April 10. 2024	PSY 340 Brain and Behavior Class 32 Learning, Memory, and Memory Loss

I. Localized Representations in Memory

Our experiences in life teach us things: putting our finger into a flame or an electrical socket will hurt, eating ice cream will usually taste really good, smiling at our boy- or girl-friend is more likely to keep them around than a frown, and failing to show up at work will usually get us fired. It seems as if learning connects one thing to another.

In the late 19th and first half of the 20th century, behavioral psychologists developed elaborate theories that we learn such connections because of our experiences.

• Ivan Pavlov developed the theory of classical conditioning which said that we learn to associate signals in the environment with the "real thing." So, bells can signal that dinner is served and our mouth may start watering as soon as we hear the bell ring. Or, the bell might signal the end of recess in elementary school and we begin to feel a little unhappy because we now face more work in the classroom. In our classroom here at Le Moyne, the clock in the front signals the end of class and you will often be tempted to close your books up a bit too early because you've learned that class is coming to an end.

• B. F. Skinner developed the theory of operant condition which said that we are either reinforced or punished by the environment for the behaviors we do and, thus, we "learn" either to do the behaviors more frequently or to avoid them. If someone gets a $350 speeding ticket for going 88 miles an hour on I-81 through Cortland, this punishment teaches them not to speed (at least along I-81). If you meet a really nice guy or girl at a particular night spot, the reinforcement from that meeting will probably get you to go back to that night spot again if you need to find another relationship.

• Where is the learning? There is no doubt that both theories are right insofar as we do learn from the environment and our experiences.
  

• But, where does that learning wind up in the brain?
• Where is the actual physical connection between what we did and what happened to us?
• Where is that memory about the speeding ticket which prompts us to slow down ten years after getting it in the first place?

Karl Lashley's FAILED Search for the Engram

University of Chicago and, later, Harvard physiologist and psychologist, Karl Lashley, wanted to find where learning resided in the brain. In the period from roughly 1920 to 1955, Lashley searched after the "engram" -- the physical representation (or memory trace) in the brain of what has been learned.

To do so, Lashley performed two general types of experiments.

Cortical Cuts. First, he trained rats to learn how to find food in mazes. When they had learned this, he performed operation on the rats by cutting areas of the cortex. He theorized that, if there was a link between two areas of the brain as a result of learning, he might pinpoint that link by making the cuts. The diagram shows you the different places where he cut the rat brain. When each rat recovered from the operation and put back into the maze, they didn't show any evidence of loss of learning.

Tissue Ablation. The second experiments involved maze learning as well. When the rats had learned to manouver in the maze, he performed a "tissue ablation" -- that is, he cut different amounts of tissue from the rat's cortex. The rats later on did more poorly in running the maze. But, it appeared to Lashley to be the amount of lost brain tissue, not the place where the tissue was removed that was related to poorer performance.

Lashley's Principles for the Nervous System. Lashley rejected the notion of localized learning. Rather he proposed two principles:

• Equipotentiality: All parts of the cortex contribute equally to learning; one part can substitute for another part.
  
  
• Mass Action: The cortex works as a whole; performance improves when more of the cortex is involved.

We know that Lashley was wrong about both of these principles? Why? He assumed (1) the engram (memory trace) is only in the cortex and (2) all memories are the same physiologically.

The Modern Search for the Engram: Conditioning & the Lateral Pontine Nucleus of the Cerebellum

• Rabbit eyes will blink (= UR: unconditioned response) if a puff of air hits them (= US: unconditioned stimulus)
• Richard F. Thompson (Neuroscience, USC, California) conditioned rabbits using a tone (= CS: conditioned stimulus) which he paired with the US. Eventually, the rabbits learned to blink (= CR: conditioned response) when they heard the CS alone.
• Learning the CS:CR connection increased the activity level of the lateral pontine nucleus (LPN; also called the lateral interpositus nucleus in the text) of the cerebellum. Hence, Thompson tested the linkage of LPN and the red nucleus of the pons, an area to which the LPN connects. (Diagram above shows human pontine-cerebellar complex). He found
• Suppressing the LPN temporarily prevented rabbits from learning the CS:CR connection
• Suppressing the red nucleus temporarily prevented the rabbits from responding (the CR), but not the learning itself
• Conclusion: Learning seems to have taken place at the Lateral Pontine Nucleus. From this and multiple other studies, there appears to be involvement of the cerebellum in conditioned learning in humans as well.

II. Types of Memory

   Short- and Long-Term Memory

Donald O. Hebb proposed in the late 1940s a model of memory with two different components:

• short-term memory (STM; up to 20 seconds)
• Keeping items in STM requires regular rehearsal (actively calling items to mind) or else they will fade.
• George Miller noted, the storage capacity of STM is limited: 7 +/- 2 chunks of information. More recent research suggests that it is really more likely about 4 +/- 2 chunks.
• long-term memory (LTM; 20-60 seconds to a lifetime): anything that happened in the past which you can remember
• Hebb also proposed that all information enters into STM and stays there until the brain consolidates that information as LTM. Hebb argued that the shift from STM to LTM came with the "consolidation" of memories by means of a reverberating circuit within the nervous system. As the memory reverberates around the circuit, it gradually causes some type of permanent change in the chemical or structural make-up of the nervous system.

Changing Views of Consolidation

Earlier view: Consolidation is a general & simple process leading to a permanent long-term memory. But, this is no longer a viable option because

• Time for consolidation varies considerably: may take from an instant (for emotional memories) to hours (for memorizing facts). Something more than "simple" consolidation is taking place, e.g., cortisol in short term enhances consolidation, but may hinder consolidation if person is stressed for long periods.

• Memories are labile (changeable or vulnerable to alteration). When memories are recalled, they are frequently reconsolidated, that is, subtly changed or altered by new information, e.g., parent recalls a detail and child adds that detail to their memory; or, a policeman makes a remark about what a witness might have seen and the witness incorporates that remark into their memory. Recall the recent past class on the use of propranolol in helping patients with PTSD reduce the level of distress coming from memory of the event via reconsolidation. 
  

   Alan Baddeley's "Working Memory": A Modern Advance

In the early 1990s, Alan Baddeley (U York, UK) and his colleagues proposed a newer model of memory: working memory. This was revised in 2000-2001 and now includes 4 elements:

• phonological rehearsal loop: auditory & linguistic information
• visuospatial sketch pad
• episodic buffer: temporary storage of multimodal-coded information drawn from long-term memory and presented as an episodic representation (a scene)
• central executive control system: directs attention toward one or another stimuli and decides what will be put into the working memory
  

We may also have working memory systems for the other senses (touch, taste, smell), but not much research has been done on them.

Testing the "working memory" model uses delayed response tasks = respond to a stimulus that was seen or heard a short time ago with a time delay inserted between the perception and the response.

What parts of the brain are active during the delay, that is, while the working memory is rehearsing or holding the memory? Most active appears to be the dorsolateral prefrontal cortex. However, multiple other areas of the prefrontal cortex are involved in other aspects of working memory besides rehearsal.

III. Memory Loss (Amnesia)

  A. Korsakoff's Syndrome & Other Prefrontal Damage

Wernicke's encephalopathy (WE) is an acute brain disorder in which a patient coming into a hospital has (1) profound global confusion, (2) difficulty in coordinating muscle movements (ataxia), and (3) problems using their eyes. It is fatal in 10-20% of cases coming to a hospital. It is caused by a deficiency of thiamine (vitamin B-1). 80% of patients surviving Wernicke's encephalopathy go on to develop Korsakoff's Syndrome (KS).

WE often develops in individuals with alcoholism. Other conditions that may result in WE include patients who have undergone bariatric surgery for permanent weight loss, other forms of gastrointestinal surgery, cancer, and pancreatitis (Kohnke & Meek, 2021).

WE is often under-diagnosed in living patients.

  Korsakoff's Syndrome (KS; also known as Korsakoff Psychosis)

• a chronic brain disorder characterized by severe memory problems: both anterograde and retrograde memory is usually damaged. Patients also show apathy and confusion.
  

Case of Korsakoff's Syndrome in English Patient (1979) YouTube Interview by psychiatrist 2:26-4:25

The brain area damaged includes the mammillary bodies (beneath the hypothalamus) and the dorosmedial (or mediodorsal) thalamus (nucleus connected to pre-frontal cortex).

Patients with KS often show

• Confabulation: patient hides lack of memory by guessing an answer and, then, relies upon the guess as if it were an answer. The very confabulations themselves tend to prevent KS patients from learning anything new because they pay attention to their guesses rather than other data.

• Chronological reasoning difficulties: presented with several facts about events, KS patients have trouble figuring out the sequence or order of events on the basis of cues in the facts. For example: Mary had a baby when she was in college. It has been ten years since Mary first went to college. Is Mary's child older or younger than 10 years of age?

• Better new implicit than explicit memory due to the effects of priming.

Prevalence of KS. This condition is relatively rare. Consider what the number of cases might be in the US (which, in 2020, had a population of 331 million) Arts et al. (2017) note that there is very little data about the prevalence and what data there is show a range of values:

• 48 per 100,000 in The Hague, The Netherlands (1987 study) ===> would be equivalent to ca. 159K total cases in US in 2020
  
• 30 per 100,000 in North-Holland, The Netherlands (1992 study)
• 5 per 100,000 per year in Glasgow, Scotland (1990-1995) ====> would be equivalent to ca. 16.5K total cases in US in 2020
  
• No other prevalence rates appear to be available

B. Alzheimer's Disease (AD) [Sheltens et al. 2021]

YouTube Video: Screen for Dementia (ca. 4 min). A case of advanced dementia.

AD is a form of dementia. What is dementia? As the National Institute on Aging (2017) defines it, "Dementia is the loss of cognitive functioning—thinking, remembering, and reasoning—and behavioral abilities to such an extent that it interferes with a person's daily life and activities. These functions include memory, language skills, visual perception, problem solving, self-management, and the ability to focus and pay attention. Some people with dementia cannot control their emotions, and their personalities may change" (highlighting & italics added). Not that "dementia" is not itself a disease but a broad term specifying a range of symptoms found in multiple diseases like AD, Parkinson's disease, fronto-termporal dementia, and several other disorders.

The disorder was first identified and diagnosed by the German psychiatrist and neuropathologist, Dr. Alois Alzheimer (1864-1915) in 1906. A patient in the Frankfurt psychiatric asylum, Frau Auguste Deter, who showed significant behavioral symptoms including memory loss. When she died in 1906, Alzheimer analyzed her brain tissue after autopsy and discovered the characteristic presence of amyloid plaques and neurofibrillary tangles of tau (discussed below).

AD is a progressive disorder which initially involves minor forgetfulness. Over the course of about 8 to 10 years following diagnosis, AD patients experience increasing symptoms including severe memory loss, confusion, depression, hallucinations, delusions, restlessness, sleeplessness, and loss of appetite. Eventually, the disease will lead to death.

AD which develops among people over the age of 65 is described as "late onset" AD [LOAD]. This occurs in more than 90% of cases of AD. However, about 5% of AD occurs among people aged 30 to 65 and this is called "early onset" AD [EOAD]. This form of the disease appears to be strongly related to the presence of one of three specific genetic variants on chromosomes 1, 14, and 21 and other genetic risks. [https://www.nia.nih.gov/health/genetics-and-family-history/alzheimers-disease-genetics-fact-sheet]

Prevalence and Incidence of AD. What is the rate of Alzheimer’s disease in the United States? Mendez (2019) reports that among those who are 45 to 64 years old, early-onset AD [EOAD] is diagnosed each year at a rate of about 6.3 per 100,000 with an overall prevalence of 24.2 per 100,000. Thus, EOAD is actually a fairly rare (though fatal) disorder. Note that people with EOAD tend to die more quickly than in late-onset AD (LOAD) which is why the prevalence rate remains steady. 

But, as you see in the figure on the right, beginning at the age of 60, the incidence rate of AD begins to climb exponentially. It is 1% among those 60 to 64 years old, and then it doubles in each 5 year period until age 85. After 85, however, the rate soars to between 30 and 40%.

The CDC estimates that in 2020 there were 5.8 million Americans with AD. And, that number is expected to rise to 14 million by 2060. One cost estimate finds that the extra expenses to treat people with AD in the last couple of years of their life is about $250,000. That means that the current population of the United States with AD will generate about $1.45 trillion in expenses.

  Genetic Factors

• Twin studies indicate that "the risk of Alzheimer’s disease is 60–80% dependent on heritable factors" (Sheltens et al., 2021, p. 1580.) But, genetics is not the only factor in the development of AD.
  

• APOE gene. The most widely documented risk for the onset of AD in older people is one of 3 variants found in humans of the APOE gene (Apolipoprotein E)  which is "involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. The APOE ε4 allele (variant) is the major known risk-factor gene for late-onset Alzheimer's disease." ("Alzheimer's Disease Genetics Factsheet," August 2015, highlight added). Note that the APOE ε3 allele (variant) appears to have no relation to AD development while the APOE ε2 allele is actually protective against the development of AD. These gene variants are found on chromosome 19.
  

• Building on earlier studies, more recent genome-wide association studies involving over 400,000 individuals with AD and age-matched controls (Jansen et al. 2019) has increased the number of genetic risks to over 40 variants. These findings also point to what may be a crucial role for cholesterol and inflammatory processes in the development of AD.
  

• Down's Syndrome: Individuals with Down's syndrome ("trisomy 21" = 3 chromosomes 21) often develop AD.

  Cellular Pathology in AD

Amyloid plaques: amyloid precursor protein in the brain is incorrectly broken down into amyloid beta protein 42 (usually called A-beta by researchers). This substance accumulates with other amyloid beta proteins and damages the membranes of axons and dendrites as these clumps develop in the space between neurons. 

Neurofibrillary tangles: the tau protein within the neuron usually supports the cell's structure, particularly the axon of neurons. However, abnormal forms of the tau protein collect inside the neuron and cause tangles to form within the neural cell.

• Many AD researchers believe that the tau protein tangles are not the cause of, but a result of other processes involved in the development of the disease.

• As you see in the figure above, the progression of AD in the brain begins usually in the temporal lobe (involving the hippocampus) and the inferior area of the frontal lobe. As the disease progresses the deterioration begins to spread widely throughout the brain.
  

  Brain Pathology in AD

• The eventual effect of these pathological cell processes in AD can be seen in the gross differences below between the brains of a normal elderly person and someone who died of AD.

• The processes leading to symptomatic AD may actually take one or two decades to develop since up to 70% of the neurons in important brain areas must die before symptoms appear (Sanders, 2011).

• A major problem for researchers is the discovery that many people with a diagnosis of Alzheimer's disease also have a mixture of other degenerative abnormalities in the brain--what is called the "co-pathologies problem"  (Couthard & Love, 2018; Robinson et al. 2018). The mixture of problems such as blood vessel wall pathology, lowered blood flow to brain tissue, and the presence of other pathological proteins (alpha-synuclein & TDP-43 [i.e., TAR DNA-binding protein 43 which contributes to frontotemporal dementia & ALS/Lou Gehrig's disease]) all make it difficult to understand the sequencing of what factors cause what damage as AD develops. 

  Infant Amnesia (Not responsible for this section; we won't be covering it)

---

References

Alzheimer's Genetics Factsheet. (2015, August). Washington, DC: National Institutes of Health, National Institute on Aging. https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-genetics-fact-sheet

Arts, N. J. M., Walvoort, S. J. W., & Kessels, R. P. C. (2017). Korsakoff’s syndrome: A critical review. Neuropsychiatric Disease and Treatment, 13, 2875-2890. https://doi.org/10.2147/NDT.S130078

Carey, B. (2008, December 4). H.M., an unforgettable amnesiac, dies at 82. New York Times. [Obituary]

Couthard, E. J., & Love, S. (2018). A broader view of dementia: Multiple co-pathologies are the norm. Brain, 141(7), 1894-1897. doi: 10.1093/brain/awy153

Genoux, D., Haditsch. U., Knobloch, M., Michalon, A., Storm, D., & Mansuy, I. M. (2002). Protein phosphatase 1 is a molecular constraint on learning and memory. Nature, 418(6901), 970-975. [PubMed Abstract]

Jansen, I. E. et al. (2019) Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature Genetics, 51, 404-413. https://doi.org/10.1038/s41588-018-0311-9

Koknke, S., & Meek, C. L. (2021). Don’t seek, don’t find: The diagnostic challenge of Wernicke’s encephalopathy. Annals of Clinical Biochemistry, 58(1), 38-46. https://doi.org/10.1177/0004563220939604

Kolata, G. (2011, April 3). Vast gene study yields insights on Alzheimer's. New York Times. Retrieved from http://www.nytimes.com/2011/04/04/health/04alzheimer.html

Kolata, G. (2019, April 8). The diagnosis is Alzheimer's. But that's probably not the only problem. New York Times. Retrieved from https://www.nytimes.com/2019/04/08/health/alzheimers-dementia-stroke.html

Mendez, M. F. (2019) Early-onset Alzheimer disease and its variants. Continuum, 25(1), 34-51. https://dx.doi.org/0.1212/CON.0000000000000687

Mental Health: A Report of the Surgeon General. (1999). Chapter 5. Older Adults and Mental Health: Alzheimer's Disease. Washington, DC. Downloaded 04/17/05 from the Web site: http://www.surgeongeneral.gov/library/mentalhealth/chapter5/sec4.html

Newhouse, B. (2007, Feb 24). H.M.'s brain and the history of memory. Weekend Edition Saturday, National Public Radio. [incudes audio recording].

Robinson, J. L., Lee, E. B., Xie, S. X., Rennert, L., et al (2018). Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain, 141, 2181-2193.

Scheltens, P. et al. (2021). Alzheimer’s disease. Lancet, 397, 1557-1590. https://doi.org/10.1016/S0140-6736(20)32205-4

 

  The first version of this page was posted on April 17, 2005