle, maybe the baby starts to complain of headache and it can have lethargy and vomiting. This conditions can be caused by an increased intracranial pressure. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 34 Arnold-Chiari or Chari spectrum of malformations This disease is characterized by 4 syndromes, the type I is the most common. It is characterized by a herniation of a portion of the cerebellum, called cerebellar tonsils; of the caudal part of the vermis; and sometimes, also the medulla oblongata through the foramen magnum. Herniating, they start to compress the lower part of the medulla and the upper portion of the cervical segment of the spinal cord. It is frequently associated with syringomyelia, a situation in which we have the formation of a cavity in the central portion of the spinal cord, in this case at the cervical level, around the central canal. Due to this, we can have the compression of the communication between the 4 th ventricle and the subarachnoid spaces, with the formation of n hydrocephalus (a non-communicating hydrocephalus). There can also be some posterior cranial fossa problems. This condition develops with time and it usually gives rise to some cerebellar signs such as ataxia (poor coordination), vertigo, nystagmus (abnormal eye movements); moreover, the brainstem is also involved, so we can have signs such as respiratory and cardiac arrest. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 35 Dandy-Walker malformation or syndrome Another developmental problem, which is the most common malformation of the posterior cranial fossa is the Dandy-walker syndrome. This malformation is caused by a lack in the formation of part of the cerebellum, especially of the vermis region, which is partly underdeveloped and partly attached to the superior part of the brain. The area of the cerebellum will form a large cystic cavity, due to the enlargement of the cavity of the 4 th ventricle What we can do is trying to reduce the pressure of the cerebrospinal fluid in the system and try to prevent worse situations. Development of the telencephalic and diencephalic vesicles In the telencephalon, we have a huge amount of neurons that are being produced, so the 2 telencephalic vesicles starts to grow also dorsally and posteriorly, together with rostrally, acquiring a C-shaped appearance and completely enveloping the diencephalon. That is why when we look at the adult brain, we do not see the diencephalon unless we tear apart the hemispheres. The only part where we can see it is from the ventral view, where the ventral portion of the diencephalon has remained uncovered by the telencephalon. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 36 Due to the movement of the telencephalon, the relative positions of the telencephalon and diencephalon, from in series become in parallel, so, since the diencephalon is surrounded by the telencephalon, in the same plane of section we find diencephalic and telencephalic structures. Development of the diencephalic vesicle At the lever of the diencephalic vesicle, we can also recognize a territory that correspond to the alar plate and a territory that correspond to the basal plate, which are separated by the sulcus limitans. If we look at the roof of the vesicle, we have the formation of the tela choroidea that will give rise to the choroid plexus of the 3 rd ventricle. In the posterior portion of the roof of the 3 rd ventricle, we have the formation of neural tissue, which will give rise to the epithalamus. On the 2 sides, above the sulcus limitans, we have the development of 2 ovoidal large structures, which collectively form the thalamus. The thalamus is a very important structure of the brain because it is the door to the cortex: most of the information that reach the cortex stop first in the thalamus. Below the sulcus limitans, the cavity of the third ventricle is becoming narrower. In the lower portion, we have the formation of the hypothalamus. At the lateral walls, we also have the formation of a subdivision of the thalamus, which is called metathalamus and correspond to where the medial and lateral geniculate bodies are going to form (which are important in the acoustic and visive pathways). Below the thalamus Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 37 and caudally and laterally to the hypothalamus, we have the formation of the subthalamus and of the nucleus pallidus. From the inferior portion of the diencephalic vesicle, we have the formation of 2 protrusions, which will form the optic vesicles. They will then move towards the periphery as to form the retina and optic nerves. From the hypothalamus there is the formation of an infundibular process, which is connected to the hypophysis. From the infundibular process, we have the formation of the pars nervosa (neurohypophysis). The development of the hypophysis is quite complicated: it requires the contribution of 2 components, one of them is the Rathkes pouch, which is a diverticulum of the stomodeum and the second component is the hypothalamus. Craniopharyngioma It can happen that this process of development does not take place as it should and usually it happens due to the Rathkes pouch and this causes the formation of a tumour called craniopharyngioma. Because of its position, this tumour may cause problems in the visual field (since it can compress the optic chiasm, nerves or tract); hypothalamic problems (like problems in metabolism that can cause obesity); endocrine problems; and increased intracranial pressure, which can cause seizures. It is most common in children, but Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 38 also in men and women in their 50s and 60s, since it is very slow to develop or can remain silent for a long time. The telencephalic vesicles The telencephalic vesicles have a roof and a vault. They start to expand and proliferate: the floor of the vesicle is characterized by lot of proliferation, with a limited expansion. It will cause a thickening of the wall, with the adhesion to the lateral wall of the diencephalon and the formation of the basal eminence, which will give rise to the deep nuclei of the telencephalon. The vault of the vesicles proliferates a lot and it undergoes a large expansion, causing the 2 telencephalic vesicles to bend on themselves and envelop the diencephalon. This portion that proliferates a lot of the telencephalon (vault) will form the cerebral cortex. This huge expansion is especially due to the presence of the neocortex. In the medial wall of the vault of the telencephalic vesicles, there is a thinning of the wall with the formation of the tela choroidea and the choroid plexuses of the lateral ventricles. From the 2 telencephalic vesicles we have the formation of the olfactory bulbs, which then connect to the olfactory nerve, the first cranial nerve. Because of this proliferation and expansion, the region of the telencephalic vesicles fuses with the lateral wall of the diencephalic vesicle; moreover, the neurons of the cerebral cortex that is being formed in the meanwhile, start to produce axons, which will extend towards the thalamus, the spinal cord, etc. At the same side, the neurons that are forming in the thalamus, start to project to the cerebral cortex. These 2 processes reaching each other, will cause a splitting of the basal eminence or ganglionic eminence into 2 compartments: 1 will remain medial to the bundle of axons that are getting formed and the other one remains lateral to them. The bundle of axons will form a very important system of white matter that is called internal capsule. The internal capsule is formed by the axons that from the cortex descend and from the thalamus ascend. During the embryological development, this capsule splits the ganglionic eminence into a medial and a lateral division. The medial division will give rise to one of the nuclei of the brain, called caudate nucleus; while the lateral division will give rise to the putamen. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 39 Formation of the choroid plexuses in the lateral ventricles Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 40 While the telencephalic vesicles are growing, we have the formation of the cerebral lobes: the most anterior portion of the telencephalic vesicles takes the name of frontal lobe (frontal because just below the frontal bone); the portion below the parietal bone will take the name of parietal lobe; the portion in relationship with the squamous portion of the occipital bone will be the occipital lobe; and then we have the formation of the temporal lobe, below the temporal bone. At 4 th month of development, the surface of the brain is pretty smooth; then, the number of neurons and circuits is always more increased and progressively the cortex becomes more a more filled with convolutions or gyri. The first fissure that appears is the central fissure, around 6 months. It separates the frontal lobe and the parietal lobe. Then we start to see the appearance of the lateral fissure of Silvius, which separates the temporal, frontal and parietal lobe. In the brain, we can also find the insula or hidden lobe, which is a lobe covered by portions of the parietal, frontal and temporal lobes. If we want to see, in the adult brain, the hidden lobe, we need to divaricate the lateral fissure and, in that point, we will find dome cortex, which is the insular lobe. The formation of the hidden lobe happens because that portion of the telencephalic vesicle does not expand too much because it is very close to where the ganglionic eminence is developing and so it remains stuck in that position. The portions of the other lobes that cover the hidden lobe are called operculum. Because of the change in shape of the telencephalic vesicle, which acquire a C-shape appearance, also the shape of the lumen of the vesicle changes and acquire also a C-shaped appearance, together with one of the deep nuclei of the brain (caudate nucleus). The change in shape of the lateral ventricles causes the formation of 3 horns (frontal, temporal and occipital horns); while the caudate nucleus is divided into head, body and tail. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 41 Hydranencephaly: congenital absence of cerebral hemispheres replaced by hugely dilated ventricles. Causes of it can be infarction (stroke) due to occlusion of internal carotid arteries in uterus, or severe necrotizing encephalitis from toxoplasma, rubella, cytomegalovirus or herpesvirus (TORCH). Commissures During the development of the central nervous system, we also have the development of commissures: axonal connections between the left and right sides of the brain, which are crucial for bilateral integration of lateralized sensory, motor and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. Most of the commissures originate from the lamina terminalis, which is situated at the end of the neural tube, the region where we have the closure of the anterior neuropore. Giuseppe Izzo 2nd Lesson Neuroanatomy Development of the nervous system 42 From the lamina terminalis we have the origin of the corpus callosum, of the anterior commissure and of the hippocampal commissure Fibers of the corpus callosum Giuseppe Izzo Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 1 The spinal cord is contained in one of the body cavities, called vertebral canal . The spinal cord ends up with the conus medullaris at the level of the intervertebral disk between L1 and L2 . The spinal cord is connected to the periphery of the body through spinal nerves . The spinal cord continues with the brain stem at the level of the foramen magnum . At the level of C1 and C2, there is a ligament called atlo-occipital ligament that extends from the occipital bone down to the atlas and it is very easy to kill someone if we insert a pen in this region of the back. Because of its position the spinal cord can be damaged when the vertebral column undergoes to a strain. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 2 The spinal cord is divided into segments . Each segment is identified by 2 pairs of root and 2 spinal nerves. Thoracic, lumbar and sacral nerves roots exit caudally to the correspondingly numbered vertebral bone. The cervical roots exit rostrally to the corresponding vertebra with the exception of C8. We have 8 cervical segments , 12 thoracic segments , 5 lumbar segments , 5 sacral segments and 3 coccygeal segments . This is the Latin classification, in the English one, the coccygeal ones are considered as 1, so the total can be either 33 or 31. Roots exit at the level of the intervertebral foramina , where they form the spinal nerves. The dorsal root ganglia are at the level of the intervertebral foramina. Once the roots have joined at the level of the foramen, we can call the joint nerve spinous nerve, which immediately divides into a dorsal and ventral ramus , which innervates the ventral and dorsal portions of the myotomes. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 3 The meninges We can notice the pia mater (orange layer), which is very thin and transparent and it adheres to the surface of the nervous system; it is that thin and adherent that whenever we have a groove, the pia mater follows it. Then we have the arachnoid (mater) , which is made of a thin level from where filaments (trabeculae) extend up to reach the pia mater. The space between the 2 membranes is called subarachnoid space ,which is filled with cerebrospinal fluid . The outermost of the meninge is the dura mater , which is attached to the arachnoid and together with it, it envelops the roots up to the level of the intervertebral foramina. Between the dura mater and the bone, we find a space which is occupied by adipose tissue and some vessels, in particular there is a venous plexus called epidural venous plexus of Batson , while the space filled with fat tissue is called epidural space . Inside the skull, the epidural space is a virtual space. The spinal cord needs to have some fixation inside the vertebral canal since we do not want it to move around while we move. In a sense, the spinal cord is already fixed: the dorsal and ventral root, at the level of the intervertebral foramina are very tightly squeezed and attached by the dura mater to the bony foramen; moreover, another fixation mean that we have are the denticulate ligaments , which derives from the pia mater. They extend inside the subarachnoid space, up to reach the dura mater. They are 2 flattened Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 4 bands of pial tissue that attach to the arachnoid-lined dura mater. Then there is an additional ligamentous device called filamentum terminalis . The veins that we find in the epidural space form the venous plexus of Batson , which has a clinical relevance. The epidural plexus on one side harvests the red bone marrow of the vertebra; on the other side, it drains in the segmental veins (cervical, intercostal and lumbar). They, on one side, drain at the level of the Azygous veins , while inside the vertebral canal they are connected to the venous plexus of Batson, which is then connected with the bone marrow. They are clinical important because responsible for draining from tissue that belongs to the breast, lungs, prostate gland, which are the 3 places where it is more common to find tumours . These segmental veins do not have valves, which means that it is more probable for tumours to metastasize and reach the vertebrae, which is one of the most common site of metastasis. Compression of a nerve root can be the first sign of a collapsed vertebra. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 5 When the nerve roots leave the intervertebral foramina, the nerve is covered by connective tissue (epineurium ). When the nerve roots are compressed, it can lead to back pain or referred pain : irritation of the root that innervates a particular dermatomeric territory may let the patient feel something in that part of the skin, even though nothing is wrong there. Among the causes that can lead to nerve root compression , we can have herniation of intervertebral disc ,which is a prolapse of the nucleus polposus ; degeneration of the spine with inflammation, called spondylosis ; or bony outgrowth, called osteophytes . Herniation of the nucleus polposus can irritate either only the roots and depending on the position, it usually gets both the ventral and dorsal roots or it can also compress the spinal cord. Other reason for an irritation of the root can be the degeneration of articular capsule with synovial inflammation, which is very frequent with age. The spine is subjected to a lot of stress, it also depends on the type of life and job, but at some point, there can be a degeneration of the capsule that surrounds the joints of the vertebral column, causing an inflammation of the synovial that lines the joints. This inflammation of the joint capsule can cause the irritation of the nerve root and consequent local pain. If the Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 6 joint is close to a position near the exit of a root, there is also referred pain in the area innervated by the root involved. Compression of roots causes problems in the myomeric and dermatomeric territories of innervation. If a ventral root is compressed, it is very difficult to have a paralysis of the muscle, but it can cause weakness and decreased reflexes of that muscle. If a dorsal root is compressed, usually there is a sensory problem in the dermatomeres innervated by that root, but there is never a complete loss because there is a bit of overlapping between adjacent dermatomeres. Lumbosacral roots One important cause of low back pain is a prolapsed intervertebral disk (herniated nucleus polposus). 95% of all disk prolapses occur immediately above or below the last lumbar vertebra . The typical herniation is posterolateral , with compression of the nerve roots passing to the next intervertebral foramen. Symptoms include backache caused by rupture of the annulus fibrosus, and pain in the buttock, thigh or leg caused by pressure on posterior root fibers contributing to the sciatic nerve. The pain is increased by stretching affected root, for example by having straightened leg raised by the examiner. If there is a herniation between L4 and L5 , the roots that are most likely compressed are the roots of the nerve L5 . It produces pain or paraesthesia over the L5 dermatome. Motor weakness may be detected during dorsiflexion of the great toe (later, of all toes and of the ankle) and during eversion of the foot .Abduction of the hip may also be weak; this movement is tested with the patient lying on one side. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 7 In the last portion of the spine, we see the conus medullaris and the cauda equina , which surrounds the filum terminale . The filum terminale is divided into filum terminale externum and internum . It is fibrous tissue covered by pia mater, which forms lots of cords that continues down in the vertebral canal, surrounded by the roots and by the dura mater. At some point the filum terminale internum crosses the dural sac and becomes the filum terminalis externum, which runs in the vertebral canal at the level of the sacral bone and exit to the sacral bone , to attach itself to the dorsal surface of the coccyx . The filum terminale is a filament of connective tissue that extends inferiorly from the apex of the conus medullaris. It is continuous with the pia mater and is described as having 2 sections: the filum terminale intermum : upper three quarters of the filum, covered by the spinal dura and arachnoid meninges; the filum terminale externum : lower quarter of the filum; fuses with the investing dura mater and continues inferiorly to attach to the dorsal coccyx. Below the conus medullaris we find only the roots of the cauda equina , which enveloped by the meninges and the subarachnoid space in this region becomes very large, as to form the lumbar cistern , which consist in the subarachnoid space from the L2 to S2 vertebral bodies. Inside this system we find the roots of the cauda equina. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 8 The roots of the cauda equina can be affected by some pathologies, like a compression . Cauda equina syndrome refers to a characteristic pattern of neuromuscular and urogenital symptoms resulting from simultaneous compression of multiple lumbosacral nerve roots below the level of the conus medullaris. These symptoms include low back pain , sciatica (unilateral or, usually bilateral), saddle sensory disturbances , bladder and bowel dysfunction , and variable lower extremity motor and sensory loss . Cauda equina syndrome is caused by any narrowing of the spinal canal that compresses the nerve roots below the level of the spinal cord. The most common causes of cauda equina and conus medullaris syndromes are the following: Lumbar stenosis (multilevel) Spinal trauma including fractures Herniated nucleus pulposus (cause of 2-6% of cases of cauda equina syndrome) Neoplasm , including metastases, astrocytoma, neurofibroma, and meningioma; 20% of all spinal tumours affect this area Spinal infection/abscess (e.g., tuberculosis, herpes simplex virus, meningitis, meningovascular syphilis, cytomegalovirus, schistosomiasis) Idiopathic (e.g., spinal anaesthesia: these syndromes may occur as complications of the procedure or at the anaesthetic agent, like hyperbaric lidocaine or tetracaine). Spina bifida and subsequent tethered cord syndrome Accessing the epidural and subarachnoid spaces If we want to do a subarachnoid anaesthesia , we do it below L2 because we have a larger subarachnoid space. The normal pressure , at the level of the lumbar system of the cerebrospinal fluid is around 8-15 mm of Hg (100-180 mm of H2O). Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 9 Sampling and analysing the cerebrospinal fluid we can understand whether the patient has some diseases related to it. The cerebrospinal fluid has a whitish appearance, transparent, and with a yellow shade. If it is pinkish or red or white, there is definitely something wrong. In our CNS we usually find 140 to 170 mL of cerebrospinal fluid and it has a rate of production of 0.2-0.7 mL/min . Meningitis Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 10 Meningitis is a very severe condition that can affect babies, toddlers, children and adults and according to the age, there can be differences in the signs and symptoms displayed. In general, if there is fever , headache , vomiting , muscle pain and fever with cold hands and feet , this could be a sign of meningitis. Another important thing to pay attention in case of meningococcal meningitis is that meningococcal bacteria reproduce in the blood stream and cause septicaemia . Blood vessels can be damaged. Faint skin rash that looks like pinpricks. Damaged vessels can cause bleeding under the skin . Blood vessels damage causes blood pressure to fall. Limbs are more affected and this can cause tissue injuries. In severe cases, it may be necessary to amputate . In the spinal cord there are 2 enlargements , called the cervical enlargements and the lumbo-sacral enlargement , which are characterized by a higher presence of matter in that zone. They are present at the level of the segments that innervate the limbs since it is necessary to have a higher control over them. The surface of the spinal cord is not very smooth: we can observe some longitudinally oriented grooves ,most of them extend all throughout the length of the spinal cord, like the anterior median groove and the anterolateral sulcus .Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 11 Fissures, septa, sulci, funiculi/cords/columns We can see a sulcus anteriorly that extend through all the length of the spinal cord, called anterior median fissure , which, at a certain point, stops and there is a territory of white matter, which derives from the floor plate and it is called the anterior white commissures and it is the region where axons can cross to the right and left side. Posterior, we find a median posterior sulcus or septum , which reaches up to the grey matter, which means that there are no commissures here and we have no crossing of axons. If we move a bit laterally, to the right and to the left, we find the anterolateral sulcus , which is formed by the exit of the ventral roots . On the posterior side, at the tip of the dorsal horn , we find the dorsolateral sulcus , which is formed by the entrance of the dorsal roots . In between the dorsolateral sulcus and the median posterior sulcus, we find the intermediate posterior septum due to the fact that this portion of the spinal cord is divided into 2 funiculi. The sulci help us to divide the white matter of the spinal cord into funiculi. The region between the dorsolateral sulcus and the median posterior sulcus is called posterior column or funiculus . The region between the dorsolateral sulcus and the anterolateral sulcus is called lateral funiculus ; the region between the anterolateral sulcus and the anterior median fissure is called anterior funiculus or ventral funiculus . In the anterior median fissure , we can find the anterior spinal artery that because of its length, it is supplied by arteries that originates from different levels of the aorta. If we look at the dorsolateral sulcus ,besides the entrance of the dorsal roots, we find 2 vessels, called posterior spinal arteries . Internal structure of the spinal cord If we look at the internal structure of the spinal cord, we can notice that there is more white matter in the superior part of the spine, while the grey matter is more abundant in the caudal portion. In the white matter of the spinal cord, we find ascending pathways , that from the spinal cord bring sensory information to the brain; and descending pathways , that from the cortex need to reach the motoneurons of the spinal cord. We find more white matter in the superior part of the spinal cord because at the cervical level we have the fibers that are going to be connected with all the spine; at the lower levels, some of the fibers exit Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 12 from the spine and thus it becomes always less prominent and the same is for the pathway that has to reach the brain. If we look at the grey matter, the ventral horns of the enlarged segments, compared to all the others, are larger because we need to have additional motoneurons that innervate the muscles of the limbs .Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 13 The grey matter of the spinal cord can be divided into laminae , which are called Rexed laminae . The uppermost lamina is called lamina I and then II, III and so on. In the thoracic segment there is no lamina VI because it contains lots of interneurons involved in motor control due to the presence of the enlargement of the spinal cord that allows a better control of the limbs. Lamina X is organised around the central canal. If we look at the thoracic region, the laminae have a regular appearance, but if we look at the enlargement at the lumbar level , we can see that the presence of the laminae is clearly visible in the dorsal horn , but in the ventral horn the organization is slightly different: it is more disorganized, mostly due to the fact that in the enlargement we have the presence of groups of motoneurons, which are organized into clusters that are sparse in the ventral horn. When we make a cross section through the spinal cord, we can see the division into laminae, from posterior to anterior. These laminae contain grooves or columns that extend from different lengths. Some columns are present all throughout the length of the spinal cord, while some others are present only in particular regions. For example, the posteromarginal nucleus , which correspond to lamina I , can be found everywhere along the length of the spinal cord, and the same thing happens for the sostanza gelatinosa of Rolando . If we consider the intermedium lateral nucleus , which corresponds to the lateral horn, we find it only in the thoracic region. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 14 Neurons of the spinal cord Radicular neurons : somatic motoneurons and visceromotor neurons . They give rise to axons that form the ventral roots . Neurons that give rise to dorsal roots are not inside the spinal cord, in fact, primary sensory neurons are in the dorsal root ganglia. Funicular neurons : we call them funicular because they send their axons in the white matter of the spinal cord, which is organized in columns or funicula . They can be divided into associative (intersegmental, commissural) and projective (they project above the spinal cord). Golgi II type neurons : propriospinal (local associative circuits), neurons whose axons does not leave the spinal cord. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 15 Radicular neurons Radicular neurons consist of somatic motoneurons , whose axons target skeletal muscles; and visceromotor preganglionic neurons , whose axons innervate finally smooth muscle cells and glands, but first they are linked to other neurons, which then innervate muscles and glands. Among radicular neurons, we have visceromotor preganglionic neurons . Their axons leave the spinal cord through the ventral roots and enters in the spinal nerve. They leave the spinal nerve through a ramus, which is called the white ramus communicantes , which connects them to the paravertebral chain , which is a chain of ganglia positioned in the posterior mediastinum; or on neurons that are not in the paravertebral chain, but that are located in front of the abdominal aorta; and then, is the axon of the neuron with which they synapse that is going to innervate muscles and glands. These neurons can be found at the level of T1-T12 , which form the lateral horn of thoracic segments; but we can also find them at the sacral level of the spinal cord and those are called the preganglionic parasympathetic neurons . In the spinal cord, we also find the somatic motoneurons (motoneurons proper), whose axons leave the spinal cord by the ventral roots and then mono-synaptically distribute to the peripheral skeletal muscles fibers forming the motor-end plate . The most well-known motoneurons are the alpha, gamma and beta . The motor unit consists of a single motor neuron (usually alpha) and the population of muscle fibers it innervates. The muscle fibers innervated by a single motor neuron are not usually adjacent to one another. When the neurons fires, a needle electrode inserted into the muscle records an all-or-none unit potential because the highly effective transmission at the neuromuscular junction ensures that each muscle fiber will contract in response to an action potential. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 16 Each muscle is controlled by several motor units . The more motor units innervate a muscle, the finer the control of that muscle can be. The less skeletal muscle fibers are innervated by a motor unit, the finer is the ability to control that muscle. Groups or columns of motoneurons are somatotopically organized, which means that they are not all mixed together. We have groups of motoneurons that innervate the axial muscles and groups that innervate the distal muscles , and they are in a different position in the ventral horn: the axials are medially localized; those that innervate the distal muscles are more laterally and, generally. Moreover, those that innervate flexors muscles are more dorsally localized than groups of motoneurons that innervates extensor muscles . The column of motoneurons innervating a muscle extends for more than one segment, and we can also have overlapping of columns. Motoneurons can be divided into alpha, gamma and beta. Inside skeletal muscles , we find very sophisticated receptors called neuromuscular spindles , which is a complex receptor, made by modified skeletal muscle fibers. In normal skeletal muscle fibers, the contractile components extend for all the length of the fiber. These fibers, called extrafusal muscle fibers , are innervated by alpha motoneurons. Inside skeletal muscles there are modified skeletal muscle fibers, called intrafusal muscle fibers . They are characterized by the fact that the contractile component is localized at the 2 extremities, while at the Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 17 centre of the fiber there are no contractile myofilaments. These intrafusal muscle fibers are innervated by gamma motoneurons . Motoneurons can be affected by motoneurons diseases: the most common is amyotrophic lateral sclerosis (ALS) or Lou Gehrigs disease . Both lower (spinal cord and brainstem) and upper motoneurons (cortical neurons at the origin of the corticospinal/pyramidal tract) are affected. Most patient with ALS present with random, asymmetric symptoms, consisting of cramps , weakness , and muscle atrophy of the hands (most commonly) or feet . Weakness progresses to the forearms, shoulders, and lower limbs. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness of movement, weight loss, fatigue, and difficulty in controlling facial expression and tongue movements soon follow. Other symptoms include hoarseness, dysphagia , and slurred speech ;because swallowing is difficult, salivation appears to increase, and patients tend to choke on liquids. Late in the disorder, a pseudobulbar effect occurs, with inappropriate, involuntary and uncontrollable excesses of laugher or crying. Sensory systems, consciousness, cognition, voluntary eye movements, sexual function, and urinary and anal sphincters are usually spared. Death is usually caused by failure of the respiratory muscles: 50% of patients die within 3 years of onset, 20% live 5 years. Survival for >30 years is rare. In progressive bulbar palsy with ALS (bulbar-variant ALS), deterioration and death occur more rapidly. Reflex activities Many interneurons of the spinal cord are involved in reflex activities . The ones involved in stretch reflex are called Ia inhibitory interneurons . While motoneurons are by definition excitatory, the interneurons can be either inhibitory or excitatory. For example, for the stretch reflex to take place, we need to have an inhibitory interneuron, which is called Ia because it receives inputs from Ia sensory fibers , which are the largest sensory fibers that we have. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 18 In the patellar tendon reflex , you tap the tendon of the quadricep muscle, making a slight stretch on the muscle. As a response to the pulling of the muscle, the muscle spindles send information to the spinal cord. They are receptors innervated by primary sensory neurons of the dorsal root ganglia, which are very large and the types of fibers that originate from this type of neurons are called Ia afferent. As response to the stimulus, the leg extends as a reflex. This reflex is a monosynaptic reflex . To extend the leg, it is necessary to relax the muscle, and we can do that by the same 1a afferent fiber, which with one branch excites one muscle, and with the other, it excites a set of inhibitory interneurons, whose target is the antagonist muscle, which gets relaxed. In conclusion, with the same stimulus, we obtain 2 actions: an excitatory action and an inhibitory action . The inhibitory actions cannot happen directly since the stimulus is excitatory, but it has to pass through an inhibitory interneurons , which takes the name of Ia inhibitory interneurons. Moreover, there are some interneurons of the spinal cord, which are involved in the flexion activity and in particularly in the flexion withdrawal reflex . This reflex consists in stopping the flexion activity and, in the meanwhile, starts the extension phase of the other limb. To perform these actions, the stimulus reaches the dorsal horn and comes into contact with excitatory interneurons , which synapse on another set of interneurons. Some of these interneurons project on the same side of the spinal cord, some others project on the other side. That is because we need to act on both side of the body and also use inhibitory and excitatory interneurons. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 19 Renshaws cells are involved in recurrent inhibition of motoneurons . A generical motoneuron sends the axon outside the spinal cord and while the stimulus exits via the ventral root, the axon also gives off a collateral, which excites an interneuron of the grey matter of the ventral horn, which is an inhibitory interneuron. The axon of this interneuron synapses on the same motoneuron from which it receives the excitatory input or on motoneurons that belongs to the same functional column. Some interneurons are involved in long and short propriospinal projections : Some other interneurons of the spinal cord are involved in generating rhythmic activity for locomotion and they are called central pattern generator (CPG) . They are network connected of excitatory and inhibitory neurons connected with each other on the same side of the spinal cord and with the same type of interneurons on the contralateral side of the spinal cord. In the spinal cord we have projecting neurons , which project from the white matter of the spinal cord to reach the brain stem and then they either synapse on specific sets of interneurons or some of them may reach the thalamus and from there they project to the cerebral cortex. White matter of the spinal cord It is organized into 3 funicula on each side: the dorsal, lateral and ventral funiculus . In the funicula we can find descending (neurons not in the spinal cord) and ascending (projecting neurons) pathways and axons of neurons that connect different segments of the spinal cord. If we look at the dorsal funiculus , it is characterized by the presence only of ascending pathways and it is divided into a fasciculus gracile and a fasciculus cuneate . In the lateral and anterior funicula we find both Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 20 the ascending and the descending pathways, which means that if we have a lesion of the dorsal funiculus, we will only have sensory problems; but if we have a lesion of the lateral or anterior funiculus, we will have problems related both to motor control and sensory problems. Then we have the associative fibers , which are neurons that project to segment of the spinal cord. Usually, they are made by axons that are situated close to the grey matter. Blood supply of the spinal cord The spinal cord is supplied by 3 vessels: by one anterior spinal artery and by 2 posterior spinal arteries .Both the anterior and posterior arteries run all throughout the length of the spinal cord and from them we have the origin of branches that distribute to the grey and white matter of the spinal cord. The anterior spinal artery is the one that supplies the largest territory: the anterior 2/3; while the posterior spinal arteries supply the posterior 1/3. Giuseppe Izzo 3rd Lesson Neuroanatomy The spinal cord 21 The origin of these vessels is the vertebral arteries , for sure for the anterior spinal artery ; the 2 posterior spinal arteries in most cases originate as well from the vertebral arteries , but occasionally one or both of them can originate from the posterior cerebellar artery , which is a major branch of the vertebral artery. Since these 3 arteries are very long, there are segmental arteries that contributes to their blood supply. Approximately 10 to 12 segmental arteries (which arise from various branches of the aorta) join the spinal arteries along their course via radicular arteries . There can be a variable presence of segmental medullary arteries that feed directly the anterior and posterior spinal arteries. Origin of the segmental arteries : posterior inferior cerebellar arteries, vertebral arteries, ascending cervical arteries, deep cervical arteries, posterior intercostal arteries, lumbar arteries, lateral sacral arteries. The largest is the artery of Adamkiewicz , which is a dominant segmental artery . It has a variable origin (from posterior intercostal arteries): more typically from the left side, between T9 and L2 . This segmental artery anastomosis with the anterior and posterior spinal arteries and it is very important because it contributes to the blood supply of the lower 2/3 of the spinal cord. The segments from T3 to T9 are more vulnerable to ischemia because the radicular vessels give a minimal input to the blood supply of the anterior and posterior spinal artery. Giuseppe Izzo Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 1 The 3 subdivisions of the brainstem are the medulla oblungata , the pons and the mesencephalon or midbrain . The brainstem is the direct continuation of the spinal cord; it begins above the exit of the C1 nerve roots of the spinal cord. The brainstem is long about 8 cm and 2-3 cm in width. Even though it is not so big, it contains a huge number of vital pathways; therefore, if the brainstem is damaged, especially the caudal part, we will die. Moreover, all the pathway that connects the spinal cord and the brain and vice versa have to pass through the brain stem. It also contains the nuclei of cranial nerves , which are important for phonation, masticatory movements, swallowing, moving eye bulbs and muscles of facial expression since everything is packed together in the brainstem, it is very easy to have major lesion of it. The brainstem lies on the anterior margin of the foramen magnum and on the clivus of the occipital bone ;on the base of the skull in the posterior cranial fossa . The brainstem forms the floor of the 4 th ventricle . From the brainstem, we have the exit of 10 of the 12 cranial nerves (III to XII) . They exit from the base of the skull from the foramina of the skull. The posterior cranial fossa is a very tight compartment because it is closed almost completely by the tentorium cerebellum , which is a layer of Dura mater. The tentorium cerebellum attaches posteriorly on the transverse groove of the squamous portion of the occipital bone; then it continues more anteriorly on the petrous portion of the temporal bone; and then it attaches on the sphenoid process of the temporal bone. The tentorium cerebellum is not continuous, it leaves an opening, called incisura tentorii , so that the brainstem can continue with the most rostral part, which is the diencephalon . The tentorium cerebelli divides the cranial cavity into a supratentorial and an infratentorial compartment .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 2 Since the space in the posterior cranial fossa is so tight, it can happen that some of the structures of the posterior cranial fossa can herniate through the foramen magnum and therefore compressing the brainstem. This would be a problem, especially because the lower part of the brainstem contains the respiratory and cardiovascular centres . The region of the cerebellum that most commonly herniates from the foramen magnum is the tonsillae of the cerebellum ; therefore, this condition can be called tonsillar herniation . An increase in pressure can also be found in the supratentorial compartment: it may happen that some structures more medially located respect to the incisura tentorii, may herniate through it and compress the upper portion of the brainstem. We might also have a herniation through the falx cerebri , compressing the corpus callosum . Also, the supratentorial compartment can be separated, although not completely, in the right and left side, and this is done through the great cerebral falx or falx cerebri . The falx cerebri attaches anteriorly to the crista galli , then on the squamous portion of the frontal bone, then to the parietal bone , then to the occipital bone , and then it attaches on the midline of the tentorium cerebelli , where we have the formation of one of the venous sinuses of the skull. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 3 Meninges and headache Headache can be caused by an irritation of the meninges . The meninges are innervated: all the meninges of the supratentorial compartment are innervated by the trigeminus , while the meninges of the infratentorial compartment are innervated by the upper cervical spinal nerves . An irritation of the meninges can be caused by meningitis . The irritation excites the sensory nerves endings of the trigeminus that send the information to the CNS and headache is generated. Meninges can be irritated also in case of haemorrhages . Headache is the most common symptom in meningitis and it is found in more than 80% of the patients. Some of the other symptoms can be nausea , vomit , fever In the spinal cord, between the meninges and the bone there was a space; at the level of the cranium, the epidural space is virtual . Very attached to the surface of the brain, we can see the pia mater ; then, right above it, we find the subarachnoid space , full of sort of filaments that extend from the arachnoid to the pia mater. Above the arachnoid mater, we find the dura mater , which is attached to it and it can be divided into 2 layers: the meningeal layer and the endosteal layer . One of them is on the side of the other meninges and the other is on the side of the bones. The endosteal layer is very attached to the bone, which causes the epidural space to be only virtual. It can become real if there is a pooling of blood in between the endosteal layer and the skull. The epidural space can also be called extradural space ; then we have the subdural space , which is in between the dura and the arachnoid, which is also a potential space. They are called potential spaces because normally they are not there, but they can become real if something starts to pool there, like in the case of haemorrhage . If we look in the subarachnoid space , we find the cerebral arteries ; between the endosteal layer of the dura mater and the internal table of the skull, we find other vessels, which are the meningeal vessels .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 4 Meningeal arteries The meningeal arteries are embedded in the endosteum of the skull. The more important and largest meningeal artery is the middle meningeal artery , which is a branch of the maxillary artery and it enters into the skull by the foramen spinosum that is found in the middle cranial fossa . The middle meningeal artery runs very close to the bone, so in case of fracture of one of the bones of the skull, there is a high risk of damaging the middle meningeal artery, especially if the fracture is near the Pterion . A blow to the side of the head can lead to an epidural or extradural hematoma , which means in between the bone and the endosteal layer of the dura mater. This would cause an initial loss of consciousness due to the concussion (we lose consciousness because the reticular formation is a bit traumatized by the concussion) and it may be followed by a lucid period of some hours (lucid interval), which can be the time in which blood can start to pool, giving rise to compression of the brain, that would cause increasing drowsiness and headache . An epidural hematoma is probably caused by a lesion in the middle meningeal artery . An epidural hematoma has to be distinguished by a subdural hematoma , which takes place between the innermost place of the dura mater and the arachnoid. In this case, the blood is typically venous and it comes from a fracture of the bridging vein .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 5 Venous sinuses of the dura mater The venous sinuses are formed in between the 2 fused layers that form the dura mater, which is lined by endothelium . We find the venous sinuses where the dura mater attaches to the skull or along its free margins. We have the superior sagittal sinus , where the falx cerebri attaches to the skull; the inferior sagittal sinus , which is at the level of the free margin of the falx cerebri; the straight sinus , which is where the falx cerebri attaches to the tentorium cerebelli; the transverse sinus , which is where the tentorium attaches to the transverse groove; the sigmoid sinus , found in the sigmoid groove, which drains in the internal jugular vein , at the level of the jugular foramen; the superior and inferior petrous sinuses ; the cavernous sinus , which is on the sides of the sella turcica. The occipital sinus is where there is a lamina of dura mater that inserts in between the 2 cerebellar hemispheres (cerebellar falx or falx cerebri) and on the other part, it attaches on the inferior part of the straight crest. The region where the transverse, occipital, straight and superior sagittal sinuses come together is called confluence of the sinuses .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 6 Cavernous sinus The cavernous sinus is found on the side of the body of the sphenoid bone . This sinus is made by a plexus of veins which are delimited by dura mater. Inside this sinus there are many relevant structures that pass from it before entering in their foramina. If we have an occlusion , an inflammation or a thrombosis of the cavernous sinus, then very commonly the nerves that run in the sinus are affected as well, causing a paralysis of the eye muscles (cavernous sinus syndrome). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 7 Cavernous sinus thrombosis is caused by injuries in the face, in particular, in the danger area of the face .An inflammation of this area, even a small one, if not threated, can be transported into the cavernous sinus, where it can lead to inflammation or thrombosis and then it can spread to the other sinuses. Initially it would give rise to symptoms related to the paralysis of the muscles of the eyes due to the inflammation of the nerves that pass in the cavernous sinus. Tumours of the meninges (meningiomas) In the US, meningiomas comprise about 32% of all primary intracranial tumours, with an annual incidence of 5.2 per 100000 population. These tumours are twice as common in women, and there is a regional variation. Patients with multiple meningiomas generally comprise less than 10% of cases. Most meningiomas are benign. In general, atypical meningiomas and anaplastic meningiomas comprise less than 10% of all meningiomas. Even though they are usually benign, while they grow, they can compress nervous tissue. # The brainstem When we observe the brainstem , we can soon realize that it is not really segmented like the spinal cord; moreover, nerves do not emerge at the same positions. Ventral surface If we look at the ventral surface of the brainstem from caudal to rostral, we can notice: The brainstem is the continuation of the spinal cord. Anteriorly, the white matter of the spinal cord forms the anterior funiculi , which form some continuity on the brainstem. They are called pyramids , and they are important because all the fibers of the pyramidal tract are clustered together as to form this pyramidal shape. A bit caudally to the pyramids, we find a structure called decussation of the pyramids , which is where 90% of the fibers of the pyramidal tract will cross on the other side. To the right and to the left of the pyramids, we find a large protrusion, which is called olive or inferior olive, and it is so large because it contains a large complex of grey matter called inferior olivary nucleus . Behind the olive, we find a retro-olivary groove , which is the site of exit of the glossopharyngeal nerve (IX), of the vagus nerve (X), and of some of the fibers of the accessory nerve (XI). They all exit from the jugular foramen . In front of the olive, we find the exit of the hypoglossal nerve (XII). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 8 We then have a groove that separates the area of the medulla from the pons, which is called bulbopontine sulcus or groove. From this groove, we have the exit of other cranial nerves; for example, close to the midline, we find the exit of the abducent nerve (VI), more laterally, we find the facial nerve (VII), which is made by 2 components, the facial nerve proper and the intermediate nerve of Wrisberg . More laterally to the facial nerve, we find the vestibulocochlear nerve (VIII). This portion from which we have the exit of this nerves, is also called supraolivary groove . These nerves are near to the flocculus of the cerebellum , so if there is a tumour of this area, the first signs that the patient may experience are signs related to the compression of this part. More rostrally, we find the ventral surface of the pons , which is characterized, on the midline, by the depression for the basilar artery . Laterally , at the boundaries between the ventral and lateral surfaces of the pons, we see the exit of the sensory and motor roots of the trigeminus (V). Then, we find the ventral surface of the midbrain and, partially, we also see the ventral surface of the diencephalon and specifically the hypothalamus . From the 2 surfaces, the axis of the brain forms an angle. When we look at the midbrain from the ventral view, we can see the cerebral crus or peduncle . Between the 2 peduncles, we find the interpeduncular fossa , where we have the exit of the oculomotor nerve (III), the most rostral of the cranial nerves that originate from the brainstem. Slightly more laterally and inferiorly, at the boundary between the pons and the midbrain, we see the trochlear nerve (IV), even though, if we want to look at the origin of this nerve, we have to look at the dorsal view of the brainstem (it is the only cranial nerve that emerges dorsally). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 9 Dorsal side To look at the dorsal side of the brainstem, we have to remove the cerebellum , which covers the 4 th ventricle and most of the pons. Starting from caudal to rostral we can notice: The white matter of the spinal cord forms the dorsal column , which can be divided into a gracile and cuneate fasciculus . In the initial portion of the medulla oblungata, we still find these 2 fasciculus, and they end up in 2 tubercles, called gracile and cuneate tubercles because the fibers that run in the previous portion will stop at the level of some nuclei that we find in the area of the tubercles. The 2 nuclei are called nucleus gracilis and nucleus cuneatus and they are part of the closed portion of the medulla ; the closed portion (which does not undergo to the book like opening during development) of the medulla is not part of the floor of the 4 th ventricle, while the open portion is part of the floor of the 4 th ventricle. At the beginning of the open portion of the 4 th ventricle, we have a region called the obex of the medulla, which is the place where there is the communication of the 4 th ventricle with the spinal or ependymal canal . When we look at the dorsal surface of the brainstem, we can notice a region with a rhomboidal shape, which is the floor of the 4 th ventricle . This part is divided into an inferior and a superior triangle. The inferior triangle is formed by the open portion of the medulla oblungata; while the superior triangle is formed by the pons (all the metencephalic vesicles undergo a book like opening). The surface of the floor of the 4 th ventricle is not smooth: we can notice the facial colliculus , the medial eminence , the lateral recess , the sulcus limitans , the trigeminal tubercle , the hypoglossal trigone , the striae medullaris , etc. All these structures represent the fact that in the tegmentum of the medulla and of the pons, there are some structures that are evident at the point to protrude from the floor of the 4 th ventricle. Laterally, we can notice the vestibular area , which corresponds to the region where we find the vestibular nuclei ; more on the midline, we can see the facial colliculus , where we find the motonucleus of the facial nerve and the fibers of the abducens on their way to exit from the brainstem and protrude below the surface of the floor of the 4 th ventricle, thus forming this colliculus. More rostrally, we find the territory of the midbrain, which did not undergo to a book like opening, but was characterized dorsally by the presence of a lamina, which is called lamina quadrigemina or tectum of the midbrain . It is called lamina quadrigemina because it is characterized by the presence of 4 structures, 2 rostral and 2 caudal, which are called superior and inferior colliculi . In between the superior colliculi, we find a structure that belongs to the diencephalon, which is called pineal gland . From here, we can observe the exit of the trochlear nerve (IV), which exits in the region between the inferior colliculi and the superior medullary vellum , which forms part of the tectum of the 4 th ventricle. The roof of the 4 th ventricle is formed by the roof plate , which is divided into superior and inferior medullary vellum . From the dorsal surface of the brainstem, we can also notice the cerebellar peduncles , which are divided into superior, inferior and middle cerebellar peduncles . The cerebellum, during development, establishes relations with the 3 parts of the brainstem, and the cerebellar peduncles contain the axons that put into communication the cerebellum with each zone of the brainstem. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 10 Roof of the 4 th ventricle and choroid plexus When we want to observe the roof of the 4 th ventricle , the best way is to use a sagittal view of the ventricle. The cerebellum lies over the roof of the 4 th ventricle, which consists of 2 veli (a very thin Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 11 structure, made of a very thin and transparent layer of white matter, which is not functional): a superior medullary velum and an inferior medullary velum . At the level of the roof of the ventricle, we find the presence of the choroid plexus , which is the region where we find an enrichment with capillaries that push inside the ventricular cavities. It is at the level of the inferior medullary velum. At the level of the choroid plexus, we have the filtration of blood inside the ventricular cavity as to form the cerebrospinal fluid . The 4 th ventricle communicates with the subarachnoid space through 3 openings: 2 lateral, which are called foramina of Luschka , at the level of the lateral recesses of the 4 th ventricle; and one median aperture, located posteriorly, which is called foramen of Magendie . The capillaries at the level of the choroid plexuses are fenestrated capillaries , thus to allow a passage of the components of blood into the space which separates the capillaries from the epithelial cells, which are ependymal cells and then to a process of filtration there is the production of cerebrospinal fluid. At the level of the choroid plexuses, we find one of the barrier of the central nervous system that is called blood-CSF barrier (blood cerebrospinal fluid barrier ). The endothelial cells and the ependymal cells are part of a barrier that separates blood from the cerebrospinal fluid produced in the ventricular cavity. If we look a section into a choroid plexus, we can notice the capillary and the outer lining by ependymal cells. From blood into the ventricular cavity, there is a filtration of wastes and unnecessary solutes. The filtrate contains glucose , oxygen , vitamins , and ions such as Na+, Cl-, Mg2+ The ependymal cells are characterized by the presence of microvilli , which allows them both to absorb and secrete substances. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 12 Lateral surface From the lateral side of the brainstem, we can first of all notice most of the structures that we could notice looking at the dorsal side. We can see the cerebellar peduncles , especially the middle one; we can see the exit of the 4 th cranial nerve, the trochlear , which emerges caudally to the inferior colliculi. The fibers that exit from the tegmentum of the midbrain enter in the superior medullary velum , they cross it, and then they exit from it. The 2 trochlear nerves contain the fibers coming from the contralateral motonucleus of the trochlear nerve, and they do not remain dorsal, but embrace on the side the midbrain, continuing ventrally and then anteriorly. From this side, we can see also the lamina quadrigemina . In particular, we can notice as both the superior and inferior colliculi are characterized by 2 brachia conjunctiva , one for the superior and one for the inferior, on both sides, that connect the superior colliculi with the lateral geniculate nucleus of the diencephalon; and the inferior colliculi with the medial geniculate nucleus . We can see the exit of some of the cranial nerves, such as the facial nerve , the vestibulocochlear nerve ;the olive and the rootlets that emerge dorsally and ventrally to it. Moreover, we can see the accessory nerve (XI), which is a little bit tricky: we classify it as cranial nerve because it exits from the jugular foramen and then it is distributed to its destinations, but some of the fibers originate from the medulla oblungata, while most of them originate from the cervical segment of the spinal cord. At the level of the obex , we have the continuation of the 4 th ventricle with the spinal canal. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 13 Internal organization of the brainstem Everywhere in the brainstem, we find a very anterior ventral region, which is called the base or foot . Dorsal to the base, we find the tegmentum , which is everywhere. Then, we have an additional region of tissue in the midbrain , which is called the tectum (involved in the visual and acoustic pathways ). The midbrain can also be called cerebral peduncle , which would comprehend the tegmentum and base of the midbrain; but for some others, the cerebral peduncle is only the base. The 2 portions that correspond to the base are also called the crus cerebri , and, in between the right and left side, there is a fossa called interpeduncular fossa ,where we have an enlargement of the subarachnoid space called interpeduncular subarachnoid space .Since the midbrain did not undergo a book like opening, rather than having a large cavity forming the ventricle, we have a small conduit, which is the aqueduct of Silvius . The base is phylogenetically the newest part of the brain stem and it is made only of white matter , with only one exception. In particular, it is made by the axons of the newest descending pathways, which means the pyramidal and the corticopontine cerebellar tract ; the exception is the base of the pons , where besides white matter, we also find the basilar nuclei of the pons . In the tegmentum we find all the rest: the descending pathways that are not new phylogenetically speaking; the ascending pathways ; the nuclei of the cranial nerves and the specific nuclei of the brainstem. The tegmentum The tegmentum contains the reticular formation , which is very important because it is both the oldest part of the brainstem and it also contains all our vital centres . There we can also find the cranial nerve nuclei ,the specific nuclei , the sensory and motor pathways (except the pyramidal and corticopontine tracts). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 14 The reticular formation The reticular formation is the oldest part of the brain. It forms a diffuse, multisynaptic, net-like meshwork (reticulum) of widely interconnected neurons in the tegmentum . The RF is involved in nearly every aspect of brain function including homeostasis , consciousness , arousal, pain , primitive motor control , muscle tone and behavioural mechanisms. Vital centers are located in the medulla and pons and control cardiovascular , respiratory , and other homeostatic mechanisms. Lesions in these centers are fatal. Examples of reticular formation mediated reflexes are: aortic body, carotid body, aortic sinus, carotid sinus, sough, swallowing, salivary and vomiting. The midbrain reticular formation gives rise to a tonic ascending barrage of diffuse, non-specific sensory data called the ARAS (ascending reticular activating system) . Acting like a battery, the ARAS stimulates the cerebral cortex and maintains the conscious state . Midbrain lesions of ARAS result in coma . Incomplete lesions may result in stupor. This mechanism is linked to the sleep cycle and circadian cycles . The reticular formation extends in the midbrain, in the pons, in the medulla, and also in the cervical segment of the spinal cord. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 15 To better classify the reticular formation, we can make a cytoarchitectonic division and a neurochemical division . The first is based on the cytological characteristics (shape and size) of neurons and it divides the reticular formation into a region close to the midline, called median/midline subdivision , which contains nuclei called raphe nuclei ; on the side, we find a medial compartment of the reticular formation, which can also be called paramedian ; and even more laterally, we find the lateral subdivision , which is the one that extends in the cervical segment of the spinal cord. The neurochemical division is characterized by the type of neurotransmitter used: we find divisions according to the production of dopamine, serotonin, acetylcholine, epinephrine and norepinephrine. Noradrenergic pathways Some of the noradrenergic nuclei project rostrally , for example to the cerebral cortex; some of them projects caudally , to the spinal cord; some others project to the cerebellum (pre-cerebellar nuclei ). The noradrenergic pathways of the reticular formation are involved in modulation of attention (attention-deficit disorders respond to noradrenergic drugs); in the sleep-wake cycle modulation; in mood modulation and consequently it is involved in mood disorders (lots of neuropsychiatry disorders are related to problems in the reticular formation); in pain modulation. Serotoninergic pathways The serotoninergic pathways are involved in several psychiatric syndromes (disorders of mood) like depression, anxiety, obsessive-compulsive behaviour, aggressive behaviours, eating disorders; in pain Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 16 modulation; in temperature regulation; in motor control ; in arousal . There seems to be a link between the serotoninergic centers and sudden infant death . 40% SIDS have abnormalities in 5HT in centres of the medulla involved in homeostatic regulation of hypercarbia and hypoxia during sleep. Which means that when we sleep, our breathing pattern changes and it is regulated by the amount of CO2 and O2 in the blood stream; it seems that the serotoninergic centers, if they do not function as they should, they cannot regulate the response in increase in CO2 during sleep. Normally, if we put the face against the pillow while sleeping, the amount of CO2 increases and this information is brought to the CNS, which allows us to autonomously move around; in case of malfunctioning of the serotoninergic nuclei, this mechanism does not work, so the baby can die. Dopaminergic pathways Some of the centers are dopaminergic . Most of them are directed rostrally and the source of dopamine is mostly at the level of the midbrain . The dopaminergic pathways can be divided into mesostriatal (movement disorders); mesolimbic (reward, addiction, positive signs of schizophrenia); and mesocortical (working memory, attentional aspects of motor initiation, negative signs of schizophrenia). Pedunculopontine nucleus It is a nucleus that extends both in the pons and in the midbrain. It has several projections, among them, we have one projection to the intralaminar nuclei of the thalamus ,which is part of the arousal mechanism of the cortex. This cholinergic group of neurons is involved in locomotion : in the tegmentum of the midbrain there is a region called locomotor region. Moreover, it also projects to the motonuclei of the brainstem and of the spinal cord and it is in continuity via the medial forebrain bundle with a group of cholinergic neurons located in the basal forebrain. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 17 Consciousness To have a consciousness , we need to have an aroused cortex . Consciousness has a content and a level (alertness, attention, awareness). The reticular formation, and especially, the pedunculopontine nucleus projects to the intralaminar nucleus of the thalamus, which then projects to the cortex; to the basal forebrain (specifically with the septal nuclei); and to the posterior nuclei of the hypothalamus. The pontomesencephalic reticular formation is the one that is most responsible for the activation of the cortex since it receives lots of inputs: the sensory pathways that ascend the brain stem; the limbic and cingulate cortex; the thalamic reticular nucleus; the limbic system; and the fronto-parietal association cortex. Neurons of the reticular formation can have very long axons: many of them can project both rostrally and caudally, influencing very distant sites. Nuclei of cranial nerves The cranial nerves originating from the brainstem are heterogeneous with respect to their composition (different from spinal nerves). On the top of it, there are additional components in some of the cranial nerves that we do not find in the spinal ones: innervation of muscles of branchiomeric origin ( special visceral innervation ), special visceral sensation (taste), special somatic sensation (vestibular and acoustic information). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 18 When we consider the grey matter of the spinal cord , we can imagine 4 functional territories . In the cranial nerves , we can find 7 territories , which are not found, though, in all the cranial nerves. The 7 components are: General somatic efferent (GSE) : motor innervation of somatic musculature Special visceral efferent/branchial motor (SVE) : motor innervation of branchiomeric musculature General visceral efferent (GVE) : parasympathetic preganglionic neurons, motor innervation of viscera General visceral afferent (GVA) : sensory input from viscera Special visceral afferent (SVA) : taste General somatic afferent (GSA) : general somatosensory input Special somatic afferent (SSA) : special senses of hearing and balance Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 19 Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 20 The image above is important to represent the components that we find in the different cranial nerves and where the nuclei related to these components are localized. If we look at the numbers on the top part, I is the representation of the motonuclei, which innervate muscles of somatic origin (first column) and muscles of branchiomeric origin (second column); II represents the viscero-motonuclei; III and IV are the visceromotor and the viscerosensory components; V is the somatosensory component; and VI is the special somatosensory component. In the scheme, we can see, then, the portion of the brainstem and spinal cord on the left, and the number of the correspondent cranial nerve. It is important to localize the position of each nuclei in the brainstem because it is used for neurological diagnosis of a brainstem lesion . III and IV cranial nerves The III and IV cranial nerves are those that originate from the midbrain . The III cranial nerve is called oculomotor nerve since it innervates most of the extraocular eye muscles (it has a GSE component); associated to it, there is the motor nucleus of the III cranial nerve, which is in the rostral part of the tegmentum of the midbrain . The origin of the III cranial nerve is at the level of the interpeduncular fossa .This nerve is not only GSE, but it is also GVE since it contains parasympathetic fibers directed to the intrinsic smooth muscles of the eye. This parasympathetic innervation originates from a nucleus located in the tegmentum of the midbrain, called Edinger Westphal nucleus , which is a parasympathetic preganglionic nucleus. The fibers of the GVE innervation, along their course, they will find a ganglion, called ciliary ganglion , on which they will synapse and then innervates the smooth muscles. Also originating from the midbrain, we have the Trochlear nerve (IV) , which is the only nerve originating from the dorsal side of the brainstem. This nerve is involved in the innervation of the extraocular eye muscles, in particular of the superior oblique muscles (GSE ). In the caudal portion of the tegmentum of the midbrain, we find the motor nucleus of the IV cranial nerve. This nerve is also the only one in which their fibers cross after their origin from the brainstem, in fact, they cross in the superior medullary velum .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 21 Oculomotor nerve palsy Oculomotor nerve palsy is a condition resulting from damage to the oculomotor nerve . The most common structural causes include: Raised intracranial pressure (compresses the nerve against the temporal bone) Posterior communicating artery aneurysm Cavernous sinus infection Trauma Other pathological causes of oculomotor nerve palsy can be diabetes , multiple sclerosis , myasthenia gravis and giant cell arteritis. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 22 The oculomotor nerve provides motor and parasympathetic innervation to some of the structures within the bony orbit. Therefore, the clinical features of CN III injury are associated with the eye: Ptosis (dropping upper eyelid): due to paralysis of the levator palpabrae superioris and unopposed activity of the orbicularis oculi muscle. Down and out position of the eye at rest: due to paralysis of the superior inferior and medial rectus, and the inferior oblique (and therefore the unopposed activity of the lateral rectus and superior oblique). The patient is unable to elevate, depress or adduct the eye. Dilated pupil : due to the unopposed action of the dilator pupillae muscle. Examination of the trochlear nerve The trochlear nerve is examined in conjunction with the oculomotor and abducens nerves by testing the movements of the eye . The patient is asked to follow a point (commonly the tip of a pen) with their eyes without moving their head. The target is moved in an H-shape and the patient is asked to report any blurring of vision or diplopia (double vision). Palsy of the trochlear nerve Trochlear nerve palsy commonly presents with vertical diplopia , exacerbated when looking downwards and inwards (such as when reading or walking down the stairs). Patients can also develop a head tilt away from the affected side. They are commonly caused by microvascular damage from diabetes mellitus or hypertensive disease. Other causes include congenital malformation, thrombophlebitis of the cavernous sinus, and raised intracranial pressure. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 23 V and VI cranial nerves The V and VI cranial nerves are the trigeminus and the abducens and they originate from the metencephalon or pons . The abducens originates in the bulbopontine sulcus , but its motor nucleus is in the pons. The trigeminus has a territory of innervation which is motor and it innervates muscles of mastication and others of branchiomeric origin ( SVE ). It has also a large general sensation territory at the level of the head and of the face ( GSA ). These sensations are carried inside the brain through 3 nuclei: the pontine or principal , the mesencephalic and the bulbospinal or spinal nuclei . The sensory ganglion of the trigeminus is called ganglion of Gasser . The abducens has only a somatic general efferent component ( GSE ) and it innervates the extraocular eye muscles, in particular the lateral rectus . The only branch of the trigeminus with a motor component is the mandibular branch , which innervates the masticatory muscles (medial pterygoid, lateral pterygoid, masseter and temporalis), but it also innervates the anterior belly of digastric, the mylohyoid, the tensor veli palatini and the tensor tympani. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 24 Corneal reflex The corneal reflex is the involuntary blinking of the eyelids; it is stimulated by tactile, thermal or painful stimulation of the cornea. In the corneal reflex, the ophthalmic nerve acts as the afferent limb, detecting the stimuli. The facial nerve is the efferent limb, causing contraction of the orbicularis oculi muscle. If the corneal reflex is absent, it is a sign of damage to the trigeminal/ophthalmic nerve , or the facial nerve . From the pons we have the origin of the abducens nerve and the motor nucleus of the abducens is very close to the midline and it is so superficial that forms a protrusion of the floor of the 4 th ventricle .Moreover, close to it, we find the motor nucleus of the facial nerve, whose fibers run over the nucleus of the 6 th on their way out of the brainstem, and the loop formed by the fibers of the facial nerve around the nucleus of the 6 th is called the Genu of the facial nerve , it also protrudes at the level of the floor of the fourth ventricle. VII cranial nerve The VII cranial nerve of facial/intermediate nerve originates from the pons , in particular its motor nucleus can be found in the pons. It exits from the brainstem at the level of the supraolivary groove , in the bulbopontine groove . The VII cranial nerve is made by a larger bundle of fibers, which form the facial nerve proper ; and by a smaller bundle of fibers, which forms intermediate component of the facial nerve. The VII nerve has several components: It has a component directed toward the facial expression muscles and other muscles ( SVE or branchiomeric ); it is linked to a motor nucleus in the tegmentum of the pons. It has also a GVE component , in particular a parasympathetic preganglionic component that is important for controlling the sublingual, the submandibular, the lacrimal, the nose, the palate and the pharynx glands . The preganglionic parasympathetic neurons are located at the level of the superior salivatory nucleus, which sends its fibers out of the brainstem, to reach the submandibular, sublingual (at the level of the floor of the oral cavity) and sphenopalatine ganglia. Another component is formed by fibers directed to collect information from the tongue, generating taste (SVA) ; this information is relayed to the most rostral part of a nucleus in the tegmentum of the medulla oblungata called nucleus of the solitary tract . It has also a small cutaneous territory, which refers to general sensation from the skin of the ear (GSA) ; these information is conveyed to the bulbospinal trigeminal nucleus . The sensory ganglion that contains the somatosensory neurons , which collects somatosensory information from the periphery; and viscerosensory neurons , which innervates the tongue, is called the geniculate ganglion . It is located inside the canal for the facial nerve , which is situated in the petrous portion of the temporal bone. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 25 Damage to the facial nerve The facial nerve has a wide range of functions. Thus, damage to the nerve can produce a various set of symptoms, depending on the site of the lesion. Intracranial lesions occur during the intracranial course of the facial nerve (proximal to the stylomastoid foramen ). The muscles of facial expression will be paralysed or severely weakened. The other symptoms produced depend on the location of the lesion, and the branches that are affected: Chorda tympani: reduced salivation and loss of taste on the ipsilateral 2/3 of the tongue Nerve to stapedius: ipsilateral hyperacusis (hypersensitive to sound) Greater petrosal nerve: ipsilateral reduced lacrimal fluid production The most common cause of an intracranial lesion of the facial nerve is infection related to the external or middle ear. If no definitive cause can be found, the disease is termed Bells palsy .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 26 Extracranial lesions occur during the extracranial course of the facial nerve (distal to the stylomastoid foramen ). Only the motor function of the facial nerve is affected, therefore resulting in paralysis or severe weakness of the muscles of facial expression . There are various causes of extracranial lesions of the facial nerve: Parotid gland pathology : tumour, parotitis, surgery Infection of the nerve , particularly by the herpes virus Compression during forceps delivery : the neonatal mastoid process is not fully developed and does not provide complete protection of the nerve Idiopathic : if no definitive cause can be found then the disease is termed Bells palsy. VIII cranial nerve In the same region where we have the exit of the facial nerve, we have the exit of the vestibulocochlear nerve or VIII nerve. It is characterized by a SSA component and it carries hearing and balance information, which comes from the cochlear and vestibular parts of the middle ear. The nuclei that receive these information are the cochlear nuclei , which are divided into dorsal and ventral ; and the vestibular nuclei , which are divided into medial, lateral, superior, and inferior . These nuclei are found in the tegmentum of the pons and of the medulla. Vestibular neuritis Vestibular neuritis refers to inflammation of the vestibular branch of the vestibulocochlear nerve . The aetiology of this condition is not fully understood, but some cases are thought to be due to reactivation of the herpes simplex virus . It presents with symptoms of vestibular nerve damage: Vertigo : a false sensation that oneself or the surroundings are spinning or moving Nystagmus : a repetitive, involuntary to-and-fro oscillation of the eyes Loss of equilibrium (especially in low light) Nausea and vomiting The condition is usually self-resolving. Treatment is symptomatic, usually in the form of anti-emetics or vestibular suppressants . Labyrinthitis Labyrinthitis refers to inflammation of the membranous labyrinth , resulting in damage to the vestibular and cochlear branches of the vestibulocochlear nerve . The symptoms are similar to vestibular neuritis, but also include indicators of cochlear nerve damage: sensorineural hearing loss and tinnitus (a false ringing or buzzing sound). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 27 IX cranial nerve The IX cranial nerve is called glossopharyngeal nerve and it originates from the medulla oblungata . It has several components: A SVE component or branchiomotor , which originates from the nucleus ambiguous and which innervates the stylopharyngeus muscle . A GVE component formed by parasympathetic preganglionic fibers directed to the parotid gland . It originates from the inferior salivatory nucleus and the fibers pass through the otic ganglion . It is involved in collecting taste information through the SVA component, which originates from the nucleus of the solitary tract in the medulla . It also collects information from viscera such as the carotid body and sinus , the pharynx and the middle ear (GVA ). It originates from the nucleus of the solitary tract . A GSA that collects general sensation from the ear , which are relayed to the bulbospinal trigeminal nucleus . It has 2 sensory ganglia: the superior and the inferior or petrosal ganglia . They are just after the jugular foramen . The glossopharyngeal nerve receives fibers also from the inferior salivatory nucleus , and these fibers will leave the glossopharyngeal nerve at some point to enter in contact with the otic ganglion and then innervate the parotid gland .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 28 Gag reflex The glossopharyngeal nerve supplies sensory innervation to the oropharynx , and thus carries the afferent information for the gag reflex . When a foreign object touches the back of the mouth, this stimulates CN IX ,beginning the reflex. The efferent nerve in this process is the vagus nerve , CN X. An absent gag reflex signifies damage to the glossopharyngeal nerve. X cranial nerve The X cranial nerve is the vagus and it originates from the medulla , at the level of the retro-olivary groove .It has a very large territory of innervation: it innervates muscles of larynx and pharynx (SVE or branchial motor) and the nucleus that gives rise to the fibers innervating them is the nucleus ambiguous ; all the viscera in the thorax and abdomen, which are innervated through parasympathetic preganglionic fibers (GVE ), which originates from the dorsal motor nucleus of the vagus nerve, situated in the medulla, and are then linked to many ganglia and ENS (enteric nervous system) The vagus also collects information from organs: we have sensory information from viscera ( GVA ) that are related to the nucleus of the solitary tract ; general sensation from the ear (GSA ), related to the bulbospinal trigeminal nucleus ; taste information from the tongue (SVA ), linked to the nucleus of the solitary tract . Taste information from the tongue is collected from the intermediate component of the facial nerve (the anterior 2/3 of the tongue); from the glossopharyngeal (which collects information from slightly more posteriorly); and then the vagus nerve, which collects information from the taste buds that are located at the root of the tongue , at the epiglottis and at the level of the initial part of larynx and pharynx. Here, we find 2 sensory ganglia, the superior and inferior or nodose ganglia . The superior contains the somatosensory neurons , while the inferior contains the viscerosensory neurons . Most of the muscles of the pharynx are innervated by the pharyngeal branches of the vagus nerve: the superior, middle and inferior pharyngeal constrictor muscles; the palatopharyngeus muscle; salpingopharyngeus; muscles of the larynx; palatoglossus and majority of the muscles of the soft palate. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 29 Since the vagus nerve innervates muscles that are responsible for the movement of the soft palate, in case of problems in the vagus nerve, we may have ipsilateral paralysis of the soft palate, of muscles of the pharynx and larynx, which can cause dysphonia , dyspnea , dysarthria , and dysphagia . Moreover, we may have loss of cough reflex . XI and XII cranial nerves The XI cranial nerve is the accessory nerve and many of its fibers originate from C1-C5 (spinal part ); moreover, there are some fibers, which originate from the medulla oblungata (cranial part ). The fibers that originate from the spinal cord enter into the skull via the jugular foramen and they join to the components originating by the medulla oblungata. The fibers which originates from motoneurons in the spinal cord are responsible for the innervation of the trapezius and sternocleidomastoid muscles (SVE ). The fibers originating from the cranial component, once they exit from the jugular foramen, they are going to abandon the XI nerve and they will join the vagus nerve .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 30 The XII is the hypoglossal nerve , which is characterized by branches of the motor nucleus located in the tegmentum of the medulla (GSE ), and it innervates the intrinsic muscles of the tongue , which have a somatic origin. Examination of the accessory nerve The accessory nerve is examined by asking the patient to rotate their head and shrug their shoulders, both normally and against resistance. Simply observing the patient may also reveal signs of muscle wasting in the sternocleidomastoid and trapezius in cases of long-standing nerve damage. Palsy of the accessory nerve The most common cause of accessory nerve damage is iatrogenic . Procedures such as cervical lymph node excision biopsy or central line insertion can cause trauma to the nerve. Clinical features include muscle wasting and partial paralysis of the sternocleidomastoid , resulting in the inability to rotate the head or weakness in shrugging the shoulders. Damage to the muscles may also result in an asymmetrical neckline .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 31 As a general rule, the nerves that emerge close to the midline are those that are mostly characterized only by GSE components ; while the furthest from the midline also have SSE components . Cranial nerves grouped by components Specific nuclei or relay nuclei Inside the brainstem , we also find the specific or relay nuclei . Most of these nuclei are located in the tegmentum , or the exception is the pontine nucleus , which is located in the base .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 32 The reticular formation could be considered as a system made by several specific nuclei, but it is better to consider it on its own. The specific nuclei of the brain stem, starting from the midbrain, are: The red nucleus , which is located in the tegmentum of the upper portion of the midbrain and it will continue also in the subthalamic region. The substantia nigra , which is divided into a pars compacta and pars reticulata . The first produces dopamine. The pontine nuclei , located in the base of the pons, keep in communication the neocortex with the neocerebellum. The nucleus of the lateral lemniscus , which is found in the tegmentum of the pons, important in the acoustic pathways. In the caudal portion of the pons, we find the superior olivary nucleus , also important in the acoustic pathways. In the medulla, we find the inferior olivary nucleus , which is important for the cerebellar circuitry. The cuneate and the gracile nucleus , which are the target of the dorsal column pathways of the fasciculus gracilis and fasciculus cuneatus that we find in the white mater of the dorsal column. The accessory cuneate nucleus , which is important for the spinocerebellar tract. Ascending and descending pathways In the brainstem, we also find ascending and descending pathways , which run in the base or foot and in the tegmentum : Ascending pathways in the tegmentum Oldest descending pathways in the tegmentum Newest descending pathways in the base or foot, in the cortico-spinal or pyramidal tract; in the corticopontine (neocortex - neocerebellum). Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 33 Brainstem cross sections Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 34 Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 35 Cerebellum The cerebellum is connected to the rest of the CNS and specifically to the brainstem by 3 pairs of peduncles . The superior peduncle is called the brachium conjunctivum and it connects the cerebellum to the midbrain; then we have the middle peduncle or brachium pontis , which is the largest and it connects the cerebellum to the pons; then we have the inferior peduncles , which are divided into restiform and juxtarestiform bodies , they connect the cerebellum to the medulla oblungata. When we look at the cerebellum, we can see that it is characterized by a central region, called the vermis ;and by 2 larger divisions, called cerebellar hemispheres . If we consider the cerebellum in its anatomical position, we can distinguish a superior and inferior surface . The superior surface is in contact with the tentorium cerebelli and consequently to the occipital lobe of the brain; the inferior surface, instead, is in contact with the posterior cranial fossa .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 36 The cerebellum can be divided into 3 lobes and many lobules . If we look at the superior surface, we can appreciate the anterior lobe (red), which is separated by the posterior lobe (green) through a fissure, called primary fissure . The anterior lobe is made partly by the vermis , on the midline, and partly by the cerebellar hemispheres , and it can be divided into quadrangular lobule , central lobule and culmen . The posterior lobe also continues on the inferior surface of the cerebellum. It is made both by vermian and hemispherian territories. Some of the lobule that compose the posterior lobe are the declive , the folium ,the superior and inferior semilunar lobule , the tuber , the pyramid , the biventer lobule , the tonsil (important to remember). The tonsils lie on the posterior cranial fossa and they are the first thing to herniate in the foramen magnum in case of increasing pressure in the posterior cranial fossa. On the inferior surface, we can also notice the flocculonodular lobe (blue), which is the oldest lobe. The posterior lobe is separated from the flocculonodular lobe by the posterolateral fissure . The flocculonodular lobe includes the flocculus and the nodule . Another important fissure is the horizontal fissure , which separates the superior surface of the cerebellum from the inferior one. Phylogenetic subdivisions of the cerebellum From the image below, we can see the cerebellum, which has been open, so that we can see better the whole surface on a bidimensional surface. The cerebellum can be divided in territories based on their phylogenetic origin. We can recognize the vestibulo-cerebellum , which is also called archicerebellum , and corresponds to the flocculonodular lobe , it is the oldest and receives mainly vestibular inputs ; then we recognize the spinocerebellum , which corresponds to regions of the anterior and posterior lobes , both belonging to the vermal-intermediate zone, it is also called paleocerebellum because it has an intermediate from the temporal line point of view origin and it is called spinocerebellum because it receives lots of spinal inputs ; then we have the lateral most portion of the anterior and posterior lobe, which is called pontocerebellum or neocerebellum , it is the newest part of the cerebellum that has been developed and it receives and sends projections to the pontine nuclei .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 37 Cerebellopontine angle The ventral most portion of the cerebellum, corresponding to the flocculonodular lobe, is in relation with the region of the bulbopontine groove, where we have the origin of 3 of the cranial nerves: the facial proper and facial intermediate nerve (VII) and the vestibulocochlear nerve (VIII). If there are tumours in this region of the cerebellum, they may compress the nerves originating in this area and the first signs showing up may not be related to functions related to the cerebellum, but they can be due to the compression of some of these cranial nerves. If we look a bit closer at the surface of the cerebellum, we can see that the cerebellar surface is not smooth, but it presents longitudinally oriented tiny grooves, which define the presence of lamellae or folia . Internal organization of the cerebellum This drawing represents a cross section through the longitudinal axis of a lamella . The most external part is the cortex and below the cortex, we have the white matter of the cerebellum. The cerebellar cortex is organized into 3 layers: the innermost layer or granular cell or glomerular layer , which is formed by a huge amount of neurons called small granules cells ; then we have the intermediate layer , also called Purkinje cells layer , which contains the cell bodies of large granule cells (also called Golgi cells ) and of the Purkinje cells, which extends their dendrites in the most superficial layer, which is called molecular or parallel fibers layer , here we also find the cell bodies of basket cells and of stellate cells . This last layer is also called parallel fibers layer because if we take one small granule cell and we look at the behaviour of the axon of this cell, it extends up to the molecular level, where it divides into a T shaped manner. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 38 Most of the cells of the cerebellar cortex are inhibitory neurons, with the exception of the small granule cells, which are excitatory. The only cortico-fugal elements of the cortex come from the Purkinje cells and they are inhibitory. If we make a cross section through the cerebellum, we can see that the organization of the grey and white matter is typical of the CNS: it will be the same in the cerebral hemispheres. We find the cortex at the surface, then we have the white matter, that in the cerebellum takes the name of arbrum vitae , and deep to the white matter, we find the deep nuclei .Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 39 In the cerebellum there are 4 deep nuclei that, from medial to lateral, are the fastigial nucleus , the globose nucleus (the oldest), the emboliform nucleus , and the dentate nucleus (the newest). In many animals in which the cerebellum has been studied, the nucleus emboliformis and the globose nucleus constitute just one single nucleus that is called nucleus interpositus . In humans we have them separated. The cerebellar cortex does not project directly outside the cerebellum, but Purkinje cells project to the deep nuclei and then the deep nuclei project outside the cerebellum. Each of the different region of the cerebellar cortex project to one or more nuclei, influencing different pathways of the CNS. The cisterna magna The behaviour of the meninges in the brain and in the spinal cord is different: the dura mater, in the brain, is attached to the endosteum , so the epidural space is virtual; moreover, compared to the surface of the Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 40 brain, the surface of the spinal cord is quite smooth, the surface of the brain, instead, is quite discontinuous. This causes the meninges to have a different behaviour: the dura mater covers the brain, but whenever there is too discontinuity between one region and the other of the brain, it simply passes over (like showed by the red line); on the other hand, the pia mater adheres to the surface of the brain; the arachnoid, instead, is characterized by a very large subarachnoid space and therefore, we have concentration of cerebrospinal fluid. At the level of the cisterna magna , there is a discontinuity between the cerebellum and the brainstem, causing the formation of a quite large subarachnoid space, which is called cisterna magna. This is not the only cisterna that we find in the brain, some other examples are the interpeduncular cistern and the quadrigeminal cistern . The cisterna magna or cerebello-medullary cistern is pretty large and it is also quite accessible, so it can be used to sample some cerebrospinal fluid if the lumbar access point is not available for some reasons. It is not so advisable to sample the fluid here because there is the risk to damage the brainstem or the cerebellum. The cisterna magna is also important to remember because it is the place where we have the communication between the ventricular system and the subarachnoid space . In case this communication is occluded, the cerebrospinal fluid keeps to be produced, but it cant flow into the subarachnoid space, so it accumulates in the brain ventricles, compressing it. The communication between the ventricles and the subarachnoid space is due to 3 openings, which are called the foramina of Luska and the foramen of Magendie . Then, the cerebrospinal fluid is reabsorbed in the granulation of Pacchioni , where it enters in the venous system and then it reaches the venous system. Giuseppe Izzo 4th Lesson Neuroanatomy The brainstem and cerebellum 41 Circumventricular organs The circumventricular organs (which are very near to the ventricular cavities) are organs in which the blood brain barrier is not very efficient, for example capillaries are fenestrated . Moreover, neurons and glial cells have particular characteristics. One of these organs is the area postrema , which is situated at the level of the 4 th ventricle, near the obex. The area postrema is important to remember because it is connected to an area of the reticular formation of the medulla, which is called the Vomition center . The area postrema acts as a chemoreceptor or emetic trigger zone for this center. In case some substances like blood-borne toxins are ingested and brought to the area postrema, this area sends signals to the vomition center, which triggers vomit to try to get rid of these substances. They also receive inputs directly from the cerebral cortex and from the stomach and other viscera through vagal and sympathetic afferents. Another of the circumventricular organs is the epiphysis , which releases melatonin into the blood stream and it is able to do that thanks to the presence of fenestrated capillaries. Then we have the median eminence of the hypothalamus , where the releasing and inhibiting factors produced by the blood stream enter the blood stream to reach the adenohypophysis via the portal circulation. Another region is the one formed by the vascular organ of the lamina terminalis and the subfornical organ , where we find neurons which are sensitive to the concentration of solutes into the blood stream. Giuseppe Izzo Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 1 General organization of the autonomic nervous system The autonomic nervous system is characterized by neurons which are inside the CNS and by neurons that belongs to the PNS . The general role of this system is the control of the internal environment (homeostasis ) by acting on glands secretion; heart (rate, force of contraction); and smooth muscle (organs, blood vessels, piloerector muscles). Visceral efferent pathways The difference between the somatic and visceral efferent pathways is due to the fact that viscera are autonomous (acts quite independently) and involuntary (it does not require a voluntary action); moreover, the synaptic chain is composed by at least 2 neurons between CNS and the target; and it can also have a possible inhibitory action . The neurons inside the CNS are called pre-ganglionic neurons , which give rise to axons that exit the CNS and are finely myelinated. Neurons in the peripheral ganglia are called post-ganglionic neurons ; they give rise to unmyelinated axons that reach the peripheral targets. Position of preganglionic neurons In general, the autonomic efferent nervous system can be divided into sympathetic and parasympathetic components. According to which of these 2 systems a neuron is related, we have 2 different location where the neurons can be. Preganglionic neurons from the sympathetic component are localized in the spinal cord , from the T1 to the L2 segments (at the level of the lateral horn). Because of the position of the preganglionic neurons of the sympathetic outflow, this can also be called thoracolumbar outflow . The preganglionic neurons that give rise to the parasympathetic neurons are located in different zones of the spinal cord: some of them can be found at the level of the Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 2 tegmentum of the brainstem , in particular we find the III CN in the midbrain, and then, in the pons and medulla oblungata, the VI, VII, IX and X CN ; the rest of the parasympathetic outflow originates from the sacral segment of the spinal cord, specifically from S2 to S4 segments of the spinal cord. Due to the position of the preganglionic neurons of the parasympathetic outflow, it can also be called craniosacral outflow . The basis for dividing the autonomous nervous system into a sympathetic and parasympathetic component is mostly made of the position of the ganglia onto which the preganglionic neurons synapse; on the type of neurotransmitters that the postganglionic neurons use; and on the base of the activity that is produced activating either the sympathetic or parasympathetic nervous system. Divisions of the efferent component of the autonomic nervous system Sympathetic Parasympathetic Enteric nervous system , which is part of the autonomic nervous system, but it is a sort of system on its own Position of ganglia The sympathetic ganglia are located on the side of the vertebral column, forming a long chain of interconnected ganglia, which extends from the base of the skull up to the coccygeal bone, in this chain, the ganglia are connected by bundles of axons and the chain is called paravertebral chain ; and in the prevertebral/preaortic plexuses which are located in front of the abdominal aorta . The preganglionic fibers of the sympathetic ganglia, which leave from the CNS and synapse to the ganglia of these chain, are short ; the postganglionic fibers , instead, which have to reach from the ganglia the periphery, are long . The parasympathetic ganglia have a completely different position: they are either close to the organ they innervate (due to this, they can also be called terminal ganglia ), so close that in some cases they can even be inside the wall or the parenchyma they innervate (in this case they are called intramural ganglia ). Due to the position of the parasympathetic ganglia, preganglionic fibers are long , while postganglionic fibers are short . In the case of the parasympathetic ganglia , because they are very close or inside an organ, they are going to act and innervate only that single organ ( localized action ); while the sympathetic ganglia are distant to the target, so when they are activated, they can innervate more than one organ, so it has a more diffuse action .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 3 Neurotransmitters Another difference between the sympathetic and the parasympathetic component is the type of neurotransmitter released by the postganglionic fibers. The neurotransmitter that is used by the preganglionic fibers is the same: they both use acetylcholine (Ach) , which means that they have cholinergic synapses . If we go at the level of the postganglionic fibers ,we can see that in the case of the sympathetic component, the neurotransmitter released is norepinephrine or noradrenaline (noradrenergic fibers); while in the parasympathetic postganglionic fibers, the neurotransmitter used is acetylcholine (cholinergic fibers). We can have some exceptions, especially in the sympathetic nervous system, where neurons that innervate sweat glands use acetylcholine as neurotransmitter. The receptors on which the postganglionic fibers act can be different, even though the neurotransmitter is the same. For example, parasympathetic cholinergic preganglionic fibers act on a receptor called nicotinic receptor (N) ; while the Ach that is released from postganglionic parasympathetic fibers acts upon muscarinic receptors (M) . If we consider the postganglionic fibers of the sympathetic nervous system, they act 2 different types of receptors, which are called alpha and beta receptor . The medullary portion of the adrenal gland is considered as a modified sympathetic ganglion . The adrenal gland is not a proper ganglion since it does not give rise to postganglionic fibers, but adrenaline and noradrenaline, which are produced by the medullary portion of the adrenal gland, are released into the blood stream. The physiological effect of the autonomic stimulation depends on the type of post-synaptic receptors. If we look at the drawing below, we can see a sympathetic ganglia with an adrenergic output; if we consider the target cell, there are different types of each receptor (alpha1, beta1 and beta2), which can have excitatory or inhibitory actions (+ or -). So, the effect that the neurotransmitter will produce depends on the type of receptor we find on the target cell. As there are postsynaptic receptors , there are also presynaptic receptors , which are localized on the same cell that is giving rise to the synaptic output. For example, the cell of the image, which has just released the adrenergic neurotransmitter , has on its surface, an alpha2 receptor , which means that the adrenaline Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 4 released in the synaptic space, also acts upon the cell releasing the neurotransmitter, thus modulating the activity of the cell. Noradrenaline , can also act on cholinergic neurons via alpha2 receptor , stimulating or inhibiting their action. The same situation is for Ach , which will be able to act on the target cell, but also the cell itself and to surrounding neurons. Major effects mediated by adrenoreceptors There are some drugs which are called beta-blockers , which can act, for example, on beta1 receptors of the heart , decreasing heart rate, contractility and conduction. We also find beta1 receptors at the level of the kidney glomerulus where renin is produced, so beta-blockers would cause a decreased renin release from renal juxtaglomerular cells. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 5 Muscarinic receptors Autonomic nervous system response The sympathetic response is defined as fight or flight ; while the one of the parasympathetic response is the rest and digest . The function of the sympathetic nervous system causes the pupils of the eyes to dilate, thus to maximize peripheral vision. The lenses of the eyes would adjust for far vision; airways in the lungs would open up wide, thus to allow oxygen to come in and increase the respiratory rate; the heart rate would increase. Blood vessels to limb muscles would dilate; while blood vessels to visceral organs would constrict. Salivary secretion, and secretion activity in the digestive system, would be greatly reduced. Brain activity, and general alertness, would be greatly enhanced. If the parasympathetic system enters in function, the pupils of the eyes would constrict; the lenses would readjust for closer viewing; airways of the lungs would constrict; the respiratory and heart rate would decrease to normal resting level. Blood vessels to limb muscles would constrict, while those to visceral organs would dilate. Salivary secretion, and secretory activity in the digestive system, would return to normal resting levels; and brain activity and the state of alertness would return to normal levels. Most of our organs have a double innervation , which means that they receive both sympathetic and parasympathetic nervous system, which act as antagonist and one system usually predominates on the other. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 6 Both in the sympathetic division and in the parasympathetic one there are also other types of neurotransmission, which are called non-adrenergic, non-cholinergic transmission (NANCS) , which means that some of the neurons of the autonomic ganglia use as neurotransmitters substances such as neuropeptides (VIP, SP), nitric oxide , dopamine , serotonin , ATP and others These different substances can act both as neuromodulators and neurotransmitters. They can be found in the airways (more frequent), in the GI tract , and in the genital tract . In this drawing, we can see some muscle cells and parasympathetic and sympathetic fibers interacting with the cells. As the axon is approaching the cells, it forms some varicosities and each of them is characterized by the presence of the neurotransmitter vesicles . In this way a fiber can influence a large portion of target cells due to the presence of these varicosities along the length of the axon. This varicosities are also called synapses en-passant . Because of the synapses en-passant, lots of neurotransmitter receptors can be influenced at the same time. There is an interaction between the immune system and the sympathetic nervous system . Adrenergic receptors are present on immune cells and receptors for substances produced by immune cells are present on nerve fibers and bodies. In the image we can see the local dialogue between a nerve terminal and a macrophage in the spleen. Upon an action potential (step 1), NE (norepinephrine) is released from nerve terminalis into the surrounding area (step 2). Neural NE binds to adrenergic receptors at the macrophages membrane (step 3). The binding of NE to adrenergic receptors decreases IL-6 (interleukin 6) secretion from macrophages (step 4). Released NE can negatively regulate its own release via auto-receptors on the terminal nerve (step 5). NE release is also regulated, for example, by TNF-alpha (tumour necrosis factor) via heteroreceptors (step 6). Arrows demonstrate a positive influence and bars a negative influence. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 7 Parasympathetic outflow With parasympathetic outflow we intend the system of nerves going from the CNS to the periphery. It is based on the presence of preganglionic neurons , which are located at the level of the brainstem nuclei and in the sacral spinal cord ( S2 to S4 ); and of postganglionic neurons , which are located in the autonomic ganglia (in the head and close to or inside viscera). The most rostral parasympathetic nucleus is called the nucleus of Edinger-Westphal , which is located in the tegmentum of the midbrain. Its axons leave the midbrain together with the 3 rd cranial nerve . Then, they travel to the periphery up to their autonomic ganglion, the ciliary ganglion , which is located at the level of the orbital cavity. The post ganglionic fibers which originates from the ciliary ganglion reach the eye bulb and are directed to the constrictor of the pupil and to the ciliary muscles. Then, if we proceed caudally, we find the superior and inferior salivatory nuclei in the caudal portion of the pons. The superior sends its fibers out of the brainstem together with the intermediate component of the facial nerve . The fibers travel in the VII cranial nerve and then they reach the pterygopalatine ganglion and the submandibular or sublingual ganglia . These fibers are important because they drive the innervation from the pterygopalatine ganglion to the lacrimal and nasal glands. On the other hand, the fibers that reach the submandibular ganglion are directed to the submandibular and sublingual glands. the inferior salivatory nucleus axons leave the brainstem through the IX cranial nerve and they reach the otic ganglion and from there, they reach the parotid gland . In the medulla oblungata, we find a very large parasympathetic nucleus, which is called the dorsal motor nucleus of the vagus nerve (DNX) . The vagus can be found in the thorax and in the abdomen, which means Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 8 that we need more than one ganglion. We have some ganglia at the level of the heart ; some others at the level of the wall of the bronchi and, from these ganglia, postganglionic fibers reach the smooth muscle cells and the glands of the bronchial wall. Then, we have all the organs that are innervated from the vagus, such as the gastrointestinal tract . Most of the ganglia in the head are close to the branches of the trigeminal nerve : some preganglionic and postganglionic fibers distribute through branches of the trigeminus. The trigeminus is not characterized by a parasympathetic component; nevertheless, peripherally, some of the parasympathetic fibers , to reach their peripheral target, they enter in the peripheral branches of the trigeminus. They are called the hitchhikers of the trigeminus . Ciliary ganglion The ciliary ganglion inside the orbital cavity is reached by preganglionic parasympathetic fibers , they synapse on the ciliary ganglion, and then, postganglionic fibers, through the short ciliary nerve , enter into the eye bulb. The ciliary ganglion is also crossed by sympathetic fibers, which are already postganglionic (originating in the territory of the paravertebral chain). In the territory of the head there are no sympathetic ganglia, so these fibers simply cross the ganglion and then they reach the eye bulb. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 9 Pterygopalatine or sphenopalatine ganglion The pterygopalatine or sphenopalatine ganglion is located inside the pterygopalatine fossa. The second division of the trigeminus ( maxillary division ) enters as well in the pterygopalatine fossa through the foramen rotundum . The fibers that originate from the maxillary division of the trigeminus contain and receive postganglionic fibers from the sphenopalatine ganglion. The pterygopalatine ganglion is receiving the preganglionic fibers from the VII cranial nerve , specifically from the superior salivatory nucleus . While the VII cranial nerve is running, it gives off some collaterals and one of them is called the greater petrosal nerve , which enters into the pterygopalatine fossa to bring preganglionic fibers to the ganglion. If we continue to follow the course of the VII, we see the corda timpani , which reaches the maxillary nerves, specifically the lingual nerve , through which, it brings the preganglionic fibers to the submandibular ganglion. In the case of the corda timpani, the mandibular division is used as a pathway both for the preganglionic and postganglionic fibers; while the greater petrosal nerve does not use the trigeminus, but reaches the pterygopalatine fossa through the pterygoid canal and there it contacts the pterygopalatine ganglion, generating postganglionic fibers that run in the divisions of the trigeminus. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 10 The IX cranial nerve , along its course, gives off a branch that is called the lesser petrosal nerve , which reaches the otic ganglion that sends postganglionic fibers into the auriculotemporal nerve , which is a branch of the mandibular division of the trigeminus, to reach the parotid gland . In this case, the trigeminus provides a root only for the postganglionic fibers. All glands above the level of the oral fissure are innervated by the greater petrosal nerve ; while all the glands below the oral fissure are innervated by the chorda tympani . Nerve of the pterygoid canal (Vidian nerve) The preganglionic parasympathetic fibers of the IX cranial nerve are associated to the lesser petrosal nerve , which reaches the pterygopalatine fossa through the pterygoid canal . Before reaching the fossa, it receives the contribution of the postganglionic sympathetic fibers that originate from the paravertebral chain. This contribution is brought inside the skull via the deep petrosal nerve . The deep petrosal nerve Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 11 and the greater petrosal nerve enter together into the pterygopalatine fossa and the association of the 2 types of fibers lead to the formation of the nerve of the pterygoid canal , which is also called the Vidian nerve . Trigeminal hitchhikers Visceral motor nerves are not a true component of the trigeminal nerve, but hitchhikers along its branches. They originate centrally from other cranial nerves and travel along sensory branches of the trigeminal nerve en route to glands. Visceral motor nerves can be subdivided into pre-ganglionic and post-ganglionic fibers. Pre-ganglionic fibers travel from cranial nerve nuclei in in the brainstem (where their cell bodies are located) to peripheral ganglia in the head and neck. These include the pterygopalatine ganglion, otic ganglion, and submandibular ganglion. Within these ganglia, pre-ganglionic fibers synapse with post-ganglionic neurons (whose cell bodies make up the ganglia). The axons of postganglionic neurons travel to innervate peripheral targets (glands and smooth muscle). The facial nerve gives rise to 2 important trigeminal hitchhikers : the Vidian nerve and the chorda tympani nerve. The Vidian nerve (nerve of the pterygoid canal, greater petrosal nerve + deep petrosal nerve) emerges from the pterygoid canal carrying preganglionic fibers to the pterygopalatine ganglion. After synapse, postganglionic fibers exit the ganglion and hitchhike along trigeminal nerve branches (maxillary division) en route to the lacrimal gland and minor salivary glands of the palate and mouth. The chorda tympani exit the skull through the petrotympanic fissure and courses extracranially to join the lingual nerve . It carries preganglionic fibers to the submandibular ganglion close to the lingual nerve. After synapse, postganglionic fibers exit the ganglion to innervate the submandibular gland and sublingual gland. The glossopharyngeal nerve also contributes an important trigeminal hitchhiker: the lesser petrosal nerve .It carries preganglionic fibers to the otic ganglion . After synapse, postganglionic fibers exit the ganglion, hitchhiking along the auriculotemporal nerve to innervate the parotid gland. The vagus nerve The destiny of the vagus is completely different since the vagus territory of innervation is related to organs present in the territory of the neck, of the thorax and of the abdomen. The vagus nerve preganglionic parasympathetic fibers travel quite a lot before they find their peripheral target ganglia. The preganglionic fibers originates from the dorsal motor nucleus ,located in the tegmentum of the medulla oblungata, they exit from the base of the skull, through the jugular foramen and they synapse either in the ENS or in ganglia close to the organs or in the wall of the organ they need to innervate. Preganglionic fibers are long, while postganglionic fibers are short because the ganglia are close to the organs they need to innervate. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 12 Cardiac nerves and cardiac plexus Collaterals of the vagus nerves bring fibers close to the heart , where they reach the base of the heart and they end into small ganglia, from where postganglionic parasympathetic fibers are going to originate. The parasympathetic innervation of the heart comes from the vagus nerve, while sympathetic innervation comes from the sympathetic trunks . Preganglionic parasympathetic neurons located in the sacral segment of the spinal cord Preganglionic fibers leave the spinal cord through the ventral roots of the spinal nerves and they leave the ventral canal by using the pathways of the spinal nerves. When they exit the vertebral canal inside the spinal nerve, then they branch off, giving rise to the pelvic splanchnic nerves . They synapse in the last portion of the enteric nervous system or in ganglia located close to organs or within the wall os viscera that are contained in the pelvic cavity . Preganglionic fibers reach their target ganglia by entering the inferior hypogastric plexus and the superior hypogastric plexus , which are located in front of the vertebral column and in front of the aorta and from there, we lose them, since they use the pathways formed by these 2 plexuses to reach their peripheral targets. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 13 Enteric nervous system Preganglionic fibers from the vagus nerve and the pelvic splanchnic nerves synapse in the enteric nervous system. The enteric nervous system is organized as a network within the wall of the digestive tract. Within this network, we find ganglia and strands of fibers (axons) whose connects those ganglia. The enteric nervous system is organized into plexuses: the myenteric plexus and the submucosa plexus .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 14 If we analyse the enteric nervous system, we see something like that: There are different types of cells that form the enteric nervous system. Some of them are sensory neurons (IPAN) and they send axons towards the mucosa, forming mechanoreceptors , sensing the distension of the mucosa of the intestinal tract. The sensory information is then used to contact the motoneurons of the enteric nervous system, which can be ascending (excitatory) or descending (inhibitory) . The first one releases neurotransmitters with an excitatory action ( contraction ) on muscle cells, and it is called ascending because most of the cells ascend along the intestinal tube; the latter uses neurotransmitters with inhibitory action ( relaxation ) on muscle cells and they are called descending because most of their output is directed caudally in the intestinal tube. Along the enteric nervous system, we can also find some interneurons , which can be both ascending (stimulus sent towards oral part) and descending (they project to the anal part). Moreover, we can have some secretory motoneurons , which facilitate the secretion from the glands in the mucosa of the digestive tube. This complex network of neurons that form the enteric nervous system can work on its own, but it is also under the control of the autonomic nervous system because it receives parasympathetic preganglionic fibers and sympathetic postganglionic fibers . The stomach glands are characterized by the release of pepsinogen, by the release of HCl, of histamine, of gastrin. The release of these substances is under the control of the enteric nervous system, but the ENS is under the control of the vagal efferent outflow, which means that also the secretion of these cells is under the control of the vagal outflow .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 15 Sympathetic outflow In the case of the sympathetic outflow , we need to consider the thoracolumbar preganglionic neurons which are located in the spinal segments from T1 to L2 , specifically in the lateral horn of the grey matter. Preganglionic fibers leave the spinal cord through the ventral roots and then they enter into the spinal nerves. Immediately after the exit from the spinal cord, the spinal nerve gives rise to a ramus, which is called the white ramus communicantes . The white rami communicantes connect the spinal nerves with the paravertebral chain of ganglia . Because only the T1-L2 segments contain preganglionic sympathetic neurons, the white rami communicantes are present only in this part of the spinal cord. Destiny of preganglionic fibers from T1 to L2. Some preganglionic fibers synapse on the closest ganglion of the paravertebral chain and that is true for the thoracic and upper lumbar ganglia because its only at that level that we have the preganglionic fibers. Some preganglionic fibers ascend or descend in the paravertebral chain and synapse in cervical or lumbosacral ganglia of the paravertebral chain. Some preganglionic fibers cross the paravertebral chain to synapse on neurons of the pre-aortic ganglia . This type of fibers is called the true splanchnic nerves (visceral nerves). Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 16 This scheme is showing us that some preganglionic fibers synapse on the ganglia very close to them, some of them ascend and synapse on ganglia which are rostrally localized or caudally localized in the paravertebral chain. Some preganglionic fibers simply cross through the paravertebral chain without synapsing in it because they need to synapse in the preaortic ganglia. Destiny of postganglionic fibers originating from neurons of the paravertebral chain Some of the postganglionic fibers enter in the closest spinal nerve or in more superior or inferior spinal nerves by way of the grey rami communicantes . They are important for the innervation of sweat glands , of vessels , and of piloerector muscles . Other postganglionic fibers leave the paravertebral chain as to form perivascular plexuses , or visceral nerves (also called splanchnic nerves )for the viscera of the thoracic cavity. The preganglionic fibers reach the paravertebral chain through the white rami communicantes . Some of the neurons inside the ganglia of the paravertebral chain leave the ganglia by giving rise to axons that re-enter into the spinal nerve via the grey rami communicantes . We call them grey and white because preganglionic fibers are myelinated, while postganglionic fibers are unmyelinated. The grey rami communicantes are present at the level of all the spinal nerves. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 17 1. Enter in the closest spinal nerve Postganglionic fibers can enter in the closest spinal nerve to distribute in the territories which are innervated from the spinal nerves from T1 to L2. When we consider the spinal segments from T1 to L2, they contain the preganglionic sympathetic neurons and many of their fibers leave the spinal nerve through the white ramus communicantes and then they synapse on the closest ganglion of the paravertebral chain and in turn the postganglionic fiber re-enter in the same spinal nerve. They will distribute to the sweat glands, vessels and piloerector muscles. 2. Enter in more superior or inferior spinal nerves The postganglionic fibers do not re-enter in the same spinal nerve, but they ascend or descend in the paravertebral chain to enter into a spinal nerve located more rostrally or caudally. That is because we need to innervate structures present in the territories of the head and upper limbs and lower limbs. 3. Leave the paravertebral chain to form perivascular plexuses There is a sympathetic nerve, called deep petrosal nerve , which comes together with the superficial petrosal nerve to form the Vidian nerve . The deep petrosal nerve is formed by postganglionic fibers, which originate and run in the perivascular plexuses, which together with the vessels enter inside the skull. Inside the skull, we have viscera and muscles that need to receive both parasympathetic and sympathetic innervation. For the parasympathetic innervation is not problem because we have parasympathetic ganglia inside the skull; but for the sympathetic innervation, we do not have sympathetic ganglia inside the skull. So, from the most rostral portion of the paravertebral chain, and, specifically, from the cervical portion, we have postganglionic sympathetic fibers that wrap themselves around the vessels that enter into the skull, like the internal carotid artery or the external carotid artery, which supplies the skin, the muscles and the soft tissue of the skull, thus forming perivascular plexuses . From these plexuses, we can reach the territories that need also a sympathetic innervation. 4. Leave the paravertebral chain to form visceral nerves (splanchnic nerves) These nerves contain postganglionic fibers and they can in general be called cardiopulmonary splanchnic nerves because they are directed to organs that are in the thorax. They originate from the cervical and from the upper thoracic portion of the paravertebral chain . They receive a preganglionic input from the neurons located at the level of the T1 to T5 segments of the spinal cord. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 18 Some of these visceral nerves, originating from the upper part of the paravertebral chain, are directed to the heart . We can notice the superior, middle and inferior cervical cardiac nerve , which are visceral nerves that contain postganglionic sympathetic fibers directed to the heart. Moreover, if we consider the upper part of the thoracic paravertebral chain, we have thoracic cardiac branches . The thoracic and cervical ganglia receive the preganglionic sympathetic input from T1 to T5 and from cervical segments of the spinal cord. We also have the contribution of the vagus nerve, which gives rise to the superior and inferior vagal nerves . In addition to the cardiac plexus, we have the formation of the pulmonary plexus .From the paravertebral chain we have postganglionic fibers which are directed through the trachea, then through the main bronchi and then they follow the course of the main bronchi, branching inside the lung parenchyma. Since the work of the innervation system is to control glands and muscles, we find the parasympathetic and sympathetic fibers up to where we find muscles and glands in the tracheobronchial tree. If we look at what enters into the hilum of the lungs , we find postganglionic sympathetic fibers that come from the upper portion of the paravertebral chain (cervical and thoracic), but we also find parasympathetic preganglionic fibers that come from the dorsal motonucleus of the vagus nerve. Along the length of the tracheobronchial tree, we find small intramural ganglia , onto which the preganglionic parasympathetic fibers of the vagus nerve synapse; and then these small ganglia give rise to the postganglionic parasympathetic fibers. Destiny of preganglionic fibers from T1 to L2 (2) Some preganglionic fibers , from T5 to L2 , cross the paravertebral chain (lower thoracic and lumbosacral portion) to synapse on neurons of the pre-aortic ganglia, thus to form splanchnic nerves and abdominopelvic nerves (visceral nerves). We have 3 groups of splanchnic nerves: The cardiopulmonary splanchnic nerves , which covey postganglionic sympathetic fibers to thoracic viscera The abdominopelvic nerves , which convey preganglionic sympathetic fibers to the sympathetic ganglia of the abdominopelvic cavity (preaortic ganglia) The pelvic splanchnic nerves that convey preganglionic parasympathetic fibers to the pelvic ganglia (close to organs or in their wall) Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 19 Abdominopelvic splanchnic nerves The preganglionic fibers to the preaortic ganglia are carried by abdominopelvic splanchnic nerves and emerge from the lower thoracic, lumbar and sacral segments of the paravertebral chain. The abdominopelvic splanchnic nerves are divided into greater, lesser, least, lumbar and sacral splanchnic nerves . They all contain preganglionic sympathetic fibers on their way to the plexuses located in front of the abdominal aorta and of the main vessels originating from it. In these plexuses, they find sympathetic ganglia (preaortic or prevertebral ganglia), on which they synapse. The segments of the spinal cord that are responsible for giving rise to the abdominopelvic splanchnic nerves are the ones from T5 to L2 . If we take the T5 to T9 segments, here we have preganglionic sympathetic neurons whose axons leave the spinal cord, enter into the paravertebral chain and gives rise to the greater splanchnic nerve . The fibers from this nerve synapse into the first 2 ganglia that we find in front of the aorta, which are called the celiac ganglia ,located in the celiac plexus . Then, if we take the segments from T9 to T10 (or from T10 to T11), they form the lesser splanchnic nerve .The sympathetic preganglionic neurons of T12 give rise to the least splanchnic nerve ;while the preganglionic fibers from L1 to L2 form the lumbar splanchnic nerve and some of them descend in the paravertebral chain as to form the sacral splanchnic nerve .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 20 All these fibers are preganglionic and they are not enough to control the viscera: they have to synapse on ganglia and give rise to postganglionic fibers. These ganglia can be found in front of the aorta and of the main vessels originating from it. Innervation from splanchnic nerves in the abdominal intestinal tube The foregut and the derivatives of the foregut are innervated by the greater splanchnic nerve (T5-T9) and they receive the arterial blood supply by the celiac artery. The midgut derivatives receive their autonomic sympathetic innervation from the lesser splanchnic nerve (T10-T11). The hindgut derivatives receive the sympathetic innervation from the least splanchnic nerve (T12), from the lumbar and splanchnic nerves (L2-L3). From this image, we can see the greater splanchnic nerve , which reaches the celiac ganglia , and from there, we have the origin of the postganglionic fibers that are going to distribute to several organs, especially organs of the suvramesocolic compartment , by following the distribution of the blood vessels. Also, the other splanchnic nerves are shown, together with their path and territory of innervation. The greater splanchnic nerves reach the ganglia located at the level of the celiac plexus ; many fibers stop here, others do not stop in the celiac ganglia, but follow the distribution of the secondary plexuses of the celiac plexus and synapse in ganglia located more distally. The lesser splanchnic nerve, instead, stops mostly in the aortic-renal ganglia , in the plexus that is between the origin of the superior and inferior mesenteric ganglia . The lumbar splanchnic nerve reaches the inferior mesenteric ganglion , which is located where the inferior mesenteric artery originates. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 21 If we look at the abdominal aorta , we can notice primary and secondary plexuses , which can be single or paired. We can see a cascade of nerve fibers plexuses, which is not only in front of the aorta, but is also continues below the bifurcation of the abdominal aorta into the pelvic cavity. The preaortic or prevertebral plexuses organize themselves around the vessels that originate from the aorta (celiac trunk, superior mesenteric artery, inferior mesenteric artery, renal arteries) and around the secondary branches that originate from those vessels. These plexuses are very complex and they contain within their core a combination of ganglia and nerve fibers. In general, plexus is a term used to describe an agglomeration of only nerve fibers, but in this case, the plexuses are ganglionated plexuses , meaning that within the plexuses we find also sympathetic ganglia . The plexuses located in front of the aorta can be divided into primary and secondary plexuses that can be single or paired. The primary plexuses are the celiac , the aorticoabdominal , the superior hypogastric and the inferior hypogastric or pelvic plexus . The aorticoabdominal plexus extends from the superior mesenteric artery to the origin of the inferior mesenteric artery . The superior hypogastric plexus is more or less at the level of the bifurcation of the aorta , and then the inferior hypogastric plexus is located in the pelvic cavity . The superior and inferior hypogastric plexuses are connected by a cascade of nerve fibers that takes the name of hypogastric nerves . From the primary plexuses, we have the origin of the secondary plexuses , which can be single or paired. These secondary plexuses contain sympathetic ganglia .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 22 The celiac plexus , which is organised around the celiac trunk, forms secondary plexuses that follow the blood vessels, and they can be paired such as the phrenic , suprarenal , renal and spermatic plexuses , or single such as the splenic , hepatic , gastric and superior mesenteric plexuses . The splanchnic nerves reach these plexuses, where they find their target ganglia. The inferior hypogastric plexus is located below the aortic bifurcation and it is also called the pelvic plexus because of its position. In the pelvis there are lots of plexuses, which are all secondary divisions of the inferior hypogastric. If we are in the male pelvis, we have plexuses around the bladder, around the prostate gland, around the last portion of the digestive tract, the rectum and the anal canal. If we are in the female, the situation is slightly different: we still have a plexus around the bladder, around the last portion of the digestive tract, but then, we will have also a plexus around the uterus and other genital organs (uterovaginal plexus, vesical plexus). If there is a trauma to the pelvic cavity, it is very easy to damage all these tiny nerves that innervates the viscera of the pelvis. If surgery needs to be performed in the pelvic cavity, it is necessary to pay lots of attention not to damage all the nerves, which are important for the autonomic control for the viscera of the pelvic cavity. The preaortic plexuses provide also a route for the distribution of preganglionic parasympathetic fibers from the vagus nerve and pelvic splanchnic nerves to their peripheral targets (ganglia and ENS). The inferior hypogastric plexus and the superior hypogastric plexus provide a route for the distribution of pelvic splanchnic nerves (parasympathetic preganglionic fibers). Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 23 From the sacral segments of the spinal cord, we have the origin of parasympathetic preganglionic fibers ,which once they have left the vertebral canal, they form the pelvis splanchnic nerves , which contain parasympathetic fibers and are responsible for the parasympathetic innervation of the viscera contained in the pelvic cavity and the last portion of the digestive tract (1/3 on the left of the transverse colon, descending colon, rectum, anal canal). These fibers reach their targets by entering in the sympathetic plexuses, in particular the inferior hypogastric plexus and, via the hypogastric nerve , they reach even the superior hypogastric plexus . So, the inferior hypogastric plexus and the superior hypogastric plexus, besides containing sympathetic fibers, they also contain parasympathetic preganglionic fibers on their way to the small ganglia that we find either within the wall of the organ or close to the organ. From the vagus nerve , it forms a plexus posteriorly to the oesophagus , and then the oesophagus enters in the abdominal cavity and we can still find the vagus nerve, but, after that, we cannot really discriminate the trunk of the vagus nerve. Below the diaphragm, preaortic plexuses provide a route for the distribution of the preganglionic fibers of the vagus nerve to their peripheral ganglia and ENS. So, also the celiac and the aorticoabdominal plexuses and their secondary plexuses contain parasympathetic fibers . Ganglia in preaortic and prevertebral plexuses are sympathetic , but fibers forming the plexus are mixed .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 24 The preaortic plexuses are formed by preganglionic sympathetic fibers ; by postganglionic sympathetic fibers (from their ganglia or from the paravertebral chain); by preganglionic parasympathetic fibers from the vagus nerve or from the pelvic splanchnic nerves; by visceral sensory fibers (mostly nociceptive and pain related). # Visceral sensation Visceral sensory neurons We can find visceral sensory neurons in the dorsal root ganglia and in the cranial nerves , especially in the vagus, glossopharyngeal and facial nerve. The vagus has a very large territory of viscerosensory innervation and it has 2 sensory ganglia associated: one of them contains somatosensory neurons and the other viscerosensory neurons (nodosus ganglion ). The glossopharyngeal nerve also has a viscerosensory territory of innervation, which is more limited if compared to the one of the vagus, and it is associated with the petrosus ganglion (also in this case we have 2 ganglia). Both the ganglia of the vagus and of the glossopharyngeal nerve are located at the level of the jugular foramen . The facial nerve also has viscerosensory innervation, in fact, along its course inside the canal for the facial nerve (inside the petrous portion of the temporal bone), we find the geniculate ganglion . In this case, it is like the dorsal root ganglia of the spinal cord, in the sense that it contains both somatosensory and viscerosensory neurons. These 3 nerves, beside collecting viscerosensory information, also innervate the tongue , collecting special viscerosensory innervation . The largest of these 3, which has the larger territory of innervation in the tongue, which means that carries the taste information, is the VII cranial nerve (it innervates the anterior 2/3 of the tongue). Problems in taste sensation are usually present in case of lesion of the facial nerve. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 25 Stimuli and central structure It is more difficult than with somatic innervation to understand which type of information are collected from the viscera that need to be carried to the CNS. For example, we can have mechanical information ,such as how much is the bladder filled, or what is the status of the different segments of the ureter, how much is the stomach dilated; chemical information , such as the pH of the stomach; nociceptive information , which are damaging or potentially damaging information (an ulcer is forming in the wall of the stomach, there is a damage in the intestine); the nociceptive information can become pain information ,but only if they are processed in a certain way in the cortex. All the stimuli are collected from the viscerosensory neurons and brought to the CNS, for example to the spinal cord; to the nucleus of the solitary tract , which receives viscerosensory information and it is associated to the vagus nerve and it is found in the tegmentum of the medulla; to the reticular formation ,directly or indirectly; to the complex parabrachialis ; to the periaqueductal grey matter ; to the thalamus ;to the cortex ; and, in particular, to the hypothalamus . The hypothalamus is really the core of the autonomous nervous system. All the information brought to the CNS are used for reflex activity such as control of circulation, control of respiration, digestion, micturition, coition Visceral pain Visceral sensations do not always reach consciousness. When they do, they give rise either to sensation of discomfort , triggering intentional changes in the behaviour, or pain sensation. Not all internal organs are sensitive to pain and some can be damaged quite extensively without the person feeling a thing. Many hollow organs are sensitive to pain (contact with the external environment, thus being subjected to potentially harmful agents). Visceral pain has five important clinical characteristics: 1. It is not evoked from all viscera (organs such as liver, kidney, most solid viscera, and lung parenchyma are not sensitive to pain); 2. It is not always linked to visceral injury (cutting the intestine causes no pain and is an example of visceral injury with no attendant pain, whereas stretching the bladder is painful and it is an example of pain with no injury); 3. It is diffuse and poorly localised ; 4. It is referred to other locations ; 5. It is accompanied with motor and autonomic reflexes , such as the nausea, vomiting, viscero-visceral reflexes and lower-bac muscle tension that occurs in renal colic. How viscerosensory fibers reach their peripheral target Viscerosensory fibers reach their peripheral targets through the cranial nerves ( Vagus ): the centrifugal branches enter the cranial nerve to which the ganglion was associated and, through that, they distribute to the visceral organ. They can also distribute through the anterior and posterior branches of the spinal nerves : dorsal root ganglia contain viscerosensory and somatosensory neurons, which means that the spinal nerves contain viscerosensory fibers that are carried in the posterior and anterior divisions of the spinal nerve. Moreover, they can also travel through splanchnic nerves : spinal nerves contain viscerosensory neurons, some of these fibers remain in the spinal nerve, but some others leave the spinal nerve, enter into the white rami communicantes , reach the paravertebral chain and then they follow the distribution of the nerves that originate from the paravertebral chain. Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 26 Viscerosensory fibers that form nociceptors at the periphery (those that can lead to a pain sensation) usually run together with sympathetic nerves ; while viscerosensory fibers that simply collect general information (not pain related) from the viscera run together with the parasympathetic nerves . Referred pain location to segments of the spinal cord: Foregut : oesophagus, proximal duodenum, liver pancreas, gallbladder greater splanchnic nerve (enter T5-T9) Midgut : distal duodenum to transverse colon lesser splanchnic nerve (enter T10-T11) Hindgut : descending colon to the pain pelvic line least splanchnic nerve and lumbo-sacral splanchnic nerves (enter T12-L3) Below pelvic line : pelvic splanchnic nerves (S2-S4) Splanchnicectomy is the procedure used mainly for the control of intractable visceral pain : cutting the splanchnic nerve bringing fibers with pain receptors to an organ, we avoid this information to be sent at the CNS. Pelvic pain line Threshold determining the course of visceral pain sensation . Associated with the inferior peritoneum .Structures above or in contact with the inferior peritoneum convey visceral pain sensation via sympathetic splanchnic nerves ; structures below the inferior peritoneum convey visceral pain sensation via parasympathetic pelvic splanchnic nerves .Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 27 Innervation of the urinary bladder The superior surface of the bladder is covered by peritoneum; this portion is above the pelvic pain line. Remainder of bladder is below the pelvic pain line. Visceral pain from superior surface of urinary bladder is conveyed via lumbar and sacral splanchnic nerves . Visceral pain from remainder of urinary bladder is conveyed via pelvic splanchnic nerves . Innervation of the anal canal The anal canal has a double origin from the embryologically point of view: the upper part originates from the hindgut, while the lower portion originates from the proctodeum. In the area superior to the pectinate line (hindgut derivative), the sympathetic innervation is carried via the lumbar and sacral splanchnic nerves ; the parasympathetic innervation is carried via the pelvic splanchnic nerves . Below the pelvic pain line both visceral pin and visceral non-pain fibers are conveyed via the pelvic splanchnic nerves .In the area inferior to the pectinate line (proctodeum derivative), the somatic innervation is carried by the inferior rectal nerves (branches of pudendal nerve). Giuseppe Izzo 5th Lesson Neuroanatomy Autonomic nervous system 28 The enteric nervous system The wall of the intestinal tube receives a viscerosensory innervation, which comes from the vagal nerve ;but it also receives viscerosensory fibers from dorsal root ganglia, which usually travel with sympathetic fibers , conveying pain and discomfort reflexes. Moreover, within the wall of the intestinal tube we have the intrinsic primary afferent neurons , which behave similar to the primary sensory ganglia of the dorsal roots or the nodose ganglion, but they act for triggering local reflexes . Pain coming from viscera can be referred to somatic territories . The mechanism of referred pain is due to the fact that at the central level there is a converge of somatic and visceral information on the same projecting neuron. Signals from nociceptors in the viscera can be felt as pain elsewhere in the body. The source of the pain can be readily predicted from the site of referred pain. Convergence of visceral and somatic afferents may account for referred pain. According to this hypothesis, afferent fibers from nociceptors in the viscera and afferents from specific areas of the periphery converge on the same projection neurons in the dorsal horn. The brain has no way of knowing the actual source of the noxious stimulus and mistakenly identifies the sensation with the peripheral structure. In (A) pictures, we can see areas of deep referred pain in myocardial infarction and angina. Giuseppe Izzo Giuseppe Izzo 6th Lesson Neuroanatomy The brain 1 Development of the brain The cerebral hemispheres need to be able to host lots of neurons, which means that the 2 telencephalic vesicles grow more and more during the development. In the meanwhile, the bones of the head are forming, so they start to bend dorsally, posteriorly and inferiorly, up to reach a C-shaped appearance ,surrounding the diencephalic vesicles . While the vesicles grow, they come into contact with the bones of the skull , which are called according to the relation of the correspondent part of the skull. Because of the change in shape of the vesicles, also the cavity which is within each of the 2 telencephalic vesicles acquire a C-shaped appearance, and it is called the lateral ventricular cavity . This cavity extends partly in the frontal lobe , in the occipital lobe and in the temporal lobe . The diencephalon , since it has been enveloped by the telencephalon, it is not any longer in series with the telencephalon, but in parallel with it. If we look at the adult lateral ventricles , we can see the anterior or frontal horn , a central part , an occipital or posterior horn and a temporal horn . The region where the 3 horns of the ventricle come together is called atrium . The 2 lateral ventricles remain in communication with the 3 rd ventricle, at the level of the interventricular foramina . In a radiological image of the brain, we find some spaces, which have different densities because they contain the cerebrospinal fluid and they correspond to the ventricular cavities .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 2 The hippocampus In the floor of the 4 th ventricle , we find the hippocampal formation , which is the oldest portion of the cortex. Originally the hippocampus was dorsally localised, like it was in the embryo brain. If we look at the adult brain, it is not dorsally localised anymore, but it will be ventrally localised . If we look at the image below, the purple region is the archicortex or hippocampus ; then, anteriorly, we have a territory called basal forebrain (where we find the anterior commissure ). Since the 2 territories are near to one another, the hippocampus starts to make connections with the basal forebrain. In this same region, the medial wall of the cerebral vesicles becomes also thin in some places, with the formation of the choroid plexuses . While the telencephalic vesicles are growing and bending, the hippocampus gets displaced first dorsally posteriorly and then ventrally and medially. While it moves, it leaves behind a trail of fibers that will form the fornix . During the process of bending of the telencephalic vesicles, also the choroid fissure , in which the choroid plexus is forming, acquires a C-shaped appearance. Moreover, from the telencephalic vesicle, we have the formation of one of the deep nuclei of the brain, the ganglionic eminence , from where we will have the formation of most of the deep nuclei of the brain . Because of the formation of the fibers of the internal capsule , one of these deep nuclei will remain located medially to the internal capsule and one will remain laterally located. The one located medially is called the caudate nucleus , which acquires as well a C-shaped appearance. In the region of the basal forebrain, where the anterior commissure is also forming, we will have the formation of the corpus callosum , which is the communication of the 2 hemispheres. The fibers in the corpus callosum run from left to right and they are commissural fibers . Fusion of the telencephalic vesicles with the diencephalic ones Because of the bending of the 2 telencephalic vesicles , at some point, they come to the side of the diencephalic vesicles , causing a fusion between the lateral wall of the diencephalic vesicles and the medial wall of the telencephalic vesicles. Thanks to this fusion, the cortex can know project directly to the brainstem without crossing the diencephalon. If the telencephalic vesicle and the diencephalic ones would remain in series, whenever the cortex needs to send an axon to the brainstem or spinal cord, it needs to pass though the diencephalon; instead, being them in parallel, it can simply pass on the side of the diencephalon. During the process of bending and fusion of the telencephalic vesicles, there is also the formation of the ganglionic eminence . It is caused because there are some regions that proliferate very much, but would not expand so much. The region of the telencephalic vesicle that does not expand too much, but proliferates a lot, gives rise to the ganglionic eminence or corpus striatum . It is formed by a huge number of neurons, all grouped together. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 3 At some point, neurons of the cortex want to start to form connections with the motoneurons of the brainstem or spinal cord . On their way to the brainstem or to the spinal cord, they have to pass through the ganglionic eminence that is forming in the meanwhile. Moreover, the thalamus , which is the door to the cortex, starts to project to the cortex to form connections with it and also the axons of neurons that are in the thalamus and want to project to the cortex needs to pass through the basal eminence. Because of the formation of the fibers of the internal capsule ,the ganglionic eminence gets divided into 2 compartments, one medial and the other lateral to the internal capsule. The region that remains lateral is the putamen ; the region that remains medial is the caudate nucleus . The nucleus pallidus is also considered a deep nucleus of the brain, which is located medially to the putamen. The internal capsule The internal capsule is made of ascending and descending fibers . If we take a horizontal section of the brain, we see the internal capsule, the head of the caudate nucleus , the putamen , part of the nucleus pallidus , and the thalamus . The internal capsule can divided into an anterior limb , in between the head of the caudate and the putamen; a genu of the internal capsule ; and the posterior limb of the internal capsule. In the internal capsule there are also other 2 subdivisions which are the retro-lenticular division and the sub-lenticular division . Some fibers of the internal capsule that, from the thalamus, need to go to the cortex and therefore they pass below the lenticular nucleus , and those are called the sub-lenticular fibers; while there some other fibers that correspond to the most distal part of the posterior limb of the internal capsule that need to reach the occipital lobe and they have to pass behind the lenticular nucleus, so they are called retro-lenticular fibers. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 4 In the adult, the only visible portion of the diencephalon is the ventral part. The hidden lobe The telencephalic hemispheres keep on expanding, but this expansion is not completely uniform: there is a portion of the vesicles that does not grow very much and this region is called the insula or hidden lobe . The cortex adjoining it grows very much and therefore, the cortex progressively grows over the insula, which gets covered. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 5 In an adult brain, the insula is not visible, unless we divaricate the lateral cerebral fissure . The portion of the adjoining lobes (frontal, parietal and temporal), which grows over the insula is called the opercula . The putamen does not acquire a C-shaped appearance because this deep nucleus is close to the region of the cortex that does not expand too much and therefore it does not force the nucleus to change its shape. Fissures and sulci When the hemispheres start to bend, we start to see the formation of sulci and grooves, which separates lobes and gyri or circumvolution of the cortex. In this drawing, we can see the appearance of the 3 main sulci in a fetus of 28 weeks . The main sulci are the central sulcus , the lateral sulcus and the calcarine sulcus . The central sulcus can also be called Rolandos sulcus and it develops very early and it is important because it separates the frontal lobe from the parietal one. Then, the lateral sulcus or Silvius sulcus is used to separate the temporal lobe from the frontal and parietal lobes. The Calcarine sulcus, instead, is visible if we look at the medial or mesial surface of the brain; it is within the occipital lobe and around it we will have the organization of the primary visual cortex . Brain lobes Giuseppe Izzo 6th Lesson Neuroanatomy The brain 6 The hemispheres can be divided into lobes and, in each lobe, there will be anatomical structures called gyri or circumvolution , and in some of them, there will be functional areas of the brain. The frontal lobe is the largest one and we can identify its posterior limit by the central sulcus or sulcus of Rolando. Posteriorly to the central sulcus, we find the parietal lobe ; then we can see the temporal lobe , which is separated from the other 2 by the lateral sulcus or Silvian sulcus . If we move posteriorly, we find the occipital lobe , which is not separated from the others by a very deep sulcus, but if we look at the medial aspect of the hemispheres, we have a parietal-occipital sulcus , which is quite evident on the medial surface. If we imagine to turn the curve of the brain, it continues on the lateral side, so that it can help us to identify the borders between the lobes. Many of the lobes that we see on the lateral surface of the brain, are also visible on the medial surface .There is a portion of the frontal lobe that extends also on the medial surface of the hemispheres; also, there is a portion of the parietal, occipital and temporal lobe. On the ventral surface of the brain, the frontal, temporal and occipital bone are still visible. Looking at the medial surface, we notice the limbic lobe , which is made by areas of the cortex that belong to the frontal, parietal and temporal lobe. It is separated from the other lobes by sulci, such as the cingulate groove (which is near the cingulate gyrus ), then we have the parahippocampal gyrus , which separates the limbic lobe from the temporal by the collateral groove and the rhinal sulcus . The limbic lobe is only visible on the medial and ventral surface, and it includes the cingulate gyrus and the parahippocampal gyrus . Gyri of the lobes In front of the central sulcus, we have the precentral gyrus , which contains the primary motor cortex (frontal lobe). Since the frontal lobe also extends on the medial aspects, also the central sulcus extends on the medial surfaces, and also the precentral gyrus follows this pattern. Posteriorly to the central sulcus, in the parietal lobe, we have the post-central gyrus , which is important because it is the site of the primary somatosensory cortex and it also extends on the medial surface of the hemispheres. In the most anterior part of the frontal lobe, also called the prefrontal cortex , which is very much developed in humans because it has to do with the decision making , personality , motivation , we find the superior, middle and inferior frontal gyrus . The inferior frontal gyrus is then divided into an opercular part (that covers the insula ), the triangular gyrus and the orbital part . In front of the primary motor-cortex (precentral gyrus), we find the premotor cortex that also extends on the medial aspects of the cerebral hemispheres. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 7 The parietal lobe is divided into superior parietal lobule and inferior parietal lobule , which is divided into a supramarginal gyrus and angular gyrus . The superior one is mostly involved in representing the body and for the body skin: it is an area where somatosensory, visual information come together and then from there they are sent to other parts of the brain. The inferior parietal lobule is more important for language, understanding, deciding which phoneme needs to be chosen In the temporal lobe , we find the superior , middle and inferior temporal gyrus . Where the superior temporal gyrus bends, we find the primary auditory area , surrounded by the secondary auditory cortex .Moreover, a lot of the temporal lobe is involved in understanding what we are seeing, in particular, the medial surface of the temporal lobe is important for visual functions . The occipital lobe is all devoted to vision : there are the primary and secondary visual areas of the cortex. The primary visual area is situated on the medial aspect of the occipital lobe, around the calcarine groove ;while surrounding it there are other visual areas. Medial aspects of the cerebral hemispheres Giuseppe Izzo 6th Lesson Neuroanatomy The brain 8 If we look at the medial surface of the hemispheres, we can still see the central groove , which means that here we can still find the precentral and postcentral gyrus . From here, we see the calcarine sulcus , which divides the cortex into a superior ( cuneus ) and inferior part ( lingual gyrus ). When we look at the medial surface, we can see structures belonging to the limbic lobe , which is the mammalian brain, very important for behaviour, affection, learning and memory. The structures belonging to the limbic lobe are the cingulate gyrus , which is separated from the frontal and parietal lobes through the cingulate groove ; moreover, we have the parahippocampal gyrus , which continues with uncus , which is part as well of the limbic lobe. The cingulate gyrus is in very close relationship (right above) with the corpus callosum . Ventral surface of the hemispheres If we look at the ventral surface of the hemispheres, we can see the occipital , temporal and frontal lobe . In the frontal lobe, we can recognize the orbital gyri , which are in relation with the orbital cavity; then we have a system of gyri called straight gyri (called like that because they are of straight shape), which are still in relation with the orbital cavity . If an object enters into the orbital cavity and it breaks the floor of the cavity, it is easy for it to penetrate the brain. On the ventral surface, we also find the olfactory bulb and olfactory tract , which are involved in the olfactory pathways. Part of the temporal lobe , the part that lies in the middle cranial fossa, is made by the uncus and by the parahippocampal gyrus (from the limbic lobe); and if we move more laterally, we find the lateral occipital-temporal gyrus , the inferior-temporal gyrus . Some of them are in continuity between the occipital and temporal lobes. The rhinal sulcus (more medially) is important to identify the structures of the temporal lobe which are part of the limbic lobe: the uncus and the parahippocampal gyrus, even though they are part of the temporal lobe, they are considered as part of the limbic lobe. Above the midbrain, on the ventral surface, we can notice the anterior and posterior perforated substances , which are perforated because around this area, we have the circle of Willis , which supplies the Giuseppe Izzo 6th Lesson Neuroanatomy The brain 9 brain with blood. From the circle of Willis and from the initial part of the large cortical arteries , we have perforating vessels that enter into the brain parenchyma from ventral to dorsal. Hippocampus and fornix If we want to find the hippocampus , we have to go at the level of the floor of the inferior horn of the lateral ventricle . The hippocampus is in continuity through a bundle of white matter that is called the fornix .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 10 If we make a cross section through the hippocampus, we see that it is coiled on itself because originally it was laterally localised, and then dorsally, and then it is pushed ventrally and dorsally and since there is no more space, it starts to coil on itself. The lateral ventricles have a C-shaped appearance in the form of horns : one horn that extends into the white matter of the frontal lobe ( anterior horn ); one that extends into the occipital lobe ( posterior horn ); and one that extends into the temporal lobe ( inferior horn ). The fibers that originates from the hippocampus from the right and from the left gives origin to the fornix. The hippocampus is connected to the basal forebrain and mammillary bodies of the hypothalamus by the fornix , a system of white matter. Below the cingulate gyrus, we find the corpus callosum. Below the corpus callosum, we find the fornix, which is even more curved than the corpus callosum. Together with the hippocampus, in the inferior horn of the lateral ventricle, medially and dorsally to the hippocampus, we have the choroid fissure and the choroid plexus . During development, they acquire the same shape as the fornix and that is why we find them also at the level of the inferior horn of the lateral ventricle. The hippocampus proper takes also the name of cornu Ammonis because it looks a bit like the horns of the god Amun. The hippocampus can be divided into areas, which are called CA1, CA2, CA3, CA4 . In that coiled area, we find the hippocampal formation and the hippocampus belongs to the hippocampal formation. During development, at the beginning, the different areas are one after the other, but with the Giuseppe Izzo 6th Lesson Neuroanatomy The brain 11 growth of the brain, they start to coil. The hippocampal formation also contains the dentate gyrus , the subiculum , the presubiculum , and the parasubiculum . At the level of the parahippocampal gyrus we find the entorhinal area of the cortex, which is very important because it receives information from any area of the cortex, and then it sends them to the hippocampal formation. The hippocampus is a very sensitive region of the brain. It is damaged very early in Alzheimer disease or in other types of dementia. Damage to the hippocampus can result from Hypoxia (especially CA1), medial temporal lobe epilepsy , encephalitis The most common type of epilepsy in adult is hippocampus and medial temporal lobe epilepsy . Bilateral hippocampal damage causes the Korsakoffs amnesia (e.g., following hypoxic-ischemic encephalopathy). Memory disorder characterized by inability to retain new information ( anterograde amnesia ) and a less severe defect of recall of old memories ( retrograde amnesia ). Hippocampal amnesia affects more severely episodic memory and less semantic memory . Memory can be divided into procedural and declarative memory. Procedural memory is the one of learning skills e.g., how to write with the left; and the declarative , which is divided into semantic (memory for facts) and episodic (memory for personally experienced events). Amigdala (called like that because it has the shape of an almond) In front of the hippocampus, we find a large nucleus complex called amigdala . The amigdala is very close to structure that are important in olfactory processes and belonging to the limbic system. Together with the limbic lobe, the amigdala belongs to the limbic system , which is important for emotion, memory, learning, behaviour. It includes many structures located medially in the temporal lobe, which are often very curved. They include the cingulate gyrus, the fornix, the amigdala, the olfactory area of the cortex, some areas of the hypothalamus The amigdala modulates the autonomic responses on the bases of learning and previous experiences (especially if emotionally charged). It has a role in how sensory information guides behavioural responses (anxiety, fear ). It mediates aspects of sensory perception that have an emotional charge and it is responsible for emotional learning , memory modulation, sexual orientation, aggressive behaviour , alcoholism and binge drinking (substance abuse), anxiety, post-traumatic stress disorders. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 12 Kluver-Bucy Syndrome This syndrome is characterized by a bilateral lesion of the mesial or anterior temporal lobe structures . It leads to oral tendencies , need to explore everything , memory loss , emotional changes, extreme sexual behaviour , placidity , indifference, problem in processing visual information, uncontrolled appetite for food. It can be caused by trauma, encephalitis (post-herpetic encephalopathy), temporal lobe epilepsy, Alzheimer, Pick disease, heat stroke. Lesions of the amigdala In this image, we can see the outcomes of lesions of certain areas of the brain. For example, the empty triangles are located at the level of the amigdala, so lesions there will cause placidity behaviours . This is why the amygdala was a popular target during the era of psychosurgery ,specifically for the treatment of intractable aggression. It was performed especially in prisoners, to treat very aggressive behaviours. Disorders of mood The amigdala is involved in disorders of mood ,which are very spread among the population. They are characterized by disregulation of feeling of happiness and sadness. If we look at the blood flow of an individual with unipolar depression, there is an increased blood flow in the amigdala , in the dorsomedial nucleus of the thalamus (part of the limbic circuitry), and in the prefrontal cortex (responsible for personality and behaviour). Giuseppe Izzo 6th Lesson Neuroanatomy The brain 13 Amigdala and stria terminalis The amigdala is located in the inferior horn of the lateral ventricle, in front of the hippocampus. From the amigdala we have the origin of a bundle of white matter that is called the stria terminalis , which continues dorsally in the thalamus and then it goes down in the basal forebrain . It keeps in communication the amigdala with very anterior and ventral structures of the brain coinciding with the area of the basal forebrain. The fornix , as well, is keeping the hippocampus in connection with the basal forebrain. The stria terminalis ends up in a nucleus that is called the bed nucleus of the stria terminalis , and it is important for sexually dimorphic , homeostasis , behaviours , fear , valence monitoring, defensive responses during uncertain threat anticipation (amygdala more acute danger), mood disorders In case of fear, we have an autonomous and involuntary response because the amigdala is connected to the hypothalamus, which is at the head of the autonomic nervous system. Primary and secondary areas of the cortex Giuseppe Izzo 6th Lesson Neuroanatomy The brain 14 There is the primary motor cortex in the precentral gyrus that continues medially, always in the precentral gyrus. In the postcentral gyrus, we find the primary somatosensory cortex ; and if we go slightly behind to it, we find the secondary somatosensory cortex . In the superior temporal gyrus, we find the primary auditory cortex , surrounded by the secondary auditory cortex . Behind the auditory cortexes , we find a territory important for understanding what hearing and to be able to understand the correct words while talking. In the occipital lobe, we find the primary visual cortex . On the medial side, in the upper part of the temporal lobe, we find the uncus , which is part of the primary olfactory cortex . In the frontal lobe, we find the premotor cortex , which is very important for planning movements. Brodmann classification Giuseppe Izzo 6th Lesson Neuroanatomy The brain 15 Brodmann studied the cytoarchitecture and the characteristics, with very simple histological staining, of the layers of the cortex of the brain. He started to divide the cortex into areas and giving them numbers, according to their characteristics. When functional studying on the brain were performed, came out that there was a very good coincidence between a certain number and a specific function. For example, the precentral gyrus of the frontal lobe, which contains the primary motor cortex , corresponds to area 4 of the Brodmann classification; the premotor cortex corresponds to area 6 ; in the postcentral gyrus , we find areas 3, 1, 2 , which correspond to the primary somatosensory cortex ; area 17 corresponds to the primary visual cortex , in the occipital lobe; area 18 and 19 , in the occipital lobe, correspond to the secondary visual cortex ; area 41 , in the temporal lobe, corresponds to the primary auditory cortex Giuseppe Izzo 6th Lesson Neuroanatomy The brain 12 Amigdala and stria terminalis The amigdala is located in the inferior horn of the lateral ventricle, in front of the hippocampus. From the amigdala we have the origin of a bundle of white matter that is called the stria terminalis , which continues dorsally in the thalamus and then it goes down in the basal forebrain . It keeps in communication the amigdala with very anterior and ventral structures of the brain coinciding with the area of the basal forebrain. The fornix , as well, is keeping the hippocampus in connection with the basal forebrain. The stria terminalis ends up in a nucleus that is called the bed nucleus of the stria terminalis , and it is important for sexually dimorphic , homeostasis , behaviours , fear , valence monitoring, defensive responses during uncertain threat anticipation (amygdala more acute danger), mood disorders In case of fear, we have an autonomous and involuntary response because the amigdala is connected to the hypothalamus, which is at the head of the autonomic nervous system. > BNST (bad nucleus of the stria terminalis) : it is located in the basal forebrain . It is a complex made by 18-20 smaller nuclei and it is involved in many aspects of our emotional and > visceral life . it is sexually dimorphic and involved in maintaining homeostasis , behaviour, > fear , valence monitoring (giving a value to certain types of stimuli), defensive responses during uncertain threat anticipation (amygdala more acute danger), mood disorders Primary and secondary areas of the cortex Giuseppe Izzo 6th Lesson Neuroanatomy The brain 13 There is the primary motor cortex in the precentral gyrus that continues medially, always in the precentral gyrus. In the postcentral gyrus, we find the primary somatosensory cortex ; and if we go slightly behind to it, we find the secondary somatosensory cortex . In the superior temporal gyrus, we find the primary auditory cortex , surrounded by the secondary auditory cortex . Behind the auditory cortexes , we find a territory important for understanding what hearing and to be able to understand the correct words while talking. In the occipital lobe, we find the primary visual cortex . On the medial side, in the upper part of the temporal lobe, we find the uncus , which is part of the primary olfactory cortex . In the frontal lobe, we find the premotor cortex , which is very important for planning movements. Brodmann classification Brodmann studied the cytoarchitecture and the characteristics, with very simple histological staining, of the layers of the cortex of the brain. He started to divide the cortex into areas and giving them numbers, according to their characteristics. When functional studying on the brain were performed, came out that there was a very good coincidence between a certain number and a specific function. For example, the precentral gyrus of the frontal lobe, which contains the primary motor cortex , corresponds to area 4 of the Brodmann classification; the premotor cortex corresponds to area 6 ; in the postcentral gyrus , we find areas 3, 1, 2 , which correspond to the primary somatosensory cortex ; area 17 corresponds to the primary visual cortex , in the occipital lobe; area 18 and 19 , in the occipital lobe, correspond to the secondary visual cortex ; area 41 , in the temporal lobe, corresponds to the primary auditory cortex Giuseppe Izzo 6th Lesson Neuroanatomy The brain 14 Organization of the white matter of the cerebral hemispheres The white matter is organised into commissural fibers (connect the 2 sides of the brain), associative fibers (connect areas of the same cerebral hemisphere) and projecting fibers (they are connection of the cortex with external regions). The commissural fibers of the 2 cerebral hemispheres form the corpus callosum , the anterior commissure and the commissure of the fornix (the 2 hippocampal formations are connected by this commissural system. The association fibers are divided into short and long ; the projecting fibers correspond to the internal , external and extreme capsules , and the fornix , which is also considered a projecting system. Corpus callosum The corpus callosum is made by commissural fibers , which connects the 2 cerebral hemispheres. Specifically, they connect homologous areas of the 2 hemispheres. Macroscopically, when we observe the fornix from above, we can see the corpus callosum. In it, we can distinguish different compartments: the forceps major (connects areas of the occipital and parietal lobes) and minor (connects area of the frontal lobe), which are the anterior and posterior area of the fornix; in between the forceps major and minor, we have the radiated fibers ; the splenium is the most posterior region of the corpus callosum (better viewed on a sagittal view); the induseum griseum is visible if looking dorsally to the corpus callosum, and it is a tiny strip of grey matter, which is not functional in humans. If we look at the corpus callosum with a sagittal view , we recognise a very posterior region, called the splenium , that corresponds to the forceps major , if compared to the horizontal view; then we have the central part , which is called the trunk of the corpus callosum , that correspond to the tapetum or radiated fibers ; then we find the genu of the corpus callosum (anteriorly), and inferior to it, we find the rostrum of the corpus callosum .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 15 If we consider the relation between the corpus callosum and the fornix (specifically its anterior region, called column of the fornix), we can see that in between the ventral aspects of the corpus callosum (anteriorly: genu and initial part of the trunk) and the column of the fornix , there is a very thin layer of tissue that is called septum pellucidum . The septum pellucidum is important because it forms the medial wall of the anterior horn of the lateral ventricle ;moreover, it is a good reference point to identify a group of nuclei that are part of the forebrain and that are called the septal nuclei . Ventral and anteriorly to the septum pellucidum, we find a small region of grey matter that correspond to the basal forebrain, and, in this region, close to the septum pellucidum, we find a group of cluster of nuclei called septal nuclei. This means that we can use the septum pellucidum to localize the basal forebrain (or basal telencephalon) and the septal nuclei. Anterior commissure If we go anteriorly to the anterior column of the fornix , we find the anterior commissure , which is a commissural system that connects the 2 sides of the brain. If we do a cross section through the region where there is the anterior commissure through the coronal plane, we find above the corpus callosum ,Giuseppe Izzo 6th Lesson Neuroanatomy The brain 16 and below it the septum pellucidum . The anterior commissure is important because it keeps into communication certain areas of the brain. It is divided into an anterior and a posterior division . The anterior division is important because it connects areas of the brain that process olfactory information , specifically, it connects the olfactory tracts and the olfactory cortexes (7 and 9). The posterior division keeps in communication gyri of the temporal lobes, typical the middle gyri (22), but also the amygdale (13); moreover, it contains some fibers of the stria terminalis (17), in particular the fibers that connects the amigdala with the basal forebrain. So, this anterior commissure keeps in communication older and more hidden region of the brain with respect to the corpus callosum. Some of the fibers that originate from the hippocampus and from the adjoining area of the hippocampal formation forms the fornix . The posterior region of the fornix, in the center part, is called the crura or legs of the fornix (the crura originates from the fimbria hippocampi). These parts come together to form the body of the fornix, which then splits, anteriorly, as to form the column of the fornix . The anterior commissure is in front of the columns of the fornix. The fibers of the fornix, where they reach the region where there is the anterior commissure, split in some fibers that continue posteriorly to the anterior commissure and some fibers that continue anteriorly to the anterior commissure. So, the fibers that enter into the column of the fornix split into pre-commissural fibers (anterior) and post-commissural fibers (posterior), where the pre-commissural fibers are directed to the septal nuclei , and the post-commissural fibers are connected to the mammillary bodies of the hypothalamus and to the anterior nuclei of the thalamus . Thanks to the anterior commissure , the hippocampus and the hippocampal formation are in relationship with the basal forebrain , which is very important because it has to do with behaviour , decision making ;while the mammillary bodies are important because the hypothalamus is the regulator of our visceral life ;the connection with the anterior nuclei is important because they are then connected to the cingulate gyrus (part of the limbic lobe). Giuseppe Izzo 6th Lesson Neuroanatomy The brain 17 In between the crura of the fornix, we find a system of fibers called commissure of the hippocampus ,which keeps in communication the hippocampus on the left with the one on the right. Septal nuclei and cholinergic nuclei of the basal forebrain In this drawing, we can see the hippocampus , the amigdala and, in blue, the fornix . Near the anterior column of the fornix, we have the septal nuclei (green). They produce a lot of acetylcholine : they are cholinergic nuclei. In particular, the basal telencephalon , overall, is rich in cholinergic nuclei , for example, also the BNST is characterized by the presence of acetylcholine as neurotransmitter. The septal nuclei receive the fibers from the hippocampal formation, but also, they project cholinergic axons towards the fornix and the amygdala. This is important because in some degenerative pathologies of the brain, such as Alzheimer , some of the earliest histopathological changes are found in the basal forebrain, and in particular in cholinergic nuclei. In case of malfunctions of cholinergic nuclei, the cholinergic projections, from the basal forebrain to the hippocampus, start to be reduced, which means that the hippocampus does not work very well. Another important cholinergic nucleus that is part of the forebrain and it is called the basal nucleus of Meynert , which is a bit more ventral. This nucleus project to the hippocampus, to the amigdala, but it also gives rise to an extensive projection to the neocortex . Problems in this nucleus cause the overall cholinergic projections to the neocortex to be reduced. Nucleus accumbens (ventral striatum): reward system In the region of the forebrain, we have the nucleus accumbens , which correspond to the ventral striatum .The oldest part of the striatum, which correspond to the deep nuclei of the brain, is called the ventral striatum and it correspond largely to a big nuclear complex that is located in the basal forebrain and is called nucleus accumbens. The nucleus accumbens is important for the reward system , and our behaviour is driven by reward mechanisms that act also when we take some drugs or in feeding. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 18 Association fibers The association fibers are those fibers that connect areas of the same hemispheres. There are very short association fibers that connects gyri that are adjacent to one another; or long association fibers, such as the inferior longitudinal bundle or fasciculus, which connects the occipital lobe with the most anterior region of the temporal lobe, or the superior longitudinal bundle , which connects the occipital lobe with the frontal lobe. Projecting fibers The majority of the projecting fibers are organised into capsules . In the brain we have 3 capsules that from superficial to deep are the internal , external and extreme capsule . The extreme capsule is in between the insular cortex and the claustrum nucleus ; then we have the external capsule , which is the white matter in Giuseppe Izzo 6th Lesson Neuroanatomy The brain 19 between the putamen and the claustrum ; and then we have the internal capsule , which is the most clinically relevant, and it can be appreciated in a horizontal or coronal section . The internal capsule is made of fibers running from the thalamus to the cortex and from the cortex to the thalamus, brainstem and spinal cord. Close to the cortex, the internal capsule is very open because the surface of the cortex is large, but then, deeper, the fibers of the internal capsule come together, becoming closer. A lesion of the brain where the internal capsule is very open, we will have damages only to few fibers; a lesion in a deeper area of the internal capsule, will cause damages to lots of fibers of the internal capsule. The part of the section of the internal capsule that goes from the thalamus to the cortex is also called the corona radiata . The internal capsule has a relationship with the ganglionic eminence from which the basal ganglia originate. It is important to know the position of the fiber tracts in the brain because, in case of surgery, we want to save as much nervous tissue as possible. Basal ganglia Deep in the white matter of the brain hemispheres, there are the deep nuclei of the brain , also called basal ganglia . Saying basal ganglia, we are talking about a complex of nuclei. With basal ganglia we mean the caudate nucleus , the putamen and the nucleus pallidus , which is divided into an internal and external part . The embryological origin of the nucleus pallidus is from the diencephalic vesicles. The caudate and the putamen are also called the striatum , and the striated appearance is given by the passageway of the fibers of the internal capsule in the ganglionic eminence during development, separating almost completing the caudate from the putamen. The putamen and pallidus are also called the lenticular nuclei . Collectively, the caudate, the putamen and the pallidus take also the name of corpus striatum . The red region is the oldest and ventral most part of the corpus striatum, which is located in the basal forebrain and corresponds largely to the nucleus accumbens .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 20 The caudate nucleus The caudate nucleus is very big and with a C-shape , which allows it to have several relationships with the surrounding structures. For example, it has an important relationship with the thalamus : the caudate nucleus remains with respect to the internal capsule medially and therefore on the same side of the diencephalon. Coloured in blue, we can see the thalamus , and we can see that the anterior part of the caudate nucleus, called the head of the caudate nucleus , is located anteriorly to thalamus, while the body of the caudate nucleus is located dorsally to the thalamus, it does not cover completely the dorsal surface of the thalamus, but the lateral aspects of the dorsal surface. The tail of the caudate nucleus turns below the thalamus, but then it moves laterally, to the point that it can be found in the roof of the inferior horn of the lateral ventricle. Basal ganglia are important for posture and movement control . The acute onset of a unilate ral choreiform movement disorder in a child with a recently documented febrile illness or streptococcal pharyngitis is suggestive of Sydenham chorea . An 8-year-old girl developed bitemporal headaches associated with a mild fever (38.5). The next morning, she developed left arm and led choreiform movement. Facial weakness and drooling were present, and her speech was slurred. No other symptoms were noted. There was no known exposure to toxins or heavy metals. Physical examination documented choreoathetoid movements of her left arm and leg, which made the examination for strength difficult. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 21 Divisions of the internal capsule: posterior limb, anterior limb, genu (knee), sub and retro lenticular. The internal capsule can be divided into divisions: we recognize in it an anterior , a posterior , a genu , a sub and a retro lenticular portion . Many fibers that need to reach the occipital cortex run in the retro lenticular portion; fibers that need to reach the temporal lobe or the insula run in the sub lenticular portion. The corticospinal tract runs in the posterior limb. In the drawing below, we can see different types of fibers as they run in different subdivisions of the capsule. # Cerebral cortex Neocortex (most of the cortex) The neocortex is organised into 6 layers , which are numbered from superficial to deep , from I to VI .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 22 In this drawing we can see different types of cells: the excitatory (85-90%) are black, the inhibitory are red. We can distinguish 2 main categories of neurons: the pyramidal cells and the nonpyramidal or stellate cells . The pyramidal cell, whose cell body has a triangular shape, are characterized by an apical dendrite that extends in the layers above the one where the soma is localised, and a tuft of dendrites that extends around the soma, in the layer where the cell body is localised, then we have the axon , which in most cases abandons the cerebral cortex ( corticofugal axon ). Even if the axon abandons the cortical layers, it usually gives rise to a recurrent collateral , which is important in the circuitry of the cortex. The rest of the cells, which are not pyramidal, can be called nonpyramidal cells , granule cells , stellate cells or interneurons of the cerebral cortex . These cells can be distinguished according to their inhibitory or excitatory action, while pyramidal cells are all excitatory cells. The granule cells can also be divided into spiny or smooth granule cells . The formers are excitatory, while the latter are inhibitory. The excitatory ones are typically with a lot of dendritic spines , the inhibitory are smooth or with very few dendritic spines. Different classes of cortical interneurons are distinguished on the basis of their morphology, neurochemical content, intrinsic electrophysiological properties and pattern of connectivity. The main source of cortical interneurons is the caudal ganglionic eminence (CGE), the medial ganglionic eminence (MGE) and the preoptic area (POA). Generation and organization of the principal excitatory neurons of the cortex: pyramidal cells The process of interkinetic nuclear migration leads initially to a proliferation of progenitor cells , and then, progressively, they will leave the mitotic cycle , which takes place at the lever of the ventricular side and differentiate, either into neurons or into glial cells. When proliferating neurons exit the cycle to differentiate, they would move in the final position using as a sort of scaffold a special population of cells of the neural tube called radial glial cells .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 23 The radial glial cells , beside serving the purpose of being a scaffold for the migration of differentiating neurons, are also themselves progenitor cells . Formation of the cortical layers The differentiating neurons will organize themselves into 3 territories around the lumen of the neural tube: the territory closer to the lumen is first called the ventricular layer and then it becomes the ependymal layer ; the majority of neurons would cluster themselves around the ependymal layer as to form the mantle layer ; whereas, the axons of neurons would organize themselves in the most peripheral layer, called the marginal layer . The cortical layers are formed through a mechanism called inside out . Initially we have the formation of the ventricular zone ; at some point, we have a first wave of migration : some cells leave the ventricular zone, and the proliferative cycle, and migrate to differentiate in the more superficial layer of the wall of the neural tube as to form a region that is called the pre-plate region (that will become layer 1 of the cortex). At this point of development, we can recognize the pre-plate, an intermediate zone made by the axons of the neurons situated in the pre-plate, and the ventricular zone. Then we have a second wave of migration as to form the cortical plate. They perform this migration by splitting the pre-plate into 2 compartments: a marginal zone and subplate region , and, in between them, we have the cortical plate . The cortical layer will become layer 5 and 6 of the cerebral cortex. Then, the neurons that need to form layers 2, 3, and 4 migrate forming the correspondent layers. Very early, the proliferative area of the neuroepithelium involves the additional formation of what is called sub ventricular zone (SVZ) , which is an additional proliferative zone for progenitor cells. When the layers are formed and we do not need any more proliferation, the ventricular and sub ventricular zones will become the ependymal layer. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 24 Role of basal glial cells in gyrification During the formation of human cerebral cortex , we need the correct expansion of the neocortex to take place correctly. The process of gyrification is mostly due to the presence of basal glial cells. The radial glial cells are important for the migration process, and they are called apical radial glial cells (aRGC ). Then we have the basal radial glial cells (bRGC ), which impose a tangential migration to neurons that are migrating during differentiation. They add in a fan-like manner to the pre-existing scaffold. Imposition of tangential migration to neurons and consequent tangential expansion of the cortical surface and folding. This process is a very complex and long process that begins very early during pregnancy and continues also for many years after birth. The movement of differentiating neurons can be disrupted by more than one mechanisms, leading to a defective development of the cortex .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 25 There is a protein that is called lissencephaly (LIS1 ), which is very important because it is a link between the cage of microtubules that forms around the nucleus to push it and the centrosome. If this mechanism is disrupted, the cell cannot migrate correctly. We may have a condition called lissencephaly which causes the brain to be smooth and not well developed. Generation of non-pyramidal neurons The non-pyramidal cells or interneurons of the cortex reach the layers of the source mostly from the ganglionic eminence , which is a highly proliferative area of the telencephalic vesicles that leads to the formation of the deep nuclei of the brain . In this image we can see that while the interkinetic nuclear formation and the inside out mechanism is taking place, from the ganglionic eminence , we have the migration of neurons through a tangential migration within the layer of the cortex that are forming and organize themselves with the pyramidal cells . If this mechanism does not take place correctly, the overall organization of the cortex will not be as it should. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 26 In primates and in humans, most of these neurons originate from the ganglionic eminence , but some of them originate from the ventricular zone , with the same mechanism through which pyramidal nucleus originate. Among the non-pyramidal cells, there is a population of inhibitory neurons, which is mainly formed by GABAergic interneurons and, in experimental animals, they can be isolated from the embryo and then injected in areas of the adult brain of the animal, where they are able to integrate themselves in the adult circuitry. This is interesting because there are many pathologies of the cortex or of the deep nuclei of the brain that originate from a defective development of the GABAergic interneurons. That is why they are used in experimental models to treat seizure disorders , Parkinsons diseases, pain and stroke , anxiety and psychosis (such as schizophrenia). Differences in the neocortex If we make sections through different regions of the neocortex , we can see that the layers do not have the same thickness in different regions of the cortex. Moreover, different regions of the cortex do not have the same thickness. For example, if we look at layer IV in the primary sensory cortex , it is quite thick as compared to the primary motor cortex , where it is very thin. The differences in thickness are due to the functions of the area of the cortex that we are looking at. Sensory information that reaches the cortex from the thalamus end up in layer IV, especially those coming from specific nuclei of the thalamus. On the other hand, layer V is the layer of medium sized or large pyramidal cell layers and, if we look at layer V in the primary sensory cortex and in the motor cortex, we can see that in the primary motor cortex it is thicker and it has much more cells, and many of them are so big that they are called giant pyramidal cells . If we look at the association cortex , we can see that all the layers are well represented and with an average thickness. Granular, agranular, polar, frontal and parietal cortex It is not only a question of the thickness of the layer, but it is also a question of the thickness of the cortex: for example, there are some areas that are thicker than others. According to the characteristics of the layers, we can classify the different types of cortex in granular , agranular , frontal , parietal and polar . Agranular are the regions of the cortex where there are lots of pyramidal neurons and a very small population of granular cellular. In the granular type of cortex, we find lots of granular cells. The typical agranular cortex is the one corresponding to the primary sensory area. Another way to differentiate the different types of cortex is by calling them homotypical or heterotypical . Homotypical means that all the six layers are well represented and well distinguishable ,Giuseppe Izzo 6th Lesson Neuroanatomy The brain 27 while the heterotypical cortex are the areas of the cortex that have the six layers not very well distinguishable . Archicortex and paleocortex During the phylogenesis of the cerebral cortex, the paleopallium and the archipallium decreases in size, while the neopallium becomes dominant, occupying almost all surface of the brain. In the human brain, if we want to find the archi and paleocortex, we really have to go deep and ventral to the brain. The cortex is divided into allocortex and the isocortex . The isocortex is the neopallium , which is divided into 6 layers; the allocortex can be divided into paleopallium and archipallium , and we do not have 6 distinguishable layers (less than 6 layers). The paleocortex is the oldest cortical area of the telencephalon which contains 2 to 5 layers of neural cell bodies. Paleocortex includes the olfactory bulb , the olfactory tubercle (approximately at the anterior perforated area) and the piriform cortex (approximately the uncus and the anterior part of the parahippocampal gyrus). All those cortical and non-cortical areas which are related to the sense of smell are summarized as the rhinencephalon or olfactory brain . The archicortex is constituted by 3 to 4 layers of neurons and includes the hippocampus and related structures. The neocortex occupies approximately 90% of the total cerebral hemispherical surface and it has 6 layers of neural cell bodies. Archicortex The archicortex corresponds with the hippocampal formation , which includes the dentate gyrus , the hippocampus proper , the subicular area , the presubiculum Giuseppe Izzo 6th Lesson Neuroanatomy The brain 28 and the parasubiculum , and for some authors even the entorhinal area that belongs to the parahippocampal gyrus. The dentate gyrus is organized in 3 layers according to the typology of cells we find in each layer. We have the polymorph layer , the granular layer and the molecular layer , which is the most superficial. If we go to the hippocampus proper , we have also 3 layers: the polymorph , the pyramidal and the molecular layer . Lateral ventricles The lateral ventricles are the cavities that we have inside the cerebral hemispheres and that are the remnants of the original lumen of the neural tube. In this image, we see the ventricular system and in the middle part we find the 3 rd ventricle , which communicates with the lateral ventricles via the interventricular foramina . In the lateral ventricle, we find a frontal horn , the central part (considered part of the frontal horn), an atrium , which continues posteriorly with the occipital horn , and then we have a temporal horn . Boundaries of the lateral ventricle The frontal horn proper medially is delimited by the septum pellucidum , which delimits both the right and left horns. Anteriorly, it is delimited by the fibers of the corpus callosum and because of the position of these fibers, they correspond to the genu of the corpus callosum. Inferiorly, the floor of the frontal horn is formed by the rostrum of the corpus callosum. The roof of the frontal horn is made by the corpus callosum . Laterally, the wall is formed by the head of the caudate nucleus . If we move to the central part of the lateral ventricle, laterally, it is still delimited by the caudate nucleus ,both by the head and by the body. The floor of this part is determined by the dorsal surface of the thalamus , while the medial wall is determined by the presence of the septum pellucidum . The roof is formed by the corpus callosum .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 29 The posterior horn extends deep into the white matter of the occipital lobe and the roof of the posterior horn is formed by the corpus callosum ; the lateral wall and the medial wall are formed by the fibers of the corpus callosum as well. The floor of the inferior horn is mostly made by the hippocampus ; the roof of the inferior horn is made by the tale of the caudate nucleus , and by the stria terminalis ; the medial wall is characterized by the presence of the choroid fissure through which the choroid plexus enters into the inferior horn of the lateral ventricle. The communication between the third ventricle and the lateral ventricle takes place through the interventricular foramina , also called foramina of Monro . The interventricular foramina of Monro are located on each side at the junction between the roof and the anterior wall of the third ventricle. The foramen is bounded anteriorly by the junction of the column and body of the fornix and the anterior pole of the thalamus posteriorly. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 30 Choroid plexus cysts Sometimes in the choroid plexuses there can be the formation of some cysts , which are radiological visible, but they are usually an accidental finding, since they do not give any clinical problems usually. Diencephalon The diencephalon gives rise to the thalamus , the metathalamus (which corresponds to the medial and lateral geniculate bodies ), the hypothalamus , the epithalamus , and the subthalamus . During development, the diencephalon remains medial to the internal capsule. When we make a coronal section through the cerebral hemispheres, we also find the diencephalon because of the folding of the cerebral vesicles. In the same plane of section, we find diencephalic structures and telencephalic ones. Thalamus Starting to slice the brain from above, we first find the corpus callosum , then we have the fornix , and if we remove it, this is what we see: In this picture we can see the epithalamus , and, in front of it, we have the thalamus . The thalamus is made by 2 ovoidal structures , which are not parallels with respect to one another, but they are slightly oblique lateral to medial and from posterior to anterior. Anteriorly, they come into contact to each other in a region called interthalamic adhesion . In humans it is only an adhesion, but in other animals, it contains Giuseppe Izzo 6th Lesson Neuroanatomy The brain 31 fibers that keep the 2 thalamic ovoid in communication. In the thalamic structure, we can recognize an anterior pole and a posterior pole , which is larger than the anterior one. The posterior part is called the pulvinar , which is a large nucleus of the thalamus and the most posterior and largest portion of the thalamus. In between the 2 thalamic ovoid, there is the tela choroidea of the roof of the 3 rd ventricle. Close to where the tela choroidea comes in contact with the medial margin of the thalamus, there is a stria of white matter that is called stria medullaris , which does not belongs properly to the thalamus since it is attached to the lateral aspect of the thalamus. It is a bundle of white matter through which the epithalamus is in communication with other regions of the brain. If we look at the dorsal surface of the thalamus, we can see the stria terminalis , which is a bundle of white matter that connects the amigdala with the basal forebrain (bad nucleus of the stria terminalis) and it runs over the dorsal surface of the thalamus, right where the thalamus is over-road by the presence of the caudate nucleus . The caudate nucleus has lots of relationships with the thalamus: the head of the caudate nucleus is relation with the anterior pole of the thalamus; part of the head covers part of the dorsal surface of the thalamus; the body of the caudate nucleus covers part of the dorsal surface of the thalamus. From this picture, we can also see that the choroid plexuses that are present at the level of the roof of the 3rd ventricle, via the foramina of Monro continue and become the choroid plexuses of the lateral ventricles. Anteriorly, the anterior pole of the thalamus is in continuation with the pillar or column of the fornix .Posteriorly, in between the 2 thalamic ovoid, we find a very small region called epithalamus , which is made by the pineal gland and by a very small region that is called the trigone of the habenula , which contains the habenular nuclei . The trigone of the habenula gives rise to the stria medullaris , and they together are part of the circuitry of the limbic system . Below the trigone of the habenula, we find a bundle of white matter that is called the posterior commissure , which keeps in communication the 2 sides of the brain. Besides the posterior commissure, there is also another commissure that is the habenular commissure , which keeps in communication the habenular nuclei on the right and on the left. If we lift the pulvinar and look ventral to it, we find the medial and lateral geniculate bodies or metathalamus . In this image we can see the posterior and habenular commissure . Below the pineal gland , where the cerebral aqueduct opens into the 3 rd ventricle, we find a small commissural system, which is the posterior commissure . Dorsal to the posterior commissure, in front of the pineal gland, we find the habenular commissure .Giuseppe Izzo 6th Lesson Neuroanatomy The brain 32 Posterior commissure and pretectal area The light reflex is a consensual reflex, meaning that if we shiny one of the pupils, we will have constrictions not only of the pupil that has been shined, but also on the contralateral pupil. If everything is fine, it has to be consensual. This reflex is consensual because the visual pathway brings the information to the pretectal area , which is exactly where we find the posterior commissure . In this pretectal area we find the posterior commissure and the pretectal nuclei .Because of the presence of the posterior commissure, we have a communication between the pretectal nuclei on the 2 sides, which are important to trigger the constriction of the pupils by activating the Edinger-Westphal nucleus , which in turn reaches the ciliary ganglion, causing the constriction of the pupil. Below the posterior commissure , where the Sylvian aqueduct opens into the 3 rd ventricle, we have the sub-commissural organ , which is important because it seems to produce substances important to keep the patency of the mesencephalic aqueduct and of the ventricular system. Moreover, it appears that the sub-commissural organ also secretes in the cerebrospinal fluid some substances important for neurogenesis . If the mesencephalic aqueduct is not patent or narrower than normal, we have the cerebrospinal fluid that is accumulated in the lateral and 3 rd ventricles, not reaching the 4 th one. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 33 Division of thalamic nuclei The thalamus is made by 2 ovoidal structures, which converge from lateral to medial and from posterior to anterior. It can be divided into several compartments and nuclei. The grey matter of the thalamus can be divided into an anterior , lateral and medial compartment . Within the core of grey matter of the thalamus, we have a lamina, called internal medullary lamina , which subdivides the thalamus in the 3 nuclei: medial and median , anterior , and lateral nuclei . The lateral division includes the pulvinar , which corresponds to the most posterior portion of the ovoid. Below the pulvinar, ventral to it, we have the metathalamus (medial and lateral geniculate nuclei). In the lateral nucleus we have several divisions, such as ventral-anterior, ventral-lateral, ventral-posterior complex (divided in 3 parts) When we observe the thalamus in a cross section, we can see that, besides the internal medullary lamina ,there is also an external medullary lamina , which is a bundle of white matter, which envelopes the thalamus mostly laterally, and separates the rest of the nucleus of the thalamus from the reticular nucleus .It is called reticular because it is crossed by the fibers that from the cortex reach the nuclei of the thalamus and vice versa (thus having a reticular appearance). Within the internal medullary lamina, we find some clusters of neurons (grey matter) that form the intralaminar nuclei of the thalamus . Most of the projections that reach the cerebral cortex stop in the thalamus nuclei and then we have neurons that from there projects into the cortex. Functionally speaking, all the nuclei that we find in the thalamus can be divided into specific relay nuclei , association nuclei , and non-specific nuclei . The specific relay nuclei are formed by those neurons that project to a very well-defined area of the cortex; the association nuclei can be defined as nuclei that project to associative areas of the cortex; then we have the non-specific nuclei, which have very extensive projections to the cortex. Thalamic peduncles The thalamic peduncles are the bundles of white matter that connects the thalamus with the cortex. They are part of the corona radiata, and they are classified as posterior, superior, anterior and inferior. Giuseppe Izzo 6th Lesson Neuroanatomy The brain 34 Subthalamus The subthalamus is below the thalamus , in the part before the hypothalamus and after the tegmentum of the midbrain . Some nuclei that are in the tegmentum of the midbrain, such as the red nucleus and the substantia nigra , continue also in the subthalamus. Giuseppe Izzo Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 1 # Hypothalamus If we look at the lateral wall of the 3 rd ventricle and we want to distinguish the thalamus by the hypothalamus , we can use the hypothalamic sulcus , which is used to divide the thalamus and hypothalamus. It corresponds to the sulcus terminalis found during the development of the neural tube. The hypothalamus anteriorly is lined by the lamina terminalis and by the anterior commissures .Posteriorly, it is delimited by the midbrain , and inferiorly by the hypothalamus itself: we find the infundibulum of the pituitary gland , the mammillary body and the optic chiasm . The hypothalamus is visible on the ventral aspect of the brain, and, compared to the bony structure, it corresponds to the sella turcica of the sphenoid bone. On the ventral side of the brain, we see the optic chiasm , the infundibulum with the tuber cinereum , and the mammillary body .Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 2 The hypothalamus also marks the position of the circle of Willis , which surrounds the hypothalamus. This part of the brain is a crossway for at least 3 systems: the autonomic nervous system, the endocrine system, and the limbic system. The hypothalamus is small compared to the rest, but it is packed with the nuclei and with bundles of white matter. The hypothalamus can be divided in the coronal plane from medial to lateral. If we make a coronal section through the brain, including the hypothalamus, starting from the ventricular cavity, we can distinguish some groups of neurons close to it, which form the periventricular region ; then we have a medial and a lateral region .These 2 last regions are separated by the pillars or column of the fornix and by the mammillothalamic tract (bundle of white matter). The pillar of the fornix runs over the thalamus, then comes down in front of it, gets in touch with the anterior pole of the thalamus , and then reach the mammillary bodies . What remains medial to the pillar of the fornix is the lateral hypothalamus (red), while the part coloured in yellow is the medial hypothalamus .Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 3 Medial forebrain bundle in the lateral hypothalamus The lateral hypothalamus contains, apart from some nuclei, important bundles of white matter, such as the medial forebrain bundle . This structure is important because the medial forebrain bundle is an important system of fibers that connects the ventral tegmentum area of the midbrain (dopaminergic) with the most anterior region of the brain ( basal forebrain ), where we find the septal nuclei and the nucleus accumbens. The nucleus accumbens correspond mostly to the most anterior and ventral most part of the caudate and putamen . It is also called the ventral striatum and, in that area, we find also the olfactory tubercle and the amygdala . The medial forebrain bundle is part of a complex circuit that has to do with reward and pleasure . For example, the nucleus accumbens is important for the reward mechanism: if we get addicted to something is because of the dopaminergic projections to the nucleus accumbens, which is potentiated somehow. In the image above we are looking at the ventral surface of the brain and we can see the optic chiasm and the infundibulum of the pituitary gland. Seeing from the ventral surface of the brain, the basal forebrain extends from the optic chiasm to the infundibulum, and it includes the anterior perforated substance (or substantia innominata ), perforated because of the central vessels penetrating from the circle of Wills .Laterally, it extends up to the region where we find the amigdala . In the second row, we see 3 cross sections made in the basal forebrain. If we take the most rostral section (C), we find the nucleus accumbens , where the head of the caudate nucleus and the putamen are very close together and very little separated from the fibers of the internal capsule. In this same area, we find the BNST , which is a nucleus to which the amigdala project to the stria terminalis; we find the septal nuclei (cholinergic); the nucleus basalis of Meynert , which is an important cholinergic nucleus. Regional division in the sagittal plane We can divide the hypothalamus in periventricular, medial and lateral (coronal or frontal plane), and each region contains some nuclei, but we can also divide the hypothalamus going from anterior to posterior (in a sagittal plane). According to this division, we identify the most anterior region, called suprachiasmatic region (because it is the region that lies above the optic chiasm); then we have the middle region, called tuberal region (where the hypothalamus communicates with the pituitary gland; and the we find the most posterior region, called mammillary region (it corresponds, ventrally, to where we find the mammillary body). Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 4 Areas and functions of the hypothalamus Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 5 Activities of the hypothalamus Feeding behaviour The hypothalamus is very important to decide whether to eat, what to eat, when to eat, and how much to eat. We have the lateral hypothalamus and the ventromedial hypothalamic nucleus . The first is also called the hunger center ; the second one is the satiety center . Food intake is regulated in complex way The CNS integrates input from long-term energy stores (for example, leptin) and short-term meal-related signals (nutrients and gut-derived satiety signals) to regulate food intake and energy expenditure in a manner that maintains stable body fat stores over time. Food intake is also regulated by reward mechanisms . In this drawing we see a circuit that involve the arcuate nucleus of the hypothalamus that is connected with the ventral tegmental area of the midbrain (dopamine) that via the middle forebrain bundle projects to the nucleus accumbens , which is important in the reward mechanism. Regular foods and highly palatable foods are anticipated by different parts of the brain. Anticipation of regular food by food-restricted rats activates the medial hypothalamic regions involved in the homeostatic regulation of food intake such as the paraventricular hypothalamic nucleus (PVN) and the dorsomedial hypothalamic nucleus (DMH). Anticipation of sucrose activates the brain reward system, which includes the prefrontal cortex (PFC), nucleus accumbens (NAcb), and lateral hypothalamus (LH). The paraventricular thalamic nucleus (PVT) is Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 6 activated by anticipation of both diets and seemingly provides a relay between the homeostatic and reward systems. Excitatory neurotransmission from the PFC to its projecting area including the NAcb and LH may be facilitated by a decrease in expression of the PFC cannabinoid CB1 receptor by palatable food. Obesity Obesity is one of the most significant global health and social problems, with rates rising dramatically over the past few decades. While the basic drivers of obesity are obvious (more energy consumed than expended), the causes are multifactorial and complex. A decade ago, it was suggested that exploring the ways in which the built environment influenced physical activity and dietary behaviours might provide fertile ground for investigation. Whilst lesions in the 2 nuclei do cause weight problems, the global increase in obesity is likely to reflect a changed top-down motivation of feeding, caused by the high availability of easy to obtain, palatable, salient (noticeable/desirable) foods that override the regulatory functions of the hypothalamus. Supraoptic nucleus and paraventricular nucleus The hypothalamus controls the homeostasis of our body, and among the various processes that helps to maintain the homeostasis, we have the water balance . We can produce the antidiuretic hormone or vasopressin that acts upon the kidneys, increasing water reabsorption. In the hypothalamus there are 2 nuclei producing this hormone: the supraoptic and the paraventricular nucleus . These 2 nuclei act in association with the subfornical organ , one of those organs where the blood brain barrier is not that efficient. The subfornical organ is at the level of the roof of the 3 rd ventricle, and these 2 nuclei, together with the subfornical organ are able to detect the osmolarity of blood . There are cells in the nuclei, which responds to dehydration by shrinking, thus to change the membrane excitability. These cells are osmoreceptors , they detect the changes in osmolarity: if the osmolarity increases, they shrink and the action potential becomes higher. This finally triggers the release of more antidiuretic hormone from the neurohypophysis. These 2 nuclei also produce oxytocin . Diabetes insipidus There is a type of diabetes, which is due to the release of large amount of urine with poor concentration. It can be caused by central causes such as damage to the hypothalamus or pituitary gland; or by peripheral causes, such as kidney problems (insensitivity of receptors for ADH); it can also be caused by gestational problems. Oxytocin The supraoptic and paraventricular nucleus produce oxytocin , which is considered a social hormone . It has been shown that high levels of oxytocin have been associated with trust and trustworthiness , positive physical contact with a partner. It has also been shown that in patients with depression, there is a reduced Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 7 amount of oxytocin into the bloodstream. It seems also to be associated to the ability of recognising emotion in other individuals. Moreover, it has also a role in cognitive functions. Key roles throughout mammalian evolution in the regulation of complex social cognition and behaviours, such as attachment, social exploration, recognition and aggression, as well as anxiety, fear conditioning and fear extinction. Recently, studies have begun to provide evidence that the function of these neuropeptides is impaired in mental disorders associated with social deficits. Both the antidiuretic hormone and oxytocin are released though the neurohypophysis through the hypothalamus-hypophysial tract , which links directly the nuclei of the hypothalamus to the neurohypophysis. It has to be distinguished to the other type of control that the hypothalamus exerts on the adenohypophysis : there are some nuclei of the hypothalamus that produce the releasing or inhibitory factors, which through a portal circulation that delivers these factors to the adenohypophysis, where they promote or inhibit the release of hormones. One of the nuclei important in producing these substances is the arcuate or infundibular nucleus . In this region, we also have the production of dopamine , which controls the release of prolactin . Prolactin is important for mechanisms of immunotolerance . Suprachiasmatic nucleus The suprachiasmatic nucleus lies above the optic chiasm and it is involved in the sleep and wake cycle . This nucleus receives directly retina inputs and it is connected to the epiphysis . Another connection is the one with the reticular formation , especially with the part that belongs to the activating system (inhibiting it). Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 8 Medial preoptic nucleus The medial preoptic nucleus is in the preoptic area , slightly anteriorly to the preoptic chiasm , medially localised. It is important because it regulates the activity of gonadotropins hormones from the adenohypophysis. It is a sexually dimorphic nucleus. Preoptic nucleus Involved in thermoregulation are the preoptic nucleus and some regions of the reticular formation . The hypothalamus is involved in thermoregulation, which is a process that involves a continuum of neural structures and connections extending to and from the hypothalamus and limbic system through the lower brainstem and reticular formation to the spinal cord and sympathetic ganglia. This area appears to be very important in determining the thermal setpoint (35.5 37 C). During fever , something changes the thermostat, which decides that the temperature has to be higher, like 39. There are lots of mechanism in our body, such as increased metabolism , shivering , that tries to maintain the temperature assigned to 39. Dorsomedial nucleus There are some nuclei of the hypothalamus that, because of their connection, can change the behaviour of the individual. For example, we have the dorsomedial nucleus that is involved in the savage behaviour . Paraventricular nucleus Then we have the paraventricular nucleus that is important in stress response . Stress can be a mechanism in which we can response to a condition by activating a stress response within a physiological range. It involves the release of the corticotropin-releasing factor . This acts upon the adenohypophysis , which can produce adrenocorticotropin hormone . This hormone acts upon the adrenal gland, specifically on the adrenal cortex , in order to release glucocorticoids , such as cortisol . Moreover, we have also an action upon the medulla due to the action of the sympathetic nervous Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 9 system, which is particularly active during stress situations. The medullary portion of the adrenal gland produces adrenaline , which is released into the blood stream. Cortisol then communicates with the hypothalamus and with the adenohypophysis. In both of the situation, we have an inhibitory action upon the hypothalamus , where the corticotropin-releasing factor is produced, but also a negative feedback effect on the adenohypophysis . Corticotropin-releasing factor (CRF) mediates the central effect of stress There are more than 1 receptors for the CRF ,which can attach to 2 types of receptors (type 1 and type 2). Through the type 1 receptor , it acts on the pituitary gland ; this same hormone can act on other regions of the hypothalamus, and in this case, it acts upon the type 2 receptors , reducing the food intake, increasing the energy mechanism and decreasing obesity (anorectic effect). This same releasing factor can also act on the septal area and, by acting on type 2 receptors, it can reduce the food intake and increase the level of anxiety. Through this system of receptors, a hormone can act both peripherally and centrally, driving different types of behaviours. Moreover, this hormone can also act very peripherally, such at the level of the gastrointestinal tract , on receptors found along the digestive tube, causing an activation of the mast cells , causing increasing permeability of the wall of the intestinal tube, which causes an increase in bacterial translocation , but it also causes visceral pain . In the same area, it can also activate the enteric nervous system , thus increasing motility, transit, secretion and defecation and causing diarrhea . Autonomic functions of the hypothalamus The hypothalamus is involved in the autonomic functions . The anterior part is involved in excitatory effects on the parasympathetic nervous system; while the posterior hypothalamus is involved in excitatory effects on the sympathetic nervous system. Limbic system In the hypothalamus there are the mammillary bodies , which together with other nuclei are part of the limbic system. The mammillary bodies are connected to the hippocampus and they project to the anterior nuclei of the thalamus through the mammillo-thalamic tract , also called the Vicq dAzyr tract . Moreover, they project to the reticular formation through the mammillo-tegmental tract .Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 10 Circuit of Papez This is the core circuit of the limbic system and if we start from the hypothalamus , and then from the mammillary bodies , we can see that they project to the anterior nuclei of the thalamus . They project to the cortex, to the cingulate gyrus , above the corpus callosum (part of the limbic lobe), which then communicates to the parahippocampal gyrus (close to the hippocampal formation). The parahippocampal gyrus then communicates with the entorhinal cortex , which is then into communication with the associative areas of the neocortex and with the hippocampus through the perforant pathway . Inputs to the hypothalamus We can classify information entering the hypothalamus in 2 categories: neural and the blood-borne (humoral). Outputs from the hypothalamus Giuseppe Izzo 7th Lesson Neuroanatomy Hypothalamus 11 Hypothalamic syndrome When we have a lesion in the hypothalamus , we have a condition called hypothalamic syndrome , which is characterized by a collection of symptoms that can all be present or just some of them. We can have endocrine-metabolic disorders (e.g., diabetes insipidus, obesity); vegetative disorders (e.g., blood pressure and heart rate alterations, hypothermia, hyperthermia); and mood and behavioural disorders (e.g., depression, hypersomnia, hypersexuality). Periventricular organs Neurons of the hypothalamus can sense blood-born factors in regions that lack effective blood-brain barrier . Around the 3 rd ventricle, there were the periventricular organs , which are areas where the blood-brain barrier was not that efficient. Besides the fact that in these areas there are neurons that can sense blood-born factors, there are also some hypothalamic nuclei that can sense blood-born factors. In the central nervous system, there is more than one barrier: we have a blood-brain barrier , a brain-CSF barrier and a blood-CSF barrier .Giuseppe Izzo Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 1 Spinal nerves The spinal nerve is a mixed nerve , which means that it is formed by somatomotor , somatosensory , visceromotor and viscerosensory components. This mixed nerve that comes from the fusion of the dorsal root and ventral root then divides into 2 terminal branches: a posterior branch or dorsal branch or ramus, and an anterior or ventral branch .Each of these branches is still a mixed nerve, so it contains the 4 different components. Besides the dorsal and anterior rami, we need also to consider that it has collateral branches , which are divided into recurrent or meningeal branches and white and grey rami communicantes . Recurrent or meningeal branch, also called sinuvertebral nerve The recurrent meningeal branch is a branch of the anterior ramus and contains sensory fibers and sympathetic fibers from grey rami communicantes. They contain sensory fibers, which are important because, re-entering into the vertebral canal, they innervate the intervertebral disks (discogenic pain, chronic back pain), meninges , ligaments ,vertebral periosteum . They also contain sympathetic fibers for vasomotor regulation . Face joint are innervated by medial branch of the posterior rami , and they are an additional source of chronic back pain . Pain generators in the spine can be, especially in the lumbar area, discs, zygapophyseal joints, dura mater Embryological origin of the muscular territory of innervation of the dorsal and ventral division of spinal nerve The myotome divides into epimere and hypomere . The epimere is placed more dorsally, while the hypomere more ventrally. All the axons coming and going to the spinal cord start to synapse, but some muscles are located dorsally and some others are ventrally, so the spinal nerve divides into an anterior and posterior division . The posterior division is going to innervate the muscle originating from the epimere , while the anterior division is going to innervate the muscles that originate from the hypomere . Most of the muscles that originate from the epimere are the intrinsic muscles of the back, and most of them are the extensors of the spine; the ventral branches innervate the muscles that form the wall of the thorax and of the abdominal cavity , but also the muscles that are going to migrate and form the limbs . The territories that the anterior division needs to innervate is larger and more complicated, also because most of the muscles that need to be innervated have multi-segmental origin and they mix with one another. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 2 Posterior rami The posterior rami maintain a segmental distribution , they divide into medial and lateral division, so they do not anastomose with one another. The territory of innervation is cutaneous , but they also distribute to the deep or intrinsic muscles of the back . Also, the posterior rami are involved in the innervation of the zygapophysial joints , the posterior portion of the vertebral bodies and some of the ligaments . There are some of the posterior rami that may be mentioned individually. For example, the posterior ramus of C1 is also called the sub occipital nerve because it innervates the suboccipital muscles . The meninges of the posterior cranial fossa are also innervated by the first 3 spinal nerves (posterior rami). If there is an irritation of the meninges of the posterior cranial fossa, we can have a contraction of the suboccipital muscles. Then we have the posterior ramus of C2 , which has a very large sensory medial branch that is called greater occipital nerve of Arnold , and it is responsible for the innervation of the skin of the posterior part of the head. Occipital neuralgia or C2 neuralgia An irritation in the greater occipital nerve can give rise to a condition called occipital neuralgia or C2 neuralgia . It causes paroxysmal shooting or stabbing pain in the dermatomes of the greater occipital nerve ad the lesser occipital nerve, from an origin in the suboccipital region, the pain spreads throughout the vertex, particularly in the upper neck, back of the head and behind the eyes. Due to the pain in the region of the head, it causes headache . To try to reduce the pain, it is possible to try through electrical stimulation, or by injecting some blockers into the nerve. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 3 The first cervical nerves ( C1, C2, C3 ) also innervate the meninges of the posterior cranial fossa , together with the contribution of the vagus and of the glossopharyngeal nerves . Infratentorial meningitis is associated with occipital cephalea and reflex retraction of the head because the same segments of the spinal cord, that receives the sensory information from the posterior cranial fossa and from the meninges, has a connection between the sensory and motor fibers. So, since the first cervical nerve innervates the suboccipital muscles, when it is irritated, it generates a reflex that retracts the head. Ventral rami The ventral or anterior rami form plexuses , which means that they start to exchange fibers with one another, with the exception of the anterior rami of the thoracic segments of the spinal cord. This exchange of fibers among the different segments is because one muscle originates from more than one myotome and one myotome gives origin to more than one muscle. We have a cervical plexus , made by the anterior divisions of the spinal nerves from C1 to C4 and with a small contribution from C5 ; a brachial plexus , which is formed from C4-C5 to T1 , and with a small contribution from T2 ; then we have the lumbar plexus , from L1 to L4 ; the sacral plexus , from L4 to S3 ; and then we have the pudendal and coccygeal plexuses , which are made respectively from S2 to S4 and from S5 and Co .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 4 Cervical plexus The cervical plexus is right on the side of the vertebral column, in the posterior triangle of the neck , which is superficially delimited anteriorly by the posterior margin of the sternocleidomastoid and the anterior margin of the trapezius . The cervical plexus is made by the anterior rami of C1-C4 . The roots of the nerves are located between the anterior scalenus and vertebral transverse processes , middle scalenus , splenius and levator scapulae .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 5 The anterior rami of these spinal nerves divide into ascending and descending branches , each of them except the first that only give rise to a descending nerve, and they start to come together, exchanging fibers, forming 3 anastomotic loops . The anastomotic loops are divided into superior , anterior and inferior .From these loops, there are anastomotic branches that are directed to the hypoglossus , which is the XII cranial nerve; to the accessory nerve (XI cranial nerve); and then to the brachial plexus , especially, some of the fibers from C4 do not remain into the composition of the cervical plexus, but it goes down to reach and contribute to the formation of the brachial plexus. Moreover, we also have 4 to 5 grey rami communicantes , which come from the paravertebral chain . From this plexus we have origin of cutaneous branches , muscular branches and then we have a terminal branch that correspond to the phrenic nerve . Collateral cutaneous branches The cutaneous branches supply territories of the neck , shoulder , thorax , parotideal , mastoideal and ear regions. It is the territory coloured in yellow in the image below. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 6 There is the nerve point of the neck , also called Erbs point , which is more or less half-away in the posterior border of the sternocleidomastoid muscle , from which the cutaneous branches of the cervical plexus exit to distribute to the territory of cutaneous innervation. The 4 superficial cutaneous branches of the cervical plexus are the supraclavicular nerves , the transverse cervical nerve , the lesser occipital nerve , and the great auricular nerve . From the clinical point of view, this point is very easily accessible, so we can perform anaesthesia of these branches, obtaining a cervical plexus block . This type of anaesthesia can be used for superficial surgery on the neck, shoulders and thyroid. Its most common use is in carotid endarterectomy . The collaterals of the cervical plexus innervate muscles that are close to it. For example, we have some muscular branches of the plexus that innervate the prevertebral muscle and the lateral muscles of the neck, such as the anterior and lateral rectus capitis , longus capitis and colli , middle scalenus and levator scapulae ; moreover, we have innervation of the sternocleidomastoideus (accessory nerve XI), trapezius (accessory nerve XI), some suprahyoideal muscles (through the hypoglossus), some infrahyoideal muscles (through the ansa cervicalis ). Some of the muscles that are innervated by the cervical plexus are innervated through the hypoglossus and the ansa cervicalis. Very close to the loops of the cervical nerves, we have the hypoglossus , which runs to reach the floor of the oral cavity. Some fibers from the C1 and C2 segments of the spinal cord, enter the loops of the spinal plexus, but they soon leave the loops to enter the hypoglossal nerve. Some of the fibers, that reach the hypoglossus, enter into a loop that is called ansa cervicalis . The ansa terminalis is a nerve root, formed by a superior root , apparently originating from the hypoglossus, and by an inferior root ,which originates from the root of the cervical plexus itself. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 7 The ansa cervicalis is a loop of fibers that innervate muscles in the anterior triangle of the neck. It is made by fibers from C1 to C3 . The ansa cervicalis is made by a superior root , also called descending hypoglossal ,and it contains fibers coming from the C1 segment of the spinal cord; and by an inferior root , also called descending cervical , made by the fibers from C2 and C3 . Some of the fibers from C1 remain in the hypoglossus. The muscles innervated via the hypoglossus are the genio-hyoid muscle and the thyrohyoid muscles .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 8 The ansa cervicalis innervates some of the infrahyoideal muscles : the omohyoid , the sternohyoid ,and the sternothyroid . The ansa cervicalis has a very close relationship with the vascular bundle of the neck ,a bundle made by the carotid artery , the internal jugular vein and the vagus nerve . This bundle is enveloped in a fascial device and the ansa cervicalis lies on this vascular bundle of the neck. Phrenic nerve (check image on Netter) The largest branch of this plexus, the only terminal branch, is the phrenic nerve . The phrenic nerve originates from C4 , with a contribution from C3 and C5 . The nerve runs above the anterior surface of the anterior scalenus muscles , then it passes between the subclavian artery and vein , above the clavicle ; then in front of the apex of the lungs (a tumour in the apex of the lungs can infiltrate the phrenic nerve); it runs in the mediastinum , adhering to the mediastinal surface of the lungs, in front of the hilum of the lungs ; it runs in the mediastinal surface of the pleura, attached to the pericardium ; then it branches and reaches the diaphragm . On its course it does not innervate anything in the neck, but in the thorax, it innervates part of the pericardium , part of the pleura , it reaches and crosses the diaphragm and contributes to the innervation of the peritoneum . Since the diaphragm is the major respiratory muscle, in case of lesion in the cervical segments of the spinal cord, we may need to be artificial ventilated for the rest of the life because we lose the ability to control the diaphragm. In the neck, the phrenic nerve runs attached to the anterior surface of the anterior scalene muscle, then reaches the level of the subclavian artery and vein, passing in between them and entering the superior thoracic inlet and then reaches the mediastinum . Irritation of the diaphragm may give rise to shoulder pain . This is because the phrenic nerve pain is referred to the region innervated by C4 and C5. Irritation of the diaphragm can be caused by liver , gallbladder , and duodenum . Diaphragmatic paralysis is due to an interruption in its nervous supply. This can occur in the phrenic nerve, cervical spinal cord, or the brainstem. It is most often due to a lesion of the phrenic nerve : Mechanical trauma : ligation or damage to the nerve during surgery Compression : due to a tumour within the chest cavity Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 9 Myopathies : such as myasthenia gravis Neuropathies : such diabetic neuropathy. Paralysis of the diaphragm produces a paradoxical movement . The affected side of the diaphragm moves upwards inspiration, and downwards during expiration. A unilateral diaphragmatic paralysis is usually asymptomatic , and is most often an incidental finding on x-ray. If both sides are paralysed, the patient may experience poor exercise tolerance, orthopnoea and fatigue. Lung function tests will show a restrictive deficit. Management of diaphragmatic paralysis is 2-fold. Firstly, the underlying cause must be identified and treated. The second part of the treatment deals with symptomatic relief. This is usually via non-invasive ventilation, such as CPAP (continuous positive airway pressure) machine. Brachial plexus The brachial plexus is formed by the anterior rami of C5 to T1 , with some contribution from C4 and T2 . The muscular territory of innervation of the brachial plexus are the muscles of the shoulder girdle , the toraco-appendicular muscles , spinoappendicular muscles and muscles of the upper limbs . The plexus is organized into roots , trunks , divisions , cords , collateral branches and terminal branches . Symptoms associated with disorders of the brachial plexus are pain, sensory loss, weakness or paralysis in the shoulder, arm and hand. These can be caused by compression : mid form (paraesthesia, intermittent), demyelination (pain, weakness, persistent), Wallerian degeneration (retrograde damage to neurons); by transection , nerve ischemia or infarct, radiation , inflammation , focal degeneration, metabolic disorders. The initial part of the plexus is located in the supraclavicular region , between the anterior scalene and the middle scalene muscles. If the passageway between these 2 muscles is too narrow, congenitally, then the inferior part of the plexus can be compressed, or if we do physical activities that makes me use a lot the muscles of the neck, they develop too much and compress part of the plexus. Moreover, if there is a too close relationship between the subclavian artery and the inferior part of the plexus, the pulsation of the artery may irritate the plexus, or maybe if there is an aneurism of that vessel. Because of its position, the inferior part of the plexus can be affected to either the scalenus syndrome (inflammation of the scaleni) or it can be involved in the thoracic outlet syndrome . Thoracic outlet syndrome is a group of disorders that occur when blood vessels or nerves in the space between the collarbone and first rib (thoracic outlet) are compressed. This can cause pain in shoulders and Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 10 neck and numbness in fingers. Common causes of thoracic outlet syndrome include physical trauma from a car accident, or sports-related activities, certain anatomical defects (such as an extra rib) and pregnancy. In the supraclavicular region, right above the clavicle, we find the apex of the lungs , so we may have problems in the inferior part of the plexus because there is something wrong in the lungs. In this region, the plexus is in close relation with the clavicle and if we have a fracture of the clavicle, we may have problems in the brachial plexus due to fragments of the bone. This type of fracture can also be dangerous for the vessels passing near it. More distal branches (cords) The most distal branches of the plexus, or cords, enter the axilla through the axillary inlet . In the axillary cavity, we find the relation with the axillary lymph nodes , which can cause irritation or infiltration (in case of tumour) of the branches of the plexus. The cords of the brachial plexus are organised around the axillary artery. Systematic of the plexus In the plexus we recognise the roots, the trunks, the divisions, the cords, collateral branches and terminal branches. The terminal branches are the ulnar , median , radial and musculocutaneous nerves; moreover, we then have the axillary nerve , which is by some authors considered a big collateral, and then also the medial cutaneous nerves of the arm and of the forearm are considered by some authors terminal branches. The roots are considered as the anterior divisions of the ventral rami from C5 to T1 , plus C4 and T2 .They come together as to form the trunks : we recognise a superior or upper trunk formed by C4 to C6 roots; a middle trunk , formed by C7; an inferior or lower trunk , that is formed by C8 to T2 roots. Each of the trunks divides into an anterior division and a posterior division . All the posterior divisions come together as to form the posterior cord , at Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 11 the level of the axillary region; from the posterior cords, as terminal branches, we will have the formation of the radial and axillary nerve . The superior and middle anterior divisions come together as to form the lateral cord , which finally will give rise to the musculocutaneous nerve and to part of the median nerve (part of it comes from the lateral cord and part of it comes from the medial cord). The anterior division of the inferior trunk forms the medial cord , which gives rise to the ulnar nerve and contributes to the median nerve . The positions of the different nerves are according to the axillary artery. Around the axillary artery, forming a V-shaped pattern, we have the contribution of the lateral and medial cord that come together as to form the median nerve, this is called the fork of the median nerve . Shoulder dislocations In the axillary region, we have a very mobile joint: the gleno-humeral joint . If this joint undergoes dislocation, especially if this is posterior or inferior , it can cause a compression of the plexus and of the vessels. Lesions at the level of the roots or trunks The plexus can be lesioned and the lesion can take place at the level of the roots or of the trunks, in the supraclavicular space. Among the trunks, 2 of them are more likely to be damaged, the superior and the inferior trunk . Waiters tip position or Erbs palsy If we have a lesion of the superior or upper trunk , which receives fibers from the C5 and C6 roots of the plexus, this causes the Waiters tip position , which can be either complete or partial. This position is caused by loss of abduction of the arm, of flexion of the forearm, of supination of the forearm, and of extension of the wrist. It may also be caused by an obstetric problem : if the shoulder is stuck at the level of the promontory of the sacral bone, pulling too much can cause a lesion of the brachial plexus. It can also be caused by a motor accident, due to the helmet. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 12 The burner syndrome The upper trunk is most commonly involved, due to downward traction of the shoulder. Burner syndrome is characterized by an immediate, severe, burning pain and prickly paraesthesia that radiates from the neck, extending circumferentially to the arm or fingers. Backpack palsy (also known as rucksack paralysis and cadet palsy) Painless arm and/or shoulder weakness , usually unilateral, after wearing a backpack or similar apparatus for a prolonged period of time, resulting most often in an upper trunk lesion. Some sensory loss is also present in the same distribution. The lesions are predominantly demyelinating conduction block . Inferior lesions and Klumpkes palsy A lesion in the inferior trunk , also called Klumpkes palsy can be due to an excessive traction of the lower part of the plexus, or during birth, if the baby is pulled by the hand. One condition that can cause a lesion in the inferior part of the plexus is the thoracic outlet syndrome : the inferior trunk is the one closer to the axillary inlet, so it can be more easily compressed in the passage way between the clavicle and the first rib, or in the passage way between the anterior and middle scalenus. Moreover, it can also be caused by the Pancoasts syndrome , which refers to a tumour of the base of the lungs that infiltrate the brachial plexus and the paravertebral chain. The more inferior the lesion is, the more distal are the muscles which are affected. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 13 We can have a paralysis of the intrinsic muscles of the hand , causing a problem in the flexion of the wrist due to problems in the innervation of the flexor carpi ulnaris, but also problems in flexing the fingers due to the innervation of the ulnar half of the flexor digitorum profundus. We may have problems in controlling the lumbricals and the dorsal and ventral interossei , and these 2 sets of muscles are important for flexing the metacarpophalangeal joint and extending the distal and proximal interphalangeal joints. Problems in these muscles can cause hyperextension at the metacarpophalangeal joints and flexion of the interphalangeal joints. this will cause the patient to have a mix between a claw-hand and an ape-hand . Pancoast syndrome It is most commonly due to non-small cell lung cancer in the superior sulcus (pleuropulmonary groove, adjacent to subclavian vessels), and is associated with a Horner syndrome in 3/4 of patients. Weakness and atrophy of the intrinsic muscles of the hand , or pain and paraesthesia of the fourth and fifth digits and the medial aspect of the arm and forearm. Abnormal sensation and pain in the T2 territory (the axillary and medial aspect of the upper arm) may also be an early finding, and the triceps reflex may be lost .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 14 Collaterals of the roots One of the collaterals of the roots is from the C5 root, which is called dorsal scapular nerve , and then we have the long thoracic nerve , which originates from C5, C6, and C7 .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 15 Cutaneous innervation of the upper limbs There are several territories of innervation in the upper limbs: we have the axillary nerve, the musculocutaneous nerve (lateral side of the forearm on the anterior surface) Dorsal scapular nerve The dorsal scapular nerve innervates the levator scapulae , the rhomboid major and the rhomboid minor . The dorsal scapular nerve syndrome typically presents with a weakness of the levator scapulae and the rhomboid muscles, and results in a winged scapula . A winged scapula is where the scapula protrudes from the patients back and can affect the ability to lift objects or pull and push. The winging of the scapula seen with dorsal scapular nerve syndrome is not as severe as seen as injury or paralysis of the serratus anterior muscle. Shoulder elevation The muscles involved in shoulder elevation are the trapezius (innervated by the XI CN ), the levator scapulae and the rhomboids (innervated by the dorso scapular nerve ). In order to asses impairment, we can test for weakness or paralysis when elevating the shoulder under resistance on the impaired side of Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 16 the patient. denervation is accompanied by shoulder droop from muscle atrophy. There are no cutaneous nerve deficits. Long thoracic nerve The long thoracic nerve innervates the serratus anterior muscle . It inserts on the medial border of the scapula , that is why if we have a weakness on this muscle, which is very important to keep the scapula tightly associated to the back, we will have a wing scapula that is even more evident that the one we would have if the rhomboids and the levator scapulae were weakened. The serratus anterior muscle is important for the protraction (advancement of the scapula to an anterior position or abduction) and rotation of the scapula; it keeps the medial border and inferior angle of scapula opposed to the thoracic wall; moreover, it facilitates abduction of the shoulder . Shoulder abduction The muscles that contribute to the abduction of the shoulder are the serratus anterior , innervated by the long thoracic nerve ; the supraspinatus muscle , innervated by the suprascapular nerve ; the deltoid muscle , innervated by the axillary nerve ; and the trapezius muscle ,innervated by the accessory nerve . In normal subjects, the supraspinatus initiates the first 15 degrees of abduction along the vertical plane. The deltoid functions from 15 to 90 degrees, while synergistic actions of the trapezius and serratus anterior abduct from 90 to 180 degrees by rotating the scapula laterally. Denervation is accompanied by muscular atrophy , shoulder adduction , winged scapula , and cutaneous deficit along the distribution of the axillary ( superior lateral brachial cutaneous ) nerve. Collaterals of the trunks We have 2 collaterals of the trunks, and they are from the superior trunk . The collaterals of the superior trunk are the suprascapular nerve and the nerve to the subclavius muscle. Suprascapular nerve The suprascapular nerve crosses the suprascapular notch to innervate the supraspinatus and the infraspinatus , which are part of the rotator cuff (extrarotators). The supraspinatus is important for abduction of the arm at the shoulder joint; the infraspinatus is involved in external or lateral rotation of the shoulder. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 17 Shoulder lateral rotation The shoulder lateral rotation is performed by the infraspinatus muscle, innervated by the suprascapular nerve and by the deltoid and teres minor muscles, innervated by the axillary nerve . The neuromuscular deficit is perceived as weakness or paralysis when rotating laterally at the shoulder joint under resistance. Denervation is accompanied by muscular atrophy, internal rotation of the shoulder, and cutaneous deficit along the distribution of the axillary (superior lateral brachial cutaneous) nerve. Nerve to the subclavius muscle The subclavius is important in the stabilization of the clavicle during movements of the shoulder and arm. It is involved in depression of the clavicle and elevation of the first rib . Collaterals of the lateral cord Collaterals of the lateral cord are formed by just the lateral pectoral nerve (C5, C6, C7), which innervate the pectoralis major . The terminal branches of the lateral cord are the musculocutaneous nerve and the lateral root of the median nerve . The pectoralis major is involved in flexion , adduction and medial rotation of the arm at shoulder joint. Shoulder flexion Shoulder flexion is carried out through the action of the pectoralis major muscle (lateral pectoral nerve); of the deltoid muscle (axillary nerve); of the long head of biceps brachii and coracobrachialis muscles (musculocutaneous nerve). Damages to these nerves or muscles cause weakness or paralysis when flexing the shoulder joint under resistance. Denervation is accompanied by muscular atrophy and deficit along the cutaneous distribution of the axillary (superior lateral brachial) and musculocutaneous (lateral antebrachial cutaneous) nerves. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 18 Collaterals of the medial cord The medial cord has, as collaterals, the medial pectoral nerve (C8, T1); then we have 2 important cutaneous branches: the medial cutaneous nerve of the arm (or medial brachial cutaneous nerve) and the medial cutaneous nerve of the forearm (or medial antebrachial cutaneous nerve). The terminal branches are the medial root of the median nerve and the ulnar nerve . Medial pectoral nerve The medial pectoral nerve innervates the pectoralis minor and contributes to the innervation of the pectoralis major . The pectoralis minor contributes to moving the scapula forward and downward. Collaterals of the posterior cord Collaterals of the posterior cord are the superior or upper subscapular nerve , the thoracodorsal nerve and the inferior or lower subscapular nerve . The terminal branches from the posterior cord are the radial nerve and the axillary nerve . The superior subscapular nerve innervates the subscapularis muscle , which is a very important medial rotator of the arm. The thoracodorsal nerve innervates the latissimus dorsi ; while the inferior subscapular innervates the subscapularis and the teres major (adducts and medially rotates the arm). The thoracodorsal nerve is very vulnerable to surgery when we act on the axillary cavity, especially during surgery in the inferior part of the axilla or during mastectomy (removal of axillary tail of the breast). Shoulder extension Shoulder extension is performed by the teres major , latissimus dorsi and deltoid muscle , which are respectively innervated by the subscapular , thoracodorsal and axillary nerve . Denervation is accompanied by muscular atrophy and deficit along the cutaneous distribution of the axillary (superior lateral cutaneous nerve). Shoulder medial rotation Shoulder medial rotation involves the medial and lateral pectoral nerves (pectoralis major muscle ), the axillary nerve (deltoid and teres major muscles), subscapularis nerve (subscapularis muscle), and the thoracodorsal nerve (latissimus dorsi muscle ). Denervation is accompanied by muscular atrophy, lateral rotation of the shoulder, and cutaneous deficit along the distribution of the axillary (superior lateral brachial cutaneous) nerve. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 19 # Terminal branches Musculocutaneous nerve (perforating nerve of Casserius) The musculocutaneous nerve is also called perforating nerve of Casserius because it perforates one of the large muscles of the anterior compartment of the arm. This nerve innervates all the muscles in the anterior compartment of the arm. After passing the region of the cubital fossa , it gives rise to a cutaneous branch ,so the most distal portion of this nerve becomes only sensory (cutaneous). The functions of this nerve are flexion of the arm at the shoulder joint, flexion of the forearm and supination of the forearm when the elbow joint is flexed. Elbow flexion The elbow flexion is performed by the brachialis and biceps brachii muscles (innervated by the musculocutaneous nerve ) and by a contribution of the brachioradialis muscle (innervated by the radial nerve ). Flexion with the forearm in the pronated position assesses the functional integrity of the brachialis. However, flexing the elbow with a supinated forearm evaluates both the brachialis and biceps brachii. Denervation is accompanied by muscular atrophy, extension of the elbow, and deficit along the cutaneous distribution of the musculocutaneous (lateral antebrachial cutaneous) nerve. The median nerve It originates from C5-T1 . It is important because it innervates the majority of the muscles of the anterior compartment of the forearm , with the exception of the flexor carpi ulnaris (innervated by the ulnar nerve) and the medial half of the flexor digitorum profundus (on one side it is innervated from the median nerve, while on the medial side, it is innervated from the ulnar nerve). Moreover, it also innervates some of the intrinsic muscles of the hand . Also, the median nerve has a cutaneous territory of innervation , which is limited to the territory of the palm of the hand, on the radial side, from half of the first finger to half of the third finger. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 20 The median nerve originates in the axillary cavity , it enters into the arm, runs into the anterior compartment, lateral to the axillary artery , then it crosses over the artery and ends up in the cubital fossa .From there it enters into the anterior compartment of the forearm. In the cubital fossa, it runs anterior to the medial epicondyle , while the ulnar nerve is behind it. Branches in the forearm: Muscular branches : pronator teres, palmaris longus, flexor digitorum superficialis, and flexor carpi radialis Anterior interosseous nerve : supplies the deep muscles in the anterior forearm Palmar cutaneous nerve : innervates the skin of the lateral palm The median nerve enters the hand via the carpal tunnel , where it terminates by dividing into 2 branches: recurrent branch (innervates the thenar muscles ) and palmar digital branch (innervates the palmar surface and fingertips of the lateral three and half digits, also innervates the lateral 2 lumbrical muscles). Interosseous nerve It is situated on the anterior surface of the interosseous membrane between the flexor pollicis longus and the flexor digitorum profundus . It then runs deep to pronator quadratus to end at the wrist by giving articular branches to the radiocarpal and intercarpal joints. The anterior interosseous nerve supplies flexor pollicis longus , the lateral half of flexor digitorum profundus and pronator quadratus .Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 21 In the wrist, it has 2 branches, the recurrent branch , which innervates the thenar muscles , and the palmar digital branch , which innerates the palmar surface and fingertips of the lateral 3 and half digits. Also innervates the lateral 2 lumbrical muscles . The functions are flexion and abduction of the wrist, forearm pronation, flexion at metacarpophalangeal joints and extension of proximal and distal interphalangeal joints, medial rotation, abduction, opposition and flexion of the thumb. Median nerve lesions at the elbow The median nerve can be damaged by injury to or at the elbow. The commonest mechanism of injury is supracondylar fracture of the humerus . Motor damage : almost all of the flexors and pronators of the forearm paralysed; weakness of wrist flexion and deviation to the ulnar side at flexion; loss of thumb abduction, opposition, and flexion due to loss of the muscles innervated by the recurrent branch; ape-hand (when atrophy of the thenar muscles), forearm supinated. The 1 st and 2 nd lumbricals will also be paralysed and the patient will be unable to flex at the MP of the index and middle fingers. Flexion of the terminal phalanx of thumb lost (flexor pollicis longus). The characteristic papal benediction sign will be evident when trying to make a fist. Sensory loss : there will be loss of sensation over all cutaneous areas innervated by the median nerve. Giuseppe Izzo 8th Lesson Neuroanatomy Spinal plexuses 22 Median nerve lesions at the wrist The median nerve can be damaged by injury at the wrist by lacerations proximal to the flexor retinaculum. The nerve can also be compressed in the carpal tunnel . Anterior interosseous intact (long flexors muscle work). Motor damage : there will be loss of thumb abduction and opposition due to loss of the muscles innervated by the recurrent branch. The 1 st and 2 nd lumbricals will also be paralysed and the patient will have weakened flexion at the metacarpophalangeal joints of the index and middle fingers. Wrist and finger flexion will be intact as the anterior interosseous nerve is unaffected. There will be thenar wasting ( Aper hand ) but no ulnar deviation of the wrist or papal benediction. Sensory damage : there will be loss of sensation over the lateral 3 and fingers and nail beds and the lateral side of palm. It should be noted that the lateral side of the palm can be preserved as the palmar cutaneous branch can be spared. Pronator teres syndrome The pronator teres syndrome is due to the fact that the median nerve when it enters in the forearm, it passes through the 2 heads of the pronator teres. If the passage is too narrow, we may have compression of the nerve and this give rise to an irritation of the nerve that causes pain in the volar region of the forearm, and some muscle weakness can be present. Anterior interosseous neuropathy If the anterior interosseous branch of the median nerve, which is the largest branch, is damaged, we can have problems in flexing the tip of the index finger due to the innervation by the anterior interosseous branch of the flexor digitorum profundus .Giuseppe Izzo