cortex and memory
TRANSCRIPT
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Cerebral Cortex
Intellectual
Functions of the Brain
Learning and Memory
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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
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Cortical Areas
Somatosensory Motor Cortex Association
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Functions of Specific Cortical Areas
Somatosensory area
Anterior parietal lobe
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Functions of Specific Cortical Areas
Primary Motor Cortex Area
First convolution of the frontal lobes
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Functions of Specific Cortical Areas
Association Areas
Receive and analyze signals simultaneously from multiple regions of
sensory and motor cortices
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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
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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
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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
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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
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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?
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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!
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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.
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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:
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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
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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
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Memory Storage Model
Information From Long TermThe Outside World Memory
ConsolidationSensoryRegister
Short-TermMemory
Spit Out (Forgotten)
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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 #
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Memory Terminology
3. Long-Term Memory:
Unlimited store of permanent memory
Examples: Autobiographic facts, important events
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Applying This Concept
Long Term3 Items Memory
Sensory Short TermRegister Memory
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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
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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
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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
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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
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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
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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
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Different Theories
Memories encoded as specific molecules(cannibalism in planaria, scotophobin)
Memory as a:
Warehouse
SwitchboardCellular/Synaptic/Molecular Event
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Henry Gustav Molaison (February 26, 1926 ± December 2, 2008)
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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
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Bilateral Removal of Hippocampus & Adjacent Areas
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Medial Temporal Lobes
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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
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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
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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
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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
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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!
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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
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The Hippocampal MemorySystem
Outputs(Via Subiculum)
Hippocampal ParahippocampalFormation region
Perforant Path
Subcortical Cortical AssociationStructures Areas
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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
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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
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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
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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)
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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)
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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
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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
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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.
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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
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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
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Memory Loss in the Elderly
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
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Memory Loss in the Elderly
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
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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
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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
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Differential Diagnosis
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
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Differential Diagnosis
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
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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
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Dementia in the Elderly
Dementia: A progressive decline in two or morecognitive domains that is severe enough tointerfere with the performance of everyday
activities
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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)
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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
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Alzheimer¶s - Neuropathology
Collection of senile plaques
Marked cortical atrophy
Al h i ¶ d th
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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
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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
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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.
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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®
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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