PSYC 2: Biological Foundations - Fall 2012 - Professor Claffey

Notes: Damage & Disorders

Version:
12/02/12 - original version

Damage

Stroke

 crisis of ____________________ to neural tissue
 US: 3rd leading cause of death, leading cause of adult disability
 ______________ - the area of dead/damaged tissue

cerebral ____________________
    rupture of blood vessels
    ____________________ - balloon like expanse in an artery

cerebral ____________________
    disruption of blood flow   
    thrombosis - a plug or clot that develops in place
    embolism - a plug or clot that develops elsewhere, travels through blood stream, lodges elsewhere
    arteriosclerosis - narrowing of arteries

ischemic cascade     good but detailed: wikipedia.org/wiki/Ischemic_cascade     disruption of oxygen delivery causes energy crisis & failure to     maintain cell homeostasis         fail to: ______________________         internal build up of Na+, permanent depolarization,         glutamate release     fail to: clean up ____________________         causes over stimulation of post-synaptic neurons         influx and toxic buildup of ________ in post-synaptic neuron         over-stimulation of next post-synaptic neuron, cycle repeats     damage takes days to develop     some areas more sensitive than others: hippocampus

Tumors

Benign (left) vs malignant (right) tumors Source: www.mayfieldclinic.com/PE-BrainTumor.htm

____________________     tumor originating in the meninges     usually benign, wrapped in a membrane     causes problems by displacing tissue     about 20% of brain tumors malignant / metastatic     typically originate in other areas of the body     chemical and physical disruption of other cells     about 10% of brain tumors symptoms: headaches, seizures, disruption of function

Closed head injuries

"Closed head injury" means the skull was not fractured
    contrasts with "Open head injury" in which the skull was fractured or penetrated

____________________ - damage to circulatory system     produces a hematoma (bruise)  ____________________     blow to head, loss of consciousness, no evidence of contusion     brain is colliding with skull     countrecoup - brain injury opposite location of impact ("sloshing")     repeated incidents can lead to long term deficits         currently a growing concern for football     the nature of the damage is not well understood

Infection

________________ - inflammation of brain due to the invasion of a microorganism
    bacterial - syphilis, Lyme disease, malaria
    viral - rabies, mumps, herpes
    cause deficits by interfering with cell function and producing an inflammatory response

Neuron damage & regeneration

____________________ - the ability of neuron configurations, and therefore the brain, to change with time and recover
    critical to development, learning and recovery

Damage

____________________
    programmed cell death
    slow, orderly disintegration of cells, no inflammation, doesn't disturb neighboring cells
    (Full review: Apoptosis in neurodegenerative disorders, Nature Reviews Mol Cell Bio, Mattson 2000)

____________________
    sudden, disorderly cell death
    causes inflammation, disrupts neighboring cells

_____________________ degeneration     damage between cut and synaptic terminals     this is the distal portion of the neuron _____________________ degeneration     damage between cut and cell body     this is the proximal portion of the neuron _____________________ degeneration     when a neuron dies, other neurons that are         post-synaptic, or         pre-synaptic     may also die

Regeneration

Unsuccessful in mature mammals and higher vertebrates
    CNS - virtually non-existent
    PNS - unlikely but possible

Regeneration in PNS     requires original _________________________ to be intact         neurotropic factors - chemicals that encourage tissue growth         CAMs - cell adhesion molecules, provide guidance     new growth may connect to incorrect targets It is not the neurons themselves, but the environment     CNS neurons transplanted to PNS will regenerate     PNS neurons transplanted to CNS will not regenerate

Reorganization

Example 1: Reorganization in V1 following retinal lesions
    In adult monkeys, remapping can occur within hours (Botelho et al, 2012)

Example 2: Rewiring neurons from the eye to the auditory cortex     In the developing ferret, input to MGN (auditory) is removed     MGN then "attracts" input from retinal ganglion cells     Visual stimuli produce activity in the auditory cortex Source: Sur & Leamey, Nature Reviews Neuroscience, 2001

Example 3: In newly blinded individuals, auditory and somatosensory input is processed in formerly visual areas

Example 4: Phantom limb
    somatosensory cortex that previously received input from amputated arm begins responding to neighboring input
    Example: touching a patient's cheek can feel like touching the amputated arm

  

Treatment & Recovery

____________________ - return of original function in a damaged area
    Example: after a stroke affecting the hand motor area, that tissue recovers and hand function returns

____________________ - performing a function by newly learned methods using non-damaged areas
    Example: after a stroke affecting the hand motor area, neighboring tissue learns to operate the hand

1. Reducing degeneration

        apoptosis inhibition
        nerve growth factors
        estrogen (Review: Brann et al, 2007)
            females have better incidence/outcomes in neurological pathologies
            administration of estrogen improves post-stroke outcomes in rodents

2. Promoting regeneration

        can be induced in CNS neurons by Schwann cells (Xu et al, 2004)
        physical activity promotes adult neurogenesis in rodent hippocampus

3. Transplant

        fetal substantia nigra cells for treating monkeys with Parkinson's disease-like symptoms
            limited success with humans
        embryonic stem cells in rat damaged spinal cord improved mobility

4. Rehabilitative training

        for hands, restrict the functioning limb to maximize use of impaired hand
        for spinal cord injuries, facilitated walking

5. Prevention

    rats raised in enriched environments are resistant to epilepsy, AD models, HD models
    adults that are more cognitively active have less incidence of AD

Neuropsychological Diseases

A note on terms I use:
    mechanism - what happens in the brain to produce the deficit ("pathophysiology")
    cause - what genetic/environmental factors cause the disease to develop ("etiology")

Alzheimer's Disease

Most common cause of dementia, 4th leading killer of adults

Population

    2000: 4 million Americans
    2050: estimated 14 million Americans (Evans et al, 1990)
    Typical onset at _______ years, but 10% of cases are __________________
    As the overall population grows older, more people are going to encounter the disease
    Women are more likely to have it because they __________________
    Cause is unclear

Symptoms

    initial - confusion, selective decline in memory
    severe - can not: communicate verbally, understand words, recognize self or family, care for themselves
    death due to __________________ (i.e. can't properly chew food -> inhale particles -> contract pneumonia)

Diagnosis

    Can only be diagnosed for certain in autopsy
    Behavioral observation can identify dementia, but not AD as the specific cause

Mechanism: Neurons

1. ____________________
    amyloid precursor protein (APP) - a normal protein in the neuron's cell membrane
    amyloid beta - a portion of APP that is improperly clipped off
    amyloid beta builds up as a plaque outside of neurons

    genetic basis: a mutation in the gene for APP causes a 6x increased risk of early onset AD

2. ___________________________     microtubules - "railroad tracks" of the cell, transport molecules throughout cell     in AD, these become tangled     due to improperly formed tau proteins (the "railroad ties") (click to enlarge)

Mechanism: Brain

____________________     important neurotransmitter for learning & memory     produced in the nucleus basalis         and distributed throughout cortex     in AD, there is a decrease in nucleus basalis activity         and levels of acetylcholine across the brain

Across the brain, there is widespread _____________ Most pronounced in areas for     memory (hippocampus) and language

Animal model

____________________ - genes from another species are introduced to produce a behavior or physiological condition

____________________ - an animal with characteristics like a disease used to study causes and potential treatments
mouse model of AD
    Only humans and some primates develop plaques, wild mice do not get AD
    a mouse model was developed that develop plaques in the brain and diminished memory
vaccine (Schenk et al, Nature 1999)
    a vaccine was developed that prevented/reduced plaques in mice and improved memory
    produced encephalitis in human trials, never successful

Treatments

Working on a vaccine, but not successful in humans
monoamine oxidase inhibitors (MAOIs)
    these prevent the breakdown to monoamines like _____________________________________
    boast levels across the brain
    not addressing a specific problem, just "turning up" neurotransmitters in general
NSAIDs (non-steroidal anti-inflammatory drugs)
    aspirin, ibuprofen (Advil). analgesics and anti-fever. used for many issues like arthritis.
    reduce inflammation in response to plaque damage
cholinesterase inhibitors
    prevent the breakdown of acetylcholine

Treatment Summary: There are no working direct treatments, all address the disease ________________

Parkinson's Disease

Population

Onset typically in 50s or 60s
Affects 0.3% of the population (approximately 1 million U.S. patients)
Most cases have unidentifiable causes
    possible causes: genetics if onset before 50 years old, diet, smoking, rural areas, environmental toxins

Symptoms

____________________ at rest, typically in hand rigidity ____________________ - inability to initiate movement Cognitive symptoms (dementia) are not typical

Mechanism

Review: substantia nigra distributes dopamine to the basal ganglia (in diagram, striatum is a major structures of the basal ganglia)

in PD, there is dramatic cell death in the substantia nigra causes lack of dopamine in basal ganglia, therefore dysfunction in motor _______________ and motor ____________________

Treatments

 ______________________
     a precursor to dopamine that can be absorbed through the blood brain barrier
    problems: difficulty to dose, side effects, eventually loses efficacy (effectiveness)

____________________________________ of subthalamic nucleus (in basal ganglia)
    implant a "pacemaker" into an area of the basal ganglia
    patient can turn on and off and adjust settings
    can dramatically reduce tremor
    not clear how it is having its effect
    Movie: Deep Brain Stimulation (youtube)

Other Diseases/Disorders

(Note: The choice to cover Alzheimer's and Parkinson's in depth above was somewhat arbitrary, though these both affect large populations and tend to be in the forefront of the public's attention. The following diseases/disorders are covered briefly due to time constraints in the course, not due to less severity or social relevance.)

Epilepsy

Primary symptom is ______________ (though not always)      A burst of abnormal, self-reinforcing neural activity      Usually generated internally, though sometimes by stimuli      Convulsions - motor seizures      Non-motor - can include loss of or shift in consciousness Affects 1% of population Diagnosed with EEG Treated with anti-convulsant drugs and, if necessary, surgery

Huntington's Disease

Cause: Inheritable genetic mutation (single, dominant Huntingtin gene) with a reliable genetic test
Mechanism: With the genetic mutation, there is severe damage to striatum (basal ganglia)
Symptoms:
    initial - fidgety, restless
    final - jerky uncontrolled movement of limbs (________________), severe dementia
    death approx. 15 years after onset
Onset usually not seen until around 40 years old
If your parent has the gene, there is a 50% chance that you inherited. When, if ever, would you want to be tested?

Multiple Sclerosis

Unknown cause
Progressive _______________________ disease that attacks the myelin of the CNS
sclerosis - the hard scar tissue left behind
symptoms:
    visual disturbances, muscle weakness, tremor, ataxia (loss of motor control)
Periods of remission are common

Schizophrenia

Symptoms:
    Positive symptoms: delusions, hallucinations, inappropriate affect, formal thought disorder
    Negative symptoms: lethargy, social withdrawal, flat affect, alogia (lack of speech)

Theory: caused by overactive _______________  in the brain     Increasing dopamine transmission exacerbates symptoms     Decreasing dopamine transmission is therapeutic     But for many reasons, dopamine is not the entire story Treatments:     Chlorpromazine - Dopamine __________________     calms agitated patients, activates withdrawn patients

Depression

5% of population suffer from unipolar (as opposed to bipolar) depression

Cause      there is a genetic component to depression      stress is not a likely cause of depression         sparse evidence linking stress and depression         extreme stress is more likely to cause PTSD Theory:     underactivity of _______________ and ________________ at synapses

Treatments
    Monoamine oxidase inhibitors (MAOIs) - see Alzheimer's disease treatments for details
    Tricylic antidepressants - Block reuptake of serotonin and norepinephrine
    Selective serotonin reuptake inhibitors (SSRIs)
        Prozac, Paxil, Zoloft
        Not more effective than tricyclics, but less side effects
    Selective norepinephrine reuptake inhibitors (SNRIs)
    Other: light therapy, electroconvulsive shock therapy, chronic electrical stimulation
   
2002 study
    MAOIs, tricyclics and SSRIs all get about a 50% improvement
    control subjects have ____________ improvement

2008 meta-study

    _____________ was 82% as effective as antidepressants in severely depressed individuals
    antidepressants even less effective in mildly-moderately depressed individuals