31. Psychoses: Neurobiology (Vestner)

Front 1

Why do we believe that schizophrenia is a neurodevelopmental problem vs. a neurodegenerative issue now?

Back 1

1. MRI reveal cranium is small in additional to frontal lobe/cerebrum: suggests a developmental problem

2. Neuropathology not consistent with neurodegeneration (instead of neuronal loss/gliosis there is increased neuronal density)

Front 2

What is the neurodevelopmental hypothesis?

Back 2

1. Pathologic process that begins before brain reaches adulthood
2. Genetic and environmental factors at play
3. Abnormalities lead to activation of pathologic neural circuits during adolescence that lead to + and - symptoms
4. Stress contributes to the progression/manifestation of disease

Front 3

What are some environmental/fetal risk factors for developing scz?

Back 3

1. Early fetal factors: ob complications, maternal nutrition, influenza (winter-spring birth excess)
2. Environmental risk factors: urban residence, migration, childhood adversity, stress

Front 4

Approximately ___% of the risk of acquiring scz can be assigned to genetic transmission.

Back 4

80%

*complex mode of transmission compatible with multi locus model; NOT AD

Front 5

What types of candidate genes are suspected to be involved? (i.e., what processes are they involved in?)

Back 5

neurodevelopment, neuroplasticity, and neurotransmission

Front 6

1. What is COMT(catechol-o-methyltransferase) involved in? What are the two genotypes?

2. What did the COMT genotype x Marijuana (Caspi et al.) reveal about gene-environment interactions?

Back 6

1. COMT is involved in metabolizing dopamine after it has been released into the synapse. There are two COMT genotypes: val (BAD at cleaning up) and met (GOOD at cleaning)

2. The study revealed that genetic and environmental factors both play a role in developing scz. Adolescents with the val/val allele (genetic risk factor) who smoked marijuana (environmental risk factor) were more likely to develop scz than those with met/met or val/met alleles (or val/val w/o marijuana use).

Front 7

What is the effect of in utero maternal depression and parental psychosis on offspring having scz?

Back 7

A Finnish study showed that offspring who had both risk factors (maternal depression and parental psychosis) were at a MUCH higher risk of scz than with either factor alone (multiplicative effect?).
*the red line

Front 8

Where are changes are evident in the gross anatomy of the brain?

Back 8

1. Enlarged lateral and third ventricles
2. Reduced whole brain size; reduced cortical gray matter volume
3. prefrontal cortex
4. medial temporal lobe
5. thalamus (medial dorsal nucleus)

Front 9

1. Where are there progressive reductions in the brain? 2. Where is there NO volumetric change?

Back 9

1. Reductions in:
whole brain, whole brain gray matter, frontal lobe volumes
white matter: frontal, parietal, and temporal lobe
grey matter: starts at parietal cortex and spreads into temporal and prefrontal cortices
(also, ventricles are increasing over time)
2. No changes in medial temporal lobe subregions (amygdala, hippocampi)

Front 10

There is an increased density of _________ neurons in the ________ prefrontal cortex (PFC) of patients with scz.

Back 10

pyramidal, dorsolateral

**Increased density due to decrease size, dendrite length, and spine density of pyramidal neurons

Front 11

1. What is hypofrontality?
2. What scz symptoms does this explain?
3. Is there a decrease or increase in dopamine activity in this particular area?

Back 11

1. A phenomenon in which patients cannot activate the prefrontal cortex.
2. Explains cognitive insufficiency symptoms. Decrease in executive functioning (planning, initiating, monitoring), increase in apathy, behavioral problems
3. decrease

Front 12

What sorts of dysfunction is seen in the medial temporal lobe?

Back 12

1. Mild cortical atrophy
2. Cortical neuronal disarray
3. Smaller hippocampal size
Functional MRI abnormal (less blood perfusion) when performing declarative memory tasks (hippocampus-related)

**medial temporal lobe structures: amygdala, entorhinal cortex, hipocampus

Front 13

1. What specific area of the thalamus is affected in scz? 2. How could this explain some of the cognitive symptoms of scz?

Back 13

1. Mediodorsal nucleus (MD nucleus); decreased glucose metabolism is seen
2. The mediodorsal nucleus has projections to the prefrontal cortex. Thus, deficits in this area could contribute to difficulties filtering stimuli and focusing attention.

Front 14

You are a neonate monkey who just suffered some sort of anoxic injury that has caused a lesion in the hippocampus. Given the "feed-forward effect" of neural circuitry, what do you suspect may also be affected?

Back 14

Lesions in the hippocampus lead to prefrontal cortex abnormalities. Lesions in the prefrontal cortex lead to excess dopamine in the basal ganglia. Excess dopamine in the basal ganglia not only leads to psychotic symptoms but also feeds back to prefrontal cortex regulation.

**seems pretty speculative

Front 15

What are the three key neurotransmitters that are dysfunctional in scz?

Back 15

dopamine, glutamate, GABA

Front 16

What supports for the dopamine hypothesis? (the hypothesis being that excess dopamine is related to scz)

Back 16

1. All antipsychotics block D2 receptors. (ex. thorazine)
2. Dopamine agonists can cause psychosis (ex. amphetamine)
3. The higher the affinity for D2 receptors an antipsychotic has, the lower the effective treatment dose is.

Front 17

What are the four dopamine pathways and what are they involved in? How are they dysregulated in scz?

Back 17

1. Nigrostriatal: movement (parkinsonism)
2. Mesolimbic: emotional behavior (increased in scz, results in + scz symptoms like delusion)
3. Mesocortical: cognition/behavior (decreased in scz, results in - and cognitive symptoms of scz)
4. Tuberinfundibular: prolactin regulation (side effect of scz meds)

Front 18

What does concept does this graph illustrate?

Title: Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.

Back 18

Increase in D2 receptor occupancy at baseline was associated with a greater response to treatment with neuroleptic medication. Patients with a higher occupancy responded better to treatment (because the treatment directly affected their problem: excess dopamine); patients who did not have a high baseline occupancy did not respond well (dopamine was not their problem) suggesting there are other mechanisms besides dopamine that lead to psychosis in some patients.

Front 19

What clinical findings suggest that glutamate could be involved?

Back 19

PCP + Ketamine-- antagonists at the glutamate NMDA receptor-- can induce a SCZ-like psychotic state. Tehy can also induce the NEGATIVE symptoms of scz, unlike dopamine.

Front 20

Explain regulatory effects of the direct and indirect glutamate pathways (glutaminergic neuron) on a monoaminergic neuron.

Back 20

1. Direct: Glutamanergic neuron directly stimulates a monoaminergic neuron to fire; acts as an accelerator
2. Indirect: Glutaneurgic neuron first hits a GABA interneuron which then inhibits firing of a monoaminergic neuron; acts like a brake

Front 21

How do problems with glutamate receptors dysregulate the mesolimbic and mesocortical pathways?

Back 21

1. Mesolimbic: Glutamatergic neurons from the prefrontal cortex normally inhibit firing of the mesolimbic pathway via indirect pathway. In dysfunction, there is a reduction of inhibition, resulting in increased mesolimbic activity (positive symptoms: delusion).
2. Mesocortical: Glutaminergic neurons normally promote firing of mesocortical pathway. In dysfunction, there is less stimulation, resulting in decreased mesocortical activity (negative and cognitive symptoms).

Front 22

What (broad) changes are there when there are glutamate and GABA problems?

Back 22

1. dysregulation of normal cortical function
2. dysregulation of regulatory neurotransmitters results in dysregulation of a lot of other neurotransmitters leading to problems with cell survival, function, and communication

Front 23

What type of GABA neuron is affected in scz? Do postmortem studies reveal an increase or reduction in cortical GABA?

Back 23

Chandelier neurons, decrease

Front 24

Hyperactivity of dopamine at the D2 receptors in the _______________ leads to psychotic symptoms.

Back 24

basal ganglia

Front 25

What contributes to the negative and cognitive symptoms of scz?

Back 25

problems in the prefrontal cortex (mesocortical pathway)

1. altered neurotransmitter (dopamine, GABA, glutamate) in the prefrontal cortex
2. deficits in neuronal structure/blood flow

Front 26

Fill in the neurotransmitters: __________ and _________ dysregulation may contribute to dopamine dysregulation.

Back 26

Glutamate, GABA

Front 27

True or False: Schizophrenia is likely a heterogeneous disorder.

Back 27

True.

Front 28

Big picture: Gross anatomy involved? Neurotransmitters involved?

Back 28