cortex and memory

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Cerebral Cortex

Intellectual

Functions of the Brain

Learning and Memory



I, molecular layer;

II, external granular layer;

III, layer of pyramidal cells;

IV, internal granular layer;

V, large pyramidal cell layer;

VI, layer of fusiform or

polymorphic cells

Structure of the cerebral cortex

Cortex:100 billion neurons

2-5mm, 0.25m2

3 types of neurons:

-Granular ± interneurons

(glutamate/GABA)

-Fusiform ± output fibers from cortex-Pyramidal ± motor neurons



Cortical Areas

Somatosensory Motor Cortex Association



Functions of Specific Cortical Areas

Somatosensory area

Anterior parietal lobe




Primary Motor Cortex Area

First convolution of the frontal lobes




Association Areas

Receive and analyze signals simultaneously from multiple regions of

sensory and motor cortices



Functions of Specific Cortical AreasParieto-occipitotemporal Association Area

1. Analysis of the SpatialCoordinates of the Body

(computes

the coordinates of the

visual, auditory, and body

Surroundings)

2. Area for Language

Comprehension

(Wernicke¶s area --

it is the most

important region of the

entire brain for higher intel-

lectual function because

almost all such intellectual

functions are language

based)

3. Area for Initial

Processing of Visual

Language

(Reading)

4. Area for Naming Objects



Functions of Specific Cortical AreasPrefrontal Association Area

Broca¶s Area -provides the neural

circuitry for

word formation. Here

planned and formed

motor patterns for

expressing individualwords or

even short phrases



Prosophenosia - is

inability to recognize

faces.

This occurs in peoplewho have extensive

damage on the

medial undersides of

both occipital lobes and

along

the medioventralsurfaces of the temporal

lobes

Functions of Specific Cortical AreasArea for Recognition of Faces



Comprehensive Interpretative Function of the

Posterior Superior Temporal Lobe²³Wernicke¶s

Area´ (a General Interpretative Area)

-After severe damage in

Wernicke¶s area, a person

might hear perfectly well and

even recognize differentwords but still be unable to

arrange these words into

a coherent thought.

-Person may be able to read

words from the printed page

but be unable to

recognize the thought that is

conveyed.

-Person loses almost all

intellectual functions

associated with language,

ability to read, mathematical

operations, logic



Concept of the Dominant Hemisphere

The general interpretative functions of Wernicke¶s area and the

functions of the speech and motor control areas, are usually muchmore highly developed in one cerebral hemisphere than in the

other

This hemisphere is called the dominant hemisphere

In about 95 per cent of all people, the left hemisphere is thedominant one, in 5% either both sides develop simultaneously to

have dual functions or only right side alone becomes dominant

Being highly developed in only the left hemisphere, the

interpretative areas of the temporal lobe and motor areas receive

sensory information from both hemispheres and are capable also of controlling motor activities in both hemispheres by means of ¿ber

pathways in the corpus callosum which provides communication

between the two hemispheres

Q: What will happened if non-dominant hemisphere is severely damaged?



Concept of the Dominant

Hemisphere

Q: What will happened if non-dominant hemisphere is severelydamaged?

A: Patients will be unable to:

-understanding and interpreting music-understanding and interpreting nonverbal visual

experiences (especially visual patterns) and spatial

relations between the person and their surroundings

-understanding and interpreting the signi¿cance of ³body

language´ and intonations of people¶s voices-understanding and interpreting many somatic experiences

related to use of the limbs

Conclusion: the so-called nondominant hemisphere might

actually be dominant for some other types of intelligence!



Left Handed People vs. Right Handed People

-Researchers at Australian National University discovered that left-handed people can think quicker when carrying out tasks such as

playing computer games or playing sports, as connections between

the left and right brain hemispheres are faster in left-handed people

and they tend to use the whole brain more easily.



Left Handed People vs. Right Handed People

-mathematicians, musicians, architects, and artists are more commonly left-

handers than would be expected

-in one study of more than 100,000 students taking the Scholastic Aptitude Test

(SAT), 20% of the top-scoring group was left-handed, twice the rate of left-

handedness found in the general population (10%).-Left-handedness may also reduce the risk of developing arthritis

Advantages:

-Some studies have shown problems in language development in left-

handers

-Research has shown that left-handers are more likely to have problems withreading and they also "...don't do as well on phonology (the sound system of

language) tasks..." when compared with right-handers

-Canadian psychologist Stanley Coren book ´The Left-Handed Syndrome´

mention that left-handers, on average, lived about a decade less than right-

handers do.

Disadvantages:



Higher Intellectual Functions of the

Prefrontal Association Areas

-The main difference between the brains of monkeys and of humanbeings is the great prominence of the human prefrontal areas

-Prefrontal lobotomy - severing the neuronal connections between the

prefrontal areas of the brain and the remainder of the brain

What happened with patients:-Decreased Aggressiveness and Inappropriate Social Responses

-Inability to progress toward goals or to carry through sequential

thoughts (easily distracted from central theme of thought)

-Loss of ³Working Memory´ - ability of the prefrontal areas to keep

track of many bits of information simultaneously and to cause recall of this information instantaneously as it is needed for subsequent

thoughts



Memory



What is Memory?

Never observed, always inferred

Multiple memory systems

Critical elements are more likely to be stored

Passage of time changes our memories

Remembering is reconstruction

-Bartlett, 1932



Memory Storage Model

Information From Long TermThe Outside World Memory

ConsolidationSensoryRegister

Short-TermMemory

Spit Out (Forgotten)



Memory Terminology

1.Sensory Register :

Where sensory information is briefly retained

2. Short-Term Memory:

Information this is currently being used ormay be worth storing for later

Tested with the Digit Span Test (7 +/- 2items)

Example: Telephone number,SIN card #



Memory Terminology

3. Long-Term Memory:

Unlimited store of permanent memory

Examples: Autobiographic facts, important events



Applying This Concept

Long Term3 Items Memory

Sensory Short TermRegister Memory



Memory Terminology

-Many different taxonomies exist -Best defined based on memory type

2 main memory types:1. Declarative Memory (Explicit Memory):

Memories we can recount (events & facts)

2. Non-Declarative Memory (Implicit Memory):

Procedural Memory, Reflexes, Classic Conditioning



What about forgetting?

Amnesia: A loss or disruption of memory. It is

generally divided into 2 components:

1. Anterograde amnesia:

Impairment of memory for informationacquired after the onset of amnesia2. Retrograde amnesia:

The impairment of memory for informationthat was acquired prior to the onset of amnesia



Amnesia

Insult/Injury

Period of deficit

time

Retrograde Amnesia Anterograde Amnesia

Retrograde amnesia is often temporally

graded, following Ribots Law

Thus, there is a better memory for remoteevents than for more recent events



Ribot¶s Law

Premed exam material

Time

Event producing amnesia; HypoxicInjury at BBQ Post-Exam Party

Final Physyology exam material Final

Human anatomy exam material

Biochemistry exam material



Amnesia and Brain Trauma

Amnesia is associated with injury/damage tocertain brain structures, specifically the medialtemporal lobe

Causes of medial temporal lobe damage:

Herpes simplex encephalitis

Ischemic or hemorrhagic vascular event

Trauma

Alzheimers disease



Memory

Two fundamental questions:

1. Are specific parts of the brain responsible formemory?

Memory localization

2. How are memories encoded by the brain? Memory specification



Different Theories

Memories encoded as specific molecules(cannibalism in planaria, scotophobin)

Memory as a:

Warehouse

SwitchboardCellular/Synaptic/Molecular Event



Henry Gustav Molaison (February 26, 1926 ± December 2, 2008)



H.M. ± What to do?

Surgical solution proposed by William Scoville

Experimental surgery

Bilateral medial temporal lobe resection

Performed in 1953

Rostral half of hippocampus, amygdala andsurrounding cortex



Bilateral Removal of Hippocampus & Adjacent Areas



Medial Temporal Lobes



Outcome Following Surgery

Frequency of seizures reduced

However...

Unable to recognize hospital or staff Unable to familiarize himself with new people oractivities

Never hungry, thirsty or tired

Could not remember events for roughly 2 yearsbefore the surgery



Outcome Following Surgery

Recognized his family and friends

Can recognize and name common objects

Short-term memory is intact Remote (>2 yrs.) autobiographic memory intact

Exceptions to his memory problem:

Mirror Drawing



HM.-Summary.

Severe and global anterograde amnesia

Temporally graded retrograde amnesia

Intact perceptual, motor and cognitive functions

Intact immediate short term memory

Spared remote memory



H.M. - A Highly SelectiveMemory Disturbance

A selective memory disturbance in 2 ways:

1. Entirely isolated to a disorder of memory(distinguished from other higher-orderperceptual, motor, and cognitive functions)

2. Limited to particular domains of learning andmemory capacity

Almost no capacity for new declarative learning



What H.M. Taught Us

-Based on H.M.s findings,the structures withinthe medial temporal lobe must be crucial tocertain aspects of memory

-Conversely, H.M. proved that different types of

memory are mediated by other structures

-This case guided experimentation of the

hippocampus and its potential role in memory-Potential role of the amygdala in memory

-Memory research is an expanding field!



The Hippocampal MemorySystem

No universal agreement exists on what constitutes the hippocampal memory system

Critical structures have been identified:

Hippocampal ParahippocampalFormation region

Subcortical Cortical AssociationStructures Areas



The Hippocampal MemorySystem

Outputs(Via Subiculum)

Hippocampal ParahippocampalFormation region

Perforant Path

Subcortical Cortical AssociationStructures Areas



Working Memory and thePrefrontal Cortex

-Working memory (WM) is characterized as aform of declarative memory

Described as working with operations

Can be tested using computational digit span

Research links WM to Prefrontal Cortex (PFC)

Also known as the Operation CentreExecutive/sketch pad function



Cortical Association Areas

The PFC is one example of a cortical associationarea that is involved in memoryThese areas interact with the parahippocampal

region

Other cortical association areas include:

Temporal lobe

Parietal lobe But their roles haveyet to be elucidatedCingulate

Olfactory bulb



Cellular Mechanisms of Memory Consolidation

Now that we have outlined the structuresinvolved in memory; what happens within?

D.O Hebb (1949) and cell assembly:

If two neurons are excited together theybecome linked functionally

Over time, structural synaptic changes occur:

Neurons that fire together, wire together



Cellular Mechanisms of Memory Consolidation

T. Lomo (1970s) studied the pathway from the

entorhinal cortex to the dentate gyrus

He discovered that following tetanus (highfrequency electrical stimulation), a single electrical

impulse would result in: 1. A steeper slope (rise

time) of the EPSP 2. A greater number of dentate

cells recruited

-These changes would last for several hours-days

-He named this Long-Term Potentiation (LTP)



Long-Term Potentiation (LTP)

Although LTP is not exclusive, it is touted as thecellular mechanism responsible for memory:

Prominent feature of hippocampal physiology LTP develops very rapidly

LTP is long lasting

High specificity (i.e., only those synapsesactivated during the stimulation pathway arepotentiated)



Molecular Basis for Hippocampal LTP

Induction of LTP requires:

1.Activation of presynaptic inputs2. Depolarization of the postsynaptic cell

Glutamate is the principalN

T involvedCa2+ enters the post-synaptic cell



Establishment andMaintenance of LTP

What does all the calcium do?

1. The entry of Ca2+ into the post-synaptic cell

activates various kinases2. Increases in post-synaptic [Ca2+] are linked toprotein phosphorylation, including CREB 3.These downstream constituents (such as CREBand CaMK II) are directly related to synapticstrength, learning and memory1

1. Chinese Journal of Medicine. 2006. 119: 140-147



Hippocampal LTP and Memory

Emerging evidence of altered morphology:

- New growth of dendritic spines1

-Changes in synaptic morphology2

-Reorganization of actin skeleton3

Leads to an increase in synapse size3

1. The Journal of Neuroscience. 2006. 26(6):1813-1822

2. Synapse. 2003. 47:77-86 3. Synapse. 2008. AOP.



Summarizing

Damage to/removal of medial temporal lobestructures results in memory impairment Within the medial temporal lobe exists thehippocampus

The hippocampus communicates with othercortical and neocortical areas

LTP occurs in abundance within the

hippocampus and its associated areasLTP is touted as the cellular process underlyingmemory formation



Memory Loss in the Elderly

What is memory loss?

Impairment in the ability to learn new

information or to retrieve previously learnedinformation1

As we age, intellectual functioning remains

stable until a dementing illness develops

However, some memory lapses occur withnormal aging...

1. Annals of Internal Medicine. 2003. 138(5):411-420




Memory hiccups are common in normal aging

Unable to

Forgetting whereremember all items the car was parkedon the grocery list

Misplacing small

itemsForgetting names of casual contacts




These hiccups are mainly attributed to normal age-related declines in frontal lobe function

So when do you worry?

When these memory lapses interfere with onesinstrumental activities of daily living (I ADLs) Household chores, shopping, managing finances



As a Physician - What To Do?

The clinical approach to the elderly patient withconcerns of memory loss is dealt with in thestandard fashion

Beginning with a detailed history!

But here, a close family contact can be of helpto the physician Ask them!

Family members can accurately identify patientswith dementia and memory loss1

1. Archives of N

eurology. 1993.50: 92-97



Differential Diagnosis

Before jumping to dementia, you must rule out

other causes of memory loss in the elderly:

1.Depression:

Depressed elderly patients often report memory impairment

Can screen using the Geriatric Depression Scale

Take heed with interpretation; Depression isnearly 3 times as prevalent in the dementedpopulation1

1. Journal of N

europsychiatry and ClinicalN

euroscience. 1997. 9:270-275




2 Vitamin B 12 (cobalamin) deficiency:

-Found in beef, eggs, milk

-Strict vegetarians lack B-12!

No B-12 in fruits or vegetables

-Vitamin B12 deficiency has a prevalence of

roughly 20% in the elderly population

Primarily caused by food-cobalaminmalabsorption and pernicious anemia




4. Medication-Induced:

A. Benzodiazepines:

High doses can impair acquisition of information by

interfering with hippocampal LTP

B. Anti-psychotic medications (e.g., Haldol):

Likely due to their anticholinergic effect

C.Parkinsons medication (e.g. Sinemet):,

Increased dopamine (D A) leads to confusion



Dementia in the Elderly

Y ou carefully screen your patient and find:

- No evidence of depression

- No evidence of B12 deficiency- No bloodwork abnormalities

- No offending medications

Combined with the history you gathered, yoususpect a dementia



Dementia in the Elderly

Dementia: A progressive decline in two or morecognitive domains that is severe enough tointerfere with the performance of everyday

activities



Dementia

Alzheimer¶s

-Anterograde amnesia Non-Alzheimer¶s(repeating stories)

- Apathy + Depression Fronto-Temporal:

-Behaviour Changes

Vascular Dementia: - Anomia

-Same disease of blood Dementia withvessel as in heart diseaseParkinsonism:

- Risk Factors: HTN, DM2,- Motor difficultiesCholesterol,Smoking.

Genetic (rare)



Alzheimer¶s Disease

As disease progresses,memory worsens:

Word hesitancy

Difficulty initiating conversationDisease is not limited to memory

Mood and behaviour are also affectedPoor visuospatial and executive function

Thought process become loosely connected



Alzheimer¶s - Neuropathology

Collection of senile plaques

Marked cortical atrophy

Al h i ¶ d th



Alzheimer¶s and theCholinergic Hypothesis

Both animal and human studies have found that cholinergic antagonists impair memory and

learning Postmortem studies in Alzheimers patients

show a host of cholinergic abnormalities:

Alterations in choline transport and ACh release Altered expression of ACh receptors

Ph th f



Pharmacotherapy for Alzheimer¶s

In light of the cholinergic hypothesis,medications for Alzheimers exert a cholinergicinfluence:

1. Galantamine (Reminyl®):

AChE inhibitor and presynaptic nicotinicreceptor activator

2. Donepezil (Aricept ®): AChE inhibitor



But do They Work?

Meta-analyses of first studies (2003-2005)suggested marginal clinical improvement in

1 Alzheimers

Early studies were criticized for overly narrowtargets

Recent meta-analyses (with broader end-points) have shown benefit of Galantamine inmild-moderate Alzheimers2

1. British Medical Journal. 2005. 331: 321-328

2. Cochrane Database. 2008. Issue 1.



Tips On Avoiding Memory Loss

Diet

Physical activity

Brain exercisesProtect your brain

Wear your helmet and buckle up

Dont poison your brain :

Cocaine, amphetamines, Ecstasy

Ginkoba®



Ginkoba®

The Memory Enhancer?

Ginkgo biloba

Reported to enhance mental focus and

improve memory and concentration

Conflicting results in terms of efficacy

Only in specific populations in specific areas

Does it have an effect on healthy participants?

Most scientifically sound study: NO benefit!2

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