Cours: Neurodevelopmental Diseases and Schizophrenia

Neurodevelopmental Diseases

• Neurodevelopmental diseases are characterized by abnormal mental functions and disturbed behavior.
• Prevalence of mental disorders in the US and Europe (Switzerland included): Major depression (5.3%/5.7%), PTSD (3.6%/2.3%), OCD (2.4%/0.7%), Panic disorders (1.6%/1.2%), Schizophrenia/psychotic disorder (1.3%/1.2%), Bipolar disorder (1.1%/0.7%), Autism Spectrum Disorders (0.1-0.2%/1-2%), Anorexia nervosa (0.1%/0.1%).

Schizophrenia

• Schizophrenia is a brain disorder causing abnormal mental functions and behavior.
• Key symptoms include:
  • Cognitive symptoms: impaired attention, memory, and executive function.
  • Positive symptoms: hallucinations, delusions, thought disorder.
  • Negative symptoms: social withdrawal, alogia, anhedonia.
• Emil Kraepelin, 1919, named Dementia Praecox.
• Eugen Bleuler, 1911, introduced the term Schizophrenia.
• Psychosis is a hallmark of schizophrenia (distortion of reality), with hallucinations and delusions.
• Important feature: lack of insight.

Vulnerability to Schizophrenia

• Vulnerability to schizophrenia is linked to genetic factors, evidenced by studies of families, twins, and adoption.
• The lifetime risk of developing schizophrenia is about 1% in the general population.
• The concordance rate is 50% in monozygotic twins and ~17% in dizygotic twins.
• Environmental factors also play a role.

Environmental Risk Factors

• Viral infection during fetal development.
• Exposure to toxic, traumatic, or autoimmune insults.
• Poor maternal nutrition.
• Problems during gestation (e.g., during labor/birth).

Physical Changes in Schizophrenia

• Enlarged ventricles indicate shrinkage of brain tissue.
• Reduced size of hippocampus and amygdala.
• Changes in fine structure and function of cortical connections.
• Disturbance in dopamine and glutamate transmission is seen.

Dopamine Hypothesis

• Antipsychotic drugs (D2 receptors) effectively treat some patients, suggesting excess dopamine signaling (striatal/mesolimbic areas) is responsible for positive symptoms.
• Negative symptoms are likely due to dopamine deficits in the prefrontal cortex, possibly mediated by D1 receptors.

Glutamate System

• Evidence points to a contribution of the glutamate system in schizophrenia, specifically NMDAR hypofunction.
• NMDA agonists/antagonists show effects on symptoms in healthy subjects.

Functional Changes in Schizophrenia

• Reduced activity in the frontal cortex of patients compared to unaffected counterparts, at rest and during tasks.

Neuropsychological Characteristics

• Neuropsychological characteristics differ between schizophrenic and unaffected twin siblings.
  • Eye tracking, for example, shows that schizophrenics have difficulty with smooth pendulum movements.

Neurodevelopmental Background of Schizophrenia

• Maturation processes such as apoptosis, synaptic pruning, and myelination are perturbed.
• Schizophrenia manifests more during adolescence.

Autism Spectrum Disorder (ASD)

• Autism is defined by deficits in social interaction, impaired communication, and unusual repetitive behaviors.
• The majority of patients have intellectual disability.
• First described by Leo Kanner, 1943.
• Often diagnosed in infancy prior to age three.
• Repetitive behaviors often emerge during preschool years.
• Common observations concern sensory overload and avoidance of novel stimuli.

Autistic Children

• Common characteristics in autistic children include avoidance of eye contact, resistance to physical contact, severe communication troubles (e.g., language acquisition), and repetitive or automatic actions (like rocking).
• Autistic children may or may not be affected by intellectual disability.

Diagnostic Criteria (ASD)

• These criteria are related to social interaction, communication, and behavior.

Autism Spectrum Disorder (ASD) Facts/Prevalence

• High rates of sibling recurrence risk.
• 3 to 6 per 1,000 people affected, with higher prevalence in males.
• High concordance rates in monozygotic twins (60-92%).

Autism as an "Under-connectivity" Syndrome

• Genome-wide linkage studies reveal many genes linked to synaptogenesis and axon guidance.
• This suggests an under-connectivity syndrome.

Environmental Factors (ASD)

• Examples include thalidomide use, certain viral infections (rubella, influenza, cytomegalovirus), and maternal anticonvulsants.

Problems in the Study of Autism

• Problems studying autism include the definition of brain regions most affected.
• Defining types of alterations (structural vs neurochemical) is challenging.
• Biochemical tools are needed to improve diagnosis, and issues associated with heterogeneity in the disorder must be addressed.

Most Prevalent Abnormalities (Autistic Brains)

• Reduced corpus callosum size.
• Changes in cerebellar structure.

Intellectual Disability (ID)

• Defined as significantly sub-average intellectual functioning (IQ < 70).
• Significant limitations in adaptive functioning in areas including communication, self-care, independent living, social skills, work, leisure, health, and safety.
• Typically diagnosed prior to age 18.
• Syndromic and non-syndromic forms exist (syndromic forms like Down syndrome), as well as autosomal conditions that require more study.

Intellectual Disability and Genes

• Some genes linked to ID are involved with neurite outgrowth, axon guidance, synapse formation, plasticity, and neurotransmitter release.
• ID can arise from exposure to drugs during pregnancy, such as those in alcoholic mothers.

Brain Anatomy in Fetal Alcohol Syndrome (FAS)

• Brain anatomy changes due FAS are macroscopic.