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Presented by
Pennsylvania Neurological Associates, LTD.
Charles S. Yanofsky, M.D. |
Albert. W. Heck, M.D. |
Jon L. Vickery, M.D. |
Francis J. Janton, III, M.D. |
| Liana Laza, M.D. | |
Janice Morrow, Practice Administrator
108 Lowther Street
Lemoyne, PA 17043
(717) 774-2202
Memory and Alzheimer’s disease
By Charles S. Yanofsky, M.D.
Hippocampus and Memory Circuits
If from time to time you think you have problems with your memory join the club. That is true for most people. If you’re worried or interested for someone else, read on! Your ability to recall and learn things certainly varies over time, even apart from the inevitable changes that occur in aging, that is, after the age of 40 or 50 or so. The question is whether a problem is pathological and the biggest fear, whether a certain problem means that you or a loved one has Alzheimer’s or some other dread degenerative disease. I wanted originally to give a brief discussion about memory to place Alzheimer’s in some context, also to show one logical approach to the evaluation of memory disturbances. Obviously Alzheimer’s disease is not synonymous with a memory disturbance. Alzheimer’s doesn’t just affect memory of course, but a memory disturbance is usually the first sign of the disease. There are lots more problems with memory apart from Alzheimer’s disease and I wanted to mention a few of those, also to place memory into context with higher mental processes. My intent originally was to mention some memory problems as a prelude to a discussion of Alzheimer disease. But I guess memory fascinates me and I got involved with a lot of other things. My actual discussion of Alzheimer’s will be posted later on the website. Here I will discuss memory function. Above you’ll find an outline in case you are interested in one particular topic and wish to go directly to that.
Memory is more than writing of information in the brain and its retrieval. The brain is not an inanimate recording and retrieval device. All data is placed in context and related to other information as it is stored and affects emotions and behavior even when not specifically recalled. In laying down memories we feel time passing and accumulate experience that is our life.
Have you ever wondered about what single characteristic distinguishes thinking living creatures from inanimate objects? History separates humans from machines. Machines are manufactured whole but humans develop, memory of their past shapes the present, determining behavior and response to immediate contingencies. Thus memory is more than the simple record. Our memory is a running narrative of experience, the palpable passage of time. Our personal history and the recollection of that history is what makes us unique individuals. Experience organizes by rules built in to the anatomy of the brain. Memory is us. (That is why we need not worry about human genetic clones producing identical humans. What really makes you the unique person you are is your own memory store, experience.)
The Greek poet Hesiod some 2600 years ago wrote that Mnemosyne, memory, was the mother of the all the Muses, demi-goddess symbols of artistic and intellectual creation. Zeus was their father. Surprisingly so much of scientific and artistic creativity derives from the mere process of reaching down into the recesses of memory and making new relationships, drawing disparate ideas and images together. We have more tools at our disposal for recording data. But only the brain can draw this information together. As we grow more dependent on external recording devices, we will loose ability to form relations, to think and create ideas.
We live in the golden age of memory. The computer, our faithful data manager, stores, organizes and regurgitates of billions of bits of information on magnetic and optical disks. Every single particle of data, whether conceived as a bit or engram, can be found at its own spatial coordinate, the reading device lighting at a specific location much as a record needle finds certain performance on a vinyl record. Given imperfections in the brain’s memory apparatus, humans have always needed devices to recall facts and events. The advance of civilization is traced to writing from cuneiform in clay to hieroglyphs and pictographs, finally with alphabetic script.
As far as computers are concerned all data is created equal. The computer makes no value judgments. A piece of information can always be found at a specific address. It may be totally expunged with more or less effort. Actually it isn’t as easy to get rid of information in computers as most of us think. Programs and algorithms have been devised to gather data supposedly long erased from hard drives, but obviously a machine cares not a lot about any information it stores. As long as the machine is working well and we know how to program it, information can be immediately retrieved and used. Moreover the recording device will regurgitate data with perfect fidelity every time. Alas, none of this pertains to the brain where it’s so much more difficult to write and read and nearly impossible to completely expunge information.
At first glance memory appears to be the simplest of all mental processes, far simpler than other mental tasks, recognizing faces, reading and writing sentences, creating mathematical equations, building roads and bridges or devising theories. This explains why machines are so good at recording information but don’t do so well with other mental tasks. But what appears to be the simplest of all mental processing, turns out to be more complex
Nine times out of ten Alzheimer’s disease starts as a problem with “recent memory” that is easily noticed. The subject can’t recall events of that very day, about his breakfast, where he went, what he was supposed to do or buy, what he went into that room for. Memory for distant or past events is not found wanting. In fact he (or she) has a tendency to dwell on the past, which is easier to remember. Old memories, contrary to most person’s expectations, are more resilient than newer ones, something known as Ribot’s law: the oldest memories are the most resistant.
Hippocampus and Memory Circuits:
To register recent events you use certain deep brain structures and an area of the cortex called the hippocampus, so-named for its seahorse shape. This swirl of neurons connects to the mammillary bodies, breast like excrescences, via the fornix. A whole system of circuits is involved when data in the form of words or numbers, initially implants in the brain. Some deeper structures of the brain that handle emotion, what is called the Papez circuit or limbic system, are so intimately tied to initial memory registration that they are inseparable from considerations of recent memory. Looking at the brain’s anatomy reminds us that memory is tied to emotion.
Figure 1: A rendering of the hippocampus or seahorse.
(Figure from NEUROPSYCHIATRY Barry S. Fogel, Randolph B. Schiffer & Stephen M. Rao (eds.) Williams and Wilkins, Baltimore ©1986, p.374 and www.fishbase.org)
Everyone knows that if you don’t care about something you won’t remember it. We remember most things we want to. If someone introduces you to a person and you don’t care about it or are thinking about something else, the name will escape you the next time you meet. But if it’s the name’s important you’ll likely remember it. I’ve observed some folks have an uncanny ability to remember names, whereas I’m not really that good at it. I suspect these persons often businesspersons whose livelihood depends on their recognizing other people by name, have learnt to focus on it.
It’s easier to remember something if you’ve put some elbow grease into getting the information. I tell my kids who are in school, if you want to learn you have to sweat. If you ask me, I will be able to give you definitions off the top of my head, but it won’t sink in unless you bother to crack the books and dig up the stuff yourself. Not interested in sports? You probably won’t remember who won the last game though you might have heard the score a few times.
Emotion is tied with memory. In other words each and every event in our lives if recorded, is has some emotional value. We know that some events and objects in memory are associated with high emotion. There may be traumas or terrible events that a person has witnessed or been part of, childhood sexual abuse, arguments between parents, the slaughter of war, to name just a few instances. Some stimuli or even parts of stimuli cannot be recalled without kindling an emotional response. This is the situation in post-traumatic stress syndrome as seen in some of our Vietnam veterans. The major characteristic of PTSD is the so-called flashback. An event remembered even in a dream is attached to high emotion, a sympathetic nervous discharge, palpitations, sweats, and dread. Once made, the nexus between emotion and specific memories is hard to tear asunder. The specific memory itself may be difficult to recall, but the emotional association is thrown up uncontrollably and you can’t always figure what is triggering it. Additionally the memory affects behavior in untold ways such as through avoidance behavior. The abused child may well avoid and mistrust adults and be quite unable to form relationships even though there is no specific memory of childhood events while fearing situations though unable to recall any actual events of childhood. Anxiety connected with these events potently blocks recall. Anxiety is the major obstacle to recall.
Absent high emotion, connections in the brain are hard to make. They are aided by motivation and rehearsal in which impulses reverberate around the brain enough times for a connection to be made. This concept early engaged some of the greatest minds in neural science. Donald Hebb’s conception of the reverberating circuit described in his 1949 book The Organization of Behavior had to be one of the first examples of a neural network. In this work he maintained, "When an axon of cell A is near enough to excite B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased." The basic idea was that repetition aided in formation of memories by strengthening connections between neurons. The more a connection was used within the brain, the better would develop certain connections between nerve cells representing that memory. Connections between neurons, the synapse, was implicated in the formation of memories.
Each neuron is connected sometimes to thousands of others. It is thought that memories are laid down primarily by strengthening these connections usually affecting synapses. There is some scientific evidence that bolsters this model although it is likely that other mechanisms inside individual neuron play a role as well. The individual neuron may become increasingly or decreasingly irritable, that is, more or less likely to fire as a memory is laid down. But mostly and this can be seen under the electron microscope, connections between neurons form as memories are laid down. As far as individual neurons themselves are concerned I like the analogy between neurons and individual bees or ants in a hive. Each cell is an independent agent in and of itself yet functions among a larger body of cells responding to all manner of environmental events on its own but mostly to chemical and other signals from fellow citizens. In the brain as in a hive specialized groups tend to form in order to accomplish specific tasks. These clusters of cells, in the brain called nuclei, communicate with each other electrically and chemically for the good of the organism. The brain has a modular structure more similar to a lot of modern electronic devices. Specific disorders are tied to anomalies in one or another nucleus or module. It is so interesting to see recurrent structures in nature involving individual executive units ranging from cells, to brain nuclei, to animals, even social structures of in the human family which form in Dr. Lewis Thomas’s words, ‘conjoined intelligence’. The latest example of conjoined intelligence is making use of thousands of home computers to form large internet supercomputers as in some recent efforts of SETI (Search for Extraterrestrial Intelligence) and now the Human Genome Project. What we’re witnessing is the strengthening of synapses, communications between formerly independent executive entities or nodes.
Molecular mechanisms for strengthening the synaptic connections between neurons in the sea snail Aplysia called post-tetanic poteniation.were enunciated by Eric Kandel and coworkes. For his work he was awarded the 2000 Nobel Prize in Physiology and Medicine.
All of this pertains to explicit memory. This is in essence verbal memory of recall. We test for it in office practice by having the subject store three or so unrelated words such as “pencil, tree, auto” then asking him to repeat these words in two or three minutes. The first prerequisite is that the subject has to focus on the task. He has to be motivated in other words. If he doesn’t care or is distracted he may not be able to recall after a few minutes but eventually he’ll lose the data. It is just this task that is first to be affected in Alzheimer disease.
But first it’s important to be sure the information got in to begin with. So typically the subject is asked to repeat the three words immediately to test immediate recall. That is separate from recent memory and involves attention and language mechanisms. Certain defects in language processing which neurologists call aphasias, will affect the subject’s ability to repeat. When you consider it the ability to repeat this simple phrase is a composite task whose prerequisite is intact workings of a number of subtasks. Obviously if the subject is deaf, he or she won’t hear the phrase or even the instructions to repeat the phrase, so a prerequisite is intact hearing, not only that but proper processing of sounds. Even if the ears work and a person can hear, still in order to repeat the phrase, it has to be processed intact not as gobbledygook. In order to come up with an accurate verbal rendering as part of an output, the person must receive the message intact and have intact early processing of the message. He or she need not know what the message means in its entirety though knowledge of the meaning of the words would help in reproducing them. Under the right circumstances you could successfully repeat a phrase in Chinese or some unknown language even if you don’t understand any of its meaning.
Figure 2: The "Repeat" circuit. This involves the arcuate fasciculus connecting Broca's and Wernicke's area in the left hemisphere.
The next prerequisite is intact output, a voicebox that works, the apparatus for making speech or sound. If a person were unable to talk for some reason, say he’d just had a lot of oral surgery and couldn’t use his mouth to speak, you could test some of this ability by having him write the message. As it turns out though when there is something wrong with the brain that causes a person to be unable to speak, such as some forms of language dysfunction resulting from a stroke or a brain tumor, almost always the victims of these processes are unable to write as well as to speak. So two prerequisites even for successful repetition of a phrase, something that most of us take to be second nature, are intact processes of hearing or reception and on the other side, ability to reproduce speech. But you don’t have to understand what you are saying even in order to reproduce it exactly.
There is a third requisite ability that needs to be intact in order to just repeat a phrase such as “no ifs ands or buts”. There needs to be some connection between input and output, fibers that connect receptive with expressive abilities in the brain’s left, for most of us the dominant hemisphere. The area of reception on the cortex of the language region of the brain is commonly called Wernicke’s area, that of speech or more exactly language production, Broca’s area. Wernicke’s is in the superior posterior temporal gyrus (fold) while Broca’s is in the frontal lobe. The language region of the brain lies around the deepest fissure in the cortex, the so-called Sylvian fissure for most of us in one’s left hemisphere. The arcuate fasciculus connects Wernicke’s and Broca’s areas. Make a cut or place a lesion in the arcuate fasciculus (a fasciculus coming from the word for fascicle is a bundle of fibers which connect groups of neurons, gray matter). Interrupt this connection and the person will be unable to repeat a simple phrase.
The capacity to repeat is thus seen as equivalent to an intact circuit in the brain which in this case goes from Wernicke’s area over the arcuate fasciculus over to Broca’s area on the left or language producing region of the brain. In the analogous region of the right hemisphere resides verbal inflection or expression. In repeating a phrase such expression may be absent if not heard correctly or if not expressed correctly or communicated between the receptive and expressive cortices of the brain. The right hemisphere thus houses a mirror image circuit for inflection or musicality of language or alternately adds emotional content, what is called prosody to language. These functions are well known and accepted and illustrate beautifully the principle that the complete function of the brain depends on intact circuits or modules. Overall this early basic ability to repeat has little to do with other more enduring aspects of memory, but simple repetition is a test of whether the stimulus has even reached or gotten into the brain at all or if it is blocked by some basic deficit say, in reception or hearing.
Again, you can repeat a phrase without concentrating on it at all or understanding it. Everyone has written notes in school then when you look at the notes again, you have no recollection of having written them; you have to go back an study them. That’s because in writing notes you’re simply using the circuit as shown above in the left hemisphere. The rest of the brain doesn’t have to be involved and very often isn’t. Lots of kids do very well in school who simply memorize and reproduce information given to them, without much thought and not involving very much of their brains otherwise. I always found it remarkable how well some students did who never bothered to think at all, just memorize.
But the total store of memorized material changes us. My father was required to memorize complete poems and other literature. By the time I went to school teachers looked down on rote memorization. It was marvelous to observe how much pleasure he derived from being able recall exact tracts of formerly memorized material that were readily available to him, almost a toolbox full of phrases that he could depend on when necessary.
Douglas Hofstadter has recently given a useful description of how of larger concepts and analogies are stored in memory. He asks why as we grow older, the seasons and years get shorter and blames this on the phenomenon of “chunking”. The days and years are placed in boxes of greater and greater size and so individual days and years become ever more alike and smaller by comparison as we gain experience. Concepts too become more vast and inclusive as with experience they are larger boxes of data. As we age we have available to us an ever vaster toolbox of experiences and concepts that we call upon in appropriate circumstances. We store new data too in mental files or as individual conceptualizations, groups of associations that are dredged up as the need arises. Hofstadter maintains that this information once stored in remote crevices of the brain are brought up into recent memory so that we can use them. This is not quite correct. The anatomical areas of the brain implicated in the registration of recent memories are distinct. However stored concepts and qualities are continuously accessed by our attentional processors, regions of brain that focus attention, chiefly in the frontal lobes of the brain and frontal connections, not in the hippocampus and limbic system particularly. Antatomically the focusing of attention likely takes place in the anterior cingulate gyrus, part of the frontal lobe in the midline. Eventually all of these regions of brain may become involved in recollecting a memory as emotion, vision, hearing and other senses are recruited to make an entire scene.
Figure 3: Hippocampus, limbic system and memory circuits As opposed to the previous figure this is close to the midline of the brain. .
Something white may conjure up a whole wedding scene or snow atop hemlocks and on the ground on a winter’s day, even a multisensory experience of smells and noises of wedding music or snow falling from rooftops, snowmobiles running through the snow. The associations are so much stronger if music or emotion is attached to either scene. Modern functional imaging which shows the patterns of activation of various brain regions, would find visual areas lighting up first then recruitment of widespread regions of auditory and olfactory regions, frontal attentional areas and the limbic system as the entire scene ramifies through the brain and widespread groups of neurons get recruited. One might say that this remote memory is brought to the surface of consciousness, that it reactivates the brain, by means of a “handle” by which a multisensory experience is made to occur. That handle is whiteness but other aspects of this memory are perfectly capable of bringing it to the surface as well and can activate brain, perhaps a smell, a wedding dress, the sky, – all of these are memory handles capable depending on the strength of their own connection to the event, of pulling up the entire memory. In her recent book Love, Loss, and What I wore, Ilene Beckerman brings back emotions and recollections of life events using dresses and outfits some of which she has stored away. The outfit is a handle which is capable of bringing up an entire multisensory emotional experience. I’ve often observed that the stimuli that cause me to dredge up memories are ordinarily very slight, often subliminal. In one hospital I have to walk through 10 sets of doors to see patients on a psychiatry unit. I noticed I was hearing the theme from the tv show “Get Smart” in my head. The musical theme would play at the opening of the show as he walked through various doors in order to get to a not so secret hideout a perfect connection with the psychiatry unit.
Something that I don’t show here is the interesting association between the sense of smell (olfaction) and memory. Of all the five senses, olfaction seems to be the most closely associated with memory function. For most us if we waft a certain smell that may conjure up a whole sensory panorama of some past event. Olfaction anatomically is probably the most tied to the emotional areas of the brain, namely the limbic system and the motivational areas of the frontal lobe as well. Evolutionarily olfaction appeared far before cognition obviously the chemical sense appearing early in animals who inhabit water. After a head trauma the olfactory nerve is often affected. Some few patients complain of a lack of sense of smell. The tiny fibers of the olfactory or first cranial nerve go through a sieve shaped structure called the cribriform plate where many of these are vulnerable to be sheared off in a bad head injury. Of course if the trauma is that bad, memory is affected too. Someone made the interesting observation that Alzheimer patients tend to lose their sense of smell very early. Because not a lot of people complain of a lack of sense of smell and neurologists, including myself, tend to pay not too much attention to it, the observation of loss of olfaction in elderly folks is not too often made clinically and so I have not been able to confirm definitively in my own practice that loss of sense of smell is an early sign in Alzheimer’s.
Dreams give us the best picture of looseness of association. In sleep the waking editors, or logic police, as I like to call them that normally restrict associations are at rest. Dream associations are known for their lack of logical relevance. Infantile thought processes freed from logical constraints are powerful raw material for epiphanies and prophetic visions. The Bible has revelations of foreign kings Pharaoh and Nebuchadnezzar interpreted by the Jewish wise men Joseph and Daniel. The dreamy visions of the evil prophet Balaam starkly contrast with the prophesies of Moses that occur in the light of day. Dreams are invoked by mathematicians trying to find a certain proof or solution to a problem. For days on end so the argument goes, the poor scholar obsessively struggles to find a common thread or solution to an important problem. Suddenly in sleep the mind finds a solution. Henri Poincaré, the famous French mathematician wrote eloquently of this very process in an essay entitled Mathematical Creation. Poincaré describes how subconscious associations are the key to finding solutions to difficult problems, the answers appearing suddenly at the most unusual times. “The role of this unconscious work in mathematical invention appears to me incontestable”. So much creative and this would seem to occur especially in science, is done through simple association, improbable connections made among elements of a vast storehouse of data in our minds. Many times these associations are rejected out of hand by our alert thought editors but miraculously manage to fly in, literally under the radar, of our thought editors. This tends to occur just when we aren’t paying attention to a problem, sometimes during relaxation or even sleep.
The most famous example of such scientific vision is that of Kekule who was struck in a dream with the ring structure of benzene, one of the most frequently encountered structures in organic chemistry. The benzene ring is likened to the ancient mystical picture of a Uroborus, a snake eating its own tail. In waking life our logical adult brains often edits out solutions to problems which turn out to be correct. Another obstacle that we don’t remember most of our dreams. Indeed, normals seem to have an inborn mechanism abetting the forgetting of dreams. Perhaps this is so that we can rework the material again and again unhampered by our logic editor. Disturbed neurotic patient or ones with interrupted sleep are the persons who seem to recall more than their share of dreams.
Dreams resemble free association when you actively try to make associations without editing them. That is why some psycho-analysts eventually abandoned dream interpretation in favor of free association. Classically, schizophrenics are said to be crippled by such looseness in logical associations, but it strikes me that many normals may be almost as impaired by lack of imagination that comes from excessive tightness or logic in associations, in other words an overzealous editor. Shizotypic loose associations occur to all of us. So-called clang association, the illogical connection of thoughts on the basis of similar sounds or rhymes are probably the most common. Clang association runs rampant in hip-hop and popular music genres. Most of us don’t allow happenstance association of like sounds to interfere with logical processing.
We strive to connect basic concepts by placing them in folders, or categories within the brain. Leading neuroscientists Antonio and Hanna Damasio have discovered, not surprisingly, that specific verbal categories may have an exact localization within the brain. We place hammers, screwdrivers and drills in the category of tools and it is possible to find patients who after having a stroke or brain injury, to destroy particular category, say that of tools, when a small specific brain region stops working. The tool folder is represented in a localized group of brain cells which, if lesioned, will prevent certain patients from being able to make that specific association, though they may very well be able focus their attention on the uses or characteristics of a screwdriver if shown a picture, without their being able to associate it with the category of tools. This is what I mean when I say that conceptualizations are stored in memory and have multiple handles by which they may be pulled up into current awareness when necessary.
A lot of people are alarmed by an inability to bring ancient memories into awareness. Some young patients complain about temporarily not recalling their own phone number or “forgetting” how to do something that has been second nature to them for years, unable to write their name or light a cigarette. Nine times out of ten these folks are highly anxious. What I tell them is that anxiety is the born enemy of recall. The memory engram is in the brain, only under the wrong circumstances you can’t get it out, as in stage fright or clutching a test or an interview. You bring old memories into current awareness utilizing handles but the harder you try to pull them up, by being anxious, the handle you’re depending on will break off and the memory will fall back down into the abyss of unconscious storage. This points to the difference between recording a memory and recall. Anxiety abolishes recall.
Figure 4: Yanofsky's memory summary. Engrams (individual memory units) are stored in multiple areas of cortex. They are held down by a force represented by springs, pulled up into consciousness via a handle which can be broken hampered by anxiety, drugs, brain dysfunction and other processes. The engram has a particular localization and may be brought up also by purely physical means. The famous surgeon Wilder Penfield used an electric probe on awake patients and stimulate the cortex causing them to remember details of their past. Synesthesia and visualization and other efforts allow storage in far-flung areas of brain and are thus methods for improving memory.
So these are the characteristics of remote memory. Remote or old memories reside in multiple areas of brain, and so are over-determined. This accounts for some of the frustration of one of the early memory experimenters Carl Lashley, who ran rats around mazes then lesioned parts of the rat brain. He found out he couldn’t expunge remote memories simply by destroying individual areas of rat brain. Old memories are present, depending on their complexity in visual, auditory associational areas,represented in widespread areas of cortex. Lesioning specific areas of brain couldn’t destroy these memories but eventually old memories could be destroyed if you cut out a very large portion of brain. So we have an anatomical explanation for Ribot’s law which states that older memories are more resistant to destructive forces.
We distinguish memory from recall. Memory refers to writing the engram into the brain. Recall means bringing the memory back up into awareness and finding some means to express it. Once a memory is in the brain various impairments of attentional processing such as anxiety, drugs, lack of sleep and anything that impairs the brain’s function, might interfere with recall. All of this has to do with remote memories. Memories have to be recent for a long while and then only much later are indelibly written into multiple areas of cerebral cortex. To bring a concept back from the depths of the brain into awareness you pull it up by a handle. Don’t try or pull too hard lest the handle break off and you won’t be able to retrieve it. The handle itself is usually a match in some way for some current stimulus, much like an enzyme molecule recognizing a specific shape of a receptor what chemists call a lock and key type of recognition.
What about recent memories? These form within minutes and consist of mostly single sensory stimuli, typically auditory stimuli, placed in temporary storage. As mentioned certain specific structures, most importantly the hippocampi, and limbic system are involved in the laying down of recent memories. It’s been found that people don’t have a recent memory impairment, generally speaking, unless these structures which are all paired, are affected bilaterally, that is on both sides. Generally speaking most brain lesions don’t occur on both sides of the brain. The most common scenario is interruption of blood supply to the brain in one artery on one side of the brain as occurs in a stroke and in that instance you may pick off the hippocampus in the temporal lobe, on one side only. This should not cause an impairment generally in recent memory. To affect laying down of new memories you have to involve both right and left hippocampi or other paired structure such as mamillary bodies, thalamus etc which rarely occurs.
Some Disorders Of Recent Memory:
Nevertheless we do see patients with recent memory defects and plenty of them. The model is a disorder called transient global amnesia which is a misnomer because the amnesia is not global but it does fortunately last only a short time. The victim, almost always someone of middle age 50 through 70 years old, is often ill at ease, aware that something is wrong often complaining about feeling in a cloud. They typically ask questions again and again, being unable to register answers and these most often are orientation questions, “How did I get here? What day is it?” Observers easily appreciate that something is very wrong. When tested in the middle of such an episode the subject will have lost memory for a variable period of time preceding the problem, perhaps one or two days or a week but will easily be able to come up with old, well-established facts such as the name of a spouse or children, where they live and so forth. During the period of amnesia the person will be unable to register any memories but will be able to use language, count, interpret proverbs and perform other tasks requiring intellect. After recovery there will still be a loss for a certain period of time surrounding the actual period of amnesia, much less than 24 hours. This period of time, during which the person with transient global amnesia is not recording memories, persists as an island of memory loss, literally a break in the continuum of experience. The island of loss most of the time shrinks but never fills in completely even with the help of details from friends and relatives. It is as if the person did not experience this parcel of time and that is what disturbs them.
No one knows what causes transient global amnesia. The problem for a neurologist is explaining a process that has to affect both sides of the brain. A vascular problem should not do that. It’s thought that it might be due to spasm of vessels that feed the hippocampi or midline structures as in a type of migraine or perhaps be a limited seizure or stoke. Very rarely something more serious such as a vascular tumor that steals a blood supply from the memory forming regions of the brain will cause TGA. TGA has a tendency to occur under stress but is not thought to be an emotional disorder most of the time. In persons over say 70 years or so I have a tendency to suspect an early period of confusion that occurs as a presentation for more permanent problems such as Alzheimer’s or multi-infarct dementia but that is by no means always the case.
Somewhat similar to TGA is post-traumatic amnesia. This is what happens when, as in the movies, a person gets hit on the head and suffers, though awake, a period of confusion usually for a short period of time. This amounts to confusion manifested mainly by an inability to lay down new memories and a loss of the ability to account for a period of time after the trauma or concussion as in TGA. The inability to register memories in this ways after the head injury is called anterograde amnesia. We distinguish this from retrograde amnesia, an inability to recount events that occurred for a period before the trauma - ordinarily a pretty short period. This makes the post-concussive’s recollection of the details of an accident unreliable at least until the victim of the head trauma makes a recovery. Again this island in time of memory loss will typically shrink, as recovery occurs but often never shrink to nothing. Some persons maintain that they have relatively permanent mental changes after head injuries even those that prove to be relatively trivial and may not make a recovery for years or even longer. This sometimes happens when all of our MRI, CT scans EEG’s etc gotten shortly after the injury see nothing abnormal. In other words there is no structural lesion known after a head injury, yet a period of alteration of consciousness or mental function ordinarily termed a concussion, a commotio cerebri. One thing that has come to light in recent years is that it might be particularly dangerous for a person to have repeated concussions as football players or boxers might, before they have recovered from a previous insult. There is some evidence that even though there are no known structural changes with repeated insults, there is a far greater risk of causing permanent damage. So in addition to confusion, there is a variable period of vulnerability, not yet well defined after a first head injury, in which you wouldn’t be recommended to injure your brain again. In situations where there are more persistent mental changes after an injury such as this, doctors often get into the fray of legal wrangling that complicates evaluation of patients. Different sides in these issues have their own ax to grind if they can show in a court of law, more or less harm done depending on whether they are the plaintiff or defendant. As for the neurologist or neurosurgeon, they have little objective information to go on.
The very same pattern of memory loss happens in psychiatric patients undergoing electroshock therapy. What they have is memory loss identical to having been hit on the head, a type of post-traumatic amnesia in other words. Typically the severely depressed patient will undergo repeated shock treatments and as they are repeated, the person’s retrograde amnesia retreats further and further back into the past as their confusion and inability to register current events. They are getting repeated concussions in other words. Electroshock therapy may seem an unappealing alternative but almost everyone agrees that it is extremely effective for resistant depression where other treatments fail. No one knows why this therapy works but perhaps the most attractive theory is that severe bouts of depression are relatively acute recent and short-lived events. The retrograde amnesia induced by shock therapy allows the patient to go back in time and relearn and erase the depression. But if that were the case the effectiveness of shock therapy should be proportional to the degree of amnesia. Unfortunately effectiveness is not correlated with memory loss so something else must be going on. You can place the shocking electodes over the right hemisphere affecting memory less and still the treatment is about as effective. Perhaps learning occurs with repeated shock treatments themselves and this indeed does seem to be the case as levels of certain hormones for example epinephrine and norepinephrine change with repeated treatments.
Persons who have many seizures may have trouble with memory. This is seen occasionally by neurologists. The electrical discharges in the brain that are a part of epilepsy, or perhaps just the effect of repeated seizures on awareness, impair the registration of memories. In some cases when the epilepsy is effectively treated with appropriate medication, the sufferer’s memory improves.
I’ve witnessed some dramatic cases.
A peculiar problem often associated with alcoholism is Wernicke-Korsakoff syndrome. This is actually a vitamin B1(Thiamine) deficiency that has a tendency to affect midline or limbic structures chiefly the mammilary bodies and cell groups controlling eye movements. The brain needs glucose for energy. Thiamine is a cofactor aiding glucose utilization and brain cells cannot survive without it. Therefore the manifestations of thiamine deficiency may be neurological. We see the triad of eye movement abnormalities (double vision), ataxia, and recent memory loss also usually neuropathy (numbness in feet and hands). Memory is what we are talking about here. Some patients used to come into the emergency room where they’d promptly be started on a glucose i.v. solution. You’d think that would help get more sugar to the brain but in truth it does just the opposite. If a person lacks thiamine, glucose utilization throughout the body exhausts thiamine stores and this precipitates an acute Wernicke encephalopathy in the brain. Wernicke’s is known as a hemorrhagic polioencephalopathy. What is seen under the microscope in acute cases is blood in gray (polio for gray) matter, the cell bodies or neurons in certain areas of the brain. Alcoholics are most vulnerable to Wernicke’s but non-alcoholics who have very poor nutrition may get it too. The first case was a young woman who had burnt her esophagus after swallowing sulfuric acid. Today thiamine is given routinely in emergency rooms to just about every alcoholic so that cases of Wernicke’s are exceedingly rare.
Korsakoff patients end up having almost a pure recent memory disturbance. Some of them never recover. Unlike folks with transient global amnesia they have no idea that there is a problem. They suffer from anosognosia where a person is unaware they have a problem or a disease. Korsakoff’s don’t know there is a problem with their memory so if they are asked a question requiring recall of recent events they confabulate, make something up. You can ask them if you’ve ever met and even though they don’t know you from Adam these folks will tell you that yes, you had a few together in the Rusty Nail just yesterday and were sharing a few laughs about your girlfriends etc. Confabulation may not be just not knowing that there is a problem. Some troubles with older memories are seen as well. Memories formed earlier may be recalled out of sequence, details not remembered and confabulation may be a method for filling in holes in recollection. In the very chronic stages of the disorder some awareness of the problem with memory finally sinks in and confabulation tends to lessen. Testing shows that Korsakoff patients have cognitive problems outside of the realm of memory, difficulty figuring things out and reasoning so that there are certainly non-memory deficits.
Other conditions affect specifically the hippocampus and other memory forming portions of the brain. A classic example is Herpes encephalitis. Spreading from certain ganglia this virus lives dormantly in nerve cells and has a particular propensity to attack parts of the frontal and temporal lobes of the brain, probably due to the proximity of the Trigeminal ganglia to the inferior frontal and temporal lobes of the brain. Patients who survive the acute illness have a tendency to have Korsakoff-like problems with recent memory. Many turn out to be cognitively crippled merely because of a memory disturbance. Anoxia where the brain is deprived of blood or oxygen supply and Carbon Monoxide poisoning tend to cause the same problems in survivors because certain larger pyramidal neurons in a part of the hippocampus called Ammon’s horn are much more susceptible to a lack of Oxygen.
The patient is left with a crippling disturbance of recent memory. Consider for a moment what would happen if you were unable to register memories. If taken anyplace and asked to do any task you would be disoriented. You wouldn’t be able to find your way about any new place. You wouldn’t be able to recall the day date or place without checking some record or calendar. You couldn’t be trusted to take care of yourself, show up at a job or learn what to do at your job, establish the normal routines all of us depend on. Most of all you wouldn’t be able to internalize ongoing events and would lose the experiential aspect of your life. You’d cease to function as a human person, but would be lost in some never-neverland frozen in time. There is none of that feeling of constancy or contiguity that makes us self aware, no registration of occurrences. You might well live in some distant past time. But retrograde amnesia would have to go very far back indeed for a person to forget his identity as seems to occur on some television soap-operas and theatre. That type of memory disturbance is not seen clinically, is uncommon but occurs in psychiatric states.
It is important to understand that the kind of memories we are talking about are explicit memories which to a great extent get into the brain’s recording circuits via language, mathematical and symbolic routes. A person with this kind of recent memory dysfunction can still “learn” via implicit mechanisms. For example, he will be able to improve his accuracy in basketball, or playing music by virtue of practice. Some motor learning particularly takes place in other areas of the brain, involving motor systems particularly and need not enter the brain through limbic circuits.
Nowadays the situation is no longer as hopeless for a person with a recent memory deficit. We have so many memory crutches and memory managers that such a person can have at his disposal at all times to reorient him and which are helpful in recording information. Suppose we gave a Herpes survivor a Palm Pilot or other memory device. He would still need to learn how to use it which might be difficult for him. Also keeping data on some external device is not at all the same as recording it in one’s one memory to be recalled as an actual living experience.
The recent memory cripple is a sort of philosophical thought experiment. Living memories are recorded, placed in individual sensory chambers definable in brain anatomy ready to be recalled as attention is again focused upon them. They become part of an internal running narrative of our life that all of keeps stored in the brain. Old memories, whether specifically recalled or not, are brought to conscious awareness, determine our current behavior in countless ways and determine who we are. As recorded in a Palm-Pilot, memories cannot affect a person in nearly the same way.
The above considerations provide the clinician with useful tools that help separate neurological and psychological memory conditions. We have seen that a guiding principle in memory is Ribot’s law which states that as a general rule, older memories are more resistant to memory destroying processing than are new ones. Moreover, certain memories, ordinarily much older ones, are over-determined in the brain and will never be affected unless for some reason the whole brain shuts down as in coma or encephalopathy. If a person is otherwise communicating logically he will never forget his own identity, his own childhood, nor will he forget about well-rehearsed tasks such as tying shoelaces or even complex well-learned tasks. He is unlikely to forget about his parents or his wife and children unless such memories were recently established. Memory loss is generally contiguous in time. There is an “island” of memory disturbance extending variably into the immediate past denoted as retrograde amnesia and into the future impairing new memory recording called anterograde amnesia. This is the model for true neurological memory loss which is fortunately counterintuitive for the ordinary person ignorant of these principles and feigning memory loss. As he recovers he will again record explicit memories so creating a true island of deficit, bounded by past and future time. Characteristically this island may shrink as some awareness of past events begins to creep into awareness. This is the constant pattern we witnessed above in discussion of transient global amnesia and post-traumatic amnesia and other states.
Under certain rare conditions, persons may be left with memory holes by which I mean that there may be multiple non-contiguous episodes of memory loss that they may be unable to recall from their past. These typically occur after repeated intoxications especially drug or alcohol use (such as blackouts frequently referred to by alcoholics), in conditions where a person lost consciousness or had incomplete awareness such as after multiple head traumas as in boxing and other similar endeavors or rarely with epilepsy as described above. These conditions are easy to exclude after a few moments of history taking. Absent any of these a discontinuous or kind of Swiss cheese type of memory disturbance often described by psychiatric patients shouldn’t happen from any physical process in the brain, neither should memory loss involving more resistant older memories. These are mostly psychological complaints or purely feigned.
Of course people have lots of reasons for pretending to forget. The most important motivation is to exculpate oneself in the commission of a crime or so as not to implicate someone else. In many situations that I see, there is some reason not to function because of a legal suit where a person stands to gain financially by showing impairment that resulting from an accident or mishap. In most case where this occurs one can tell that the memory loss is non-physiologic that is uncharacteristic of the memory loss models as I have described them above, not likely to be related to the known pathological processes that produce amnesia. Another common mistake of the malingerer is to claim that memory loss is progressively worse after an injury. As we have seen after a head trauma or acute event the pattern is that the worst memory loss occurs just after the incident then later improves over time. Memory and cognitive disturbances don’t worsen over time after an injury unless there are other intercurrent processes such as Alzheimer’s or other degenerative disease states unrelated to a head injury. So the pattern post injury is severe memory loss, which over time tends to improve usually quite rapidly.
Many persons claim to compartmentalize memory, to place it into certain mutually exclusive lockboxes. The idea is that it isn’t possible for the personality of Eve to get to the memories of Sheila even though both persons inhabit the same skull. Or, the victim of a type of hysteria may enter into a so-called fugue state, where memories laid down during this time become inaccessible except by employing some technique such as hypnosis or free association. Most scientific observers remain skeptical that such fugue states or multiple personalities truly exist given plausible alternative motivations of the subject.
Is it possible to get at information stored in the brain even when a person can’t recall it? In popular and pseudoscientific literature some memories that are painful or may cause distress simply cannot be recalled. The psychological techniques for unearthing these memories, which presumably inhabit the subconscious, are substantially the same. Some persons have difficulty recalling traumatic events of childhood typically sexual abuse or at a crime scene. Techniques ranging from relaxation, play therapy in children, free-association, hypnosis, various forms of psychotherapy to “truth serums” are used to get at these past events either to gather critical forensic data or to re-enact these events for therapeutic gain. Unfortunately none of these “hypermnestic” techniques has ever been shown objectively to increase recall. There is now a substantial body of evidence culled from some spectacular cases, many involving memories either recalled by children or adults of supposed childhood events, that information obtained by these means is wholly inaccurate in most instances invented either to hoodwink or please the supposed “therapist.” Of course as I discussed above, anxiety can get in the way of recall of certain memories and it may be possible for a person to recall a little more if he is relaxed. It may also be possible to coax out a little more information stored in the brain by using a kind of open-ended Socratic method of questioning. A skillful examiner such as an artist may gather some description of a perpetrator which otherwise the witness could not provide, simply because the artist has drawing skills that the witness does not possess, but apart from these limited considerations it has never been shown that any subject may be coaxed into some hypermnestic state.
It is very common to see apparent memory lapses that are really emotional disorders. One problem is depressive pseudo-dementia. This typically occurs in an older patient and in most cases it is not hard to make the diagnosis because the subject simply does not respond at all or his responses will be incredibly slow, what is termed psycho-motor retardation. Severe depression often happens in the elderly who, after all, may experience the loss of spouses, friends, a home, and possessions, cognitive and physical abilities. Many persons, not unreasonably, begin to hoard things afraid to let them go. Of course, they are keenly aware of the approach of the end of life. Some persons just give up. They are not too motivated to carry on a conversation. In other situations there may be problems that impair movements such as forms of Parkinsonism that cause a person to have lack of response. Of course, many of these folks may be much more cognizant than you give them credit for and perhaps may have intact memory.
Younger people are depressed too but their problem is more often anxiety. Anxiety blocks recall of memories so we have something a little different here. The memory engram gets into the brain but the person cannot get it out. It is just like stage fright as mentioned above. The difference in the memory disturbance is that while the performance may be affected, the person will typically recall what he should have remembered later when under less pressure. As I say anxiety is the enemy of recall. But the problem does get a little more sticky. Recall may also be affected by physical processes in the brain. Older folks with global cognitive dysfunction or strokes causing a problems with language function will also have trouble primarily with recall, not laying down memories. But a recall problem is most often caused by a process other than Alzheimer disease, more often a static problem such as a stroke. The most typical problem that they have is that a word they want isn’t readily available to them, what we call word-finding problems and that is not due to anxiety but changes in the brain. Lot’s of patients complain of a lack of sharpness or spontaneity or fluency after heart surgery or because of taking multiple medicines or drugs.
In younger people may have trouble laying down memories as well. The problem is often is preoccupation. That’s connected with anxiety and blocks the subject’s ability to focus so that literally he isn’t hearing or seeing something well enough, not noting it well enough to remember. Very often such people are so agitated and nervous they can’t learn or focus on anything.
Finally lots of intelligent individuals or those who are at least more observant, notice a subtle slowing in their memory function. When seen in the office we have to determine whether they are experiencing a serious decline or if they just feel the “normal” decline that occurs as we age typically after the mid-forties or so. One critical differentiation here is if spouses, friends, or co-workers note a problem or if it seems to be an observation of the person himself.
Stay tuned. We’ll continue with a discussion of Alzheimer Disease!
© 2001 by Charles S. Yanofsky, M.D.
I recommend a wonderful anthology: The Anatomy of Memory edited by James McConkey, Oxford University Press, New York. 1996, full of insightful essays from which some of the above discussion derives.