Lecture 7

• 1. E-I imbalance may drive some of the dopamine changes in schizophrenia progression
• New drug targets aimed at correcting the E-I imbalance
• Neuroinflammation


  Microglia release pro-inflammatory cytokines including IL-6, IL-10 and TNF-alpha. Acute - can be good. Chronic - bad. Microglia and astrocytes become activated – change shape.

  
• Neuroinflammation is not unique to schizophrenia – many conditions

  
• Many schizophrenia patients have high serum inflammatory markers which correlates with grey matter loss in the medial prefrontal cortex

  
• Activated microglia can prune or engulf synapses – i.e. reduce synapse number
• GWAS highlighted major histocompatibility complex (MHC) on chromosome 6 – including C4 gene, which has the highest association to schizophrenia from the entire genome
• C4 protein is involved in synaptic pruning. High expression of C4 was associated with increased risk of schizophrenia. Increased C4 enhances microglia-mediated synaptic engulfment - suggests inflammation may impact synapse numbers
• Traffic-related air pollution alters brain development and increases risk of schizophrenia but the direct link is unclear. Gut-brain axis is increasingly important. Immune system may link gut-brain axis
• A combination of genetic and environmental factors leads to abnormal development of the adult brain – specific changes in cortical anatomy and neurotransmitters

  
• Cognitive abnormalities in schizophrenia

  • Disruptions in information processing/sensory perception, and deficits in attention, working memory, and behavioural flexibility

  
• Reduced P50 in schizophrenia is correlated with attention and reflects deficits in inhibition – sensory overload

  
• Cognitive abnormalities in schizophrenia are a major factor that limits ability to function in society, occur early in the progress of the disease, are prodromal symptoms that could allow earlier detection, are the best predictor of outcome, and current treatments are largely ineffective

  
• Working memory


  The ability to transiently maintain and manipulate a limited amount of information to guide thought or behaviour
• Delayed match-to-sample task


  1. Sample

  2. Delay 1-90 s

  3. Match to sample

  4. Non match to sample
• Decreased fMRI signal in dorsolateral prefrontal cortex correlated with poor performance on the N-back task, which is a specific deficit seen only in schizophrenia

  
• Working memory deficits in schizophrenia lead to deficits in other cognitive functions
• Patients with schizophrenia show a more extensive network for memory compared to controls, and when controls forgot, the brain areas were less active, while patients thought they had remembered and brain activity was the same

  
• Wisconsin card sorting task


  Subjects asked to match test card to target card

  2. Subject told if correct choice

  3. Rules shift eg. from shape to colour to number

  4. Measures flexibility
• Stroop test


  Measures selective attention, cognitive flexibility, and processing speed
• Impairment on the Stroop test is not unique to schizophrenia as it is also seen in addiction, ADHD, and depression, but it reflects a prefrontal deficit

  
• Working memory is specific to schizophrenia so the focus of much research
• Disconnection hypothesis


  Disrupted coupling between brain regions could be due to faulty wiring or impairments in synaptic transmission and plasticity

  
• Brain regions involved in schizophrenia

  • Auditory cortex
  • Basal ganglia
  • Frontal cortex
  • Limbic system
  • Occipital lobe
  • Hippocampus
  • Thalamus

  
• Imaging studies have shown decreased functional connectivity between brain regions in schizophrenia

  
• In the hollow mask illusion, there is decreased connectivity between parietal and occipital cortex in schizophrenic patients
• Long range synchrony


  Synchrony between brain regions separated by more than 1 cm, e.g. across hemispheres or cortical regions

  
• Reduced long range synchrony at 20-30 Hz in response to Mooney faces is seen in patients with schizophrenia
• Patients with schizophrenia have reduced interactions between brain regions, so they cannot process images normally
• Reduced long range synchrony is a key feature of the EEG in patients with schizophrenia, consistent with the disconnection hypothesis
• Hallucinations in schizophrenia are associated with an increase in gamma oscillations in sensory areas and increases in long range synchrony
• Schizophrenia involves a complex interplay between genetics, environment, network dysfunction, structural abnormalities, and abnormal behaviour