Cerebral Cortex

Intellectual
Functions of the Brain
Learning and Memory
 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

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
 Cortical Areas

Somatosensory Motor Cortex Association

Functions of Specific Cortical Areas
Somatosensory area

Anterior parietal lobe

Functions of Specific Cortical Areas
Primary Motor Cortex Area

First convolution of the frontal lobes

 Functions of Specific Cortical Areas
Association Areas

Receive and analyze signals simultaneously from multiple regions of

sensory and motor cortices
 Functions of Specific Cortical Areas
Parieto-occipitotemporal Association Area

1. Analysis of the Spatial

Coordinates 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 Areas
Prefrontal Association Area

Broca’s Area -
provides the neural
circuitry for
word formation. Here
planned and formed
motor patterns for
expressing individual
words or
even short phrases
 Functions of Specific Cortical Areas
Area for Recognition of Faces

Prosophenosia - is
inability to recognize
faces.
This occurs in people
who have extensive
damage on the
medial undersides of
both occipital lobes and
along
the medioventral
surfaces of the temporal
lobes
 Comprehensive Interpretative Function of the
Posterior Superior Temporal Lobe—“Wernicke’s
Area” (a General Interpretative Area)

-After severe damage in

Wernicke’s area, a person
might hear perfectly well and
even recognize different
words 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 much
more 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 the
dominant 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 fiber
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 severely
damaged?

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 significance of “body
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
Advantages:

-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

Disadvantages:
-Some studies have shown problems in language development in left-
handers
-Research has shown that left-handers are more likely to have problems with
reading 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.
 Higher Intellectual Functions of the
Prefrontal Association Areas
-The main difference between the brains of monkeys and of human
beings 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 “Working 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 Term

The Outside World Memory

Consolidation
Sensory
Register
Short-Term
Memory
“Spit Out” (Forgotten)
 Memory Terminology

1.Sensory Register:
 Where sensory information is briefly retained

2. Short-Term Memory:
Information this is currently being used or
may be worth storing for later
Tested with the “Digit Span Test” (7 +/- 2
items)
 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 Term
3 Items Memory

Sensory Short Term

Register 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 information
acquired after the onset of amnesia
2. Retrograde amnesia:
The impairment of memory for information
that 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 Ribot’s Law
Thus, there is a better memory for remote
events than for more recent events
 Ribot’s Law
Final Physyology exam material Final

Human anatomy exam material

Biochemistry exam material

Premed exam material

Time
Event producing amnesia; Hypoxic
Injury at BBQ Post-Exam Party
 Amnesia and Brain Trauma
„ Amnesia is associated with injury/damage to
certain brain structures, specifically the medial
temporal lobe
„Causes of medial temporal lobe damage:
 Herpes simplex encephalitis

Ischemic or hemorrhagic vascular event

 Trauma
 Alzheimer’s disease
 Memory

Two fundamental questions:

1. Are specific parts of the brain responsible for

memory?
 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
Switchboard
Cellular/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

Rostral half of hippocampus, amygdala and

surrounding cortex

Performed in 1953
 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 or
activities
Never hungry, thirsty or tired
Could not remember events for roughly 2 years
before 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 Selective
Memory Disturbance
A selective memory disturbance in 2 ways:

1. Entirely isolated to a disorder of memory

(distinguished from other higher-order
perceptual, motor, and cognitive functions)

2. Limited to particular domains of learning and

memory capacity
Almost no capacity for new declarative learning
 What H.M. Taught Us
-Based on H.M.’s findings,the structures within
the medial temporal lobe must be crucial to
certain 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 Memory
System
No universal agreement exists on what
constitutes the hippocampal memory system
Critical structures have been identified:

Hippocampal Parahippocampal
Formation region

Subcortical Cortical Association

Structures Areas
 The Hippocampal Memory
System
Outputs
(Via Subiculum)

Hippocampal Parahippocampal
Formation Perforant region
Path

Subcortical Cortical Association

Structures Areas
 Working Memory and the
Prefrontal Cortex
-Working memory (WM) is characterized as a
form 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 Centre
Executive/’sketch pad’ function
 Cortical Association Areas
The PFC is one example of a cortical association
area that is involved in memory
These areas interact with the parahippocampal
region
Other cortical association areas include:
Temporal lobe
Parietal lobe But their roles have
yet to be elucidated
Cingulate
Olfactory bulb
 Cellular Mechanisms of
Memory Consolidation
Now that we have outlined the structures
involved in memory; what happens within?
D.O Hebb (1949) and cell assembly:

If two neurons are excited together they

become 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 (high
frequency 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 the

cellular mechanism responsible for memory:

 Prominent feature of hippocampal physiology

 LTP develops very rapidly

 LTP is long lasting

 High specificity (i.e., only those synapses

activated during the stimulation pathway are
potentiated)
 Molecular Basis for
Hippocampal LTP

Induction of LTP requires:

1.Activation of presynaptic inputs

2. Depolarization of the postsynaptic cell

Glutamate is the principal NT involved

Ca2+ enters the post-synaptic cell
 Establishment and
Maintenance of LTP
What does all the calcium do?

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

activates various kinases
2. Increases in post-synaptic [Ca2+] are linked to
protein phosphorylation, including CREB 3.
These downstream constituents (such as CREB
and CaMKII) are directly related to synaptic
strength, 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 morphology 2

-Reorganization of actin skeleton 3

Leads to an increase in synapse size 3

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 lobe
structures results in memory impairment
Within the medial temporal lobe exists the
hippocampus
The hippocampus communicates with other
cortical and neocortical areas
LTP occurs in abundance within the
hippocampus and its associated areas
LTP is touted as the cellular process underlying
memory formation
 Memory Loss in the Elderly

„ What is memory loss?

“Impairment in the ability to learn new
information or to retrieve previously learned
information1”

„As we age, intellectual functioning remains

stable until a dementing illness develops 
However, some memory lapses occur with
normal aging...
1. Annals of Internal Medicine. 2003. 138(5):411-420
 Memory Loss in the Elderly

„Memory ‘hiccups’ are common in normal aging

Unable to
Forgetting where
remember all items
the car was parked
on the grocery list
Misplacing small
items
Forgetting names of
casual contacts
 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 ones

instrumental activities of daily living (IADLs) 
Household chores, shopping, managing finances
 As a Physician - What To Do?

 The clinical approach to the elderly patient with

concerns of memory loss is dealt with in the
standard fashion…
Beginning with a detailed history!
 But here, a close family contact can be of help
to the physician… Ask them!
„ Family members can accurately identify patients
with dementia and memory loss1

1. Archives of Neurology. 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 is
nearly 3 times as prevalent in the demented
population1
1. Journal of Neuropsychiatry and Clinical Neuroscience. 1997. 9: 270-275
 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-cobalamin
malabsorption and pernicious anemia
 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.Parkinson’s medication (e.g. Sinemet):, 
Increased dopamine (DA) leads to confusion
 Dementia in the Elderly

You 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, you

suspect a dementia
 Dementia in the Elderly

„ Dementia: A progressive decline in two or more

cognitive domains that is severe enough to
interfere 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
vessel as in heart disease Dementia with
Parkinsonism:
- Risk Factors: HTN, DM2,
Cholesterol,Smoking. - Motor difficulties

Genetic (rare)
 Alzheimer’s Disease

As disease progresses,memory worsens: 

Word hesitancy
Difficulty initiating conversation
Disease is not limited to memory
Mood and behaviour are also affected
Poor visuospatial and executive function
Thought process become loosely connected
 Alzheimer’s - Neuropathology
„ Collection of senile plaques
„ Marked cortical atrophy
 Alzheimer’s and the
Cholinergic Hypothesis
„ Both animal and human studies have found that
cholinergic antagonists impair memory and
learning
 Postmortem studies in Alzheimer’s patients
show a host of cholinergic abnormalities:
 Alterations in choline transport and ACh release
 Altered expression of ACh receptors
 Pharmacotherapy for
Alzheimer’s
 In light of the cholinergic hypothesis,
medications for Alzheimer’s exert a cholinergic
influence:
1. Galantamine (Reminyl®):
AChE inhibitor and presynaptic nicotinic
receptor activator

2. Donepezil (Aricept®):
 AChE inhibitor
 But do They Work?

„ Meta-analyses of first studies (2003-2005)

suggested marginal clinical improvement in
Alzheimer’s 1
„ Early studies were criticized for overly narrow
targets
 Recent meta-analyses (with broader end-
points) have shown benefit of Galantamine in
mild-moderate Alzheimer’s2
1. British Medical Journal. 2005. 331: 321-328
2. Cochrane Database. 2008. Issue 1.
 Tips On Avoiding Memory Loss

Diet
Physical activity
Brain exercises
Protect your brain
Wear your helmet and buckle up
Don’t poison your brain :
 Cocaine, amphetamines, Ecstasy
 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

1. JAMA. 1997. 278:1327-1332 2. JAMA. 2002. 288:835-840