WEEK 11– SLEEP AND WAKING- CHAPTER 11

Biorhythms
- Behaviours that occur at regular intervals in response to ‘biological clocks’
- What are some examples of biorhythms?
- Sleep and walking cycles follow circadian rhythms– repeat roughly every 23
hours
- Zeitgebers are stimuli that helps to establish and maintain biological rhythms
- ‘Zeit’ means ‘time’ in German, ‘gerber’ means to give
- What are some examples of zeitgebers?
- The human ‘free running’ circadian rhythm is 24.2 to 24.9 hrs… why?

Individual Variations in Sleep Patterns

Result form different versions of genes responsible for our internal clocks
- ‘Larks’ are morning people
- More positive emotions and subjective well-being
- ‘Night Owls’ are night people
- Most adolescents are owls
- Can be assessed with morningness/eveningness questionnaire

Morningness-Eveningness Questionnaire– sample item

What time would you get up if you were entirely free to plan your day?

The Big Five and Morningness-Eveningness

Why Are There Many Adolescent Night Owls?

- Teens sleep patterns reflect changes in melatonin release
- Melatonin hormone produced by pineal gland in response to darkness
- Promotes sleep
- Following adolescence, many people stop being night owls
- Possibly due to the maturation of the neural systems that regulate
sleep
- Some researchers believe that stable sleep patterns following
adolescence is an important indicator of brain maturity (a marker)
- Societal accommodations may be helpful
 - Wahlstrom et al. (2014) found that shifting from a 7:15 am start time to
an 8:40 am start time improved attendance and grades of students in
Minnesota high schools

Shift Maladaptation Syndrome

- ‘Night shift’ (11pm to 7am) can conflict with people’s natural circadian rhythm
and result in health problems and poor (dangerous) workplace performance
- DSM 5 recognizes ‘circadian rhythm sleep-wake disorders– shift work type
- Symptoms: excessive sleepiness at work, impaired sleep at home, mood
dysregulation, interpersonal relationships, and other health issues
- Affects between 5% and 10% of night workers
- Middle aged and older workers are at greater risk

Jet Lag
- Fatigue, irritability, sleepiness, digestion issues, headaches, loss of
concentration
- Jet lag is worse when traveling East

Daylight Savings
- Setting clocks back one hour in the fall (fall back) is a
phase advance
- Similar to westward (north american) travel and produces little
disruption
- Setting clocks forward one hour in the spring (spring forward) is a phase
day
- Similar to eastward (north american) travel and jet lag
- Did you know? Daylight saving time was created to help save energy
during WWI

- Daylight saving change in spring correlates with more heart attacks

- The incidence ratio is computed by comparing the number of heart
attacks on the specified dau following the shift to the mean number of
heart attacks for the same day two weeks before and two weeks after
the shift
- An incidence ratio of 1.00 means there is no difference
- The likely reason for the increase is sleep deprivation, which increases
sympathetic nervous system activation and inflammation, which can be
dangerous to people with existing health problems
The Body’s Internal Clocks Manage Circadian Rhythms
- The ‘master’ internal clock is the suprachiasmatic nucleus (SCN)
- The cellular basis of circadian rhythms
- Per, tim, and, clock proteins
- The biochemistry of circadian rhythms
- Melatonin , cortisol

The Suprachiasmatic Nucleus (SCN)

- The SCN is located above (supra) the optic chiasm
- Receives inputs from special cells in the retina called
intrinsically photosensitive retinal ganglion cells(ipRGC)
- These cells do not process visual images
- Contains photopigment called melanopsin
- Provide light information to the SCN
- Also contribute to pupillary light reflex
- The SCN is only active during the day and helps
animals distinguish between day and night
- activity in the SCN produces responses in the sympathetic
nervous system, which in turn communicates with the pineal
gland.
As the sun sets:
↓SCN activity → ↓sympathetic activity → pineal gland produces and releases more
melatonin, which helps initiate sleep through the modulation of brainstem
structures

SCN… is independent
- The SCN can generate and maintain circadian rhythms independent of input
from other structures
Experimental findings
- Isolated SCN tissue cultures show activity fluctuations consistent with the
donor’s sleep-wake cycle
- Transplants of SCN tissue result in the host adopting the day-night cycle of the
original host

SCN… Adapts Quickly

- Peripheral clocks exist in most of the body’s cells. The SCN adjusts to phase
shifts faster than the peripheral clocks
- Yamazaki et al’s rat study
- Following a 6hr phase shift, the SCN adjusted after 1 or 2 cycles. Lung
and muscle tissue required 6 cycles and liver tissues required more
than 16 cycles
Peripheral clocks are more strongly influenced by daily feeding cycles
 - The SCN receives information about day/night from the retina
… but it also has its own intrinsic timekeeping mechanisms
- Cells in the SCN express genes that produce proteins that interact to create a
self-sustaining feedback loop

The Cellular Basis of Circadian Rhythms

- The 24 hour cyclical production and degradation of specific proteins enables
the SCN to ;tell time’
- The genes that produce these proteins in fruit flies are
- PER (for period)--> per protein
- TIM (for time)--> tim protein
- CLOCK (for circadian locomotor output cycles kaput)--> Clock protein
- Similar processes involving more genes and proteins occur in mammals and
humans

- High levels of per and tim proteins inhibit the production of clock
- Low levels of per and tim proteins disinhibit the production of Clock
- Clock increases the production of per and tim

Cycles of Protein Production and Degradation in Fruit Flies

The Biochemistry of Circadian Rhythms: Melatonin

- The SCN regulates the release of melatonin from the
pineal gland via the sympathetic nervous system
- Some evidence: lesions of the SCN abolish the
circadian release of melatonin, demonstrating the dependence on the
pineal gland on input from the SCN
- Melatonin from the pineal gland diffuses into the cerebrospinal fluid of the 3rd
ventricle, from which it diffuses to many areas

Remember: The SCN is only active during the day; at night, reduced SCN activity
causes the pineal gland to produce and release melatonin
- Therefore, melatonin levels:
- Are suppressed by light and very low during the day
- Begin to rise in the hours before sleep
- Peak around 4am
- Blindness, pineal gland tumors, and certain medications can interfere
with sleep by affecting melatonin
- Bright lights also interfere with sleep by affecting melatonin!
Melatonin supplementation may be helpful for improving sleep… but it can also
be dangerous
- Daytime drowsiness and grogginess: talking too much melatonin can lead to
drowsiness and grogginess during the daytime, which can interfere with
normal daily activities : melatonin can interact with other hormones in the
body, particularly blood thinners, anticoagulants, and medications that
suppress the immune system

The Biochemistry of Circadian Rhythms: Cortisol

- Cortisol levels also fluctuate with patterns of sleeping and waking
- Cortisol is a hormone released by the adrenal glands that promotes arousal
- Cortisol levels are normally highest during the early mornings and
lowest at night
- Higher levels of cortisol are associated with…
- Higher blood pressure, higher heart rate, energy levels, mental alertness

Cortisol and the hypothalamic-pituitary-adrenal (HPA) axis

- Cortisol remind in the bloodstream for 3 hours before breaking down
- Stress induced cortisol levels during the night are associated with poor
sleep quality

Effects of Cortisol
- Increases blood sugar (energy for body)
- Suppresses immune system (anti-inflammatory/promote healing)
Enhances memory: well see next week
Increases focus: cortisol can improve focus during stress, helping a person stay alert
and attentive
→ activates the sympathetic nervous system and promotes the release of
norepinephrine and dopamine

- Melatonin rises at night, guiding us to sleep tight, and awakens with morning
light
- The sun rises and sets, guiding our sleep and wakes, hormones dance to its
beat.
- As the dawn breaks, we arise, cortisol surges, our bodies energize, a new day, a
fresh sunrise

Body Temperature and Hormone Secretions Follow Circadian Rhythms

- Body temp drops as metabolic activity decreases. Melatonin also has a cooling
effect on the body → causes hypothalamus to lower set point and dilation of
skin blood vessels
 - Growth Hormone, which promotes bone and muscle growth, is released
primarily during stages 3 and 4 of non-rapid eye movement (NREM) sleep
- Cortisol levels are highest first thing in the morning and decrease during the
day

Major Depressive Disorder with Seasonal Pattern (DSM-5)

Previosusly called seasonal affective disorder, DSM-4
- Reduction in daylight hours during winter months at higher latitudes
interferes with circadian rhythms
- In sunny Florida, rates of seasonal depression are only 1.4%. In
cloudy New Hampshire, rates are 9.7%
- Serotonin levels typically drop in fall and winter
- Disruptions of melatonin release by uneven patterns of daily light
Treated by: antidepressants, light therapy

Light Therapy
- Administered with or without melatonin supplementation
- Light therapy at dawn (sunrise) helps correct cases in which people stay up
too late
- Light therapy in the evening helps correct cases in which people fel sleepy too
early
- Following light therapy, serotonin transporter binding in patients with
seasonal depression is reduced– what does this mean?
- Variations in genes that express melanopsin, the photopigment in ipRGCs
may predispose people to seasonal depression

The Neural Correlates of Waking and Sleep

- Sleep is not the absence of activity
- Both waking and sleep are active processes
- Involve reciprocal circuits of excitation and inhibition
- Waking involves the active inhibition of sleep

Sleep Research is Difficult

- Participants in sleep experiments are wired with scalp electrodes for EEG,
electrodes around the eyes to measure eye movement, and electrodes on
their major postural muscles. As if that werent enough, they are being
observed and probably filmed through a two way mirror by researchers

Electroencephalogram (EEG)
- Generally, low EEG frequencies show large synchronized
Amplitudes (dela and theta)
 - High frequencies (beta and gamma) show small amplitudes due to high
degree of desynchronization
Synchronous→ neurons firing in unison; correlated with sleep
Desynchronous→ independent action of many neurons; correlated with waking

EEG Recordings of Waking and Sleep

- Desynchronous brain activity
- Independent action of many neurons
- Correlated with alertness
- Synchronous brain activity
- Neurons are firing more in unison
- Characterizes deep stages of sleep

EEG During Waking

- Alternates between alpha (8-13 hz) and beta (13-30 Hz) patterns of activity
- Every 90-120 mins or so
- Gamma band activity (36-44 Hz) observed during sensory input
- In children and young adults, might also include brief moments of theta
waves (4-8 Hz)

EEG During NREM Sleep: Four Stages

- Alternating periods of REM and NREM sleep
- NREM sleep
- Stages 1 through 4
- Theta and delta waves, though at the onset of sleep EEGs are difficult to
distinguish from drowsy awake states
- Stage 2: accounts for 50% of sleep
- Sleep spindles, shorts bursts of EEG activity between 12-14Hz
- K-complexes, isolated delta waves
- Stages 3 and 4: parasympathetic activity → body temperature,
breathing, blood pressure, and heart rate are lowered
- Energy consumption of the brain drops by 11% to 40%
- Delta waves
- Growth hormone is released by the pituitary

Myoclonus – Early Stages of NREM Sleep

- During the early stages of sleep, the body undergoes a series of changes,
including a decrease in muscle tone and a slowing of brain waves
- Myoclonia are muscle jerks that typically occur during the early stages of sleep
EEG During REM Sleep
- After roughly 90 mins of NREM sleep, the first period REM occurs
- Muscle paralysis, eye movements, dreaming, beta waves
- Subsequent periods of REM continue the 90 to 120 min cycle observed during
waking (alpha/beta cycle), but do so as REM/NREM sleep
- 5 periods of REM in 8 hrs of sleep
- Sympathetic activity → body temperature, breathing, blood pressure, and
heart rate are increased; males get erections, females experience blood flow
around the vagina

Brain Networks Managing Waking

- Two cholinergic pathways originate in the medulla
- Ventral pathway: from the medulla to the posterior hypothalamus on onto
the basal forebrain
- Dorsal pathway: a group of cells in the midbrain reticular formation project to
the thalamus, which in turn influences the cerebral cortex
- Cholinergic mesopontine nuclei
- Modulates the amount of sensory input the cortex receives

- Locus Coreules also participates in waking

- Its the source of norepinephrine
- Most activate when people are vigilant and alert, less active when
people are relaxed
- Phasic bursts
- Raphe Nuclei are also involved
- Serotonergic connections with the POA, SCN, and cerebral cortex
- Most active when people are active during wakefulness, less active in
NREM sleep, and completely inactive during REM
The Default Mode Network
NREM Sleep Networks
- POA forms inhibitory feedback loops with waking pathways
- Sleep debt → homeostatic control of sleep in which sleep promotion is related
to the duration and intensity of wakefulness
- Continued activation by input from the raphe nuclei will eventually lead to the
inhibition of circuits promoting waking
- Electrical stimulation of “NREM-on-cells” in the POA will produce immediate
NREM sleep
- Lesioning these cells produce insomnia
- Thalamus: without inputs promoting waking, neurons in the thalamus
synchronize activity in the cortex, leading to slower and larger EEG waves, and
the cortex becomes less ‘tuned’ to the outside world.

REM Networks
- REM on areas located in pons
- Lesions to neurons in the rostral pontine reticular formation abolish
REM sleep
- During NREM, locus coeruleus and raphe nuclei reduce their activity
- During REM they are essentially silent, disinhibiting the REM-on areas
- Pons, Lateral Geniculate Nucleus, Occipital Cortex waves or PGO waves are
associated with eye moments of REM sleep
- EEG waves that originate in the pons and travel to the occipital lobe (via
thalamus)
- After 30 mins, the locus coeruleus and raphe nuclei reactivate and inhibit
REM- on areas
- Reactivation of locus coeruleus and raphe nuclei leads to either
wakefulness or another segment of NREM sleep

Biochemical Correlates of Waking and Sleep

Acetylcholine and glutamate→ high during wakefulness and REM
Histamine→ high during wakefulness, lower during REM and NREM sleep
Norepinephrine and Serotonin → high during wakefulness, drops during NREM, very
low during REM
Biochemical Correlates of Waking and Sleep
Adenosine
- Builds up during wakefulness
- Gradually drops during sleep
- Caffeine blocks adenosine receptors (they’re similar molecules; caffeine can
block the buildup of adenosine)
Melatonin
- Onset of dark cycle
- Surge before sleep

Changes in Sleep over the Lifetime

- Infancy
- 14-16 hrs per day
- 50% of time in REM
- Early childhood
- High levels of delta (NREM) wave sleep
- Delta wave sleep is particularly important for physical restoration and
recovery. It is during this stage of sleep that the body produces and
releases growth hormone
- Puberty
- 20% of time in REM
- Adulthood
- Sleep declines in midlife
- Time spent in stages 3 and 4 decreases

Sleep Patterns over the Lifespan

Young children spend more time sleeping, and their sleep contains a
disproportionately higher amount of REM. As we age, we experience
a decrease in the total amount of sleep and in the amounts of stage 3
and 4 NREM

Why do we Sleep??

Possible Advantages of Sleep

Sleep keeps us safe → prediction risk correlates with sleep patterns

Possible Advantage of Sleep

- Sleep keeps us safe → predation risk correlates with sleep patterns
 - Sleep restores our bodies → glucose metabolism produces free-radica;s
(unstable molecules; unpaired electrons), which can damage tissue and DNA
damage
- Sleep → lower body temp → repair of free radical-induced damage
- Growth hormone (GH)

Memories are consolidated during sleep

- Learning during waking strengthens connections
- Memory processes reorganized during sleep
- Dual process model (NREM → explicit memory / RE< → implicit memory
- Reconsolidation → memories get retrieved , activated, elaborated, and restored
Sleep and emotional regulation

Special Benefits of REM sleep?

- Only birds and mammals show true REM sleep
- REM sleep probably plays a role in brain development
- REM increases after new learning
- When deprived of REM sleep, humans show REM rebound– more REM than
usual in subsequent days
- Suggests REM is necessary

Dreaming
- Dreaming occurs during both REM sleep and NREM
- REM dreams and lengthy, complicated, vivid, storylike
- NREM dreams are short episodes characterized by logical single images and a
relative lack of emotion
- Threat simulation hypothesis
- Provide practice for dealing with threats
- 70% of dreams have negative emotional content
- Activation-synthesis theory
- Dream content reflects ongoing neural activity
- PGO waves randomly bombard the cortex, activating memories
- Study: volunteers sprinkled with water dreamed about rain
WEEK 12- CHAPTER 12- LEARNING AND MEMORY

Categorizing Learning and Memory

Three categories of responses to the environment :
- Reflexes
- Fixed action patterns (instincts)
- Learning (associative, nonassociative, social learning)

Reflexes Provide Fast, Reliable Responses

- The patellar reflex is an example of a monosynaptic reflex in humans
- Once the tendon is struck, your legs will kick
- For some unknown reason, your physician puts a small table in front of your
leg
- Reflexes are not flexible which can be disadvantageous if environment
changes

Fixed Action Patterns

- Species specific instinct
- Sequences of unlearned behaviour that is elicited by an environmental
stimulus (releases)
- Three spine stickleback attack males invading their nesting territory
- Male fish have a red stomach, females do not
- Regardless of shape, attack any red stimuli
- Will not stop the behaviour until the attack is complete

Types of Learning
- Associative learning: classical conditioning operant conditioning
- Nonassociative learning: habituation sensitization
- Social learning
Social Learning
- Learning by watching others allow an organism to benefit from the
experience of others without risk or cost
- Also involves many of the same circuits as classical and operant conditioning
- Can also occur in groups
Memory
THE IMPORTANCE OF MEMORY
- Memory is central to all cognitive functions
- Uses a combination of systems that help us access information
- Memory is pervasive, it impacts all aspects of our lives
- Sense of self
- Problem solving
- Routines and habits
- Social functions

STAGES OF MEMORY
Stage 1: encoding → learning and creating patterns of our experiences to imprint into
our memory
Stage 2: storage → maintenance and organization of the patterns we imprint. Can
impact retrieval
Stage 3: retrieval → recovery of stored information in response to a cue

INFORMATION PROCESSING MODEL OF MEMORY

SENSORY MEMORY
- Information that is attended to by any of our senses enters sensory memory
- Can hold a myriad of information at the expense of time
- From this information, we select what we want to attend to, the rest is
forgotten

WORKING MEMORY/ SHORT TERM MEMORY

- When we attend to information that has been received byy our senses it can
pass into STM
- Can hold 7 items (SD=2) for ~30 seconds
- If i gave you 5 numbers to remember that should be fairly easy
- If i told you to remember them and tell them to me in REVERSE order in
which I said them, that’s a lot more challenging

WORKING MEMORY/ STM

- Working memory combines:
- Central executive - visuospatial scratchpad
- Episodic buffer - phonological loop
NEURAL SYSTEM SUPPORING WORKING MEMORY
- Dorsolateral prefrontal cortex (DLPC) and anterior cingulate cortex (ACC)
support the central executive
- Object permanence
- ACC activation and working memory capacity
- Small activation accompanies maintenance rehearsal
- Large activation accompanies semantic (elaboration) rehearsal

NEURAL SYSTEM SUPPORTING WORKING MEMORY

People with larger capacities for verbal information show greater ACC activity during
memory tasks
Prefrontal lesions → errors on the Wisconsin card-sorting task

The wisconsin card sorting task (WCST) is a neuropsychological test that

assesses cognitive flexibility, the ability to switch between different tasks or
mental sets.
- Int he test, participants are required to sort a deck of cards based on
different sorting rules, which are changed periodically without warning,
forcing the participant to adapt to the new rules

OBJECT PERMANENCE TASKS

- The short term memory abilities of a young child can be assessed by hiding a
toy while the child is watching. After a delay, the child is allowed to search for
the toy. Prior to the age of seven or eight months, most children are unable to
use their memories of watching the toy being hidden to help them
successfully locate it.
- Immaturity of the prefrontal cortex might account for these results. Monkeys
with prefrontal lesions perform like young children on this task, further
suggesting a role for the prefrontal cortex

TYPES OF LONG TERM MEMORY

EPISODIC MEMORY
- Episodic memory relates to your own personal experience

NEURAL SYSTEMS SUPPORTING EPISODIC MEMORY

- Henry molaison (patient H.M)
- Intact short term and procedural memories
- Impaired declarative memories
THE MIRROR-DRAWING TASK
- H.M retained the ability to learn this task
- He did not remember ever completing the task

NEURAL SYSTEMS SUPPORTING EPISODIC MEMORY

- Delayed non-matching to sample (DNMS)
- Pick the new object from a pair to get food
- Damaged temporal lobes in monkeys reduced
performance on the DNMS task

SEMANTIC MEMORY
- Semantic memory contains basic knowledge of facts and language
- Autobiographical memory
- Interconnection between semantic and episodic memory

SYSTEMS SUPPORTING SEMANTIC MEMORY

- Semantic knowledge is widely distributed in the cortex
- Naming tools versus naming animals
- Brain damage affecting identification of living vs nonliving things

PROCEDURAL MEMORY
- Procedural memory stores information about motor skills and procedures

NEURAL SYSTEMS SUPPORTING PROCEDURAL MEMORY

- Striatum
- Caudate nucleus
- Putamen
- Nucleus accumbens
- Match procedures to context and likelihood of reward

PRIMING
- Exposure to one stimuli changes subsequent responding to another
HOW DO STM’S STORE AS LTM’S ?

THE HIPPOCAMPUS AND ITS ASSOCIATED STRUCTURES

ANATOMY SUMMARY SLIDE

THE HIPPOCAMPUS AND MEMORY

- Hyperthymesia is correlated with large amygdala
- Amygdala is also recruited during episodic memory formation
- near - perfect episodic recall
- Amygdala might make generic memories more self-relevant

INTRODUCTION TO LONG-TERM POTENTIATION

- What causes longer-lasting learning and memory?
- LTP is a process by which synaptic connections between neurons become
stronger with frequent activation
- A type of synaptic plasticity → the connection between neurons in the
brain change in strength and efficacy in response to experience and
activity
- Hebb (1949(: ‘cells that fire together wire together”

FOUR STAGES OF SYNAPTIC PLASTICITY

LONG TERM POTENTIATION

- Provides a basis for learning and memory
- A rapid series of electrical shocks to input pathways increases the
postsynaptic potentials in their target neurons
 - Long term depression (LTD) is a similar phenomenon that produces
reduced responses

LTP AS A MEMORY MECHANISM

LTP AS A MEMORY MECHANISM

- Ltp occurs in ways predicted by cellular learning model (Hebb)
When an axon of cell A is near enough to excite a cell B and repeatedly or
persistently takes part in firing it, some growth process or metabolic change takes
place in one or both cells such that A’s efficacy, as one of the cells firing B, is
increased
- Associativity
- Cooperativity
- The NMDA receptor

LTP: EXPERIMENTAL EVIDENCE

SPATIAL MAPPING
- Rats are good at spatial learning. THey can find the hidden platform in
minutes and remember the solution for months
- NMDA receptor antagonists in the hippocampus → rats do not
Produce LTP or learn
- If NMDA receptor antagonists arre applied after learning task, no effect
on LTP or learning
- Mice who lack component of AMPA receptor (GluA 1-4) → impaired
performance on spatial tasks
- when LTP compromised, memory maps are inefficient and unstable

INHIBITORY AVOIDANCE
- Rat is placed in apparatus with light and dark side
- When they enter the dark side, they receive an electric shock
- Rapid avoidance learning as increasingly hesitant to enter dark
- Analysis of CA1 area
- Same changes in AMPA receptor observed during LTP

FEAR CONDITIONING
 - Classical conditioning paradigm
- Light or sound (CS) paired with eclectic shock to feet (UCS)
- Response to CS by freezing/remain immobile

- Before the dear conditioning training, researchers ‘tagged’ AMPA receptors

- Noted that tagged receptors moved to dendritic spines

MEMORY CONSOLIDATION
- Consolidation occurs in waves over time
- Role of transcription factors
- Transcription is the copying of DNA to RNA
- Importance of CREB
- Role of translation
- Translation is production of proteins by RNA
- C/EPBβ
- IGF-2

REACTIVATION AND RECONSOLIDATION

- Synapses are weakened when information is retrieved
- Retrieval stimulates same consolidation processes responsible for original
learning
- Reconsolidation updates memory to include ongoing information at time of
retrieval
- Elizabeth loftus and reconstructive memory
- Strong, older memories less likely to be modified

THE AMYGDALA AND FEAR CONDITIONING

- A tone (CS) signals foot shocks (UCS)
- Information about the CS and UCS converges in the lateral
nucleus of the amygdala
- The central nucleus of the amygdala initiates the CR
(freezing) by contacting output areas in the hypothalamus and
periaqueductal gray

FEAR CONDITIONING DRIVES AMPA RECEPTORS INTO THE POSTSYNAPTIC

MEMBRANE
EFFECTS OF STRESS ON LEARNING AND MEMORY
- Highly arousing, negative information is more likely to be remembered than
non-arousing positive information
- Stress releases epinephrine from the adrenal glands into the circulation
- Epinephrine binds to vagus nerve which reports ot the locus coeruleus
via the nucleus of the solitary tract
- The locus coeruleus releases norepinephrine
- Norepinephrine in the amygdala and hippocampus enhances memory
formation
- Epinephrine produces glucose release from liver, supporting signal
cascades required for memory formation

STRESS AND MEMORY FORMATION

- Contradictory findings
- Repression
- Enhanced memory
- Especially vivid, flashbulb memories
- Memory flashbacks in PTSD
- Timing determines whether memory is enhanced or impaired
- Simultaneous stress and learning enhance memory
- Stress produces a refractory period ; delay between stress and learning
might impair memory

CHRONIC STRESS AND MEMORY

- Dendritic changes in the amygdala lead to hypersensitivity to stressors
- Reduced hippocampal volume
- Reversible atrophy of dendrites
- Reduced neurogenesis
- Medial prefrontal cortex
- Reversible atrophy of dendrites
- Less responsive under stressful conditions

THE EFFECTS OF HEALTHY AGING ON MEMORY

- Memory changes in healthy aging
- Slower eyeblin, reaction time, decline working
Memory, decline of new episodic memory formation,
- Possible underlying changes
White matter deterioration , bad sleep quality, difficultyclearing adenosine
- Cognitive measures remain stable due to compensations
- Comparisons bw young adults, healthy old adults, adults w AD (alzheimer) risk
- Adults w ad risk show increased hippocampal activity during encoding
- Compensation ay fail as dementia develops
WEEK 13- NEUROPSYCHOLOGY - CH 13

WHAT IS NEUROPSYCHOLOGY?
- Clinical psychology is a branch of psychology that focuses on the diagnosis
and treatment of mental, emotional, and behavioural disorders
- Neuropsychology is a speciality field within clinical psychology that focuses
on the diagnosis and treatment of patients with cognitive impairements
resulting from
- Aging
- Injury
- Disease

NEUROPSYCHOLOGY VS NEUROLOGY
- Neurologists graduate from a clinical program in a psychology department
(MD)
- Neuropsychologists graduate from a clinical program in a psychology
department (PhD)
- Often work with neurosurgeons, psychiatrists, neurologists, and other
specialist ‘CNS” doctors, like: neuro oncologists, pathologists,
radiologists, and ophthalmologists

- Neuropsychologists assess and treat the psychological consequences of

disease or injury
- Often work with neurologists and other clinical psychologists
- Neurologists assess and treat the physical consequences of a disease or injury
- For example, if a soldier experiences a consussion…
- A neuropsychologist may treat deficits in attention and memory
- A neurologist may treat potential bleeding and swelling in the brain

NEUROPSYCHOLOGICAL ASSESSMENT
- Goal is to develop an infrared treatment plan
- Choice of methods depends on the issues involved
- Standardized tests
- Comparisons with population (eg. test norms)
- Comparisons with abilities unaffected by condition
- Iq tests
- Comprehensive test battery (eg. Halstead-Reitan battery)
- Conditions might affect test performance (eg. pain, fatigue, medications)
makes interpretation more difficult

NEUROPSYCHOLOGICAL TRAINING
Montreal Cognitive Assessment (MoCA)
- Assesses multiple domains of cognitive functioning
- Short term memory
- Visuospatial abilities (understanding and manipulate spatial
relationships)
- Executive functions (planning, problem solving, abstraction)
- Attention, concentration, working memory
- Language functions
- Orientation to time and place

NEUROCOGNITIVE DISORDERS
- A disorder characterized by a decline in cognitive function following a
challenge to the nervous system
- Blows to the head
- Interruptions in the blood supply to the brain
- Tumors
- Infections
- Described in the DSM-5
- Decline in function may occur in any of the following areas
- Attention
- Executive function
- Learning and memory
- Perception and movement
- Social cognition

SOME CONDITIONS THAT CAN CAUSE NEUROCOGNITIVE DISORDERS

- Alzheimer’s disease
- Vascular (disease)
- Hemorrhagic stroke
- Ischemic stroke
- Traumatic Brain Injuries TBIs)
- Substance / Medication-Induced Neurocognitive Disorders
Eg. Wernicke-Korsakoff syndrome (alcohol induced): vitamin B1
deficiency
Prion diseases
- Mad cow disease
- Brain tumors
- infections
- Epilepsy
ALZHEIMER’S DISEASE: DESCRIPTION
- A neurodegenerative condition associated with aging that results in dementia,
a loss of normal cogntive and emotional functions
- Early stages: memory loss, especially episodic memory loss
- Disease progression” problem solbing,, language, and social behavior
deteriorate
- Hallucinations and delusional thinking may also occur
- Patients require supervision and care
- Before they pass away, many patients are bed-ridden and unable to
speak

ALZHEIMER’S DISEASE: DIAGNOSIS

- Definitive diagnosis is only possible with autopsy
- However, probable Alzheimer’s disease is diagnosed based on:
- Genetic testing or family history
- Clear evidence of learning or memory impairments
- A steady, gradual loss of cognitive function without plateaus
- Diagnostic methods for probable alzheimer’s
- Biomarkers in the CSF and blood
- PET scans (amyloid protein)
- MRI scans (small blood vessel disease)

ALZHEIMER’S DISEASE: RISK FACTORS

- Alzheimer’s disease risk increases with age
- 5% to 10% in people aged bw 60 and 74 years
- About 25% in people over 74
Genetics
- In a minority of cases, alzheimer’s disease is inherited as a dominant trait due
to mutations on one of three genres:
- Genes for amyloid precursor protein (APP) on chromosome 21
- Genes for presenilin 1 protein (PRESN1) on chromosome 14
- Genes for presenilin 2 (PRESN2) on chromosome 1
- Ꜫ4 variant of the apolipoprotein E (APOE) gene, located on chromosome 19, is
the most reliable genetic risk factor for Alzheimer’s Disease
- The APOE genes prodice a protein that combines with fats to form
lipoproteins. Lipoproteins package cholesterol and other fats and carry them
throughout the blood stream
- APOE-Ꜫ4 may not do a good job of cleaning beta-amyloid proteins,
which accumulates in people with Alzheimer’s
ALZHEIMER’S DISEASE: Ꜫ4 APOE GENE (flashback: SNPs)
- There are three alleles for the APOE gene: Ꜫ4, Ꜫ3, and Ꜫ4
- DNA is made of biochemical called nucleotides:
- SNPs occur when alleles differ with respect to a
single nucleotide
eg. allele 1: AGT TA GAA and allele 2: AGT TCT GAA
→ Allele 1: (serine) (serine) (leucine) and Allele 2: (serine) (arginine) (leucine)

MORE ABOUT THE Ꜫ4 ALLELE

- Occurs in about 25% to 30% of population but is found in as many as 40-80%
of individuals diagnosed with Alzheimer’s
- A person with two copies of the Ꜫ4 allele has a 91% chance of
Alzheimer’s
- People with an Ꜫ4 allele DO NOT lower their risk of alzheimer’s with exercise
but people with Ꜫ2 or Ꜫ3 alleles do
- People with Ꜫ4 allele also tend to have higher cholesterol levels and more
atherosclerotic plaques, increasing the risk for cardiovascular disease and
stroke
Why is the Ꜫ4 allele so dangerous?

ALZHEIMER’S DISEASE PRODUCES STRUCTURAL

ABNORMALITIES IN NEURONS
The cone shaped elements are neurofibrillary tangles

The brown clumps are amyloid plaques found in the brain of a

patient who died from alzheimer’s disease

Amyloids plaques arise from misfolded proteins called beta

amyloid, which also contributes to the detachment of tay protein
from the microtubules.

One of the functions of APOE is to break down beta amyloid

- APOE4 don't perform function well; people with the Ꜫ4 allele have greater risk
ALZHEIMER'S DISEASE: TREATMENT
- Currently, there are no treatments to reverse Alzheimer’s disease
- Current medications can only slow disease progression
- Clinical trials have shown that an antibody (a protein used by the immune
system) that targets beta amyloid can clear plaques but more research is
needed

VASCULAR DISEASE (STROKE)

- A stroke occurs when brain's blood supply is interrupted
Cerebral hemorrhage: bleeding in the brain
Ischemia : inadequate blood flow to the brain

CEREBRAL HEMORRHAGE
- Frequency: 20% of strokes
- Outcome: often fatal
- Causes: hypertension (high blood pressure) and aneurysms (balloon-like
bulges in arteries)
- If someone is rushed the ER and stroke is suspected, doctors are likely to order
a CT to check for hemorrhage
- How would a cerebral hemorrhage appear on CT? —-->

Cerebral Hemorrhages Are Not Always Fatal

- If God could sing, He would sound a lot like Andrea Bocelli.
- Born in 1958, diagnosed w congenital glaucoma in early childhood
- Opticnerve damage cuz intraocular pressure is high →visual impairment
- At 12 years, suffered a brain hemorrhage when playing soccer; completely lost
his sight

ISCHEMIA
- Frequency: 80% of strokes
- Outcomes: variable because infarcts (dead tissue) can vary in sze and location;
changes in consciousness, sensation, and movement
- Causes: atherosclerosis (thickening and hardening of artery walls) and blood
clots
- Thrombosis: a blockage that doesn’t move down from its point of
origin
- Embolism: a blood vessel blockage that originates elsewhere and travel into
smaller and smaller blood vessels until it forms a blockage
- Eg. atrial fibrillation → abnormal heart rhythm (jiggling heart)
ATRIAL FIBRILLATION AND EMBOLISM

ISCHEMIA CONT…
- Transient ischemic attacks (TIAs)-- mini stroke
- Brief episodes of stroke symptoms (24 hrs or less)
- Do not cause permanent damage
- Strong predictors of subsequent stroke
- Recognizing a stroke : F A S T
- Facial drooping
- Arm weakness
- Speech difficulty
- Time: hurry up
Other symptoms: sudden severe headache, numbness or weakness in arm/leg,
difficulty seeing, walking, maintaining balance

TREATMENT / PREVENTION FOR ISCHEMIC STROKE

- In the immediate aftermath of an ischemic stroke: clot bustin medications m
- Must be administered within 3-4 hrs after stroke, benefits offset risk of
hemorrhage
- In the longer term: rehabilitation –. Outcomes vary widely
- Brain plasticity
- Lifestyle changes and strategies for to compensate (occupational
therapy)
- Prevention strategies are key and depend on the nature of particular cases
- Eg. preventing embolisms in ppl w atrial fibrillation
- Physical activity: prevents stroke and limits that damage produced by stroke
- Lowers blood pressure
- Improves circulation (prevents plaque buildup in arteries)

OCCUPATIONAL THERAPY : compensatory techniques

Ex: having suffered a stroke, a person loses ability to voluntarily move their left arm
TRAUMATIC BRAIN INJURY (TBI)
- Physical damage to the brain
- Typically caused by some force that’s external to the body
- Open head injuries (eg. gunshot wounds)
- Penetration of the skull
- Worst consequences when injury affects the ventricles, both
hemispheres, multiple lobes of the brain
- Closed head injuries (concussions)
- blow(s) to the head
- Coup, countercoup
- Subdural hematoma
- Clotted blood that forms bw the dura and
arachnoid membranes
- Brain swelling (intracranial pressure)
- White matter damage

TBI AND WHITE MATTER INJURIES

Shearing and tearing of axons

MILITARY TBIs
- can combine open and closed injuries
- Usually more severe than civilian TBI
- Severe swelling
- Disruption of blood- brain barrier
- Damage to blood supply

TRAUMATIC BRAIN INJURY – concussion outcomes

- Brain function at coup and countercoup sites adversely impacted
- Memory loss, dizziness, fatigue, irritability, confusion are common
symptoms
- Most individual recover from concussion within a few weeks but 11% to 17% of
patients experience symptoms three months or longer
- When symptoms persist after, the patient is diagnosed with
neurocognitive disorder due to traumatic brain injury (DSM-V)
- More likely for people with pre-existing disorders (anxiety and deppr)
- Repeated TBIs are especially damaging
- Dementia pugilistica
- Slurred speech, memory impairment, personality changes, lack of
coordination, and Parkinson-like symptoms
 - Boxers with the Ꜫ4 allele are more likely to develop dementia pugilistica

Repeated TBIs are especially damaging

- Dementia pugilistica
- Slurred speech
- Memory impairment
- Personality changes
- Lack of coordination
- Parkinson-like symptoms
- Boxers with Ꜫ4 allele are more likely to develop dementia pugilistica

TRAUMATIC BRAIN INJURY : TREATMENTS

- Medical treatments vary widely
- Medications that inhibit the activity of glutamate
- Glutamate is an excitatory neurochemical
- Needs to be cleared quickly at the synapse because excess
glutamate is toxic
- After tbi, glutamate is toxic
- After TBI, glutamate levels are higher than normal
- Medications that enhance dopamine and norepinephrine activity may
also be helpful in the longer - term
- Prevention: learning about TBI / social awareness
- Rehabilitation… talk ab later

SUBSTANCE MEDICATION-INDUCED NEUROCOGNITIVE DISORDER

- Results from drug use that produces symptoms of neurocognitive disorder
outside of intoxication and withdrawal
- Alcohol, cocaine, methamphetamine, opioids, phencyclidine (PCP), sedatives,
hypnotics, anti-anxiety drugs, and others
- Individuals who begin abstinence prior to age 50 years recover more
effectively

Methamphetamine (stimulates release and blocks the reuptake of dopamine and

norepinephrine)
- Increases alertness, ‘rush’
- Increases risk of cardiovascular accidents
- Damages the blood brainbarrier

Alcohol
- Nutritional deficits: eg. insufficient vitamin B1, can damage hippocampus
 - Korsakoff syndrome: problems learning new information and recalling both
recent and past events

NEUROCOGNITIVE DISORDERS DUE TO OTHER MEDICAL CONDITIONS

- The neurocognitive disorder section of the DSM-5 lists ‘other medical
conditions’ as
- Brain tumors, hydrocephalus, oxygen deficits following cardiac arrest,
endocrine conditions, nutritional conditions, infectious diseases,
immune disorders, kidney failure, metabolic conditions, epilepsy, and
multiple sclerosis

BRAIN TUMORS
- Tumors: independent growths of new tissue that lack purpose
Primary brain tumors
- Originate in brain
- Rare
- Causes unknown, radiation is a risk
Secondary brain tumors
- Originate from metastasized cancer outside brain

SYMPTOMS OF BRAIN TUMORS

- Pressure in skull, headache, vomiting, double vision, reduced heart rate,
reduced alertness, seizures, specific disruptions related to location

TYPES OF BRAIN TUMORS

- Benign tumors
- Develop within own membrane
- Unlikely to recur after removal surgery
- Meningiomas
- Malignant tumors
- Lack boundaries, invade surrounding tissues
- Very likely to recur following surgical removal and other treatment
- Gliomas (more than 70% of all brain tumors)

WHO CLASSIFICATION
GRADE 1 →benign, slow-growing tumors
→ meningioma
GRADE 2 → malignant, likely to recur following treatment but are slow growing
→ some types of oligodendroglioma
GRADE 3 → malignant, likely to recur, and can mutate to grade 4 tumors
→ other types of oligodendroglioma
GRADE 4 → highly malignant, infiltrative, and incurable
→ astocytoma (glioblastoma)

TREATMENT FOR BRAIN TUMORS

- Surgical removal, to the extent possible
- Radiation
- Chemotherapy (Limited effectiveness
A REASON TO WASH HANDS!!

NEUROCYSTICERCOSIS
Results from infection with eggs of pork tapeworm, taenia solium
- Ingesting infected fecal matter (from a symptom free-tapeworm
carrier)
- Eggs hatch in the stomach and the larvae penetrate the intestine, travel in the
bloodstream
- Lodge themselves into soft tissues, like the brian
- Fluid filled cysts develop around the larvae (1 or 2 cm in diameter)
- In most cases, the immune system destroys the cyst… but not all cases
- Once the worm dies, the immune system flares up and symptoms
begin, usually seizures
- Treatment: anti-seizure medication; if the worm is still alive,
anthelmintic medications… surgery’s also an option

EPILEPSY AND SEIZURES

- A seizure is an uncontrolled electrical disturbance in the brain correlated with
changes in consciousness
- Have many possible causes: brain tumors, neurocysticercosis, brain
injury, etc
- Epilepsy is a disorder characterized by repeated unprovoked seizures
- Seizures are diagnosed with EEG

PARTIAL SEIZURES
- Have a clear area of origin and spread outward
- Sometimes preceded by an aura, a subjective sensory or motor
sensation (that you shouldn’t be having
- Simple partial seizures
- Cause movements and sensations appropriate to the point of origin
- No change in consciousness
 - Complex partial seizures
- Normally begin in the temporal lobes
- Changes in consciousness: patient will be very confused and have no
memory of the seizure
- The patient may sense that he or she is re-experiencing a past event or
may feel that the environment is oddly unknown or foreign

- Have a clear area of origin and spread outward

- During a partial seizure, neurons within the origin show a characteristic
electrical pattern on EEG recordings called a paroxysmal depolarizing shift
(PDS)
- Large depolarization that triggers a train of action potentials followed
by a period of hyperpolarization
- Overwhelms the GABA-inhibitory system, leading to high frequency
discharges

GENERALIZED SEIZURES
- Affect brain symmetrically and have no clear point of origin
- Result from activation circuits connecting thalamus and cortex
- Tonic-clonic (grand mal) seizures
- Tonic phase: lasts several seconds; loss of consciousness, cessation of
breathing, and muscle contraction
- Clonic phase: lasts about one minute, violent repetitive muscle
contractions
- Coma lasting about five minutes after a few tonic clonic cycles
- Absence (petit mal) seizures
- More mild; patient experiences a brief period of
unconsciousness (10 secs); 3/sec spike and wave on EEG
- Motor movements are limited; patient will remain
sitting or standing if they are already doing so

TREATMENT FOR SEIZURES AND EPILEPSY

- Antiepileptic drugs (usually GABA agonists)
- Remember GABA is the primary inhibitory neurotransmitter in the CNS
- Surger
- Ketogenic diet in children
(brain uses ketones (fat products) for energy instead of glucose; the way it
works is not well understood)
PLASTICITY AND RECOVERY
Reactive neuroplasticity
• Spontaneous development of new neurons and the growth of axons,
dendrites, and new synapses in response to damage
• Takes place within days or weeks
• The effects of rehabilitation on this process is not understood
Experience-dependent neuroplasticity
• Changes due to learning
• Depends on the growth and strengthening of synapses
• Logical target of rehabilitation
• Timeline can span many years

KENNARD PRINCIPLE
- Recovery from brain damage is related to developmental stage
- Younger brains reorganize more effectively
- Applies to language functions but not all functions

REORGANIZATION OCCURS DURING FOLLOWING BRAIN DAMAGE

- The left occipital lobe was surgically removed from the brain of this monkey 83
days after conception.
- The resulting reorganization can be seen in the differences between the right
and left inferior parietal lobule.
- The left-hemisphere inferior parietal lobule appears to be nearly twice normal
size, extending nearly to the back of the brain

COGNITIVE RESERVE
- Some people are less impacted by brain injury or neurodegenerative
processes than others
- Brain size, number of synapses
- Coping with damage by using cognitive networks in more flexible ways
- Behavioral outcomes do not always correlate with extent of braindamage
- Variables linked to cognitive reserve
- IQ
- • Educational and occupational status
- • Engagement in enriching leisure activities