Title: Announcement
1Announcement
The following material related to the visual
system will not be tested on the December
exam Lecture slides Lecture 28, slides 15-24
(on- and off-center cells, simple cortical cells,
complex cortical cells). Textbook Bottom half of
p. 294 bottom half of p. 300 figure 10.15
bottom half of p. 302 and top half of p. 303the
spatial-frequency filter model, presented on p.
303-305 of the textbook.
2Biopsychology of Psychiatric Disorders
Guest LecturerNaghmeh Shafiei
- Schizophrenia,
- Affective disorders,
- Anxiety disorders
3Psychiatric disorders
- What are Psychiatric disorders (Symptoms)?
- What are some causal contributors?
- What are some hypothesis about why how they
develop? - What are some treatment options?
4Outline
- Schizophrenia
- Symptoms
- Epidemiology
- Causes
- Heredity
- Cognitive deficiencies
- Neural abnormalities
- Cognitive abnormalities in schizophrenia
- The dopamine hypothesis
- Problems with typical antipsychotics
- Problems with the dopamine hypothesis
- The Glutamate hypothesis
- Neural Circuitry Implicated in Schizophrenia
- A new hypothesis
5Schizophrenia
- Schizophrenia
- Paranoid Schizophrenic
- Disorganized schizophrenic
- Catatonic schizophrenic
- There are also
- Schizoaffective disorder
- Schizophreniform disorder
6Symptoms
- Schizophrenia as defined by DSM IV
- Delusions Hallucinations
- Incoherence Disorganized or
Catatonic - Negative symptom
- 6 months duration, psychotic for 1 month
- Course
- Continuous
- Episodic, with or without residuals
- Single episode, partial or full remission
7SchizophreniaSymptoms
- Negative Symptoms Behavioral deficits
- Social withdrawal
- Flat affect, Apathy
- Anhedonia, lack of pleasure
- Reduced focus and motivation
- Catatonia
8SchizophreniaEpidemiology
- Onset
- Late teenage years-early adulthood
- Earlier onset in males (20-28) than in females
(26-32) - Rare onset in childhood and late adulthood
- Lifetime prevalence of 1.
9CausesCausescauses
- Heredity
- Twin studies
- Family studies
- Adoption Studies
10CausesCausescauses
- These findings indicate
- There is a strong genetic component to
schizophrenia, but - Altered genes are NOT the only cause of the
disease - Genetic component not linked to just one gene,
there may be dozens that are altered. - So why some and not others?
- Birth complications, Early infections, Autoimmune
reactions, Toxins, Traumatic injuries, Stress
11CausesCausescauses
- Alterations throughout development
- In utero influence includes
- Poor nutrition during pregnancy,
- Premature birth/low birth weight
- Physical and immune stressors during pregnancy
12Cognitive deficiencies
- Cognitive functioning is the 1 predictor of long
term outcome (better function better prognosis) - Seven primary domains of cognition that are
affected - Speed of Processing Attention/Vigilance
- Working Memory Verbal Learning/Memory
- Visual Learning/Memory Reasoning/Problem
Solving - Social Cognition
13Neural abnormalities
14Neural abnormalities
- Hippocampus brain region in temporal lobe
critical for memory formation. - Some schizophrenics have enlarged lateral
ventricles, due to smaller hippocampus and other
temporal lobe regions - Closer inspection reveals organization of
hippocampal neurons is altered in the
schizophrenic brain (neural organization occurs
during development)
15Neural abnormalitiesNeural abnormalities
Neural abnormalities
- Not brain damage per se changes in the neural
organization can disrupt the way brain regions
process information
16Neural abnormalities
- Prefrontal Cortex (PFC) frontal lobe region
critical for higher order cognition (short term
memory, planning, behavioural flexibility,
abstract thinking) - Neurons in the PFC of schizophrenics have reduced
number of dendrites, which in turn reduces
processing power of these cells.
17Neural abnormalities
- Cortical gray matter loss in adolescence in the
case of early onset Schizophrenia - No major structural abnormalities in the frontal
lobes.
18Cognitive Abnormalities in Schizophrenia
Wisconsin Card Sorting Task A classic PFC
task Test behavioural flexibility (ability to
change strategies)
19Cognitive Abnormalities in Schizophrenia
- Subjects initially sort cards by one dimension
(e.g., number) - Then task switches, subjects must ignore old
strategy and switch to new one (e.g., shape) - Damage to PFC impairs switching strategies,
patients keep sorting cards by first dimension
(keep sorting by number) - Schizophrenics also impaired on this task
20Cognitive Abnormalities in Schizophrenia
- Brain activation studies schizophrenics and
discordant identical twin controls performed
Wisconsin Card Sort - Schizophrenics had activation of the PFC at
rest showed no increase when performing task,
unlike controls - Other brain regions were activated similarly in
both groups - Schizophrenics show a dramatic decrease in PFC
function, but not other cortical regions
21Cognitive Abnormalities in Schizophrenia
During card sorting task
- Hypofrontality (reduced PFC function) is a
characteristic negative symptom of schizophrenia
22The Dopamine hypothesisTreatments
- Most of the dopamine in the brain is produced in
small nuclei in the midbrain - 1950s Chlorpromazine found to be antipsychotic
causes Parkinsons symptoms in healthy subjects - Brains of Parkinsons patients found to be
depleted of dopamine - 1960s Drugs that increase dopamine release
(e.g. amphetamine) could induce psychotic
symptoms
- Chlorpromazine and other antipsychotics found to
block dopamine receptors (Typical antipsychotics) - 1970s Dopamine receptor subtypes discovered
antipsychotic potency of a drug correlated with
binding to D2 receptors (not D1) - THUS, The dopamine hypothesis was born
- Schizophrenia is caused by an abnormal increase
in dopamine transmission, leading to
overstimulation of D2 receptors
23The Dopamine hypothesisTreatments
- How are D2 receptors being overstimulated?
- More D2 receptors?
- Unlikely Some post mortem studies report D2
receptors in - schizophrenic brains, others failed to
find this effect - Changes may be due to chronic antipsychotic
medication - More dopamine being produced?
- Probably not Schizophrenics do not show
differences in dopamine - metabolites in CSF
- More dopamine being released?
- Study imaging allows for non-invasive measure of
dopamine release in human brain - Give amphetamine to schizophrenics or controls
- Greater dopamine release in the Nucleus Accumbens
(NAcc) of schizophrenics - More dopamine release more positive symptoms
24Problems with typical antipsychotics
- Dopamine is heavily involved in motor functions.
- Long term treatment with antipsychotics (dopamine
blockers) can cause movement (a.k.a
extrapyramidal) side effects - Tardive dyskinesia occurs in about one third of
patients treated with classical antipsychotics - grimacing, tongue protrusion, lip smacking, rapid
limb/trunk movements symptoms continue after
discontinuing medication. - Drugs that are more selective for dopamine vs
other receptors usually cause the worst side
effects - Antipsychotic drugs treat psychosis (delusions,
hallucinations) Other negative symptoms rarely
improve with typical antipsychotics
25Problems with the DA hypothesis
- Antipsychotics block dopamine receptors right
away, yet drug treatment takes 2 weeks to reach
full effect - If schizophrenia is merely an increase in
dopamine, drugs should work right away - Not all schizophrenic patients respond to drugs
that block dopamine receptors - If schizophrenia is merely an increase in
dopamine, drugs should work for all patients - Dopamine blockers can alleviate psychosis, but do
not treat negative symptoms. - If cognitive deficits are due to an increase in
dopamine, these drugs should alleviate the
symptoms
26Problems with the Dopamine Hypothesis
- 4) Some drugs that reduce symptoms do not block
D2 receptors very well - Example Clozapine (atypical antipsychotic)
- Not as effective at blocking D2 receptors as
classical antipsychotics - Less likely to produce motor side effects
- Has a much higher affinity to other receptors,
like serotonin (5 HT) - Can improve negative symptoms
- (possibly via 5 HT blockade)
- If positive and negative symptoms are merely due
to overstimulation of D2 receptors, atypical
antipsychotics shouldnt work very well - Problems some patients have an adverse blood
reaction to clozapine not all patients can take
it safely
27- 5) Drugs that increase dopamine release can
improve performance on cognitive tasks - Study Schizophrenics and controls tested on a
working memory task (dependent on PFC function) - Given either placebo or low dose of amphetamine
(dose dopamine release, but not psychotic
symptoms) - Under placebo, schizophrenics performed worse
than controls - Amphetamine, improved performance in
schizophrenics, up to control levels
Errors
- If schizophrenia is just an increase in dopamine,
then why should a drug that increases dopamine
release - 1) not affect psychosis (even at low doses)
- 2) improve cognitive functions?
28The Glutamate hypothesis
- Abuse of phencyclidine (PCP, angeldust) or
ketamine (Special K) can cause psychotic symptoms
and cognitive deficits resembling schizophrenia - Long lasting effects can persist after drug use
has stopped - Can also cause degeneration of PFC neurons
- These drugs block NMDA subtype of glutamate
receptors - Block the ion channel glutamate cannot activate
receptor
- Glutamate hypothesis Schizophrenia is caused by
decreased glutamate transmission - Neurons in PFC/hippocampus use glutamate as a
transmitter - Degeneration of these neurons in schizophrenia
disrupts their function, less glutamate released
in these areas
29The Glutamate hypothesis
Working memory performance
Dopamine levels
- Rat/primate studies show that repeated PCP
- 1) decreases dopamine release in PFC
- 2) causes cognitive deficits on PFC-dependent
tasks - These effects persist weeks after drug treatment
has stopped
- Schizophrenics show decrease dopamine activity in
PFC - This model encompasses both positive and negative
symptoms of the disorder - Recent finding these drugs are also potent D2
receptor agonists (stimulate the receptors) - Negative symptoms decreased glutamate/dopamine
transmission in PFC - Positive symptoms increased D2 receptor
stimulation in NAcc
30Neural Circuitry Implicated in Schizophrenia
Cognitive functions impaired in schizophrenia
(decreased glutamate, dopamine?)
PFC projects back to VTA
Increased dopamine release in schizophrenia
related to psychotic symptoms
Nucleus Accumbens
VTA sends dopamine input to PFC and accumbens
- This connectivity suggests that prefrontal cortex
can modulate dopamine release in the NAcc
31A New Hypothesis
PFC
Nucleus Accumbens
- 1) Decreased PFC dopamine/glutamate reduces
activity, (negative symptoms) - 2) Decreased PFC activation reduces inhibition of
dopamine system - 3) Release from this inhibition leads to
increased dopamine transmission in NAcc (positive
symptoms)