Download hypofrontality hypothesis

Factors That Interact during the Development and Progression of Disease
Childhood Poverty, Cumulative Risk Exposure,
and Mental Health in Emerging Adults
• Poverty during early development increases the rate of mental health
problems for individuals as young adults
• Early and sustained poverty has the most impact
• Less impact on Internalizing symptoms: Depression, Anxiety
• More impact on externalizing symptoms: antisocial behavior such as
hyperactivity, aggression, defiance, and destructive behavior
• Increased learned helplessness, the belief that one is not an effective agent in
acting on one’s surroundings
• Because of elevated cumulative risk exposure to
• Psychosocial: violence, family turmoil, child separation from family
• Physical: noise, crowding, substandard housing
Diathesis-Stress Model
• Diathesis is vulnerability or susceptibility
– Genetic influences shown by
• concordance rate in twin studies
• family history of mental disorder
• hypothalamic-pituitary-adrenal responsivity
– Developmental
• maternal stressors
• childhood stressors
• Interaction of Diathesis and Stress
– Individuals with more vulnerability are more likely to become ill
when challenged by stresssors
Prevalence and Incidence Statistics
• Epidemiology: is the study of the patterns, causes, and effects of
health and disease conditions in defined populations.
• The term 'incidence' refers to the rate at which new cases occur in a
population during a specified period, usually each year.
• The term 'prevalence' refers to proportion “percentage” of a
population that are cases.
• point prevalence, based on a single examination, at one point in
time, tends to underestimate the condition's total frequency.
• period prevalence is defined as the proportion of a population that
are cases at any time within a stated period:
• 6 months, one year or life-time
• For example Table 16.1 shows prevalence data at 12 month
and life-time periods.
Prevalence of Serious Mental Illness among U.S. Adults
Not sure what year this represents
Gender
http://www.nimh.nih.gov/health/statistics/prevalence/serious-mental-illness-smi-among-us-adults.shtml
• A mental, behavioral, or emotional disorder (excluding developmental and
substance use disorders)
• Resulting in serious functional impairment, which substantially interferes with or
limits one or more major life activities
Disease Burden of Mental Health
The Global Burden of Mental, Neurological and Substance Use
Disorders: An Analysis from the Global Burden of Disease Study
2010. Whiteford, 2015, PLOS ONE, DOI:10.1371/journal.pone.0116820 February 6, 2015
“Mental and substance disorders were one of the leading causes of
disease burden in 2010. They were responsible for 7.4% of global
DALYs and 22.9% of global YLDs, making them the fifth leading
cause of DALYs and the leading cause of YLDs.”
• Years Lived with Disability (YLDs)
• Years lost to premature mortality (YLLs)
• Disability Adjusted Life Years (DALYs)
– the sum of YLDs and YLLs
– a measure of overall disease burden, expressed as the number of years lost due
to ill-health, disability or early death
Schizophrenia Is the Major Neurobiological
Challenge in Psychiatry
• DSM-5 Diagnosis of Schizophrenia
– Characterized by delusions, hallucinations, disorganized speech
and behavior, and other symptoms that cause social or
occupational dysfunction.
– For a diagnosis, symptoms must have been present for six
months and include at least one month of active symptoms.
– DSM-5 raises the symptom threshold, requiring that an
individual exhibit at least two of the specified symptoms. (In
the manual’s previous editions, that threshold was one.)
– The diagnostic criteria no longer identify subtypes.
A Model of the Interaction between Stress and Genetic
Influences in Schizophrenia
Living in a City Increases the Risk for Schizophrenia
Heritability of Schizophrenia
• The heritability of schizophrenia is a strong indicator of a
biological basis for schizophrenia
– Adoption studies
•
Adult schizophrenics that were adopted as children are likely
to have schizophrenic biological relatives.
– Twin studies
•
Concordance rates for schizophrenia are higher for identical
than for fraternal twins:
– No single gene has been identified for schizophrenia
• Genes may pass on a susceptibility to develop schizophrenia
The Heritability of Schizophrenia
The Heritability of Schizophrenia
• Genetic influences on Schizophrenia
• Many different genes could be responsible
• A few critical genes have been identified
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Neuregulin1 for regulation of receptors for NMDA, ACh, GABA
Dysbindin involved in synaptic plasticity
COMT for the metabolism of dopamine
G72 involved in glutamate activity
• One gene appearing abnormal in one schizophrenic family is
DISC1.
• Transgenic mice with a mutated version of this gene developed
enlarged lateral ventricles.
Brain Damage and Schizophrenia
• The negative symptoms of schizophrenia are related to brain
damage
– The neurological signs evident in schizophrenia include
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Eye tracking problems
Catatonia
Problems with blinking, eye focusing, and visual pursuit
– Schizophrenics exhibit enlarged brain ventricles, which
suggests loss of brain cells
– Regions of schizophrenic brain that are abnormal include
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Prefrontal cortex
Medial temporal lobes
Medial diencephalon
Eye Tracking in Patients with Schizophrenia versus Control
• Control of Eye movement may be an associated endophenotype
• a group of behavioral or physical characteristics that accompany
an inherited susceptibility to a particular disorder.
A Simple Scan for Schizophrenia?
Brain Damage and Schizophrenia
• The entorhinal cortex, cingulate cortex,
parahippocampus, hippocampus and amygdala are
smaller in schizophrenics than in most people.
• Because these brain areas are smaller it allows the lateral
ventricular space to become large
• Gradually larger with progression of schizophrenia
• See figures 2.13, 2.17 and 2.19
• In schizophrenics, pyramidal cells of the hippocampus
have a disorganized arrangement.
– Abnormal cellular arrangement also found in the entorhinal
cortex, cingulate cortex and parahippocampus.
– This probably occurs during early cell development.
Ventricular Enlargement in Schizophrenia
Identical Genes, Different Fates
Cellular Disarray of the Hippocampus in Chronic
Schizophrenia
Accelerated Loss of Gray Matter in Adolescents with Schizophrenia
Adolescents with schizophrenia
Hypofrontality in Schizophrenia
Cortical abnormalities include a thicker corpus callosum and altered
function in this structure.
Some studies show a loss of gray matter in the frontal lobes, and PET
shows less metabolic activity.
The hypofrontality hypothesis suggests that schizophrenia may be
caused by underactivation of the frontal lobes.
Potential Causes of Brain Damage in Schizophrenia
• The neurological symptoms of schizophrenia may be caused by
– Genetic mutations
– Birth trauma (obstetrical issues)
– Viral infections that impair neural development during the
second trimester
• Seasonality effects (schizophrenia is more likely for winter births)
– Nutritional issues (Hunger Winter: female offspring were more
likely to exhibit schizophrenia than male offspring)
– Maternal stress may compromise the immune system of the
mother and lead to a greater chance of contracting a viral
infection
Positive Schizophrenia Symptoms: Dopamine
• The “dopamine hypothesis” is that the positive symptoms of
schizophrenia involve over-activity of brain dopaminergic
synapses
• Dopamine hypothesis is based on
– antipsychotic drugs such as chlorpromazine (CPZ) block DA
receptors
– amphetamine release DA can reproduce the positive symptoms
of schizophrenia
– PET studies indicate greater release of dopamine in the
striatum of schizophrenics to a test dose of amphetamine
• Amount of dopamine released was related to the increase in positive
schizophrenia symptoms
Typical Antipsychotic Drugs Affect Dopamine Receptors
Antipsychotic Drugs That Affect Dopamine Receptors
Typical neuroleptic drugs are all antagonists at dopamine D2 receptors
Cognitive Symptoms
• 15 IQ points below the population mean
• Cognitive decline several years before the onset of other
schizophrenia symptoms
• Lower cognitive functions is stable through out the course
of the illness
• Cognitive decline should be considered an important part
of the etiological hypotheses.
Glutamate Hypothesis
• PCP and ketamine induce positive, negative and cognitive
elements of schizophrenia in humans
– PCP and ketamine are antagonists at the NMDA glutamergic
receptor
– Glutamate functions as an excitatory amino acid
• NMDA receptor (ionotropic): activation allows Na+ and Ca++ ions to
enter membrane (EPSP)
• PCP binding site: PCP binding blocks Ca++ ion entry (antagonist)
The Effects of PCP on the NMDA Receptor
Glutamate and Dopamine
• Schizophrenia may reflect a deficit in glutamate transmission
(DA effects are secondary to NMDA)
• Ketamine-induced symptoms are not reversed by DA receptor
blockade (e.g. haloperidol)
• Ketamine infusion increases the DA-releasing activity of
amphetamine in humans