Biopsychology of MemoryBiopsychology of Memory

What is Memory?

The storage of information about our experiences

Major Research Questions

• What is the biological substrate(s) of memory?

• Where are memories stored in the brain?

• How are memories accessed during recall?

• What is the mechanism of forgetting?

Early Hypotheses about the Brain Substrates of Memory

• Two prominent psychologists

- Karl Lashley

- Donald Hebb

Karl Lashley

• Studied memory of complex maze learning in rats

• Design:

-train lesions of the cortex test their memory

• Results:

- only large lesions of the cortex produced deficits

- similar deficits were obtained no matter where the

cortical lesion was located

Lashley’s Two Principles

1. Principle of Mass Action ~ Memories for complex tasks are stored diffusely throughout the neocortex.

2. Principle of Equipotentiality ~ All parts of the neocortex play an equal role in the storage of memories for complex tasks.

IMPORTANT POINT:

Lashley’s research discouraged thinking about localized regions important for memory

Donald Hebb - 1949ff

• Two memory systems

- short-term storage system

- long-term storage system

• Short-term storage = reverberatory activity

• Long term storage = structural change

• Different substrates for short- vs. long-term storage

• Transfer from short- to long-term storage =

CONSOLIDATION OF MEMORY

The Evidence for Hebb’s Consolidation Theory

• RETROGRADE AMNESIA

Russell and Nathan - 1949

- World War II concussions

- Short-term or recent memory was vulnerable

- Long-term or older memory was resistant

CONSOLIDATION MODEL OF MEMORY

Short-term (recent) memory (vulnerable)

Consolidation process

Long-term (older) memory (resistant)

Experimental Evidence for Consolidation Theory

Pinel (1969)

niche

Water bottle

Pinel (1969)

• Design:

Days 1-5 Exploration of Box, no water present

Day 6 1. Water present, rats drink

2. Electroconvulsive shock (ECS) given

at various times after drinking

Day 7 Retention Test - count niche explorations

Squire et al. 1975

• ECS treatments in depressed humans • Two memory tests - one before, one after ECS treatments - pick from a list of T.V. shows those that played for only one season - some shows were from 1-3 years before ECS, some from 4-5, 6-7, 8-9, and 10-17 years previously.• RESULTS: - Retrograde amnesia for events that occurred from 1-3 years prior to ECS - consolidation of memory can continue for a long time period

The Case of H.M.

• Epileptic seizures

• William Scoville, 1953 – Neurosurgeon

• Bilateral medial temporal lobectomy

• Brenda Milner – Neuropsychologist

H.M.’s Memory Deficit

Retrograde Amnesia - Loss of some memories for information learned before (3 years) the surgery

Anterograde Amnesia – Inability to form enduring memories for events occurring after the surgery

Intact short-term memory

H.M. - Formal Testing for LTMLong-term Memory Tests – Deficient• Digit Span + 1 test• Matching to Sample• Maze LearningPerceptual Tests - Normal• Gollin Incomplete Pictures Test• Mooney Face Perception TestLong-term Memory Tests – Normal• Mirror drawing • Rotary pursuit • Pavlovian trace eyeblink conditioning • Gollin incomplete pictures• Tower of Hanoi Puzzle

Digit Span + 1 Test

• 1,3,2,7,9

• 1,3,2,7,9,6,

• 1,3,2,7,9,6,4

• etc.

Explicit Memory(Declarative)

• Memory that is directly accessible to conscious recollection

• Memory of facts, events

- “knowing that” something happened

• Memory with record

• Impaired with medial temporal lobe damage

Implicit Memory(Procedural)

• Memory not accessible as specific facts or data• Memory that is contained within learned skills or

cognitive operations -“knowing how”• Expressed only in performance - motor skill learning - cognitive skill learning• Not impaired with medial temporal lobe

damage

What has H.M. taught us about the neural substrates of memory?

• The importance of the medial temporal lobes• There is localization of function for memory• Different brain structures for short- and long-term

memory• Medial temporal lobes contribute to memory

consolidation• Memories are not permanently stored in the medial

temporal lobes• Different brain structures for “explicit” vs.

“implicit” memory

H.M.’s MRI Scans

The Contribution of the Hippocampus

• Corsi – 1970

• Case R.B. - 1986

Zola-Morgan et al. (1986)

• Case R. B.

• Severe ischemic episode hypoxia

• Extensive memory tests

- Story recall

- Paired associates recall ~ 10 pairs of words

Dog – Umbrella

Car – Face

Mask - Pencil

- Diagram recall

Zola-Morgan et al. - cont

• R.B. died in 1983

• Obtained brain 4 hours after death

• Brain Pathology

- Hippocampus

1. CA1 subfield gone

2. 4.6 million neurons missing

• Little, if any, damage to other brain areas

HIPPOCAMPAL ANATOMY

Rempel-Clower et al. (1996)

• Three additional cases

• GD, LM, WH

• All suffered from cardiovascular problems

- hypotension

- ischemia during surgery

- seizures with respiratory distress

Patient GD

• Bilateral cell loss in hippocampal CA1 subfield

• Other hippocampal subfields intact

• Extra-hippocampal cell loss

- small region of the left amygdala

- small region of the left fornix

- region in the right globus pallidus

Patient LM

• Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields and dentate gyrus

• Extra-hippocampal cell loss

- Entorhinal cortex (layers II and III) – major source

of input to hippocampus

- minor cell loss in areas of cortex and cerebellum

Patient WH

• Bilateral cell loss in hippocampal CA1, CA2, CA3 subfields, dentate gyrus

• Extra-hippocampal cell loss

- entorhinal cortex

- subiculum

- fornix, striatum, pons

Important implications for the effects of cardiac arrest and

cardiovascular disease on brain integrity

Two Questions

• How does ischemia/hypoxia damage the hippocampus?

• Why the selective damage (e.g., CA1 damage) in some cases?

Animal Models of Ischemia• Davis – 1986 - Radial arm maze to assess spatial memory in rats - Design: 1. 30 min. ischemic period (carotid artery clamp) 2. 30 day recovery period 3. Maze training - Results: 1. ischemic rats demonstrate memory impairments 2. cell loss in hippocampal CA1 subfield

How Does Ischemia/Hypoxia Cause Hippocampal Damage?

• Microdialysis: - ischemia elevates glutamate in the hippocampus• How? ischemia/hypoxia anoxic depolarization of glutamate bouton

1. Excessive glutamate release 2. Reversal of the glutamate reuptake system additional glutamate release

Two Effects of Excess Glutamate on the Postsynaptic Hippocampal Neuron

• Early, immediate effect

• Delayed effect over a 24 hour period

Early, Immediate Effect of Glutamate

Excess glutamate release

Extended period of depolarization in postsynaptic cell

Excessive Na+ influx

Water pulled osmotically into neuron

Neurons swell and burst

Delayed Effect of Glutamate• Neurons demonstrate morphological and

biochemical signs of disintegration over 24 hour period

• Dependent on the presence of CA++ in the extracellular fluid

• Glutamate receptors: Kainate receptor AMPA “ NMDA “ mGlu “ class

The Glutamate NMDA Receptor(N-methyl-D-aspartate)

• Associated with Ca++ ion channel• At rest, Ca++ channel blocked by magnesium ion

• Sufficient depolarization from Na+ influx thru’ kainate and AMPA receptor Na+ channels

ejects magnesium ion

permits Ca++ flow into soma activation of numerous enzymes, 2nd messengers

The NMDA Receptor – cont.

Abnormally excessive glutamate release

Prolonged period of Ca++ influx

Excessive activation of enzymes

Delayed cellular disintegration

What Evidence Points to the NMDA Receptor in Ischemia?

• Gill et al. (1987)

1. ischemia elevates glutamate in hippocampus

2. lesion of perforant pathway

(major glutamate input pathway to hippocampus)

prevents ischemia cell death in CA1 region

3. MK – 801, a glutamate receptor antagonist

Protects against ischemic cell death in CA1 region

HIPPOCAMPAL ANATOMY

Why the selective damage to the CA1 region in some humans?

• Probable Answer(?)

The CA1 region has the highest concentration of glutamate receptors in the brain.

Animal Models of Medial Temporal Lobe Amnesia

• Tests of Memory

Monkey:

- Nonrecurring-Items Delayed Nonmatching-to-

Sample Test (DNMS) - Explicit memory

- Delayed Response Task - Explicit memory

- Barrier Motor-Skill Task - Implicit memory

- Lifesaver Motor-Skill Task – Implicit memory

Rats:

- Mumby Box - Explicit memory

Characteristics of Human Amnesia Produced by MTL lesions in Monkeys

• Memory impaired on several tasks including ones identical to those failed by human patients.

• Memory impairment exacerbated by increasing the retention delay.

• Memory impairment is not limited to one sensory modality.• Memory impairment is enduring.• Skill-based memory is spared. • Immediate memory is spared.

What Areas in the Temporal Lobe Contribute to Memory

Consolidation?

• Hippocampus

• Neocortex

• Amygdala

Zola-Morgan et al. (1980s-1990s)

• Is the hippocampus the only medial temporal lobe structure important for memory consolidation?

• Compared DNMS scores across experiments:

-Hippocampal plus surrounding cortex lesions (H+)

-Hippocampal plus amygdala plus all surrounding

cortex lesions (H+A+)

1. The medial temporal lobectomy monkey

Result:

The H+A+ lesion produces the greatest deficit.

Why does H+A+ lesion produce more memory impairment than the H+

lesion?• Possibilities:

1. The amygdala contributes to explicit memory

OR

2. The cortex surrounding the amygdala contributes

to explicit memory

Zola-Morgan et al.

• Five groups of monkeys

1. Group A amygdala lesion, spared the cortex

2. Group H+ hippo. lesion plus surrounding cortex

3. Group H+A hippo. lesion plus surrounding

cortex plus amygdala lesion

4. Group H+A+ Hippo. plus surrounding cortex

plus amygdala plus surrounding

cortex lesion

5. Group N Unoperated Control

Zola-Morgan et al.

• Results:

Group A no deficit

Group H+A

Group H+

Group H+A+ worse than all other groups

Conclude:

1. Amygdala doesn’t contribute to explicit memory

2. Cortex surrounding the amygdala may contribute

similar deficits

A Dissociation of Hippocampal vs. Amygdala Memory Function in

Humans

Declarative (Explicit Memory)

(Hippocampal Function)

versus

Emotional Memory

(Amygdala Function)

Bechara et al. (1995)

Three patients:

- one with bilateral hippocampal damage (H+)

- one with bilateral amygdala damage due to

Urbach-Wiethe Disease (A)

- one with bilateral medial temporal lobe

damage (H+A+)

Normal control group: no brain damage (n=4)

Bechara et al. - cont.• Pavlovian Conditioning Task

• Procedure:

- present green, blue, yellow and red slides

Blue slide 100 decibel boat horn

(Conditioned Stimulus) (Unconditioned Stimulus)

Skin Conductance Response

(Unconditioned Response)

(Sympath. Nerv. System

Activation)

Bechara et al. – cont.

• Pavlovian Conditioning:

- Over repeated slide presentations (trials):

Subject learns that blue slide predicts aversive US

Blue slide elicits learned anticipatory anxiety

indicated by the SCR

Conditioned Response

• Five minutes following conditioning trials:

- subjects asked four questions to assess declarative

memory (memory for facts)

Bechara et al. - cont.

Four Questions:

1. How many different colors did you see?

2. Tell me the names of the colors?

3. How many different colors were followed by the horn?

4. Tell me the name(s) of the colors that were followed by the horn?

Bechara et al - cont.

• Results:

• Normal group conditioned SCR

good declarative memory

• Amygdala lesion no conditioned SCR

normal declarative memory

• Hippo. lesion normal conditioned SCR

no declarative memory

• MTL lesion no conditioned SCR

no declarative memory

Bechara et al. - cont.

Conclusion:• A Double Dissociation• Amygdala contributes to the formation of

emotional memories (fear, anxiety)• Hippocampus contributes to the formation

of explicit (declarative) memories

Amygdala vs. Hippocampal Damage in Monkeys

• A double dissociation similar to humans

Why does the H+A+ lesion produce a more severe impairment than the H+A

or H+ lesion?• Is it do to damage to cortex which surrounds the

amygdala?

• What is the cortex?

Perirhinal and Parahippocampal Cortex

Entorhinal Cortex

Hippocampus

Zola-Morgan et al.

• DNMS Task

• Three groups:

1. Group N

2. Group H+A+

3. Group PRPH perirhinal/parahippocampal

lesion

Result: PRPH Group severe deficits comparable to

H+A+ Group

Conclude: The critical area may reside in PRPH cortex

What about the hippocampus by itself?

Murray and Mishkin (1998)

• Compared AH vs. perirhinal (Rh) cortical lesions in monkeys

• DNMS Test• Result:

- Absolutely no effect of the AH lesion

- Severe deficit with Rh lesion• Important point:

- Rh lesions do not produce retrograde amnesia

Mumby and Pinel (1994)

• Compared AH lesions vs. perirhinal cortex lesions in rats

• Mumby Box Test

• Results:

- Little effect of AH lesion

- Significant effect of perirhinal cortex lesion

But…..What about R.B.and G.D.???

• Rather selective damage to hippocampal CA1 subfield produced substantial anterograde memory impairments

• The Problem:

Why does limited damage to the hippocampal subfields produce significant memory deficits whereas only minimal or no deficits occur with total removal of the hippocampus???

Mumby et al. (1996)

• Three groups of rats:

1. Ischemia Sham lesion Mumby box

2. Ischemia Hippo. lesion Mumby box

3. Ischemia Hippo. Lesion Mumby box

Result??

- Group 2 demonstrated normal memory

- Group 3 demonstrated severe memory deficit

1 hr.

1 hr.

1 wk.

Mumby

Ischemia

Hypothesis

Cort.

CA1

Cort.

Cortical glutamate neuron

Perforant path

Excess glutamate release

Hippocampal CA1 neuron (becomes hyperactive and dies)Excess glutamic acid

Cortical neurons(become dysfunctional) memory impairment

Is There a Function for the Hippocampus in Memory?

The Evidence for a Function:

Selective hippocampal lesions in rats

Deficits:

1. Morris Water Maze

2. Radial Arm Maze

A Contribution for the hippocampus in spatial memory

A Hippocampal Function in Memory? – cont.

Additional evidence for a role in spatial memory:

Hippocampal size in different species of birds

- Homing pigeons have a larger hippocampus

- Birds that store seeds in wide-spread caches have a

larger hippocampus than non-seed storing species

- Black-capped chicadee:

hippocampal size increases in the fall

A Hippocampal Function in Memory?

• London Taxi Drivers - posterior hippocampal region enlarged compared to comparison group - anterior hippocampal region reduced in size - drivers with more experience have a larger posterior, but smaller anterior, hippocampus than less experienced drivers Suggests: - the experience of navigating may have led to the enlargement

Can the Adult Brain Generate New Neurons?

Gage and colleagues (1997ff.)

• Stem cells - adult mouse hippocampal dentate gyrus

- versatile cells

- resemble stem cells in the developing embryo

- continuously divide

- many die soon after division

- some mature into dentate gyrus granule cells

- the process of neurogenesis

• QUESTION: How can neurogenesis be enhanced?

Gage et al. (1997)• Adult mice – two genetically identical groups• Two living conditions for 40 days - standard laboratory cages - enriched living condition - complex environment• Results: - enriched mice 1. larger dentate gyrus (young adult) 2. 15% more dentate gyrus granule cells 3. significantly faster learning in Morris water maze

Gage et al. (1999)• Adult mice• Two living conditions: - standard cage - standard cage plus running wheel (4.78 km/day)Result: Runners - enhanced neurogenesis - enhanced performance in Morris Water maze when tested 30 days into housing condition POSSIBILITY: New neurons may contribute to improved memory???

What About Neurogenesis in the

Primate Brain?

Gould et al. (1998)

• Adult Monkeys

- neurogenesis in the adult dentate gyrus

• Stress and neurogenesis:

adult males placed in unfamilar colony

1. subjected to aggression/stress by dominant males

2. reduced number of developing dentate granule cells

3. Glucocorticoids inhibit hippocampal neurogenesis

Does Neurogenesis Occur in the Human Brain?

• Erickson et al. (1998)

- made use of DNA marker (BrdU) used in mice

- only labels DNA in cells (i.e., stem cells) preparing

to divide

- marker inherited by daughter cells and future

descendants of original dividing cell

- BrdU will be observed in mature neurons

- given to certain cancer patients to monitor tumor

growth rate

Erickson et al. - cont.

- examined hippocampus of five deceased patients

- each displayed new dentate gyrus granule cells

A Hippocampal Function in Memory??

• Hippocampal place cells

- respond when the rat is in a particular place its

environment

- their place response takes several minutes to

develop while the rat explores a new environment

CONCLUSIONS:

One specific function of the hippocampus is the storage of memories for spatial location

MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA

• Korsakoff’s Syndrome - chronic alchoholism - anterograde Amnesia - severe retrograde amnesia - damage to the diencephalon - thiamin (vitamin B1) deficiency 1. mammillary bodies (hypothalamus) 2. thalamic mediodorsal nucleus - Case N.A.

MEDIAL TEMPORAL LOBE VS. DIENCEPHALIC AMNESIA

• Diencephalic

Amnesia Similar Memory

• Medial temporal Dysfunctions

lobe amnesia

• The mammilary bodies, mediodorsal thalamus and temporal lobe structures which contribute to memory may be components of the same circuit

What are the physiological/structural changes

that form the substrate for memory?

A focus on the hippocampus

Long-term Potentiation (LTP)

• The enduring facilitation of transmission across a synapse as a function of repeated activation

• First observed in the hippocampus – 1973

• Occurs at several different hippocampal synapses

• Occurs in numerous brain areas

• Can be induced in a matter of seconds

• Can last for months

• Can be studied in the hippocampal slice preparation

LTP: TWO CONDITIONS REQUIRED

2 - Depolarization of Sufficient Magnitude

1 –Transmitter Release

1. 1 and 2 must occur concurrently.

2. Both occur with high frequency stimulation (tetanus) of the entorhinal cortex

Entorhinal Entorhinal Cortex NeuronCortex Neuron

Dentate Gyrus Dentate Gyrus NeuronNeuron

Stim-ulatehere

Perforant path

LTP from concurrent activation of two different inputs

1. 1 and 2 must occur concurrently.

2. Depolarization 1. Transmitter release

Conditioned Stimulus

Unconditioned Stimulus

Conditioned Response

Perforant path

LTP occurs here

LTP: MECHANISM

EXPERIMENT 1:

• Hippocampal slice

• Apply NMDA receptor antagonist

• Apply high frequency stimulation to induce LTP in dentate gyrus neurons

RESULT: LTP IS BLOCKED

CONCLUSION:

1. Glutamate is necessary for LTP to occur

2. NMDA receptor activation is also necessary

LTP: MECHANISM

EXPERIMENT 2.:

• Hippocampal slice

• Apply high frequency stimulation to induce LTP

in dentate gyrus neurons

• Reduce Ca++ activity in the post-synaptic neuron

RESULT:

1. LTP is blocked

CONCLUSION:

2. Ca++ is necessary for LTP

LTP: MECHANISM

CONCLUSIONS:

1. NMDA receptors are necessary for LTP

2. Ca++ is necessary for LTP

What is the Role of Calcium?

CA++ enters via NMDA Receptors

activates CA++ dependent enzymes

protein synthesis nitric oxide synthesis

(retrograde transmitter)

Structural changes Structural changes

(post-synaptic cell) (pre-synaptic cell)

What are the structural changes produced by LTP that lead to enhanced

synaptic transmission?

1. Increased Receptors or Receptor Sensitivity

2. Increased Transmitter Release

3. Increased Number of Synapses

4. Structural Change of Dendritic Spine

LTP: Mechanism – cont.

• LTP blocked by inhibition of protein synthesis

• LTP blocked by blocking nitric oxide synthesis

Is There a Relationship Between LTP and Memory?

• Several lines of evidence point to one

1. NMDA receptor antagonists injected into the hippocampus or amygdala produce learning/memory deficits in different tasks

Some controversy in the results

2. LTP develops in the hippocampus or amygdala

during different forms of learning

3. Genetic alterations of LTP mechanisms

The Relationship Between LTP and Memory during Fear Conditioning?

• Rogan et al. (1997)

- Pavlovian fear conditioning in rats

- Tone (CS) footshock(US) (paired trials)

- Tone comes to elicit fear reflected in freezing (CR)

over trials

- Lesions of the lateral amygdala block freezing CR

Rogan et al. – cont. Design:

- two groups of rats:

1. Group 1 Paired trials

2. Group 2. Unpaired trials

- recorded population response to tone from lateral amygdala

- three phases of the conditioning procedure

1. Pre-training– recorded response to tone alone

2. Training – recorded response during paired and

unpaired trials

3. Test phase (1 day later) – recorded

response to tone alone

Rogan et al. - cont Results:

- Population response became larger in rats receiving paired trials than in rats receiving unpaired trials

- Larger population response was present in rats receiving paired trials during the test phase 24 hrs. after training

Conclude:

- Response of lateral amygdala neurons to tone is

enhanced as a function of learning

- Suggests that an LTP mechanism may be the

substrate for the enhancement

Genetic Alterations of LTP Mechanisms and Effects on Learning

• The “Knock-out” mouse model - mice deficient in the genes necessary for the production of NMDA receptors, CA++ - dependent

enzymes, etc. Recall: 1. CA++ enters the NMDA receptor channel 2. CA++ activates enzymes Structural changes LTP

Tsien et al. (1996)

• Created a “knockout mouse”

- deficient in gene responsible for an essential

subunit of hippocampal CA1 NMDA receptors

- renders the CA1 NMDA receptors non-functional

Results:

- deficient in LTP at CA1 synapses

- deficient in learning in Morris water maze

What happens if you increase the function of NMDA receptors?

Will you facilitate LTP and learning?

Tang et al. (1999)

• Created a mouse with a type of NMDA receptor that stays open longer More CA++ influx

- the Doogie mouse - new receptor is located in various brain regions • Result: Compared to control mice Doogie mice

demonstrate - enhanced hippocampal LTP - enhanced fear memory - enhanced learning in the Morris water maze - enhanced visual object recognition memory

What are the Ca++ dependent enzymes?

• There are several called protein kinases

- Protein kinase C

- Type II Ca++/Calmodulin-dependent protein

kinase or CAM-KII

- Tyrosine kinase

What if we create a knockout mouse for CAMKII?

• Silva et al. (1992)

- CAMKII abundant in hippocampus

- Developed a mouse deficient in CAMKII mRNA

1. examined hippocampal LTP

2. examined spatial learning in Morris water maze

- Result:

1. deficient LTP

2. retarded Morris water maze learning

Will excess CAMKII produce LTP?

• Petitt et al. (1994)

- inject the hippocampal slice (CA1) with a virus

- virus causes CA1 cells to manufacture

LTP Develops During learning

• Mitsuno et al. (1994)

- Radial arm maze

- Experiment 1.

Two groups of rats:

1. Experimental group - maze learning

2. Control group – handled

Measured LTP in the hippocampus after 7 days of

maze training or handling

Result: Enhanced population spike in trained rats

Mitsuno et al.- cont.

• Experiment 2

- determine the amplitude of population spike each

day after maze training

Result:

- Population spike gradually increases over training

days in maze-trained, but not in handled group

Question: Does the increase in the population spike

really reflect memory or simply some

performance variable??

Does Learning Affect Neurogenesis in the Hippocampus?

• Gould et al. (1999)

Morris water maze training in rat

enhances survival of new neurons

in hippocampal dentate gyrus

net increase in number of new neurons

Question: Implications for Memory???

What other brain structures contribute to memory?

• The Dorsolateral Prefrontal Lobes

• Working memory = memory in the active state

- the memory that the organism needs and uses for

the performance of acts in the short term

- often called Short Term Memory

The Prefrontal Lobes and Working Memory

Fuster et al. (1995)

- monkeys

- cryoprobe to cool the dorsolateral prefrontal cortex

- delayed matching to sample task

- Result:

deficits at short delay intervals (e.g., 8 seconds)

Recall: Lesions of medial temporal lobe structures do

not produce delays at such short delay intervals

The Dorsolateral Prefrontal Lobes and Working Memory

• Fuster et al.

- delayed response task

- recorded from cells – dorsolateral prefrontal cortex

• Result:

- a type of neuron that only becomes active during

the delay period

- activity is specific to the memory task

- working memory cells???

The Dorsolateral Prefrontal Cortex and Working Memory

• Humans - frontal lobe damage

- damage produces deficits in delay tasks

- deficits similar to that observed in monkeys

• Humans – PET scan during working memory task

- Petrides et al. (1993ff)

- verbal working memory task

Petrides et al. (1993) – cont.

3. Externally ordered condition - experimenter reads numbers from 1-10, omitting one number - subjects asked to monitor the numbers carefully in order to determine which number was omitted• Pet scans performed under all conditions• Results: Increased activity in dorsolateral prefrontal cortex during the self- and externally-ordered conditions

Petrides et al. (1993)

• Verbal Working Memory Task

- three conditions

1. Control condition

- Count aloud from 1 to 10 repeatedly for 60

seconds

2. Self-ordered condition

- Say aloud the numbers 1-10 in random order

without repeating a number

- Start a new trial with the number 1

ALZHEIMER’S DISEASE

• The most common form of dementia.

3 Pathological Changes in the Brain:– Extensive Neural Degeneration

– Neurofibrillary Tangles• threadlike tangles in the neural cytoplasm

– Amyloid Plaques• Spherical clumps of scar tissue composed of

degenerating neurons interspersed with an abnormal protein called amyloid

ALZHEIMER’S DISEASE

ALZHEIMER’S DISEASE

• Pathological changes are prevalent in the structures of the medial temporal lobe and the basal forebrain.

• In addition to retrograde and anterograde amnesia, AD patients show some short-term memory loss and some implicit memory loss.

ALZHEIMER’S DISEASE

Patients with AD show a reduction in cholinergic (ACh) activity:

• Less acetylcholine• Less choline acetyltransferase (synthesis)• Less acetylcholinesterase (breakdown)

– Also lower levels of NE & 5-HT

ALZHEIMER’S DISEASE

TREATMENT

• Acetylcholine agonists tried as nootropics (memory-improving drugs), but have failed.

• Now developing acetylcholinesterase inhibitors that seem to be working (e.g., Rivastigmine; a.k.a. Exelon)– Shown to improve CNS function and daily

living over 6 month period.