BIOSCI N165 - Unit 8

Three Stages of Memory (in formation and retrieval)

Memory — An organism's mental ability to store, retain, and recall information

1. Encoding/Registration — attending to or maintaining current sensory or internal information

2. Storage — creating a permanent record of the encoded information

3. Retrieval/Recall — bringing back stored information in response to some cue for use in a process or activity

Sensory Memory

The EARLIEST and FASTEST stage of memory.

Sensory information from the environment is stored for a very brief period — generally no longer than ~500ms for visual information and 3-4 seconds for auditory information.

Cannot be prolonged via rehearsal.

Capacity: ~12 items (demonstrated by George Sperling — UCI Professor in Cognitive Science!).

Short-Term / Working Memory

Limited, active, transient traces of experiences that happened in the very recent past. Interchangeable with working memory — the processes used to temporarily store, organize, and manipulate information.

Duration: ~2 seconds without rehearsal; can be maintained with rehearsal.

Capacity: limited to ~3-4 objects in visual working memory.

The "RAM" of human memory.

Examples: repeating a phone number; replaying a question when you were tuned out.

Baddeley & Hitch Model (1974)

A model of working memory with three main components:

1. Phonological Loop — stores verbal/auditory information

2. Visuospatial Sketchpad — stores visuospatial information

3. Central Executive — supervisory system that performs operations on stored information

Likely associated with the PREFRONTAL CORTEX.

A fourth component was added in 2000:

4. Episodic Buffer — bridges short-term and long-term episodic memory

Phonological Loop

A component of Baddeley's working memory model that supports VERBAL (auditory) working memory.

Stores phonological traces and supports mental rehearsal of verbal information. Easily disrupted by competing VERBAL tasks.

Examples: repeating a phone number in your head; holding a sentence in mind while reading.

Visuospatial Sketchpad

A component of Baddeley's working memory model that supports VISUAL working memory.

Stores object features, their location, and perhaps their movement. Easily disrupted by competing VISUAL tasks.

Examples: holding a mental map in mind; visualizing an object's shape.

Dual-Task Paradigms

Experimental paradigms used to test working memory independence.

If two tasks can be completed with as much efficiency as one, they are likely drawing on INDEPENDENT mental resources (e.g., auditory + visual tasks can be done simultaneously).

Two tasks requiring the SAME resource will interfere (e.g., two auditory tasks OR two visual tasks will interefere with each other).

Long-Term Memory

Storage of information over an extended period — seconds to decades.

The "hard drive" of human memory.

Encoded via LONG-TERM POTENTIATION (LTP) — a structural change in neurons.

Long-term memories are often outside of conscious awareness but can be called into working memory when needed. Frequently accessed memories become stronger and easier to recall.

Declarative / Explicit Memory

Long-term memory that can be CONSCIOUSLY declared (facts, events).

Includes:

1. Semantic memory — factual knowledge independent of time and place (e.g., how a pencil works)

2. Episodic memory — theoretical knowledge of a specific moment in time and place (e.g., what you did yesterday).

Most types of amnesia affect EPISODIC memory.

Semantic Memory

A type of DECLARATIVE long-term memory involving factual knowledge INDEPENDENT OF TIME AND PLACE.

Examples: knowing the names of countries on a map, knowing what a pencil is for, general knowledge about the world.

Contrasted with episodic memory, which is tied to specific events.

Episodic Memory

A type of DECLARATIVE long-term memory involving knowledge of a SPECIFIC MOMENT IN TIME AND PLACE.

Examples: what you did yesterday, your high school graduation, your first day of college.

Most types of amnesia discussed in this course affect episodic memory.

Procedural / Implicit Memory

Long-term memory involving memory for PROCEDURES, SKILLS, and ACTIONS. Mostly unconscious and unintentional (things people don't purposely try to remember).

Not verbally articulated. Focused on step-by-step processes needed to complete a task.

Thought to be encoded by the CEREBELLUM and BASAL GANGLIA.

Examples: riding a bike, driving a car, knowing how to dress yourself.

Preserved even in severe amnesia cases (e.g., H.M., Clive Wearing).

Hippocampus

A "curly," seahorse-shaped structure in the MEDIAL TEMPORAL LOBE, one on each side.

Very important for EPISODIC MEMORY (anterior + body) and SPATIAL NAVIGATION (posterior).

Key for memory consolidation — acts as a "gateway" or "pointer" system to distributed long-term memory.

Damage → anterograde amnesia and some retrograde amnesia.

Site of LONG-TERM POTENTIATION (LTP).

Larger in London taxi drivers with more experience.

Long-Term Potentiation (LTP)

A "coincidence detector" that changes neuron STRUCTURE and is thought to underlie the formation of long-term memories.

Occurs at the hippocampus.

When two neurons fire together repeatedly, their connection strengthens — "neurons that fire together, wire together."

The cellular basis of memory formation.

Mammillary Bodies

A pair of small round bodies on the undersurface of the brain, part of the LIMBIC SYSTEM. Part of the diencephalon.

They play a key role in MEMORY FORMATION.

Damaged in KORSAKOFF'S SYNDROME and in patient N.A. (damage from a fencing foil).

Korsakoff's Syndrome

An IRREVERSIBLE syndrome usually caused by CHRONIC ALCOHOLISM → vitamin B1 (thiamine) deficiency → lesions in MAMMILLARY BODIES and THALAMUS.

Symptoms:

• Abnormal eye movements

• Loss of coordination (ataxia)

• Tremors

• Confusion

• CONFABULATION

• Apathy

• SEVERE ANTEROGRADE and some retrograde memory impairment.

Compare to reversible Wernicke's encephalopathy.

Can lead to Alcohol-Induced Dementia.

Confabulation

The unconscious fabrication of false memories — the patient believes them to be true and is not deliberately lying.

A hallmark symptom of KORSAKOFF'S SYNDROME.

Patients fill in memory gaps with invented information without awareness that they are doing so.

Wernicke's Encephalopathy

The REVERSIBLE precursor to Korsakoff's syndrome.

Abrupt onset of classic triad:

1. Encephalopathy (brain disorder)

2. Ophthalmoplegia (eye paralysis)

3. Ataxia (loss of coordination).

Caused by THIAMINE (Vitamin B1) DEFICIENCY, usually from chronic alcoholism.

REVERSIBLE with thiamine treatment — if untreated, may progress to irreversible Korsakoff's syndrome.

Can lead to Alcohol-Induced Dementia.

Amygdala

A structure located in the medial temporal lobe near the hippocampus.

Plays a key role in EMOTIONS such as fear and pleasure. Involved in EMOTIONALLY CHARGED MEMORY STORAGE.

Central to the limbic system together with the hippocampus.

Key structure damaged in Klüver-Bucy syndrome.

Thalamus

The "relay station" to the cerebral cortex; also involved in memory through diencephalic pathways

Amnesia

Memory loss caused by brain damage or disease (also temporarily by sedatives/hypnotic drugs). Memory can be wholly or partially lost depending on the extent of damage.

Key symptoms:

1. Memory loss

2. INABILITY TO IMAGINE THE FUTURE — amnesiacs with damaged hippocampus cannot imagine future events because they use past experiences to construct future scenarios

Caused by:

• Traumatic brain injury

• Infection

• Surgery

• Psychological trauma

Anterograde Amnesia

Memory loss where NEW EVENTS ARE NOT STORED in long-term memory — inability to transfer new information from short-term to long-term store.

Patient examples: H.M., Clive Wearing, and N.A.

Working memory and procedural memory are typically PRESERVED.

Patient H.M. (Henry Molaison)

The most famous brain in psychology.

Surgery to cure severe epilepsy removed bilateral parts of temporal lobes (hippocampus, amygdala, entorhinal cortex).

Left with SEVERE ANTEROGRADE AMNESIA and mild retrograde amnesia.

NO/mild problems with short-term or procedural memory — could learn new motor skills (e.g., mirror drawing) → Demonstrates that declarative and procedural memory are dissociable.

Died December 2008; donated brain to science.

Patient Clive Wearing

Struck by herpes virus encephalitis in the 1980s → profound amnesia.

Prior to illness: rising musician.

Left with SEVERE ANTEROGRADE AND RETROGRADE AMNESIA.

Memory window: ~30 seconds.

Still capable of playing complex piano and organ pieces (procedural memory SPARED!).

Greeted his wife joyously every time they met, even if she had just left the room.

Diary entries: "Now I am really, completely awake." — crossed out and repeated minutes later.

Patient N.A. — Mammillary Body Damage

At age 21, accidentally stabbed in the right nostril with a fencing foil by a roommate.

Damage: dorsomedial THALAMIC NUCLEUS and MAMMILLARY BODY.

Symptoms: severe anterograde amnesia, normal cognitive ability, ~2 years of retrograde amnesia.

Demonstrates that the mammillary bodies and thalamus are also critical for memory formation — not just the hippocampus.

Retrograde Amnesia

Memory loss with the INABILITY TO RECALL MEMORIES OF THE PAST, beyond ordinary forgetfulness.

Two types:

1. Temporally-graded — older memories are BETTER preserved than more recent ones (most common); memory worsens closer to the time of the brain injury

2. Non-graded/temporally-ungraded — information about a specific time frame is ABRUPTLY missing.

Patient example: Benjaman Kyle.

Benjaman Kyle

Found severely beaten outside a Burger King in 2004 with retrograde amnesia.

Remembered only fragments: believed he was born in Indianapolis, first name was Benjamin, probably attended Catholic school.

Forensic DNA testing in 2015 finally identified him as William Burgess Powell. No one knows what happened to him for ~20 years prior to the beating. His memory has not returned.

Transient Global Amnesia (TGA)

A sudden, TEMPORARY episode of memory loss generally lasting LESS THAN 24 HOURS (average = 6 hours). Recall of recent events simply vanishes. Personal identity is maintained. Otherwise normal cognition.

Triggered by physical or emotional stress. Increased risk with age and migraines.

During episode: person sounds like a "broken record," repeatedly asking questions.

When over: can make new memories, but no memories of the episode remain.

Mild Cognitive Impairment (MCI)

A TRANSITION STAGE between the mild cognitive decline of normal aging and the more serious decline of dementia.

~20% of population over 70. About 50% progress to dementia within 5 years; some never get worse; a few get better.

Criteria:

• Deficient memory (confirmed by another person)

• Essentially normal judgment and reasoning

• Largely normal activities of daily living

• Reduced performance on cognitive tests

Dementia

Progressive decline in cognitive function due to damage or disease beyond what might be expected from normal aging.

A SET OF SYMPTOMS arising from one of many specific disorders — NOT a single disease.

May occur at any adult age (earlier = developmental disorder). While likelihood increases with age, it is NOT a normal part of aging.

NOT the same as delirium.

Delirium

The ACUTE, common symptomatic manifestation of early brain dysfunction, for any reason.

Rapid, FLUCTUATING course developing over hours to days. NOT better explained by pre-existing dementia.

Key distinction from dementia: ACUTE and usually REVERSIBLE.

May be hyperactive (positive symptoms: agitation, hallucination, combativeness) or hypoactive (negative symptoms: flat affect, little speech, inability to follow commands).

Dementia vs. Delirium

Dementia: gradual onset (months-years), stable progressive course, usually NOT reversible.

Delirium: ACUTE onset (hours-days), rapid fluctuating course, usually REVERSIBLE.

Both involve cognitive decline but differ critically in speed of onset and reversibility.

Delirium is a common reason for incorrect dementia diagnosis.

Mini Mental State Exam (MMSE)

A widely used neuropsychiatric test with specific ranges to determine severity of dementia.

NORMAL > 27/30.

Lower scores indicate increasing severity of dementia.

One of the two main types of neuropsychiatric testing for dementia (the other is the CDR).

Clinical Dementia Rating (CDR)

A 5-point scale used to characterize six categories of cognitive and functional performance:

0 = None

0.5 = Very mild

1 = Mild

2 = Moderate

3 = Severe

Often used for selecting patients who can enter a clinical trial.

Laboratory Tests for Dementia

Rule Out Treatable Causes — Dementia symptoms could be secondary to another disease, and thus possibly treatable. Curing underlying medical conditions can stop or reverse dementia symptoms.

Tests include:

• Vitamin deficiency (e.g., B1/thiamine)

• Thyroid problems

• Liver problems

• Electrolyte alterations (e.g., calcium)

• Kidney function

Imaging Studies for Dementia

• Structural imaging (MRI/CT): Rule out treatable structural causes such as Normal Pressure Hydrocephalus (NPH)

• Functional imaging (PET scan): Check changes in brain metabolism — dementia is associated with lower overall brain metabolism

Normal Pressure Hydrocephalus (NPH)

IMPORTANT TO RULE OUT when considering dementia.

A chronic type of hydrocephalus in which increased CSF reaches stable elevated pressure but BRAIN TISSUE BECOMES COMPRESSED (not missing — unlike true dementia).

Classic triad:

• GAIT difficulties

• URINARY INCONTINENCE

• MENTAL DECLINE

Often misdiagnosed as Parkinson's, Alzheimer's, or senility.

Potentially TREATABLE unlike true dementia.

Alzheimer's Disease (AD)

The MOST COMMON form of dementia.

~26.6 million patients worldwide (2006). Most common > 65 years old, but early onset forms exist.

Also seen in DOWN'S SYNDROME (30-40 years old) — beta-amyloid gene is on chromosome 21.

Primary dementias differ by LOCATION of brain changes.

Nothing yet significantly delays or reverses AD.

Early Alzheimer's Disease

May begin 20+ years before diagnosis.

Initial problems with:

• LEARNING and MEMORY (especially recently learned facts — older memories maintained longer)

• PLANNING

• LANGUAGE (shrinking vocabulary, decreased word fluency)

• FINE MOTOR TASKS (apparent clumsiness from apraxia).

Moderate Alzheimer's Disease

Stage lasting about 2-10 years. Usually DIAGNOSED at this point.

Symptoms:

• Memory problems interfere with work/social life

• Personality changes

• Problems recognizing family/friends

• Language problems

  • Problems with speech production/comprehension; increasing paraphasias; reading/writing progressively lost

• Motor

  • Loss of coordination

  • Urinary incontinence

  • Inability to perform activities of daily living (ADLs)

• WANDERING

• SUNDOWNING

• LABILE AFFECT

~30% develop delusional misidentification syndromes (Capgras, Fregoli).

Wandering, Sundowning & Labile Affect

WANDERING: in AD patients, specifically refers to patients wandering AWAY/ESCAPING from their home.

SUNDOWNING: alteration/worsening in behavior in sync with circadian rhythm; co-occurs with wandering; proposed causes include fatigue and lower light levels in the evening.

LABILE AFFECT: excessive or rapidly changing emotional displays that do not match the situation (e.g., laughing at a funeral).

Severe Alzheimer's Disease

Most of cortex is seriously damaged and atrophied:

• Lost ability to communicate

• Cannot recognize family members

• Cannot care for self

• Language reduced to single words

• Extreme apathy and exhaustion

• Muscle mass deteriorates; patient becomes bedridden

• Death usually caused by external factors (e.g., pneumonia, pressure ulcers)

Plaques (Beta-Amyloid)

EXTRACELLULAR abnormal clusters of protein fragments that build up BETWEEN nerve cells in Alzheimer's disease.

Formed when sticky beta-amyloid protein pieces clump together. May block cell-to-cell signaling and activate immune cells causing inflammation and cell death.

NOTE: In Summer 2022, the key 2006 study suggesting beta-amyloid plaques are an important part of AD pathogenesis may have been FABRICATED.

Neurofibrillary Tangles (Tau Protein)

INTRACELLULAR twisted strands of tau protein found inside dead and dying nerve cells in AD.

Normally, tau protein helps keep intracellular transport tracks straight (like railroad tracks).

In AD: tau collapses into twisted tangles, tracks disintegrate, and transport of nutrients across the cell body and axons is INTERRUPTED.

Contrast with plaques: plaques are EXTRACELLULAR; tangles are INTRACELLULAR.

Theories About Causes of AD

1. Cholinergic hypothesis: acetylcholine deficiency — but current drugs not effective

2. Amyloid protein misfolding: beta-amyloid plaques — but vaccine that clears plaques doesn't help

3. Tau protein misfolding: do tangles cause neurodegeneration?

4. Herpes simplex virus: long-term inflammation

   1. Antidepressants (SSRIs)

   2. Sleep deprivation speeds onset

   3. The protein REST (active during fetal brain development) switches back on later in life to protect aging neurons; REST is down-regulated in AD patients

   4. Long-term inflammation from any cause

Treatments for Alzheimer's Disease

Nothing yet significantly delays or reverses disease.

• Prevention: mental stimulation, exercise, diet

• Drugs to help symptoms:

  • Acetylcholinesterase inhibitors — block the breakdown of the neurotransmitter acetylcholine

  • NMDA receptor antagonist — blocks overstimulation of NMDA receptor (which has a role in LTP)

• Drugs to modify disease:

  • Antibody-based immunotherapies — use antibodies to target plaques/tangles for clearance

  • BACE inhibitors — interrupts beta-amyloid production; current clinical trials not going well

  • RAGE inhibitors, tau-aggregation inhibitors, Ca-channel blockers

• Drugs to prevent disease:

  • Currently the same as disease-modifying drugs, but used very early in disease

Dementia with Lewy Bodies (DLB)

2nd most common cause of neurodegenerative dementia > 65.

Location: Diffuse + basal ganglia

Symptoms:

• FLUCTUATING COGNITION (great variations in attention/alertness hour to hour)

• Recurrent VISUAL HALLUCINATIONS

• MOTOR FEATURES OF PARKINSONISM

Overlaps with BOTH Alzheimer's (loss of cholinergic neurons) AND Parkinson's (loss of dopaminergic neurons).

Cognitive and motor symptoms occur CLOSE IN TIME.

Lewy bodies = protein clumps (alpha-synuclein + ubiquitin) inside neurons.

Fronto-Temporal Lobar Dementia (FTLD)

2nd most common dementia < 65; 4th most common > 65.

Strong GENETIC link.

Heterogeneous disorders with ATROPHY IN FRONTAL AND TEMPORAL LOBES with SPARING of parietal and occipital lobes.

Also called Pick's disease.

Most common dementia diagnosed BEFORE AGE 60.

Three main subtypes:

1. Fronto-temporal dementia — personality changes, disinhibition, problems with executive function

   1. Location: Frontal + temporal lobes

1. Semantic dementia — progressive naming loss, dramatic increase in visual creativity

   1. Location: Anterior temporal

2. Progressive non-fluent dementia — quiet, word production loss (also called Primary Progressive Aphasia)

   1. Location: Left Broca’s area

Posterior Cortical Atrophy (PCA)

More RARE.

Location: Posterior cortex

Previously called visual variant Alzheimer's disease.

Onset > 50 years old.

Symptoms:

• Initial PROMINENT VISUAL SYMPTOMS (visual field defects, contrast sensitivity, color discrimination, feature recognition problems)

• ACALCULIA (loss of math skills)

• LITTLE INITIAL DECLINE IN MEMORY (distinguishes it from typical early AD).

May eventually cause memory decline.

May be a variant of AD, Lewy body dementia, or other conditions.

Vascular / Multi-Infarct Dementia

2nd most common form of dementia overall.

Caused by LOTS OF TINY STROKES (multi-infarct). At least PARTIALLY PREVENTABLE.

Symptoms:

• Problems with recent memory

• Wandering

• Shuffling walk

• Loss of bladder/bowel control

• Emotional lability

• Difficulty with instructions

• Problems handling money

• Deficits may be PATCHY and LATERALIZED.

Risk factors: 80% history of HIGH BLOOD PRESSURE; also high cholesterol and diabetes — treat these to slow progression.

Chronic Traumatic Encephalopathy (CTE)

Also called Dementia Pugilistica.

Severe form of CHRONIC TRAUMATIC BRAIN INJURY from REPEATED CONCUSSIONS.

Affects career boxers (~15%), wrestlers, football players. Symptoms may begin YEARS OR DECADES after last brain trauma.

Symptoms:

• Declining mental ability

• Memory problems

• Parkinsonism

• Tremors and/or lack of coordination

• Speech problems

• Unsteady gait

• Inappropriate or explosive behavior

• Depression, anxiety, suicidality

• Brain changes

TREATMENT: NONE

Subcortical Dementias

Dementias that predominantly affect the BASAL GANGLIA along with cognitive decline.

Examples: Parkinson's disease, Huntington's Chorea, subdural hematoma, syphilis, AIDS dementia complex.

Symptoms:

• SLOWNESS OF MENTAL PROCESSING

• Forgetfulness

• Impaired cognition

• Apathy

• Depressive symptoms

• Loss of social skills

• EXTRAPYRAMIDAL FEATURES (tremors and abnormal movements)

• In Huntington's: first clinical feature is often PERSONALITY CHANGE

Cortical vs. Subcortical Dementia

CORTICAL dementia (e.g., Alzheimer's):

• Earliest symptoms are HIGH-LEVEL BEHAVIORS — memory, language, problem-solving, abstract thought

• Prominent apraxia and agnosia

• Motor features appear later

SUBCORTICAL dementia (e.g., Parkinson's):

• Earliest symptoms are SLOWNESS OF PROCESSING, apathy, and movement issues

• High-level behaviors less affected early

• Extrapyramidal features (tremors, abnormal movements) are EARLY and PROMINENT

Primary dementias differ by LOCATION

Secondary dementias differ by CAUSES