Learning and Memory: How it Works and When it Fails

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 think I'm doing better but 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 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 that is learning and memory I remember all too longingly as an undergraduate having a kind of photographic memory and being able to really envision every page in my organic chemistry text that's long gone along with most of the other things that come with aging but here we are at night tonight to reminisce and better understand the process and 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 grew up in Southern California and San Diego where he went and did his undergraduate work as well as his graduate work is MD and PhD at the University of California at San Diego then he moved north bypassing Stanford for reasons that I've never understood to UCSF and he did some great things there and was very active in what is in fact a wonderful neurology program and then took a detour east to the University of North Carolina where he became chair of the department of neurology and did a fantastic job in developing that department and I know it well because I visited him there 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 to be our chair of neurology among his 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 takes a toll on all of us in the human condition which is dementia and his laboratory has been very focused on developing novel small molecules to try and deal with his very challenging issue but tonight we've asked him to speak even more broadly than that and to talk about the whole issue of learning and memory 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 you well thank you Phil for that kind introduction the topic tonight is very broad this is a topic that could be approached in your philosophy course could be approached in a psychology course could be approached in a neurology course could be approached in a psychiatry course could be approached in a criminal law course so the massive topic 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 consists of so that hopefully by the end of the session you'll have a good idea of what it is we'll be able to apply it to a number of fields now there are broad definitions of memory and learning and during the evening I think you'll become an expert on it there is no official definition memory is generally regarded as the ability to record new information to the brain and have it stick basically if you want a technical definition and learning and memory the meanings overlap quite a bit learning is the ability to retain to take that information and respond differently to given situation obviously a key requirement for survival not only amongst us and other mammals but a wide range of animals all the way down to animals with or consisting only of a few cells so that's the the basic range of the definitions we're dealing with and of course memory has been of a great interest for a long time probably from the very beginnings long before a written history was possible people recognize the importance of having a good memory to survive to pass on traditions etc in fact the Greeks by the time we got to the Greeks they had a very sophisticated thoughts and knowledge about memory and where does the word come from this is the Greek goddess Mnemosyne no macine I underlined the MOS remember to really put the emphasis on loss Nemus een and she 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 the Zeus nine nights in a row in fact and had nine children that the nine muses and how that happened we have can't explain that biology yet but this was quite an intellectual family and each each Muse had a talent and these are the nine talents that go along there and it was recognized that having a an exceptional memory would be fundamental would be a foundation for having any of these talents so their mother was really the source of that know the other gods appreciated her skills also so did the Oracles this was the this is the Oracle of truffaut Gnaeus and people went to him to get wisdom and 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 from the spring of Mnemosyne shown right here they found it in Greece and by drinking from that spring one would remember the Oracle had said if one didn't like what the Oracle said one would bring a drink from the spring of leth and forget everything and these were key endeavors because even today we're working on creating something that will do this and and what we'll get to that there are many things that will do this that already exist and of course many brilliant people have had something to say about memory we can look at Cicero sweet as the memory of past troubles and I thought that managed matched somewhat to Dante's quote there is no greater sorrow than to recall happiness in times of misery so you just can't quite get it right and the course Enrico Fermi the famous particle physicist said if I can remember the names of all these particles that'd be a botanist so clearly he had a lot of other cognitive skills that made up for that memory 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 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 motor and movement olfaction gustatory etc and in previous lectures I know that you're now experts on visual and auditory input anyway these inputs come in through our sensory systems to various parts of the cerebral cortex that you've probably seen and they end up and a in a register a sensory register and only for very brief times for example if one looks at something the vision might be there for half a second or a second it's a very fleeting existence an auditory input might last longer for five seconds for example one example that's used to illustrate the auditory sensory register is as follows one might have 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 century 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 short-term 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 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 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 and then if somebody in a few seconds later set a number phone a second phone number it might displace the first one so we're vulnerable to displacement in the short-term memory now we have this seven plus two meaning and interestingly that the short-term memory seems to be able to hold up and 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 we can handle if we go beyond that it becomes difficult now I'll show you some some data regarding that but that's characteristic of short-term memory now once something is in short-term memory we've got it there for a few seconds if it's important to us we'll want to commit it to long-term memory we have to do something that's generally consist of some kind of rehearsal which leads to the 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 fire and we'll look at that in more detail one feature of long-term memory is it's thought to be somewhat limitless no one's really defined a limit on long-term memory at least now we have limits on our short-term memory capacity but long term in practical sense seems to be somewhat unlimited and it can theoretically last for a hundred years or as long as we live with some decay 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 considerably we'll get to that interestingly we bring it back into the short-term memory mechanisms to finally be able to recognize it now we can layer on top of this original model and this is the Central Executive this is even higher order parts of our brain there that are managing and running all this and this is 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 and an ultimately conscious thought and that this central executive is considered to have two interesting loops one is the phenomenological loop ie our inner voice when we're thinking we're easing that inner voice to think about things or when we're thinking we're using a visual sketchpads so-called 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 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 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 sort of loosely speaking about memory although experts will argue that technically working memory is not exactly the same thing as short-term memory working memory can draw from both short-term and long-term 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 they're the 13 there if 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 a new short-term memory there of course we get much more complicated forms of executive function but that's the basic idea now another one we see patients in the neurology clinic will ask them to spell the word world so easy I can do that wrld 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 word world is in the long-term memory move it into the short-term memory change letters around its executive function hold it an executive function start DL much more challenging and by 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 functions quite vulnerable in in early Alzheimer's disease let's look further at this fascinating entity of short-term memory one way to test it is the digit span and back in the 1950s George Miller a very well-known psychologist was just was characterizing short-term memory giving people sequences of numbers and seeing how many they could remember ie a digit spam and he's the one that arrived at the observation that most people seem to do pretty well with seven numbers so here looking at his data we have the number of digits that's that are given to the person these are generally in verbally saying the numbers in a real even-paced 3 8 to 7 not not grouped together and looking at the 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 some people quite a few people these are averages here took two trials we move up to nine try nine numbers more trials so the more digits more trials are necessary and you seem to be peaking 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 this range these were patients with various types of memory disorders and of course even for seven digits for example they we had to do many trials before they could get that right so this was a fascinating phenomena in the the term magic the magic seven 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 because we could remember that now 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 now but when we get to the area code though actually gets us to this phenom called chunking if we group things together they're easier to remember so by putting that little - they're three eight four oh seven three eight for my short-term 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 - 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 but if you asked me to remember 7 - 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 get have better short-term memory we'll get to some other other tricks 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 one of the classic scales is the Wechsler 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 testing a person with this takes several hours basically we start with orientation we ask the the 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 there were really assessing language communication because if there's an issue with language communication orientation delirium where it's really no longer becomes a valid memory test then we move on to other things logical memory will read to short stories will wait about 20 minutes in the clinic waiting 15 or 20 minutes is our way of getting to long-term memory now as you recall short-term memories up to about 30 seconds anything beyond that so we're talking minutes hours days weeks months years enters into the wide range of long-term memory so we're checking long-term memory wait about 20 minutes somewhat arbitrary we'll ask them to retell the story and several yes-or-no questions so I happen to have one of these stories here you can see what this is like this will be a short story and I'll give you a friendly warning ahead of time remember everything I'm saying about this you're in our clinic now here's the story two semi say 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 in a nearby residential area the governor will ask the president to declare the town a major disaster area now we don't have time to lecture tonight we could come back 20 minutes from now now if I let you sit there silently for 20 minutes you can move 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 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 the 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 but just to give you a feel question number one was the story setting in West Palm Beach okay was the storm on Wednesday Wow good did the storm hit an airport in a shopping mall okay with someone killed in the storm okay so almost every or perhaps everybody here managed to move these things into their long-term memory now perhaps because I gave you a warning and we'll get into that how other factors feed into the ability to move things from short to long-term memory okay well what can we do what would we do next the next thing we would do or provide photographs of 24 phases and these 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 phases 24 them being the prior one and then 24 new faces we'd asked a simple question have you seen this face before and we have a score how many they got right then we would try verbal paired associates we give 8 word pairs and then 20 minutes later we just give one word and say what went with it and they would be nonsensical pairs so one pair we give is truck and arrow now of course 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 that can be interpreted and they're shown and that it's some time 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 we would have an expectation of how many can repeat and will typically give the word list four times so here's a word list ready see how many you can remember chiminey lemon bus pants pair train window hat seller Apple shoe boat okay now in the real life will let you do this three more times we'll go through it four times really give you a good rehearsal this is the intake No so we're giving you a good shot at intake an acquisition but because what we're really testing is retention the long-term memory now was anybody using any particular tricks during that yes items of clothing fruit in places in the house so that's two approaches and that's what I tried to do two one is to create a sequence a lemon went down the chimney and ended up on a bus where the bus driver was only wearing pants and but you have to be quick and making this story up now if this were written in front of you would be easier to make up that story and that's association technique the other course is grouping there are two or three fruits or foods grouped them together so that's good you really came up with two of the principle techniques if you don't have a technique this can be very difficult any other techniques yes sketching okay a visual sketching that's another one and we'll get to a famous person that rule is really great at memory that use something like that visualization okay a visual reproduction will show the subject five designs they'll get to see each design for ten seconds and then we'll come back and have them draw as many of these designs as they can spatial span a series of numbered blocks and a board I'll show you that and finally the digit span you saw examples of doing it in the forward order most people can get seven digits forward and then if we give them the digits they can do five backwards so it's seven forward and five backwards as a rule of thumb we did the word list 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 one seven four three they'll wait a few minutes the last subject to touch the same blocks in the same order that's not too difficult and then they'll Surprise them say okay not 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 Stroop test is it gets a little bit beyond memory this is more executive function this is a fun test 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 everything to try it just say them to yourself you could probably do more than one per second okay not too difficult part to read the word to yourself red green blue 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 we would confirm that they can read English well and that's that 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 red that's pretty good but you're only doing about one a second I think you've slowed down considerably I hope that I hope back here you weren't saying red green blue probably not I think people are considerably more difficulty why is that it's because the the language part the reading part is so well entrained in our brains that's dominant here and that's really the overriding part 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 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 validate 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 critical for understanding memory and us in our society 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 when we graduated from high school when we got married events that we remember happening where we were when some where were we when Kennedy was shot or the more modern where were we when 9/11 happened etc our personal autobiographical journey through life facts are facts about the world who was a 21st president what's the capital of Indiana etc they aren't personal to us facts about the world we either remember them or we don't this includes remembering what an object is for how to work a remote control etc or a laser pointer and remembering a language now of course these are intertwined one can remember a fact that 9/11 happened but can tirely forget where we were so this this this episodic and semantic memory are somewhat intertwined but they do tend to happen in separate parts of the brain and they're they're distributed and we'll get more into the brain structures the medial temporal lobe and the diencephalon will 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 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 neural networks 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 have that memory and they could reinforce each other in an associative way but smell is actually the moan of the most powerful stimulants of pulling out memories procedural memory is one of my favorite parts motor skills are easiest to think about they also include cognitive skills so if we think about tennis Roger Federer has amazing procedural skills and he does not thinking about them consciously in fact if you talk to any elite athlete when they're at their peak 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 these are procedural skills or in the striatum and cerebellum the parts of the brain that are not really involved with consciousness the perceptual representation is another form of non-declarative memory this consists of priming so we can prime certain parts of the memory and this is tested using words and partial words so we can show a person that has complete amnesia for events in facts we can show them the word table and then come back a few minutes later and show the letters ta B and ask them how quickly they can finish that now they have no memory that they were showing the word table but if they've seen table before they'll put it in that L lead very quickly if we didn't show them table a few minutes ago they might put le T 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 Pavlov's dogs so when he brought the dogs meat he rang a bell and then F 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 dogs brains quote remembered that the Bell was associated with meat but it wasn't necessarily conscious thought and that happens on the human level too involving the amygdala and the cerebellum and finally we can have pure reflex paths that aren't cautious habituation for example if we present say an animal with a tone and initially the first time the animal here is it'll be concerned but if we just have that same tone occurring many times after a while it's not concerned about it at all it's not necessarily a conscious thing just it's habituated and that's another form of non conscious memory well spend most of the evening on declarative memory it has really fascinating tie-ins to society that we'll get to but this is a more recently really well formulated area non-declarative 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 and toward the middle of the brain we have the hippocampus and that's really where input comes to form memories so basically we have the neocortex or we just say cortex for short this is really well evolved in mammals especially well evolved in humans the hippocampus goes all the way to reptiles dinosaurs and birds it's a much older part of the brain anyway we might get visual input coming into our occipital cortex we might get touch sensation coming into our parietal cortex we've got the frontal cortex that's managing all this these things it's a two-way street come in to the hippocampus get processed and go back out 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 with this just a quick overview yes yeah that's an important question how do we deal with memory that's dealing with many parts of this for example playing the piano with it's it's tactile there's music memory or all kinds of memory and its really an important concept because in the old days people thought that piano lessons were just in one place and people will joke if you slip in the operating room there go the piano lessons but as as your question implies different components are the memory are in different regions so the memory is really distributed this is the idea that 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 we'll get to that more later but that's a real fundamental question in memory and forgetting is a broad term but it can imply problems anywhere along the line 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 and so it 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 so the hippocampus will use this term quite a bit it's it comes from the latin term 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 what a seahorse in the Latin term for seahorses hippocampus and this is a hippocampus that image that we can attain by modern day imaging of a living human and so you can see the three ways of thinking about the hippocampus this is another way of looking at the brain in terms of different memory functions 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 basal ganglia is another the striatum is part of the basal ganglia the putamen is part of the basal ganglia these two areas are where our motor procedural memory are located finally our working memory is really the prefrontal cortex is much of it here the ability to take things in our short-term memory and do something 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 associated with some kind of event this could be a traumatic brain injury it 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 is the Center for mediating formations of memory and for managing long-term memory so this event happens at a certain point along a timeline so in this event happens the person will have what we call an anthro grade amnesia that might last days weeks in this example it 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 are two months of anterograde ie moving forward amnesia now they may have also had a retrograde amnesia ie moving backward from the time of the accident they couldn't remember anything for the prior six months leading 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 hippocampus 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 and we and different patients have different mixtures of these things but two basic kinds 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 famous patients in all of Medicine he unfortunately had a normal life up to 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 thought that the epilepsy originated in the medial temporal lobe that's where the hippocampus is and that by resecting the medial temporal 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 it was that was justified at the time that this fairly dramatic neurosurgery was justified and so this patient HM had the procedure in the mid 1950s and after the procedure his neurosurgeon dr. Scoville a neurosurgeon in Connecticut realized that this patient was no longer able to form new memories because his life had been entirely disrupted and Milner was a psychologist who worked with dr. Scoville to characterize the patient she's actually studied this patient for some 30 years after this and hundreds of papers have been published by her and many other people on patient and so he had a normal short-term memory he could do that seven digits ban pretty easily but he had severe anterograde amnesia he could not he can bring things into a short-term memory but he could 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 could remember anything for the three years prior to the surgery but if one asked him about things prior to the three years he had those and so that retrograde amnesia is often graded 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 ten years earlier and we can recall those events normally so that's what we mean by a graded retrograde amnesia that grading is important to know about we get to the idea of fake amnesia and we'll get to that so patient HM taught the world many things believe it or not prior 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 functions just one big cap complicated black box intellectual function we knew 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 I had its own parts of the brain and its own mechanisms the fact that this patient was pretty good at doing 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 was seen to be realized was realized with his patient to be critical for new memories but that old memories especially those prior to three years for this patient were stored beyond the injured medial temporal lobe and finally one surprise was that this patient still had good visual motor learning which is a non declarative learning the way this learning is often tested it's interesting people learn how to read when something is 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 for a few days you get better and better at it and after a while you can read normally through a mirror so that's a learned skill so when they tested patient HM they thought that he wouldn't be 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 is well fact better than average so that's a procedural memory and it was unaffected by this injury so it separated out that's where the idea was born that some memories are declarative they really depend on this medial temporal 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 HM yes yeah no that's a really good question the doctor Miller have to reintroduce herself and yes she did I mean in fact I'll show you a number of other cases I'll show you a video that patient hm every every few moments he was starting from scratch he didn't know who anybody was around him so anybody around him how to continuously introduce themselves yes to his brain 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 lobes here and here and toward the middle what we call medial this area shown in red those are the parts removed by the neurosurgeon and that red area contains the hippocampus so the hippocampus was removed in parts of the temporal lobe adjacent to the hippocampus were also removed they assert the operative reports at about 8 centimeters of temporal lobe was removed and then and they later on they did MRIs on him they decided it was only 5 centimeters you wouldn't want 5 centimeter chunk removed from your temporal lobe but that's that's basically what the injury was a dramatic decrease in epilepsy but he still had some seizures and we still deal with this issue today we still surgery still performed on patients with seizures who respond to no medication and the seizures are disabling but we have much better technology for controlling today what's cut out yes 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 he knew that by by cooperating with all these doctors like dr. Milner that he he he said he was hoping to help other people he had some sense of that so he had some sense that something happened that rendered him less functional but apparently was not depressed they 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 will really address your questions now so do we ever have a case so the first patient HM had a lot of anterograde amnesia and a significant retrograde amnesia I mean 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 ie 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 look at that it's very common in criminal courts so it's really important to know can it happen if it can how often well anything in Neurology could happen at least rarely here is a rare case of what we call dominant retrograde amnesia we're 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 to physicians and reported that he had lost and she didn't use these terms but basically what she was dealing with it 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 remote past of childhood his difficulty forming new memories ie 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 lobe the hippocampus is in the medial ie toward the middle temporal lobe the damaged part is here where I've put the red circle these are just two different levels his injury led to damage primarily of the lateral not medial lateral temporal lobes somewhat of an atypical injury pattern largely sparing the hippocampus and the critical medial part of the temporal lobes so that might explain why his antio grade ie ability to form new memories was relatively spared and it was this unusual pattern of having more difficulty with past memories there's larger parts of the temporal lobe are critical for dealing out digging out those past memories yes well in this case with head damage there would be bleeding be a contusion in the brain which is another word for bruise with head injury the small blood vessels in the brain rupture so we have blood in the brain tissue the neurons are moved around by sheer force and sometimes their axons the connections between the neurons actually break off the the neurons so the neurons no longer able to communicate those would be the two primary mechanisms of brain injury with head trauma yes learn what this past has been and to limit it very limited extent the yes but there wouldn't be enough connections to other things and be very artificial way of learning and they'd still be functionally impaired with another question yes yes now the question is how our memories laid down in neurons and how can we compare that to the computer we'll get to that so we're gradually working our way down to the cellular and molecular level starting with the big picture here interestingly when they were testing his episodic memory they're asking him in semantic memory they asked him a question where is Mount Kilimanjaro apparently for most people 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 success apparently largely through Tanzania and his interesting his wife you know let the physicians know he'd actually climbed Mount Kilimanjaro before when he was asked if he had ever been to this Mount and he said no never never seen it never been there but when they asked him where it was he knew exactly where it was so it's a he had a dissociation having climbed it gave him a procedural memory and unconscious procedural memory but his semantic or episodic memory his episodic memory of actually having climbed it entire entirely wiped out no recollection whatsoever climbing so these injuries teach us referring to the earlier question the 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 addresses some of the questions that a few of you just asked this is the story of Clive wearing he's born in 1938 a very well-known musicologist it's a conductor a keyboardist London it was one of the top musicologists and conductors 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 anterograde and retrograde 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 encephalitis so the herpes virus fortunately rarely that just about everyone 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 a second wife he forgot his first wife and he forgot his the names a lot of features about his his initial set of kids I don't think he had children with the second wife he has a diary that's fascinating and we will see a distinction here between episodic versus procedural memory this is him sitting in a keyboard all of our sacks wrote an article on him in The New Yorker in September 2007 that's where this pictures from has been a movie made about him his wife wrote a book about him has been quite a bit of this if it 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 oh my god swear you got men sitting down no I don't believe in here about two minutes to move had no knowledge be my eyes I started working now and I've seen the whole thing I can see indigo is that and don't feel absolutely normal absolutely no no thank you and completely confused thank you yes never eaten anything never tasted never touched enough husband what right he was similar like you are yes but I like to know what the hell's been going on why blow and outstanding he would take his work very seriously at the same time so much that teachers really screwed himself into eternity five was a musician of enormous integrity he was the world's expert on unlesss one of the fifth or great composers of the Renaissance and he also what great deal in contemporary music was chorus master for London Sinfonietta which is Europe's foremost room music flowed out of him whether he's singing or playing or conducting five wearing through accruals Vista fortune shows us how fundamental consciousness and memory are to our lives is something in good-looking conscious before I came to the fourth I wish you have anything I don't see anything at all and complete compiled no tests so this is the first test let's go Cleopatra's Cheers absolutely first time yes I've never seen anything the whole time you know her black and white nothing Janome like em any arrivals but I don't have writing in this unconscious my patient I mean that's the first time I've seen any guards yes yes remember starting a game it all started with a headache I'd came home one day as I 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 I've suffered from viral encephalitis which has led to the damage of the left and the right temporal lobes plus a good portion of the left frontal lobe and the temporal lobes contain a structure called the hippocampus which we know is implicated in memory function and in client is almost certainly been completely destroyed in both sides of his brain as this that's primarily responsible for his severe memory impairment in addition he damaged his frontal lobes also causes a number of additional memory problems which are manifest mostly in terms of him repeating himself a lot and generally showing an emotional highly emotional behavior lies 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 it so it's a moment-to-moment consciousness as it were a time vacuum and everything before that moment is completely void and Heaphy so I just want to make what 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 1530 seconds so take that 30-second window and move through life like this that's what he's doing if it happened before 30 seconds gone so that's that's what his wife's doing a great job describing feels as if he's were awakening afresh the whole time he always thinks he's been awake for about two minutes and that's why he looks at his watch all the time to record it to record the fact I broken up I'm this is an important event therefore I will write it down in my diary so he writes 1154 a.m. I am now completely awake for the first time and he underlines births time patience begins because he's always playing patience and the whole diary every page is his accession eventually saying almost the same thing a first awakeness and when he goes back and looked 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 it quite often he'll he'll follow out what he's written before and so his life is a never repeating moment of first awakening the strongest thing in his life I believe his Diaries bear that out is his love for me and that's absolutely wrong and each time I walk into that room it is as if it's the first time he's seen me for years you surprised to see me first time son anybody at all business you're not saving the folder that moving boy how you walk there back there its first time as an individual you know in countries before I been mother for this I've seen here you're having to I'm not seeing anything at all then complete combined alter sit remember me arriving at all no no I don't remember that your arrival yes rifle good I bet use I love to see what you've written in Mitchell II on that page you've mentioned me on this page my first thought I adore Deborah fraternity right people's entries in this area rubbish what does that mean murder did you write that of no conscious of no is it your handwriting learner nothing with so how do you think it got there hundred others in the doctor pen name you must be pleased empty nice ain't no any exactly that haven't seen the book of total man that's me that means I haven't seen it I have no knowledge of it at all that's all there's no no that wasn't are new to me judges your dentist and that's a common ginger you put I don't know but no no no it oh and say you've enjoyed your fencing I printed it letter fighting we use your intelligence client gets extraordinarily angry and who wouldn't because here you're not dealing with somebody who's demented 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 lobes and when we see patients with frontal lobe damage they often have a lack of emotional control and what we call this emotional spillover so there are multiple components here 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 that 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 you know I don't know we can only guess maybe he's reinventing now I don't know these subjects are very difficult to study because it might not be a hundred percent of his of his memory of his anterograde memory he might be forming new memories here and there it's just very difficult to detect them yes yeah I didn't know that so but yeah so maybe it's available he thinks about it and if it's not you won't occur to him he's a bilious whose dog are you are dealing with a perfectly lucid 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 grouse what's wrong with him cuz even as you're telling him he's forgetting the previous sentence okay so so any other points of people how to make so yes as our do between the right and left hippocampal functions not big differences I mean in the parietal lobes vast differences language on the left spatial on the right etc we'll see examples of differences in memory differences in memory do exist for the frontal lobes I'll show you that not huge differences for the hippocampal yes question is what about concussions we hear a lot about those a concussion injury has a wide spectrum from mild moderate severe moderate severe there can be memory loss and some of the elements of this can occur this is this is the most live wearing is the most severe characterized case of memory loss in medicine today see if you look at it extreme but the extremes teach us a lot yes I'm gonna go across this memory reset or is it like a lag keeps moving he's basically 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 life and that might be part of non-declarative memory I don't know if you notice 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 you know which is interesting he considered 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 autumn you know automated person at the piano but apparently there's all the full emotion of an elite musician at the piano and the emotions different every time so again the non declare much of the non-declarative memory is intact again the injury's teaching us that the brain separates separates out these different modes of memory yes language different part pride allo and a lot of non-declarative yes well he so you're asking the important questions ago they did lobotomies that's largely separated frontal lobes from the rest of the brain he had some element a frontal lobe damage but not his entire frontal lobes his primary damage were the medial temporal lobes including the hippocampus so he's not a full frontal lobe type of patient the full frontal lobe patients can't execute can't plan can't really do anything and that's why frontal lobotomy is so disabling yes yes yeah I'm not sure yeah yeah I think you can but I don't want to say I'm not I'm not sure 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 how to read music but I doubt if he could do anything with the 30 seconds later but as he's going along he can do it yeah each measure at a time certainly on measures well under 30 seconds yes yes well apparently for the first five years or so he was quite depressed he had some insight that something horrible happened and he won't no longer could do what he wanted to do and then as beyond that apparently his mood improved 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 I think so patient HM recently died but Clive wearing still alive as far as I know okay so we're going to go 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 report 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 hot as 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 pair hippocampal 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 hippocampus 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 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 gracious and vanillin men on in neurology and psychiatry really collaborated doing advanced processing a functional MRI in a way that hasn't been done anywhere else in the world to really derive networks in the brain neurons that are working together and networks that have not been previously noticed and for example here's one here are the hippocampus Kampai they're connecting to the cingulate gyrus and other 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 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 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 so this patient was given 40 nouns and asked to remember them and during the encoding when they were trying to commit them to long-term memory the encoding we can see the hippocampal lighting up on both sides then they were given a five to ten 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 but given thirty two of the old nouns sixteen new ones in a randomized way and they have to identify whether this down belong to the first set or not so in other words they're retrieving from their long-term memory and during this retrieval we see the hippocampus lighting up this side somewhat more this time somewhat more so on the left but it's not clear that this asymmetry 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 overlaid right here so it's an example of how we're using this technology to see what parts of the brain are lighting up in response to forming memories or retrieving them this time instead of concentrating on the hippocampus we'll move to 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 nameable 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 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 depended on it it's called prosopagnosia the inability to remember a face everything else is intact probably because there's part of the brain it's responsible for faces yes I'm James is that number one is that sort of if you truly all that have the same potential as names for all 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 isn't variability and I'll show you a case in a few minutes that I think each of those domains can be superior 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 encode proteins that are important for memory so I think there is some variation across people yes the names right right so you had a friend that could remember nouns 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 it could be anything these are very segmented categories in different parts of the brain which is just fascinating yeah yeah so dr. Pease was asked about developmentally why can't most of us remember episodic events from when we were two and that we'll get to that when we look at the cellular molecular basis but just the myelination alone you know the insulation around the nerve fibers is so critical for their 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 21 22 that's the main theory of why teenager judgment is so poor because the myelination is last in the frontal lobes where our judgment lies 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 interesting layer here the the hotter colors 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 Karlis shots probably talked about this of course when they're reading something this lights up and then other areas of brain parietal frontal areas a temporal lobe hippocampus a light up for this associate of the cool colors interestingly and this was the surprise here our decreases in activity so really we're looking at a complex situation certain parts of the brain get more active certain parts get less active so it's complex complicated changing of pattern activation here here's an example of long-term memory retrieval long term meaning ie a day one day later so the first two days they're their 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 superior temporal areas inferior parietal areas lighting up that's where sound goes one day later they try to recall it interestingly a part of the same areas light up for pictures is that we used to memmer it and during recall part of the areas that we used to remember the sound light up to recall it this is fascinating this remember this suggests that memory is really a replay or an activation of the same areas that provided input to the hippocampus during the encoding so during the encoding ie the remembering the hippocampus kind of organized working with the cortex organized where the cortex would record this so this network activity and the cortex is the recording and 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 so we really are 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 play back we can't perform that play back this was an interesting study that involves sleep these 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 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 a recognition performance how well they did versus how much slowed away sleep duration they have 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 and during the on day 3 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 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 of 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 imaging area we can see if they psychologist guesses were accurate and it's so it's as if we're creating hippocampal space for new memory formation remember we said this hippocampus is somewhat limited capacity so by moving things to the cortex which apparently as far as we know is unlimited we're making room for new memories and the more we sleep the better this happens now what about lie detection and the your 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 so in this study they show the subjects 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 seventh the second examiner asked them have you seen any of these faces before and the subjects were allowed two 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 was a memory study so they probably were proud of the fact that they remembered it would 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 it 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 in red so in other words there were different brain responses to functional MRI of whether the person was telling the truth or a now they only could find this differences they average 20 or 30 subjects together it doesn't work that well for just one subject and that's why this is by no means an accurate technology to detect attic lies but that won't stop commercial applications so you can pay for this just as you can go out and get a private a traditional lie detector test you can hire somebody to do a functional MRI and tell you whether your quote or whether the person is lying or not 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 the legal worlds already you know assessing this technology now I want to introduce the idea of Sheba schemas and that 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 animals now explain the animal version we'll come back to the human version so what's it what is a pre-existing knowledge structure in this experiment here rats were 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 will randomly happen on the one with bacon and that's a good event for the rep 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 quantitated now that wasn't too surprising the interesting part of the study in the surprise that's why I was reported in science just recently is you could once that rat got pretty good going directly from here to here so learned it you could take that rat several days later or a long time later give it an entirely new food group watermelon or something put it in an entirely different position and it would only take two trials to learn it much more efficient next time around and the speculation was it had by that first round it had it created for its first time had never done this had 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 while I barely know how to golf and I'm one I went golfing with one of my friends who's an outstanding golfer and I suffered through 18 holes my goal is just to survive and see if I could make it occasionally in under 10 shots 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 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 had for all 18 holes he doesn't have a great memory but he has a pre-existing matrix for that activity he had something he had a matrix to put those new memories into I had nowhere to put those new memories other than frustration 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 matrix so let's get into the popular culture memory is so important that it pervades everything yes yes they're a body of work or an organized way to develop a pre-existing existing matrix matrices not that I'm familiar with but maybe just going to school for endless years is a way of doing that but I think it's a good question there might be more efficient or focus ways of doing that for whatever task you're interested in and they're probably informal ways that we do that so with its 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 movies that have a theme of memory and the Bourne series plays big in that in fact there's Jason Bourne right there 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 memento I think did pretty well let's take a look at that 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 figure of amnesia and he's trying to figure out who killed his wife whoops see if I get this to work I have this condition the condition is my memory it need you okay let me stop them right there they got that wrong okay he has a severe anterograde inability to form new memories we all learn that's anterograde amnesia in hollywood speak because he can remember his I'm sorry he's having trouble forming new memories he's but in Hollywood speak amnesia usually meets just loss of old memories that's why 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 next time I see you I'm not gonna remember this conversation what's the last thing that you do remember my wife that's sweet ready I guess I've already told you about my condition oh well Oni 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 talking just woke up when you find this guy what are you gonna do maybe I can help you find him I'm sure you want this my wife deserves vengeance do not trust her she's gonna use you to protect herself this one'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 yourself who did this you do I want why are you asking me I can't remember what 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 figure out how we started the next time I see you I'm not going to miss conversation I don't even know if I've mentioned before I've told you this before haven't I so he had a 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 those are he's using tattoos as notes too so he doesn't lose his notes she was taking pictures putting notes on his body that's his memory just like Clive Waring's writing all these notes okay what about real versus fake memory loss we are running out of time is the heart stopped at 8:40 is that a 20 I meant to say okay so we'll see we might have to prioritize a few things no once you get past age 40 the there's a few things so 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 becomes an important issue so this is Anna Anderson she claimed that she was Anastasia Romanov so nickel the tsar 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 me the only caveat was that she forgot the entire period of her life that she was with the royal family so ie selective retrograde amnesia but no anterograde amnesia she was doing find in the current life again highly atypical pattern so people have collected these kinds of patients and these are the a typical patterns that are thought to go along with fake memory loss no anterograde 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 poor than chance would predict inconsistency face versus events if you really do have this retrograde amnesia generally affects both of these to some extent could be differential but you'll have people that will forget events typically especially during the crime they committed be but be able to name faces easily from that same time period inability to recall one's name we can wipe out almost everything and most people will retain the name lack of imaging evidence for brain and brain injury with the modern imaging even mild memory loss we generally can see something on the MRI scan there's a frequent premorbid psych history for more typical full focal retrograde amnesia that's real we generally see brain injury by imaging there's a graded retrograde amnesia the amnesia is more severe right up before the injury getting less severe as we go back in time there's generally some kind of some degree of mild anterograde amnesia accompanied in the retrograde amnesia and the deficits are more consistent that's how we look but you never know a hundred percent 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 Hussey's myelinated insulation the action potential the electrical action potential travels along the axon gets to a synapse so the presynaptic terminals here there's the synapse the space in between the post synaptic terminal that's generally a spine and the spine is sitting on a dendrite ie one of those things so this neurons transmitting to the next neuron that neuron will transmit to the 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 communit lectric will communication between the neurons is fully dependent on that spine so not good to loose spines but they're very delicate we lose them with Alzheimer's age 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 enteral cortex that's the cortex next to the hippocampus they come in through the perforin pathway to the hippocampus and these fibers are synapsing on granule cells here's a granule cell right here here it's dendrites fibers or synapsing on it and the granule cells are sending fibers along through the mossy fiber pathway to pyramidal cells these triangle neurons here synapsing on those and then those pyramidal cells are sending their axons to other pyramidal cells and finally these pyramidal cells are sending their axons to the output tract output back to the 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 were 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 some of you in here are computer scientists or engineers 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 new right this axon coming in here synapsing on this granule cell and the discovery there are three ways to modify these synapses the first is by this concept of long-term potentiation or LTP that was discovered in 1973 now is the idea that if we stimulate with an electrode this incoming acts making it more active and then record at the receiving neuron when we stimulate we get a week looking at 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 it once we'll still get this exercise extra-large peak so in other words when this connection was stimulated and was used a lot it became more efficient a secondary neuron responded with a bigger response there's an opposite phenomenon called long term depression where the peak actually gets smaller this is the key electrical change that results for more firing if this axon is more active we're actually building the strength that synapse and that's called long-term potentiation what's the chemical a protein basis of long-term potentiation we get we've got this presynaptic axon coming in this is the spine this is the receiving end so the presynaptic axon 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 cleft 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 factor called CREB that causes gene activation and the gene activation causes neuron to make more of these receptors so that they can handle even more of these transmitters and fire in an even more powerful way that's the molecular version very briefly of how this firing from the presynaptic terminal enhances the ability for this postsynaptic axon neuron to fire we can get more advanced and we can look at the associate of LTP and this deals with the question that was asked earlier we can have one neuron here its dendrite and we have three different nerve Ron's here synapsing on different parts of this den dry we can have a weak input and the weak input from this drawn might not be enough to activate this neuron so the message would stop right here we could have a strong synapse where if this neuron fires that's enough to activate this and we can have another weak synapse here so this strong synapse might be coming from the amygdala 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 I'm showing you example of a handful of neurons here there might be a hundred thousand neurons and synapses involved 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 will fail to remember the name will 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 amygdala neuron will fire if that's a strong synapse that's capable of activating this neuron and there's a principle that if this neurons 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 is along as a strong synapse that's part of this 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 amygdala neuron firing this synapse here are strong enough to trigger this neuron and so we have 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 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 new that's the new memory that's the long-term memory we have long term memory it means permanently changing the pattern of these networks by changing the synaptic strength so we can illustrate that here we're getting visual auditory and tactile input from arc from the cerebral cortex it's coming down to the knees role temporal cortex and hippocampus the black lines are strong send 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 synapses even though even after the sensory inputs gone it's stabilized into a stabilized change in the network resulting in the successful conversion of that membrane from short to long term now if we take 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 for a given input and this was done in the 1990s and the mice ended up being smarter than regular mice this was a very prominent paper reported in nature and they're called Doogie mice named after Doogie Howser MD in the 1990s does that show about some young kids a physician and they call these Doogie Howser mice because he's myself performed any other mice that had ever been tested and they were just expressing extra amounts of this NMDA receptor now what does that mean in human terms and since then over 30 proteins have been found that if you express extra amount of that protein all regulate all related to this synapse function the mice are smarter and so we get to the whole human element 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 Lauria he has this book published in 1968 where he describes a numinous a man named s that could read remember amazing amounts but it turned out he was really using a mnemonic trick more so than probably exceptional memory 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 he 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 hundred objects in his mind he would take a walk down Gorky road say yes fruit banana etc so very powerful visual technique but more recently we have this case published in 9 2006 which I'll show a video of the woman who can't forget maybe she Michael 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 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're looking at encyclopedia 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 date times what she was doing what we were doing what was happening in history hard to describe for her being able to forget is it 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 every end of every relationship or you know anything it's it's it's hard but it is 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 her to bear chose not to reveal herself to the world for several years you can imagine it yourself 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 administrator 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 into a taped interview good morning thank you again can I throw some more questions 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 lives so when when was jr. shot on Dallas when he was shot or when did he find out who was he was shot who shot him oh he was shot on March 21st 1980 and we found out November 21st 1980 what about the end of all in the family well that was a 19 March a march of 1978 what about Nancy Kerrigan attacked something that interested you January 6 1980 Oh Lord you're right the LA riots they started on April 29 1992 Unabomber arrested Ted Kaczynski arrested and April 3rd or 4th 1996 April 4th 1996 does this mean you were good in school I wasn't happening 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 as Beth tell me about the burden tell me about what it is to be able to remember every single painful incident in her life it's horrendous small things everything yeah regrets choices but I could literally go back to the exact moment 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 two different kinds of members 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 to semantic 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 the medical literature formally like this two or three others claimed to have this and they're being investigated but this is a relatively new phenomenon my own speculation is it 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 that some synapses are incredibly strong in one out of you know millions of people will see as time goes on I'm going to try to wind down here because I know I have two minutes over but I wanted to show you a second way of synapse can change because to me it's incredibly inspirational many people think you had a lecture on the heart the heart has elegant movement the brain is kind of boring it doesn't move it just sits there in fact here are some heart cells grown in tissue culture right here they'd be that's really cool and for all of us who have grown cells and tissue culture including myself we've all we've put the heart cells in there and you can see them be it's really fascinating you wouldn't expect a brain cell to have any movement like this 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 finds moving because they're looking to establish new connections with this imaging technique we're just looking at the receiving and the spines 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 whose active that connection can stabilize if that incoming axon is not active it's not attractive we won't have a stable relationship form the brain is incredibly dynamic it's a very much use it or lose it organ we can look at this as a close-up look at this thing look at this this is looped here we see these connections forming changing reaching out looking for a connection and if there's an active input coming here this connection will be stabilized so we have a hundred billion neurons probably over a hundred trillion spines doing this right now if we can stabilize a long term memory this is what's going on in our mind so my friends in cardiology say the friend brain is boring because it doesn't move this is this is amazing this is amazing let's talk fair thank you Wow use it or lose it you say alright well I think this has been a fascinating display obviously and a wonderful presentation Frank Longo thank you so much for that incredible all right I'm sure you're going to get lots of questions and you're all going to descend on him 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

Channel: Stanford

Views: 244,817

Rating: 4.866735 out of 5

Keywords: science, biology, medicine, physician, doctor, biochemistry, anatomy, technology, learn, memory, short term, sensory input, cerebral cortex, attention, displacement, importance, rehearsal, consolidation, color, number, stroop test, executive function, mul

Id: a_HfSnQqeyY

Length: 113min 48sec (6828 seconds)

Published: Tue Jun 08 2010