Transcript for:
Insights from Dr. Longo on Memory

[Music] Stanford University good evening everybody great to see you here again this evening I'm pleased to say that I won't have to exit tonight to go to the pharmacy I think I'm doing better but uh self-medication goes a long way so how many of you remember the topic of two weeks ago I'm glad you're here tonight uh so tonight's topic is on an issue that all of us are concerned about I think I'm increasingly concerned about it as time goes by and that is learning and memory I remember um all too longingly as an undergraduate having a kind of photographic memory and being able to uh really Envision every page in my organic chemistry text that's long gone uh along with most of the other things that come with aging uh but here we are night tonight to reminisce and better understand the process and uh uh I think we're in great hands tonight because we have Dr Frank Longo who is going to be our speaker Dr Longo is actually a California boy he uh grew up uh in Southern California in San Diego where he uh went um and did his undergraduate work as well as uh his graduate work as MD and PhD at the University of California in San Diego Then he moved North bypassing Stanford for reasons that I've never understood um to UCSF and uh he did some great things there and was very active in what is in fact a wonderful neurology program uh and then took a detour East um to the University of North Carolina where he became chair of the uh Department dep of Neurology and did a fantastic job uh in developing that department and I Know It uh well because I visited him there um to begin the process of recruiting him back to Stanford and he did so well there that we wanted him to join us which he did in 2006 um to be our uh chair of Neurology among his um many talents and interests as the broad field of Neurology but he has also in his own research been very focused on a disease which increasingly um takes a toll on uh all of us in The Human Condition which is dementia uh and his laboratory has been very focused on developing novel small molecules to try and uh deal um with this very challenging issue but tonight we've asked him to speak even more broadly um than that and to talk about the whole issue of learning in memory um when it really works and when it doesn't and all of us know there are times when it doesn't but we'll celebrate tonight on the time that it does so thank [Applause] you well thank you Phil for that kind introduction uh the topic tonight is very broad uh this is a topic that could be approached in your philosophy course uh could be approached in a psychology course could be approached in a a neurology course could be approached in a Psychiatry course uh could be approached in a criminal law course this is a massive uh topic uh but what we'll do tonight is synthesize some of the key Parts some of the key foundations of what memory is and what learning uh consists of uh so that hopefully by the end of the session you'll have a good idea of what it is and we'll be able to apply it to a number of fields now there are broad definitions of memory and learning and uh during the evening I think you'll become an expert on it uh there is no official definition uh memory is generally regarded as the ability to record new information into the brain and and have it stick basically if you want a technical uh definition um and learning in memory the meaning is overlap quite a bit learning is the ability to retain to take that information and respond differently uh to a given situation obviously a key uh requirement for survival not only amongst us and other mamal but a wide range of of animals all the way down to animals consisting only of a few cells um so that's the the basic um U range of of the definitions we're we're dealing with and of course memory has been of a great interest for a long time um probably from the very Beginnings long before a written history was possible uh people recognize the importance of having a good memory to survive to pass on Traditions Etc in fact the Greeks um by the time that we got to the Greeks um they had very sophisticated thoughts and knowledge about memory and where does the word uh come from this is the Greek goddess nasin nemine and I underlined the MOs to remember to really put the emphasis on Moss nemine and she U really had the power of memory and could bestow this power on on humans if they were fortunate and she was one of the more intellectual Greek gods in fact she got together with Zeus uh nine knights in a row in fact and had nine children um the nine Muses and how that happened we haven't we can't explain that biology yet um but this was uh quite an intellectual family and each each Muse had uh a talent and these are the nine talents that go um along there and it was recognized that having an exceptional memory would be fundamental would be a foundation for having any of these uh talents so their mother was really the uh source of that now the other gods appreciated her skills also so did the oracles this was the this is the Oracle of tronus and people went to him to get wisdom and uh sometimes they were happy with what he said and sometimes they weren't now if they were happy with what he said they would drink uh from the spring of NE nemine uh shown right here they found it in Greece and by drinking from that spring one would remember what the Oracle had said uh if one didn't like what the Oracle said one would bring drink from the spring of leth and forget everything um and these were um key um Endeavors because even today we're working on creating uh something that will do this and and we'll we'll get to that uh there are many things that will do this um that that already um exist um and of course uh many brilliant people have had something to say about uh memory we can look at Cicero sweet is the memory of past troubles and I thought that managed match somewhat to Dante's quote there is no greater sorrow than to recall happiness in times of misery um so you just can't quite get it right um and of course enrio fery the famous particle physicist said if I could remember the names of all these particles i' be a botanist um so clearly he had a lot of other cognitive skills that made up for that that memory um uh challenge but pretty much every famous person has an Insight on memory and I imagine everyone in this room has considerable insight and memory let's Jump Right In and organize our thinking about memory now memory has been around since before the Greeks but it's fascinating to me that it wasn't until Atkinson and shiffrin who were here at Stanford in the mid-60s um were the first really to organize a working model of memory that has persisted and that people could work with now since then there have been many modifications of this model but this is generally regarded as the first formal model of memory even though we've been thinking about memory for thousands of years and here's basically how they organize it basically all of us have a number of sensory inputs visual auditory uh motor and movement olfaction gustatory Etc and in previous lectures I know that you're now experts on Visual and auditory input anyway these um inputs um come in through our sensory systems to various parts of the cerebral cortex that you've probably seen and they end up in a in a register a sensory register and only for very brief times for example if one looks at something the uh Vision might be there for half a second or a second it's a very fleeting existence an auditory input might last longer four or five seconds for example one example that's used to illustrate the auditory sensory register is as follows one might have a a teenager sitting in front of a television set engrossed in watching what's ever on television and the parent might be talking to that teenager talking to them about whether they've done their homework etc etc and the teenager has completely excluded what the parent is saying finally the parent gets upset and says you know I don't think you've heard a single thing I said and it's very angry and suddenly the teenager sits up and can remember in this sensory buffer about the last five seconds and the teenager will say of course you were just talking about my math homework if that's what came out in the last five seconds and that's our we've all experienced that that's our sensur sensory register if we're not attending to something these are fleeting registrations of the world around us now if we provide some attention in that case the parent finally got the attention of the teenager if we can add some attention to the mix we can move these things into our shortterm memory now in this stage things can last up to about a half a minute seconds to a half a minute we can hold on to these things um an example might be if somebody gave us seven digits like a phone number if we weren't paying attention at all and somebody next to us said seven digits it would wouldn't make it into our short-term memory we at least have to pay some attention but if we pay attention it'll get in there it only lasts a few seconds um and then if somebody a few seconds later said a number phone a second phone number it might displace the first one so we're vulnerable to displacement in the shortterm memory now we have this uh 7+ two meaning and interestingly that the short-term memory seems to be able to hold up in most people about seven objects or seven things to remember Plus or minus two would be the range so that's why seven-digit phone number for most of us uh we can handle if we go beyond that it becomes difficult and I'll show you some some data regarding that but that's characteristic of short-term memory now once something's in short-term memory we've got it there for a few seconds um if it's important to us we we'll want to commit it to long-term memory we have to do something that's generally consists of some kind of rehearsal which leads to the ter term consolidation and if those two things occur we have a chance of moving it into long-term memory and when something is moved into long-term memory we're actually changing the connections in the brain we're creating new patterns of neurons firing and we'll look at that um in more detail um one feature of long-term memory is it's thought to be somewhat Limitless no one's really defined a a limit on long-term memory at least now we have limits on our short-term memory capacity but longterm in Practical um sense seems to be somewhat um unlimited and it can theoretically last for 100 years or as long as we live with some Decay um with aging now once we get something to long-term memory of course we may want to retrieve it and that process of retrieval has been studied uh considerably we'll get to that interestingly we bring it back into the short-term memory mechanisms to finally um be able to recognize it now we can layer on top of this original model and this is the central executive this is the even higher order parts of our brain that are that are managing and running all this and this is uh the part that's thought to give us the ability to plan to execute to organize to even organize how we might use our memory um and and ultimately conscious thought and this Central executive is considered to have two interesting Loops one is the phenomological loop I.E our inner voice when we're thinking we're using that inner voice to think about things or when we're thinking we're using a visual sketch pad so-call inner eye these two Loops are a major part of the central executive and it's the central executive that allows us to look down so to speak on these memory functions and actually be conscious of this gee how do I get this to my long-term memory what kind of tricks can I use to get it to my long-term memory so it's not an automatic unconscious part necessarily although there are automatic parts of memory uh that we'll get to so anyway this is just a basic model of organizing what people had probably seen for thousands of years but it allows us to think about it and modify and test it and look for the biology behind it another term that we'll hear is so-called working memory now this term is often used interchangeably with short-term memory um sort of loosely speaking about memory although experts will argue that technically working working memory is not exactly the same thing as short-term memory um working memory uh can draw from both short-term and long-term um contents so therefore it's not exactly short-term memory and what's an example of working memory this is the ability to hold something in short-term memory and do something with it so if I say that if I give you two numbers 40 and 13 40 and 13 you're holding them in your short-term memory now some of you some of you might be able to move it to your long-term memory now if I say take 40 and subtract 13 you have to do two things you have to hold 40 there and 13 there you have to hold them there in the short-term memory now you have to do something do the subtraction that's your executive function your ability to manipulate that data that's sitting in your short-term memory there of course we get much more complicated forms of executive function but that's the Bas basic idea now another when we see patients in the neurology clinic we'll ask them to spell the word world so easy I can do that wld D and then we'll say spell it backwards now this is much more challenging they have to hold this and bring it out of the long-term memory the world world is in the long-term memory move it into the short-term memory change letters around that's executive function hold it in executive function start D L much more challenging and my patients with even very early forms of Alzheimer's disease will have considerable difficulty spelling the word world backwards because the short-term memory this executive function is quite vulnerable in in early Alzheimer's disease let's look further at this fascinating entity of of short-term memory one way to test it is the digit span and back in the 1950s George Miller a very well-known um psychologist was just was characterizing short-term memory giving people sequences of numbers and seeing how many they could remember I.E a digit span and he's the one that arrived at the observation that that most people seem to do pretty well with seven numbers numbers so here looking at his data we have the number of digits that's that are given to the person these are generally done verbally saying the numbers in a real even Pace 3 8 2 7 not not grouped together and looking at the uh mean mean trials to Criterion how many times did they have to hear the number and repeat it to get a perfect score so when his subjects were given five numbers only one time to get it right six trials six numbers one trial to get it right seven numbers one trial to get it right but eight numbers uh some people quite a few people these are averages here uh took two trials uh we move up to uh nine Tri nine numbers more trials so the more digits more trials are necessary and we seem to be um uh peing at about seven or eight trials once you get beyond that it doesn't help much and people really can't get much very few people can get Beyond Beyond this range these were patients with various types of memory disorders and of course even for uh seven digits for example they had to do many trials before they could get that right so this was a fascinating phenomena the term Magic The Magic 7 came out of a paper that he published in the 1950s he actually had an interaction with bell Laboratories and that is apparently the reason why the seven numbers was picked for our phone number uh because we could remember that now how about the area code yeah the area code they weren't anticipating area codes I think the whole country might have been the same area code at that point um now but when we get to the area code though actually gets us to this phenomena called chunking if we group things together they're easier to remember so by putting that little hyphen there 384 0738 for my shortterm memory it's almost as if I'm only having to handle two things and that's a lot easier than handling seven and that's why that hyphen uh was was put there so that's I'm using a trick it's called chunking I'm putting groups together if you ask me to remember 14 numbers might think that's fairly hopeless um but if you ask me to remember seven two digits number another two digit numbers another way of chunking I could probably handle that so again by grouping things we can force more things into the short-term memory a number of Tricks we can use to to get have better a short-term memory get to some other other tricks um later now let's switch over to long-term memory and probably the one of the best ways to describe the phenomena of long-term memory is just to look at see how we test it in the neurology clinic um one of the classic scales is the wesler memory scale and I'll briefly discuss some of the main parts of that scale I'm not going through all of the parts this is a very large scale this this um testing a person with this takes several hours um basically we start with orientation um we asked the the uh patient or the subject basic orientation questions what's the day the month the time the Year where are you where do you live how did you get here today and they were really assessing language communication because if there's an issue with language communication orientation delirium it's really no longer becomes a valid memory test then we move on to other things logical memory we'll read two short stories we'll wait about 20 minutes and in in the clinic waiting 15 or 20 minutes is our way of getting to long-term memory now as youall short-term memories up to about 30 seconds anything beyond that so we're talking minutes hours days weeks months years be enters into the wide range of long-term memory so we're checking long-term memory we wait about 20 minutes somewhat arbitrary we'll ask them to retell the story and they we'll ask several yes or no questions so I happen to have one of these stories here you can see what this is like uh this will be a short story um and I I'll give you a friendly warning ahead of time remember everything I'm saying about this um you're in our clinic now here's the story two semi semi two semi-trailer trucks lay on their sides after a tornado blew a dozen trucks off the highway in West Springfield one person was killed and 418 others were injured in the Wednesday storm which hit an airport and nearby residential area the governor will ask the president to declare the town a major disaster area now we don't have time in the lecture tonight to we could come back 20 minutes from now um now if I let you sit there silently for 20 minutes you can maybe try to rehearse this try to get some of it to long-term memory or I can apply a distractor and that means I'm going to keep you busy doing something else for 20 minutes that makes it much more challenging so there are many ways many ways of doing this so we'll omit the 20 minutes I get I just threw in a small distractor now I'll start with a question and these are yes no questions and if we had the buttons where people could press yes no I'd love to take a poll of the audience um but just to give give you a feel question number one was the story setting in West Palm Beach okay was the storm on Wednesday yes wow good did the storm hit an airport in a shopping mall no okay was someone killed in the storm yes okay so almost every or perhaps everybody here manag to move these things into their long-term memory now perhaps because I gave you a warning um and we'll get into that how other factors feed into the ability to move things from short uh to long-term memory okay what can we do uh what would we do next the next thing we would do are provide photographs of 24 faces and these are are not famous people people that we haven't seen before we would again have our 20 minute delay or so and then present 48 faces 24 of them being the prior ones and then 24 new faces and we'd ask a simple question have you seen this face before and we'd have a score of how many they got right then we would try verbal paired Associates we'd give eight-word Pairs and then 20 minutes later we'd just give one word and say what went with it and they would be nonsensical pairs so one pair we give is truck and an arrow now of course A A Memory trick would be to picture a truck with an arrow going through the windshield okay now my executive function is what helped me work my memory in that way so I'm getting more out of my memory by imposing my executive function on it family pictures these aren't our own families but just other families there are scenes where they can be interpreted and they're shown and then at sometime later we ask people to recall the information that was in those pictures word lists we give 12 semantically unrelated words wait 20 minutes and then ask to see how many words people can repeat I mean there are and for each age range all of this is age adjusted uh we would have an expectation of how many can repeat and we'll typically give the word list four times so here's a word list ready see how many you can remember chimy lemon bus pants pair train window hat Cellar Apple shoe boat okay now in the real life we'll let you do this three more times we'll go through it four times really give you a good rehearsal this is the intake now so we're giving you a good shot at intake an acquisition but because what we're really testing is retention the the long-term memory now was anybody using any particular tricks during that yes well I first of all I put the lemon down the chimney but then I began to see that was going to work for the whole thing so I began to group things items of clothing fruit and places in the house so that's um two approaches um and that's what I tried to do too one is to create a sequence a a lemon went down the chimney and ended up um on a bus uh where the bus driver was only wearing pants um and but you have to be quick in making the story up um now if this were um written in front of you it'd be easier to make up that story and that's Association technique the other of course is grouping if there are two or three uh fruits or Foods Group them together so that's good you really came up with two of the the principal techniques um if you don't have a technique this this can be very difficult any other techniques yes sketching just visual sketching sketching okay have visual sketching that's another one and we'll get to a famous uh person that was really great at memory that Ed something like that visualization okay uh visual reproduction will show the subject five designs they'll get to see each design for 10 seconds and then we'll come back and have them draw as many of these designs as they can uh spatial span a series of of numbered blocks in a board I'll show you that and finally the digit span you saw examples of doing that in a forward order most people can get seven digits forward and then if we give them dig digits they can do five backwards so it's seven forward and five backwards um is a rule of thumb um so we did the word list um here are this the spatial blocks so what the examiner will do these are real blocks in a real board they'll Touch without saying anything blocks in a certain order 1 7 4 3 they'll wait a few minutes the last a subject to touch the same blocks in the same order that's not too difficult and then they'll surprise them say okay now touch them backwards so a little bit of memory plus some executive function there and all of these things can be scored we did the short story the stro test is it gets a little bit beyond memory this is more executive function this is a a fun test that that I like to show people has three parts we can all do it right now the first thing you'll do and we can do this silently to ourselves but typically this would be done out loud and scored first we'll just look at the color and go down the list and just say the color to yourself green red yellow blue Etc so every going try it just say them to yourself you could probably do more than one per second okay not too difficult part two read the word to yourself red green blue you could probably do well more than one per second go ahead and if this were done out loud we would confirm the person's not colorblind uh we we would confirm that they can read um English well and that's that's sometimes an issue of course now we'll get to the hard part part three now as quickly as you can name the ink color reded blue green that's pretty good but you're only doing about one a second I think you've slowed down considerably I hope that um I hope back here you weren't saying red green blue probably not I think people had considerably more difficulty why is that it's because the the the language part the Reading part is so well entrained in our brains that's dominant here and that's really the the overriding part um saying the color of course we know what red looks like it's not quite so dominant so we're taking that that somewhat automatic relationship and using our executive function to reverse it okay but it's requiring our executive function to do that and in early Alzheimer's and early memory disorders that executive function is lost and and people will take forever just to get through that first row they'll make many mistakes because they've lost their executive function people that lose their executive function very likely that when we took their history which we would have done by this point can't plan can't prepare a meal can't multitask can't get through the day Etc but this is the way we we validate um that history okay so let's organize what we've learned about memory we have long-term and short-term memory but we have several types of long-term memory so we're delving deeper now into long-term memory and these categories are are critical for understanding memory in us and our society um as you will see so long-term memory can be divided up into two main categories declarative and non- declarative declarative that's our conscious memories that we can consciously think about consciously use and we're consciously aware whether we remember them or not and our declarative memory can be divided up into events or facts events are also called episodic memory these are events in our life uh when we graduated from high school when we got married um events that we remember happening uh where we were when something happened where were we when Kennedy was shot or the more modern where were we when 9/11 happened Etc our our personal autobiographical journey through life facts are facts about the world who was the 21st president um what's the capital of Indiana Etc they aren't personal to us facts about about the world we either remember them or we don't um this includes remembering what an object is for um how to work a re a remote um control Etc or a laser pointer um and remembering a a language now of course um these are intertwined one can remember a fact that 911 happened but entirely forget where we were so so this this this episodic and semantic memory are somewhat um intertwined but they do tend to happen in separate parts um of the brain um and they're they're distributed and we'll get more into the brain structures the meteor temporal OE and the dlon we we'll Point those out the non- declarative memory is memory we're not directly conscious of yes and feel free to ask questions by the way the Epic memory sometimes or at least for me TI to we we'll get to that but that's a great question why is episodic memory tied to a smell and when we look at the the neuronal networks um that'll make sense but it's basically coming into the hippocampus which we'll look at we have inputs from the olfactory region inputs from the part of our cortex that um have that memory and they can reinforce each other in an associative way but smell is actually the one of the most powerful stimulants of pulling out memories um procedural memory is one of my favorite Parts motor skills are easiest to think about they also include cognitive skills um so if we think about tennis Roger Federer has amazing procedural skills and he is not thinking about them consciously um in fact if you talk to any Elite athlete um when they're at their Peak um they're not thinking about what they're doing other than higher order strategies but so if Roger Federer ever stopped and thought about the technique of his forehand and thought about what his coach told him about his forehand when he was six years old it would foul up his forehand entirely uh um these are procedural skills are in the strium and cerebellum the parts of the brain that are not really involved um with with with Consciousness the perceptual representation is another form of non- declarative memory this consists of of priming um so we can prime certain parts of the memory and this is tested uh using words and partial words so we can show a person that has complete amnesia for events and facts we can show them the word table and then come back a few minutes later and show the letters t a b and ask them how quickly they can finish that now they have no memory that they were shown the word table but if they've seen table before they'll put it in that LE very quickly if we didn't show them table a few minutes ago they might put l they might spell anything so their memory was primed but they have no consciousness of it it's not a direct conscious memory and that's called priming classical conditioning is pavo's dogs um so when he brought the dogs meat he rang a bell and then a after a while he just rang the bell and the dog salivated just as much as if he brought the meat so something in the dog's brains quote remembered uh that the Bell was associated with meat but it wasn't necessarily conscious thought and that happens on the human level too involving the amydala um and the cerebellum and finally we can have pure reflex paths that aren't conscious habituation for example if we present say an animal with a tone um and initially the first time the animal hears it it'll be concerned uh but if we just have that same tone occurring many times after a while it's not concerned about it at all um it's not necessarily a conscious thing just it's habituated and that's another form of non-conscious memory we'll spend most of the evening on declarative memory uh it it's has really fascinating tiin to society that we'll get to um but this is a more recently really well formulated area non- declarative uh memory so we can take these conceptual parts of memory and begin to move them into the anatomy of the brain and we'll be discussing quite a bit the hippocampus this is the temporal lobe down here and within the temporal lobe toward the middle of the brain we have the hippocampus and that's really where input comes um to form memories so basically we have the Neo cortex or you just say cortex for short this is really well evolved in mammals especially well evolved um in humans uh the hippocampus goes all the way to reptiles dinosaurs and birds it's a much older uh part of the brain anyway we might get visual input coming into our occipital cortex uh we might uh get touch uh sensation coming into our parietal cortex we've got the frontal cortex um that's managing all this uh these things it's a two-way street come into the hippocampus get processed and go back out uh for long-term storage hippocampus really regulating short-term memory but being necessary for long-term memory so we've got encoding things coming in to the hippocampus we have storage things being sent out to various parts of the cortex retrieval the ability of getting these long-term memories out of the cortex back to the hippocampus and back into Consciousness we'll go into more detail in all of those areas but this is just a quick overview yes how do you deal with a memory that touches many parts of this like playing the piano yeah there's tactile there's encoding there's yeah that that's an important question how do we deal with memory that's dealing with many parts of this for example playing the piano it's it's tactile there's music memory there all kinds of memory and it's really an important concept because in the old days people thought the piano lessons were just in one place and people will joke if you slip in theice operating room there go the piano lessons but um as as as your question implies different components are the memory are in different regions so the memory is really distributed this is the idea of distributed networks distributed throughout the brain so if there was brain damage in one place we might lose a component of that skill but not the entire skill and we'll get to that more later but that's a real fundamental question in in memory and forgetting is a broad term but it can imply problems anywhere along the line uh not being able to store something in the first place or having it in storage and not being able to retrieve it and there's plenty of debate as to well if you can't retrieve it did you forget it or not um and gets into more of a philosophical debate so things that we may never remember again might still be in our brains till the day we die but what good does that do US unless we can retrieve it um so the hippocampus will use this term quite a bit um it's it comes from the Latin term uh so this is a real human hippocampus dissected out and of course the Romans and probably even the Greeks had a separate term for it but the Romans thought that this piece of tissue here resembled um what their a seahorse and the Latin term for seahorse is hippocampus and this is a hippocampus that image that we can attain by modern-day Imaging of a living human um and so you can see the three ways of thinking about uh the hippocampus this another way of looking at the brain in terms of different uh memory functions uh we've got the semantic memory that we talked about much of this is in the the temporal lobe the hippocampus is tucked away on the the middle side of the temporal lobe there we talked about procedural memory that ability to hit a forehand in tennis would be using the cerebellum and the the striatum the basil gangle is another the strum's part of the basal gangle the paman part of the basal gangle these two areas are where our motor um procedural memory are located finally our working memory is really the prefrontal cortex is um much of it here the ability to take things in our short-term memory and do something is prefrontal cortex so we'll look at some case histories of Amnesia but before we do that we really need to understand what amnesia means so Amnesia is typically often um associated with some kind of event this could be a traumatic brain injury could be electroshock therapy for depression could be a cardiac arrest any kind of event that's damaging or causing injury to the hippocampus this this Center for mediating formations of memory and for managing long-term memory so this event happens at a certain point along a timeline so when this event happens um the person will have what we call an anterograde Amnesia that might last days weeks in this example it lasts lasted for two months this means for the two months following the head injury they weren't able to lay down new memories moving into the future they couldn't lay down new memories it lasted two months after two months they regained the ability to lay down new memories they had two months of anterograde I.E moving forward Amnesia now they may have also had a retrograde amnesia I.E moving backward from the time of the accident they couldn't remember anything for the prior six months leading Le up to the accident but before that they could remember events so that would be retrograde amnesia so these are two entirely different things so these injuries damage the hippocampus the hippocampus is quite vulnerable and it's located in that medial part of the temporal lobes particularly vulnerable area for many events and so that's why we're often dealing with anterograde or retrograde amnesia we and different patients have different uh mixtures of these things but Two basic kinds of of Amnesia so let's look at our first case study patient hm now hm is probably the most famous patient in all of Neuroscience and perhaps one of the most P famous patients in all all of medicine he unfortunately had a normal life up to I I believe it may have been late teens early 20s when he had a trauma and he ended up having post-traumatic epilepsy epilepsy is not uncommon after head trauma many of the troops coming back from Iraq surviving injuries they otherwise wouldn't survive but having head trauma are now coming back with epilepsy and at that time we didn't have most of the up epilepsy drugs that we have now and so in the 1950s the field of neurosurgery came up with the idea they they thought that the epilepsy originated in the medial temporal lobe that's where the hippocampus is and that by resecting the medial temper lobe they could remove the source of the seizures and the patient wouldn't have seizures and for patients with severe seizures that were disabling they couldn't work couldn't function the seizures could lead to death um it was that was justified at the time that this fairly dramatic neurosurgery uh was justified and so this patient hm had the procedure in the mid uh 1950s and after the procedure his um neurosurgeon Dr Scoville a neurosurgeon in Connecticut uh realized that this patient uh was no longer able to form new memories his life had been entirely disrupted and Milner was a a psychologist who worked with Dr Scoville to characterize the patient she actually studied this patient for some 30 years um after this and hundreds of P papers have been published by her and and many other people on patient hm and so he had a normal short-term memory he could do that Sev digigit span uh pretty easily uh but he had severe anterograde Amnesia he could not he could Mo bring things into a short-term memory but he couldn't move them to the long-term memory he could not acquire stable long-term memory he had about three years worth of retrograde amnesia moving back he couldn't remember anything for the three years prior to the surgery but if one asked him about things prior to the three years had those and so that retrograde amnesia is often graded and by graded we mean the if we go back in time the timeline right preceding the injury is most affected and as we move back early in our years less and less affected and finally we might get five and 10 years earlier and we can recall those events uh normally so that's what we mean by a graded retrograde amnesia that grading is important to know about when we get to the idea of fake Amnesia and we'll get to that so um patient hm taught the world many things Believe It or Not uh prior uh to the publication of this paper in 1957 people just mixed memory in with all the other intellectual functions and people couldn't separate memory from any other intellectual function it was just one big cap complicated Black Box intellectual function we knew it was in the brain we had some idea about which parts of the brain might be important for the broad term of intellectual functions it sounds obvious now but people had no idea if memory was a specific intellectual function that had its own parts of the brain and its own mechanisms the fact that this patient was pretty good at doing a had a lot of other intellectual functions independent of memory really provided the first sense that memory is somehow separate from other intellectual functions the medial temporal lobe uh was seen to be realized uh was realized with this patient to be critical for new memories um but that old memories especially those prior to 3 years for this patient were stored beyond the injured medial temper lob and finally uh one surprise was that this patient still had good visual motor learning which is a non- declarative form of learning the way this learning is often tested it's interesting people learn how to read um when something's held up to a mirror it's backwards the words are backwards and when you first try to read that it's difficult you really stumble through it but if you tried a few times times for a few days you get better and better at it and after a while you can read normally uh through a mirror so that that's a learned skill so when they tested patient hm they thought that he wouldn't be able to learn how to do this because learning requires memory and he had lost all the forms of memory that they had tested so far but when they tested this they were shocked because he acquired this as well in fact better uh than average so that's a procedural memory and it was unaffected um by this injury so it separated out that's where the IDE idea was born that some memories are declarative they really depend on this medial temperal lobe but the non- declarative memories to a large extent reside in other areas so fundamental things that we take for granted today were really derived from 30 years of publications of this one patient um hm yes did Dr Milner have to reintroduce herself to this patient yeah no that's a a really good question did Dr Miller have to reintroduce herself and yes she did um in fact I'll show you a number of other cases I'll show you a video of that um patient hm um every every few moments he was starting from scratch um he didn't know who anybody was around him so anybody around him had a continuously introduce themselves yes what exactly did they do to his brain um what I should have pointed out here these are images of his brain so we're looking at a coronal section so if I cut my brain facing you just like this these are the temporal loes here and here and toward the middle what we call medial the area shown in red those are the parts removed by the neurosurgeon and that red area contains the hippocampus so the hippocampus was removed and parts of the temporal lobe adjacent to the hippocampus were also removed the the operative report said about 8 cm of temporal lobe was removed and then they later on they did MRIs on him they decided it was only 5 cm you wouldn't want 5 cm chunk removed from your temporal lobe um but that's that's basically what the injury was he had no more epileptic seizures a dramatic decrease in epilepsy but he still had some seizures and we still deal with this issue today we still um surgery still performed on patients with seizures who respond to no medication and the and the seizures are disabling but we have much better technology for controlling today what's cut out yes was he aware that he had this condition or did and also yeah was he aware of this condition how did it affect his quality of life was he depressed his he had apparently had remnants of memory and remnants of in some kind of insight he knew something happened um he knew that by all by cooperating with all these doctors like Dr Milner that he he said he was hoping to help other people he had some of that so he had some sense that something happened that rendered him uh less functional but apparently he was not depressed he apparently functioned as well as he could not being able to form new memories I'll show you a video of another another another patient that really address your questions now so do we ever have a case um so the first patient hm had a lot of anterograde Amnesia and a significant retrograde amnesia and in most head injury most injuries there's more anterograde Amnesia than there is retrograde amnesia in other words people have considerable difficulties with most form of injuries of laying down new memories it would be unusual for somebody as a result of an injury to show up and say have normal anterior grade memory no problem laying down new memories I.E pretty much day-to-day normal life but yet I can't remember the past I have a pure retrograde amnesia now this is very common in Hollywood and in movies and we look at that it's very common in Criminal Courts um so it's really important to know can it happen if it can how often well anything in neurology can happen at least rarely here is a rare case of what we call dominant retrograde amnesia where following the injury it was the retrograde amnesia that was much worse than the anterograde this was a 41-year-old gentleman who fell off a horse completely normal prior to falling off the horse by age 45 four years later by then his wife couldn't take it anymore she brought him uh to Physicians and reported that he had lost and she didn't use these terms basically what she was dealing with that he had lost most of his episodic and autobiographical knowledge of his life he just couldn't recall much of anything prior to that injury in his life unless he went to the severe uh remote past of childhood his difficulty forming new memories I.E the anterograde Amnesia was relatively minimal so clearly an atypical pattern and sure enough when they looked at his scans the the hippocampus here's the temporal L the hippocampus is in the medial I.E toward the middle temporal lobe the damaged part is here where I've put the red circle and these are just two different levels his injury led to damage primarily of the lateral not medial lateral temper LOE somewhat of an atypical injury pattern largely sparing the hippocampus and the critical medial part of the temporal loes so that might explain why his anterograde I.E ability to form new memories was relatively spared and it was this unusual pattern of having more difficulty with past Memories the larger parts of the temperal lobe are are critical for dealing out digging out those past memories yes could you define what you mean by damage well in this case with head damage there would be bleeding be a contusion in the brain which is another word for bruise um with head injury the small blood vessels in the brain rupture so we have blood in the brain tissue the neurons are are are moved around by sheer force and sometimes they axons the connections between the neurons actually break off the the uh neurons so the neurons no longer able to communicate those would be the two primary mechanisms of brain injury you with head trauma yes could someone in that situation learn Lear what his past had been and sort of recovered in that way to limited very limited extent um yes but there wouldn't be enough connections to other things it'd be a very artificial way of learning it and they'd still be functionally impaired um was there another question yes um are you going to get in later to how memory is laid down in the neurons similar to yes memory in computer yeah the question is how are memories laid down in neurons can we compare that to the computer we'll get to that so we're gradually working our way down to the cellular or molecular level starting with the big picture here interestingly uh when they were testing his episodic memory they were asking him in semantic memory they asked him a question um where is Mount kilamanjaro and apparently for most people it's it's a difficult question there might be some people here who've climbed it and most of us know it's in Africa but what country it's in and it's largely in Tanzania I guess it's right on the border with Kenya there but it's acccessed apparently largely through Tanzania and it's interesting his wife you know let the Physicians know that he'd actually climbed Mount Kilimanjaro before when he was asked if he had ever been to this mountain he said no never never seen it never been there but when they asked him where it was he knew exactly where it was um so it's a he had a dissociation um having climbed it gave him a procedural memory an unconscious proced memory um but his semantic uh or or episodic memory his episodic memory of actually have inclined it entire entirely wiped out no recollection what so all ever inclined so these injuries teach us um referring to the earlier question that memory is broken down into different components and these components is these components are distributed throughout the brain with an injury we might be limiting one component and not the other now here's a more recent patient that uh addresses some of the questions that a few of you just asked this is the story of Clive weing he's born in 1938 a very well-known musicologist as a conductor a keyboardist in London and was one of the top musicologists and and conductors in in England in the 1980s in 1985 one day he came home with a headache and by the fourth day of this headache he was no longer able to recognize his four-year-old daughter and he went on from there to lose all of his anog grade and retrograde uh memory capability he lost all ability to form new memories moving forward he lost his retrograde memory going back 20 years to 1965 before 1965 he could tell you things after that 20-year Gap so he had herpes and sephtis so the herpes virus fortunately rarely that just about everyone car carries occasionally tracks back through the nerves into the brain it has an affinity for the temporal lobe and it can wipe out the temporal lobe including the hippocampus causes death 50% of the time 50% of people survive many of the survivors end up with damage to the hippocampus and temporal lobe he's one of them I'll show you a video and I want you to note a few things his interactions with his wife this is his second wife he forgot his first wife um and he forgot his the names and a lot of features about his his initial set of kids I don't think he had children with his second wife um he has a diary that's fascinating um and we'll see a distinction here between episodic versus procedural memory this is him sitting on the keyboard um Oliver Sachs wrote an article on him in the New Yorker in September 2007 that's where this picture's from there's been a movie made about him his wife wrote a book about him there been quite quite a bit of this if are any of you familiar with Clive wearing maybe three or four people just wanted to get an idea okay let's watch a this video is four or five minutes here you know how we got here don't remember sitting down no I reckon we've been here about 10 minutes at least I have no knowledge my started working now and what I've seen the whole time I've been seen any all is that and do you feel absolutely normal not absolutely normal no completely and completely confused confused yes you never eaten anything never taste anything never touched anything never smell anything what right you assume your like but you are apparently yes but I'd like to know what the hell's been going [Music] on Clyde was a an outstanding magician he would take his work very very seriously at the same time he loved music so much that he just really threw himself into it totally fly for was a musician of enormous Integrity he was the world's expert on on lassus one of the fful great composers of of the Renaissance and he also worked a great deal in contemporary music and was chorus Master of the lon syona which is Europe's foremost group music flowed out of him whether he's singing or playing or conducting Clive wearing through a cruel Twist of Fortune shows us how fundamental Consciousness and memory are to our lives so how are you feeling this morning I'm conscious with the first time it's the first time I've seen anybody not been conscious before no I've been here before this I haven't seen you before no you haven't no I've not seen anything at all before been completely blind the whole time no taste at all this is the first taste I've had that's the first coffee you've had yes cheers cheers and how are you seeing things normally the first time Colo yes I've never seen anything the whole time I've been ill no black and white nothing do you remember me arriving no I don't remember any arrival I don't remember writing any of that nothing to do with me consciously me unconscious writing what are you doing here well I didn't any pous but I mean that's the first one time I've seen any cars it yes do you remember starting again it all started with a headache Clive came home one day and said he had a very bad headache the headache didn't lift it didn't respond to analgesics by the fourth day he developed quite a high fever and on the evening of the fourth day for a little while he forgot his daughter's name by the fifth day he was very Delirious CL suffered from viral in keytis which has led to the damage of the left and the right temporal loaves plus a good portion of the left frontal Lo and the temporal loes contain a structure called the hippocampus which we know is implicated in memory function and in CLI it has almost certainly been completely destroyed in both sides of his brain it's this that is primarily responsible for his severe memory impairment in addition the damage to his frontal loes also causes a number of additional memory problems which are manifest mostly in terms of him repeating himself a lot and generally showing um emotional highly emotional Behavior C's world now consists of a moment with no past to Anchor it and no future to look ahead to it is a blinkered moment he sees what is right in front of him but as soon as that information hits the brain it fades nothing makes an impression nothing registers everything goes in perfectly well because he has all his faculties his intellect is virtually intact and he perceives his world as you or I do but as soon as he's perceived it and looked away it's gone for him so it's a moment to moment Consciousness as it were a a Time vacuum and everything before that moment is completely void and he so I just want to make one you should be getting one key Point his view of the world is limited to that short-term memory capability remember we said it's 15 30 seconds so take that 30 second window move through life like this that's what he's doing if it happened before 30 seconds gone um so that's that's what his wife's doing a great job describing it feels as if he's Awakening aresh the whole time he always thinks he's been awake for about 2 minutes and that's why he looks at his watch all the time to record it to record the fact ah I've woken up I'm this is an important event therefore I will write it down in my diary so he writes 11:54 a.m. I am now completely awake for the first time and he underlines first time patience begins because he's always playing patience and the whole diary every page is a succession of entries saying almost the same thing of first awakeness and when he goes back and looks at his own entries he doesn't acknowledge that they are genuine he says he knows it's his handwriting but as far as he's concerned he was unconscious when he wrote them so he he quite often he'll he'll score out what he's written before and so his life is an Ever repeating moment of first Awakening the strongest thing in his life I believe and his Diaries bear that out is his love for me and that's absolutely raw and each time I walk into that room it is as if it's the first time he seen me for years good hello you surprised to see me first time I've SE anybody a dra first person se you have not seen me before this morning no I have been here you or six times you walked in that day the First time seen anybody been conscious before no I've been here before this I haven't seen you before no you haven't no I've not seen anything at all before been completely blind the whole time don't remember me arriving at all no no I don't remember that you arriving me at all no no I don't at all look I bet you if I look to see what you've written mention me on that page you've mentioned me on this page my first thought I adore Deborah for eternity that people's entries in the diary are rubbish what does that mean no do did you write that I've no conscious cons sh me now for the first time but it's is it your handwriting yes it is I know nothing about it at all so how do you think it got there I don't I presume the doctors don't know but you must no I haven't who's listen to me please don't say when I say no I mean exactly that I just haven't seen the book at all till now no I'm all I'm said no that's mean that means I haven't seen it I have no knowledge of it at all that's all there's no knowledge of that book all it's entirely new to me just use your intelligence that type of comment which is intelligence but you put who would put that if I don't know no no oh I Haven say use intelligence for mistake I fny we use your intelligence Clive gets extraordinarily angry and who wouldn't cuz here you're not dealing with somebody who is demented so just to make one point this anger part of it might be frustration but the the herpes virus infection also damaged part of his frontal loes and when we see patients with frontal lobe damage they often have lack of emotional control and we call this emotional spillover so there are multiple uh components here remember to be angry well we'll get to that so there's declarative and non- declarative memory his declarative memory is really dependent on that what was damaged but as we'll talk about his non- declarative memory many of those things are intact and that's part of non- declarative memory in fact he can still play the piano extremely well that's non declarative that's procedural that's that procedural non- declarative memory Yes W the 100 times every day Howes you remember you got right um you know I don't know we can only guess maybe he's Reinventing that I don't know the these subjects are very difficult to study because it's might not be 100% of of his of his memory of his anterograde memory he might be forming scant new memories here and there it's just very difficult to detect them yes I'm not mistaken they tried taking the book away and he never asked for it yeah that I didn't know that so um but yeah so maybe it's available he he thinks about it and if it's not he won't occur to him who is oblivious who is gar you are dealing with a perfectly loose highly intelligent man who has been robbed of knowledge of his own life and he feels deeply humiliated to be put in that position very very frustrated that he can't grasp what's wrong with him because even as you're telling him he's forgetting the previous sentence okay so um so any other points that people want to make so yes is there a difference between the functions performed in the right hypothalamus versus the left is there a difference between the right and left um hippocampal functions not big differences I mean in the parial loes vast differences language on the left spatial on the right um Etc we'll see examples of differences in memory differences in memory do exist for the frontal loes I'll show you that not huge differences for the hippocampi though yes I'm Rel this I was going to ask one of the features of accidents in the news these days a great deal are concussions for in footall wonder you never read of any failing memories out of potential Yeah question is what about concussions we hear a lot about those concussion injury has a wide spectrum from mild moderate severe with moderate severe there can be memory loss and and some of the elements of this can occur this is this is the most Clive wearing is the most severe characterized case of memory loss in medicine uh to date so you're looking at extreme but the extremes teach us a lot yes I'm going to go across does the memory reset or is it like a lag that keeps moving he's basically as a moving window as a moving window right so he can only look back about 30 seconds so if you disappeared for 30 seconds walk back in starting all over who are you now he does recognize his wife and that might be part of non- declarative memory I don't know if you noticed in the diary there he says how much he loves his wife that's his main constant that's the one solid thing he has he recognizes his wife and he tells her that he loves her I guess part of non- declarative or procedural memory in that case um you know which is interesting he can sit at the piano and perform flawlessly now people have asked is that if that's pure procedural memory is he like a machine is like an auto you know automated person at the piano but apparently there's all of the full emotion of an elite musician at the piano and the emotion's different every time so again the non declar much of the non- declarative memory is intact again the injur is teaching us that the brain separ separates out these different modes of memory yes are language functions just in a totally different part of the brain or are they part of non declarative or language different part pralow and a lot of non- declarative yes years ago when they did I thought they did them in the front theal Lo which is the same area that I thought he was well so you're asking important question years ago they did lobotomies that's largely separating frontal loes from the rest of the brain um he had some element of frontal lobe damage but not his entire frontal loes his primary damage were the medial temporal loes including the hippocampus so he's not a full frontal um L type of patient the full frontal frontal low patients can't execute can't plan can't really do anything and that's why frontal L bottomy is so disabling yes when you say he can still play piano there are a couple of things um he can still play from memory music that he learned 20 plus years ago yes he can still read music um from the music yeah I'm not sure I thinking still do that yeah I I think he can but I don't want to say I'm not I'm not sure I would wonder if he could read music and then later play the music that he recently read yeah my guess is if he read new music Beyond 30 seconds he wouldn't be able to play it so maybe he can still has the procedural memory of H to read music but I doubt if he could do anything with it 30 seconds later reading but as he's going along he can do yeah each measure at a time certainly you measures well under the 30 seconds yes yes do his disposition change so is one day he happy and the next day sad or is it pretty much much a constant disposition well apparently for the first 5 years or so he was quite depressed he had some insight that something horrible happened and he no longer could do what he wanted to do um and then as beyond that apparently his mood improved to somewhat of a normal mood you know given given the situation so I'll take maybe one or two more questions but we have a lot more to go yes is he still alive I think so patient hm recently died but Clive wearing's still alive as far as I know okay so we're going to go um into Imaging and a lot of other many people have commented on memory Tennessee Williams said life is all memory except for the one present moment that goes by you so quickly you hardly catch it going and this really Clive wearing experience you know reminded me of this quote so we've seen a handful of patients and there have been many more reported in literature no two injuries are the same but these patients with injuries have taught us quite a bit about what part of the brain might do what it's an indirect way of learning and in the modern era of Imaging we have a whole second chapter of learning about where in the brain memory works and I'll show you a few examples of this and then we'll get down to the cellular level of really how does a neuron capture memory so we get back to this idea of distributed networks we've got the hippocampus down here we've got the the region around the hippocampus called the par hippocampus region we're still in the temporal lobe and finally we have these connections that are reciprocal going back and forth between various neocortical areas throughout the cortex and it's these networks throughout the system that are regulating memory sensory comes in comes down to the hpoc campus gets integrated during short-term memory if that occurs successfully can go up to long-term memory if we want to recall it comes from long-term memory back down through here and into our our Consciousness what does all this mean on scanning well we're still discovering the networks that exist in the brain I mean just doing looking at the brain anatomically tells us a lot about structure but we really know very little about the functional networks within the brain and in fact much of the exciting work is being done here at Stanford Mike gracius and benon Menan in in neurology and Psychiatry really collaborated doing Advanced processing of functional MRI uh in a way that hasn't been done anywhere else in the the world to really derive networks in the brain uh neurons that are working together um and networks that have not been previously noticed and for example here's one here are the hippoc pair of hippocampi they're connecting to the singulate gyrus another area thought to be important for memory and that's connecting to the frontal lobe here so this is just one of many networks that they've just recently identified in the past few years that are telling us a lot more about where memory is in the brain we can go beyond just looking at the lesions these messy lesions that patients have um and we can use functional MRI to see what parts of the brain are activated we can put patients on the scanner and have them do tasks and see which parts of the brain are activated during MRI um so this patient was given 40 nouns and asked to uh remember them and during the encoding when they were trying to commit them to long-term memory the encoding we can see the hippocampi lighting up on on both sides then they were given a five to 10 minute distractor task so we would see how much gets committed to long-term memory and then after that we're in the long-term memory phase now they given 32 of the old nouns 16 new ones in a randomized way and they have to identify whether this noun belonged to the first set or not so in other words they're retrieving uh from their long-term memory and during this retrieval we see the hi hippocampus lighting up this side somewhat more this time somewhat more so on the left but it's not clear that this as is necessarily significant these are coronal sections of the brain cut like this if we do A sagittal section cut like this this is where the hippocampus is right here lighting up um o overlaid right here so it's an example of how we're using this technology see what parts of the brain are are lighting up in response to uh forming memories or retrieving them um this time instead of concentrating on the hippocampus we'll move to the the frontal cortex and again we can look at that during encoding during the attempt to remember words we see this is left and right a lot more activity in the left versus right frontal cortex remembering namable objects more on the left but bilaterally somewhat faces interestingly more on the right compared to the left so an example of how we're learning what parts of the brain are important for encoding different things so memory is not just all one big thing words a little bit different than faces um Etc and that's why that finally explains why in the neurology clinic we can have a patient whose memory is entirely intact except they can't remember a face if their life dependent on it it's called prap agnosia the inability to remember a face everything else is intact it's probably because there's part of the brain that's responsible for faces yes um one question so do we all let's say bird have the same potential for memory in in same memory area you do it often talk people I'm terrible with names um is that number one is that sort of a myth more than anything number two is it true that we all would have the same potential for remembering faces as names um or or is that is that a developed time right so the question is do we all have similar capabilities across these different domains of memory or might some of us truly be better things than others I think there is variability and I'll show you a case in a few minutes um that I I think each of those domains can be um Superior or inferior and they can that can happen differentially in different people it's probably because different genes are expressed in different areas and like many other genes we have slight variations in those genes and those genes and code proteins that are important for memory so I think there is some variation across people yes I problem and I guess that would be the names about prouns you use to talk right so you had a friend that couldn't remember nouns um that can happen you can have people that can't remember names of vegetables they're fine with fruits plants trees just cannot remember the name of vegetable could be a noun could be anything these are very segmented categories in different parts of the brain which which is just fascinating Frank what about you know most of yeah yeah so Dr P was asking about developmentally why can't most of us remember you episodic events from when we were two and that we'll get to that when we look at the cellular molecular basis but um just the myelination alone you know the insulation around the nerve fibers is so critical for their uh conducting ability and we have so such little myelination that these networks probably depend on adequate timely conduction and the myelination is just not there the insulation or the myelination really doesn't complete until around age 2122 that's the main theory of why teenager judgment is so poor um because the mation is last in the frontal loes where our judgment lies so okay let's keep moving we'll run out of time here this is just another Imaging study this is an associative memory Paradigm where the subjects are asked to associate two things and to remember that Association and interestingly here the the hotter colors are are parts of the brain that picked up their activity during this Association here we've got the occipital cortex where the vision comes in Carla chat's probably talked about this of course when they're reading something this lights up and then other areas brain parietal frontal areas a temperal lob hippocampus um light up for this associative the cool colors interestingly and this was the surprise here are decreases in activity so really we're looking at a complex situation per certain parts of the brain get more active certain parts s get less active so this comp complicated changing of pattern activation here here's an example of long-term memory retrieval longterm meaning IE a day one day later so the first two days they're they're encoding they're trying to remember pictures or sounds while they're memorizing pictures occipital lobe Vision lighting up while they're trying to remember sounds inferior um Superior temporal areas inferior parial areas lighting up that's where sound goes one day later they try to recall it interestingly a part of the same area is light up for pictures is that we used to memor it and during recall part of the areas that were used to remember the sound light up to recall it this is fascinating this REM this suggests that memory is really is a replay or an activation of the same areas that provided input to the hippocampus during the encoding so during the encoding I.E the remembering uh the hippocampus of organized working with the cortex organized where the cortex would record this so this network activity and the cortex is the recording in the cortex and we remember it a day later we're activating some of that cortical function to remember it it's almost as if we're just playing it back um so we really are uh taking a previous time and playing it back at the present time the hippocampus is in charge of organizing all that if we damage the hippocampus we can't access that playback we can't perform that playback this was an interesting study that involves sleep uh these uh subjects were shown 320 pictures and then they were asked to go ahead and take a nap some napped more than others they didn't know why they were taking a nap but most of them took advantage of it after the nap they were shown new 80 new pictures and then scans were done as they tried to recall which pictures they had seen before or not so they were shown 80 of the old pictures 80 recent and 80 new and they were asked to tell me if if the picture you're looking at was in the first set of 80 so clearly you'd have to remember this first pictures from this first 320 so if we looked at these recognition performance how well they did versus how much slow W sleep duration they had from 0 to 50 minutes the more sleep they had during this nap the better they did on this picture recall so direct evidence supporting the recent hypothesis that during sleep the hippocampus and the cortex are working back and forth to solidify these memory patterns and if we don't get enough sleep that that solidification just doesn't work as well um and during the um uh on on day three fairly early on when they try to remember we can see the hippocampus is quite active but what happens when they waited for 3 months they looked at activity in the prefrontal cortex out in a cortical area and in the hippocampus so during the 90 days after this experiment the activity in the frontal cortex got higher and higher and higher while at the same time the activity in the hippocampus lower and lower and lower it's as if during those three months the memory is gradually migrating from the hippocampus up to the cortex supporting the theory that the psychologists have had for many decades but now in the in the image in area we can see if the psychologist guesses were accurate and so it's as if we're creating hippocampal space for new memory formation remember we said this hippocampus is somewhat Limited in capacity so by moving things to the cortex which apparently as far as we know is unlimited we're making room uh for new memories and the more we sleep the better this happens now what about lie detection and there you know recently people have said well maybe if we can image different networks that light up during memory we can distinguish an accurate memory versus a deceptive report of a memory uh so in this study they showed the subjects uh one face and then came back a second examiner came back and showed them three faces somewhat similar it's not the same guy and the SE the second examiner asked them have you seen any of these faces before and the subjects were allowed to the subjects never know what the purpose of an experiment is generally that's important but they were given permission to lie whenever they felt like it so they might have said never seen any of them but but in their mind they knew they had seen this guy and they knew it was a memory study so they probably were proud of the fact that they remembered it they saw this guy so that was in their mind but they told the examiner haven't seen any of them and so they took scans for each report and then they divided up into the scans they went back later and separated out the lies versus the truths and the difference in scanning is indicated by their color and red so in other words there were different brain responses to functional MRI of whether the person was telling the truth or a lie now they only could find this difference if they average 20 or 30 subjects together it doesn't work that well if it's just one subject and that's why this is by no means an accurate technology to detect lies but that won't stop commercial application so you can pay for this uh just as you can go out and get a private uh traditional lie detector test you can hire somebody um to do a functional MRI and tell you whether you're quote or whether the person is lying or not um it's thought that maybe in some number of years this will be perfected it'll be interesting when that happens and the courts and and the legal worlds are already you know assessing this um technology I want to introduce the idea of Shas schemas and that's these are pre-existing knowledge structures and these were been speculated to exist in humans but no one had any idea if they existed in in animals now explain the animal version we'll come back to the human version so what's a what is a a pre-existing knowledge structure in this experiment here uh rats were um uh introduced to a food flavor it might have been bacon apparently rats like bacon a lot and then these are little sand a little holes in this chamber filled with sand and you could put a little piece of bacon under the sand and that would prevent it from being smelled from a distance apparently and then the rat is introduced into one of three one of four doors to go into this chamber and it'll go around exploring sniffing everything including each of these sand pits and it'll randomly happen on the one with bacon and that's a good event uh for the rat and then you could take the rat out wait let some time pass leave the bacon in the same place and the rat will again go around sniffing pretty much everything now after enough trials five or six trials it'll finally get somewhat more efficient just going directly here or perhaps only going here then here you know less mistakes getting more and more efficient it's learning but it's taking five or six trials to learn the location it's committing the location to memory likely and all of this can be quantitative now that wasn't too surprising the interesting part of the study the surprise that's why I was reported in science just recently is you could once that rat got pretty good at going directly from here to here so learned it um you could take that rat several days later or a long time later give it an entirely new food group watermelon or something uh put it in an entirely different position and it would only take two trials to learn it much more efficient next time around and this speculation was it had by that first round it had it created for its first time it never done this had it never had this experience before a pre-existing Matrix to think about this situation and once it had that pre-existing Matrix its ability to acquire a new long-term memory was much more efficient what's the human equivalent of that well I I barely know how to golf and I want I went golfing with one of my friends who's who's an outstanding golfer and and I suffered through 18 holes my goal is just to survive and see if I could make it occasionally in under 10 shots and typically somebody might make three three shots to get in a hole and so afterwards it was a blur to me I remembered two or three of the holes a few of my shots and I was amazed that the friend of mine remembered every single shot where it was where it went exactly how many he had for all 18 holes he doesn't have a great memory but he has a pre-existing Matrix for for that activity he had something he had a a matrix to put those new memories into I had nowhere to put those new memories other than frustration um for me my Matrix is medicine I recently saw a patient and they brought a 500 page stack of old medical records and you know it took me about 15 minutes to go through it and after doing that I could tell you what medications are on all their medical problems Etc if somebody gave me a 500 page legal brief I could probably spend a week on it and tell you absolutely nothing about it because I don't have any pre-existing Matrix for that so these pre-existing matrices support the rapid acquisition the rapid creation of long-term memory in fact some people think that's so powerful that might be one of the few times that an input could go straight to long-term memory skip the whole short-term memory thing if you have a very robust pre-existing uh Matrix so let's get into the uh popular culture memory is so important that it pervades everything yes devop Dev very posi things yeah is there a body of work or an organized way to develop a pre-exist an existing Matrix matrices not that I'm familiar with but maybe just going to school for Endless years years is is a way of doing that but I think it's a good question there might be more efficient or focused ways of doing that for whatever task you're interested in and there probably an informal ways that that we do that um so it's a popular culture is a very useful vehicle for thinking and learning about memory so it's not just entertainment and you can actually look here at the top 20 grossing by grossing opening weekend uh movies that have a theme of memory and the the born series plays big in that in fact there's Jason Bourne right there um and these generally involve retrograde amnesia without anterograde Amnesia and as we've learned that's extremely atypical but it fits the plot it's a good plot device now occasionally somebody will get it right in momento I think did pretty well uh let's take a look at that uh so this is a gentleman his wife was murdered and during while he was trying to protect her he suffered a severe head injury and now he's trying to Fig and he has a form of Amnesia and he's trying to figure out who killed his wife whoops let me see if I can get this to work here I have this condition the condition it's my memory Amnesia no no no no no it's different from that okay let me stop them right there they got that wrong okay he has a severe anog grade inability to form new memories we all learn that's anterograde Amnesia in Hollywood speak because he can remember his um I'm sorry he's having trouble forming new memories he's but in Holly would speak Amnesia usually means just loss of old memories that's why I saying he doesn't have amnesia it's different than Amnesia but this is amnesia since my injury I can't make new memories everything fades if we talk for too long I'll forget how we started and next time I see you I'm not going to remember this conversation what's the last thing that you do remember my wife that's sweet dying ly I guess I've already told you about my condition oh well only every time I see you you don't remember where you've been or what you've just done no I can't make new memories it's like waking it's like you just woke up when you find this guy what are you going to do I'm going to kill him maybe I can help you find him are you sure you want this my wife deserves Vengeance do not trust her she's going to use you to protect herself I think someone's me trying to get me to kill her own guy you can question everything you can never know anything for sure Teddy don't believe his lies you wander around playing Detective well maybe you should start investigating [Music] yourself who did this to you you did I want my life back why are you asking me I can't remember what I've done I have no short-term memory since my injury I can't make new memories everything Fades if we talk for too long I'll forget how we started and next time I see you I'm not going to remember this conversation I don't even know if I've mened before I've told you this before haven't I so he had traumatic brain injury and he can't make new memories that's pretty good so it's not the typical Hollywood where they just have no trouble making new memories but forget everything in the past so those tattoos they he those are um he's using tattoos as notes to so he doesn't lose his notes so he's taking pictures putting notes on his body that's his memory just like Clive wearing's writing all these notes okay uh what about real versus fake uh memory loss we are running out of time is a hard stop at 840 is that um 820 I meant to say okay so we'll see we might have to prioritize a few things no um once you get past age 40 the um there's a few things so um so how do we know if somebody's faking or not and if you've had the pleasure of seeing patients brought from the jail which I have when I worked up at San Francisco General this this becomes an important issue um so this is Anna Anderson she claimed that she was Anastasia Romanov so Nichol thear Nicholas II and his family were all killed in the early 1900s and there was a rumor that the youngest child daughter Anastasia escaped and might still be alive somewhere so an Anderson in Florida said well that's that's me um the only caveat was that she forgot the entire period of her life that she was with the royal family so I.E selective retrograde amnesia but no anterograde Amnesia she was doing fine in in the current life again highly atypical pattern so people have collected these kinds of of patients and these are the atypical patterns that are thought to go along with fake uh memory loss no antire Amnesia we've talked about that a memory score poorer than chance you can actually fake people out and do this testing so that you can actually be poorer than chance would predict um inconsistency uh face versus events if you really do have this retrograde amnesia generally effects both of these to some extent could be differential but you'll have people that will um forget events typically especially during the the crime they committed uh be but be able to name faces um easily from that same time period uh inability to recall one's name we can wipe out almost everything and most people will retain the name um lack of Imaging evidence for brain IM brain injury with the modern Imaging even mild memory loss we generally can see something um on the MRI scan and there's a frequent premorbid psych history for a more typical F focal retrograde amnesia that's real we we generally brain injury by Imaging there's a graded retrograde amnesia the Amnesia is more severe right up before the injury getting less ofe as we go back in time uh there's generally some kind of some degree of mild anterograde Amnesia accompanying the retrograde amnesia and the the deficits are more consistent that's how we look but you never know 100% still a difficult area so recollection is the only Paradise from which we cannot be turned out so again interesting thought about memory let's get down to the cellular mechanisms the gentleman asked earlier about that let's get down to the neuron I think you're all educated about neurons at this point we've got the cell body we've got the dendrites messages are coming into the dendrites typically going out the axon the axon has these melinated insulation the action potential uh the electrical action potential travels along the axon gets to a synapse so the pre synaptic terminals here there's the synapse the space in between the post synaptic terminal this generally a spine and the spine is sitting on a dendrite I one of those things so this neuron is transmitting to the next neuron and that neuron will transmit to the neuron after that and on these dendrites so here's another image of dendrites if we blow this up we see these spines and these spines are delicate critical processes because the synapse the connection between the neurons the Comm electrical communication between the neurons is fully dependent on that spine it's not good to lose spines but they're very delicate we lose them with Alzheimer's age um Etc now this is sort of a complicated diagram but this is the hippocampus we're looking on the cellular basis we've got memories that have come in through the senses into the cortex they come down to the ental cortex that's the cortex next to the hippocampus they come in through the perforant pathway to the hippocampus and these fibers are synapsing on granal cells here's a granal cell right here here are its dendrites fibers are synapsing on it and the granular cells are sending fibers along through the mossy fiber Pathway to paramal cells these triangle neurons here synapsing on those and then those paramal cells are sending their axons to other paramal cells and finally these paramal cells are sending their axons to the output track output back to the hi um cortex and so we see into the down from the cortex this Loop through the hippocampus through this chain of neurons and then back out up to the cortex so this is this hippocampal cortical coordination we talked about when we create memories we're modifying these connections we're making a given connection stronger or weaker that's the bottom line change that occurs to form a new memory if some of you in here are computer scientists or Engineers I'll I'll welcome your comments on this I'm not as we move on a little further so if we magnify this here we've got this again we've got this neurite this axon coming in here synapsing on this granal cell um and the the discovery there are three ways to modify the synapses the first is by this concept of long-term potentiation or ltp that was discovered in 1973 and that was the idea that if we stimulate with an electrode this incoming axon making it more active and then record at the receiving neural on when we stimulate we get a we look it on oscilloscope and we stimulate this black line is the normal Peak we would get the first time we did it but if we stimulate it a lot 100 pulses a second we get a much higher Peak a much bigger response from that receiving neuron and if we go away for a few hours or days or even weeks and we come back and just stimulate at once we'll still get this extra size extra large Peak so in other words when this connection was stimulated and was used a lot it became more efficient the secondary neuron responded with a bigger response there's an opp Opposite phenomena called long-term depression where the peak actually gets smaller this is the key electrical change that results uh from more firing if this axon is more active we're actually building the strength of that synapse and that's called long-term uh potentiation what do what's the chemical or protein basis of long-term potentiation again we've got this pre synaptic axon coming coming in this is the spine this is the receiving end so the pr synaptic ax on the electrical impulse the action potential travels down here hits the terminal releases the neurotransmitters that are in these vesicles they're released into the synaptic Clift these neurotransmitters glutamates one shown in purple bind to these receptors one's called the nmda receptor when it binds to that receptor that receptor opens a channel calcium comes blasting through when calcium comes in it activates a whole chain of signaling proteins that activate this uh Factor called kreb that causes Gene activation and the gene activation causes this neuron to make more of these receptors so that they can uh handle even more of these transmitters and fire in an even more powerful way so that's the molecular version very briefly of how this firing from the pr synaptic terminal enhances the ability of this post synaptic uh axon neuron uh to fire we can get more advanced and we can look at the associa of ltp and this deals with a question that was asked earlier we can have one neuron here it's dend and we have three different neurons here synapsing on different parts of this dendrite we can have a weak input and the weak input from this neuron might not be enough to activate this neuron so the message would stop right here we could have a strong synapse where if this draw fires that's enough to activate this and we can have another weak synapse here so this wrong synapse might be coming from the amydala the emotional part of the brain this neuron might be coming from part of the brain that's responsible for remembering somebody's name a weak synapse now to remember this person's name ultimately we want this neuron to fire now I'm showing you an example of a handful of neurons here there might be a 100 thousand neurons and synapses involved in remembering a name if we try to remember this name with just this connection this synapse is not strong enough this neuron won't fire we'll fail to remember the name we fail to move it to long-term memory changing these connections is the process of forming long-term memories however if we're trying to learn the name of somebody that gives us an emotional element to us this person triggers some kind of emotion in us the amydala neuron will fire if that's a strong synapse that's capable of activating this neuron and there's a principle that if this neuron's already activated when this weak synapse fires this weak synapse will convert to a strong synapse that's part of associative long-term potential this will remain stable as a long as a strong synapse that's part of this the stable retention of a memory so next time we want to remember that person's name we don't need the emotional input we don't need the Amala neuron firing this synapse here is strong enough to trigger this neuron and so we've succeeded in forming that long-term memory of remembering that person's name so I know that might be a little confusing but that's what's going on at the synapse uh level and that's long-term potentiation so long-term potentiation reshapes the population of which cells are being activated by given input and it's the changing of that Network that's the that's the new memory that's the long-term memory we have long-term memory means permanently changing the pattern of these networks by changing the synaptic strength so we can illustrate that here we're getting visual auditory in tctl input from our from the cerebral cortex it's coming down to the meal temporal cortex and hippocampus the black lines are strong our connections with strong synapses the the blue lines are weak we can put in some new event from the world that causes a change in the pattern of strong synapses it's transient but if we can rehearse it convert it to a stable change in synapsis even though even after the sensory inputs gone uh it stabilized into a stabilized change in the network resulting in the successful conversion of that membrane from short uh to long term now if we take go go back and look at these proteins some of these proteins that are responsible for this what if we design a mouse that has extra receptors so that this synapse will fire even more readily uh for a given input and this was done in the 1990s and the mice ended up being smarter than regular mice uh this was a very prominent uh paper reported in nature and they're called doy mice named after doie Houser MD in the in the 1990s there that show about some young kids a physician and they call these Doogie Houser mice because these mice outperformed any other mice that had ever been tested and they were just expressing extra amounts of this nmda receptor now what does that mean um in human uh terms and since then over 30 proteins have been found that if you express extra amount of that protein all regulate all related to the synapse function the the mice are smarter um and so we get to the whole human um element of of hyperthymesia the ability to remember extreme amounts of information better than other humans can and the first case was described by the Russian psychologist HR luua he has this book published in 1968 where he describes uh aist a man named s uh that could re remember CR amazing amounts but it turned out he was really using a pneumonic trick more so than probably exceptional memory um and if you gave him a list an incredibly long list of items somebody asked about visual technique he had memorized every nook and cranny of Gorky road so well that if you gave him a list of a hundred things in his mind he would Place each object at a certain part along Gorky Road and then the next day if you asked him to recite the 100 objects in his mind he would take a walk walk down Gorky Road say yes fruit banana Etc so very powerful uh visual technique um but more recently we have this uh case published in N 2006 which I'll show a video of uh the woman who can't forget maybe she they call her AJ the subject of most medical studies are usually Anonymous she's a woman with the most amazing memory known to science by understanding how her her brain does this we may help write a new chapter of memory research it's got to be just like any reference I mean you go to the internet you look in an encyclopedia or you ask my sister AJ remembers details of what she did every single day since she was 14 instantly recalling dates of news events in her lifetime she has the ability in a split second to tell you dates times what she was doing what we were doing what was happening in history it's hard to describe for her being able to forget isn't easy she became a Fascination around the world the human calendar doctors journalists wanting to meet her her voice heard on the radio just once if I'm able to cure a disease it's a gift but to remember like the end of end of every relationship or you know anything it's it's it's hard but it has formed who I am because I remember everything until now she's been Anonymous dealing with the interest in her brain her life almost too much for her to Bear she chose not to reveal herself to the world uh for several years you can imagine it yourself uh if if suddenly the whole world knows about you there's a lot of people out there and we are joined Now by AJ who is really Jill Price we're saying it on television A 42-year-old School admin ad ministrator from Los Angeles and as I said it is her first ever live appearance on television and we had a chance to sit down earlier and do a taped interview good morning you again can I throw some more questions sure I love that you don't mind that we keep testing this way all right I know television is one of the things that that you remember the what you saw on television on the days in your life so when when was Jr shot on Dallas when he was shot or when did you find out who was he was shot who shot him uh we were shot on March 21st 1980 and we found out November 21st 1980 what about uh the end of All in the Family well that was in 19 March of March of 1978 what about Nancy carrian attacked something that interested you January 6 1994 Oh Lord You're right the LA r riots they started on April 29th 1992 unibomber arrested Ted kazinski arrested um April 3rd or 4th 1996 April 4th yeah 1996 does this mean you were good in school I was not good in school see this is inconceivable you you didn't have the ability to take a poem and then suddenly recall it my memory is autobiographical so I could tell you my life but to memorize a poem or a monologue was very excruciating for me which raises this old question that we have talked about a lot which is we all think it would be Bliss to be able to remember every day of Our Lives is it more of a comfort or a burden it's both tell me about the burden tell me about what it is to be able to remember every single painful incident in your life it's horrendous Small Things uhuh everything yeah regrets choices and I could literally go back to the exact moment I I was in that fork in the road where I could have made this choice but I made this Choice and then that leads to this which leads to that and I just can't I can't forget that okay so too much memory she didn't she wasn't a great student school and this really points out to different kinds of member as she said autobiographical so a part of her declarative episodic memory she's really good at but these are things that related to her if you ask her it doesn't fall flow necessarily into semantic or or World Knowledge so again just a subset of memory is exceptionally good in her she's the first case in the literature that's been described in medical literature formly like this two or three others claim to have this and they're they're being investigated but this is a relatively new phenomena my own speculation is that just just like all of our genes all of our proteins you know we all have slight variations you know of the 30 or 40 proteins relevant to that synapse might there be rare variations that people have uh that some synapses are incredibly strong in in one out of you know millions of people we'll see as time goes on I'm going to try to wind down here because I know I'm two minutes over um but I want to do show you a second way a synapse can change because to me it's incredibly inspirational um many people think you you you had a lecture on the heart the heart has elegant movement the brain's kind of boring it doesn't move it just sits there um in fact here are some heart cells grown in tissue culture right here uh they beat that's really cool and for all of us who have grown cells in tissue culture including myself we've all we've put the heart cells in there and you can see them beat it's really fascinating you wouldn't expect a brain cell uh to have any movement like this um however these are dendrites and those little things coming off them are spines and if you ask me as a neurologist to to share with you the most powerful Vision I have of the brain in my 30 years of Neurology I'm going to share it with you right now and this is it this is brain tissue it moves why are those spines moving because they're looking to establish new connections with this Imaging technique we're just looking at the receiving end the spines uh the axons coming in that want to meet with them are not being visualized here but they're there okay so if a spine is randomly searching around if it happens to find an incoming axon who's active that connection can stabilize if that incoming axon is not active it's not attractive we won't have a stable relationship formed the brain is incredibly Dynamic it's a very much use it or lose it um organ we can look at this as a closeup look at this thing look at this this is looped here uh we see these connections forming um changing reaching out looking for a connection and if there's an active put coming here this connection will be stabilized so we have 100 billion neurons probably over 100 trillion spines doing this right now if we can stabilize a longterm memory this is what's going on in her mind so my friends and Cardiology say the friend brain is boring because it doesn't move this is this is amazing this is amazing here let St okay thank you [Applause] wow use it or lose it you say all right well I think this has been a fascinating uh display obviously and a wonderful presentation Frank Longo thank you so much for that incredible uh all right I'm sure you're going to get lots of questions uh and you're all going to descend on him uh right now and please do for the rest of you who don't remember anything you've heard tonight go home and come back next week all right thank you again for more please visit us at stanford.edu