T3 L2. Schizophrenia Neurobiology and Treatment (NS).pptx

Theme 3 Schizophrenia: Neurobiology and Treatment Dr Natasha Sigala [email protected] Module 202: Neuroscience & Behaviour Outline • Aetiology : Genes and Environment • Neuropathology: Structural changes • Neurodevelopmental model • Neurophysiology: Functional changes • Psychopharmacol...

Theme 3 Schizophrenia: Neurobiology and Treatment Dr Natasha Sigala [email protected] Module 202: Neuroscience & Behaviour Outline • Aetiology : Genes and Environment • Neuropathology: Structural changes • Neurodevelopmental model • Neurophysiology: Functional changes • Psychopharmacology: DA and Glu • Cognitive impairments 2 Learning outcomes Explain the role of genes and the environment in schizophrenia Give examples of structural and functional brain changes associated with the disease Explain the neurodevelopmental model of schizophrenia and support it with experimental evidence Compare and contrast typical and atypical antipsychotics and give examples of each Explain and provide experimental evidence for the dopamine and glutamate hypotheses Aetiology of schizophrenia - what causes it? Genes and environment Genetic Risk: 1% general population up to ~50% risk in monozygotic twin Partial penetrance (interaction of genes and environment) Likely to be polygenic multiple susceptibility genes Presence of these and environmental factors triggers schizophrenia from Bear, Connors, Paradiso Genes “Genes do not encode hallucinations, delusions or thought disorganisation per se. Genes determine the structure of simple molecules in cells, usually proteins, and these proteins affect how cells process and respond to stimuli. A variation in the sequence of a gene… could lead to changes in the interactions that cell has with other cells, in the connections and cell assemblies that develop, and in how such assemblies and networks operate as functional systems” Daniel Weinberger, World Psychiatry, 2002 Van Os et al., Nature, 2010 5 Genes and Environment Onset of schizophrenia males 20-28 years, females 26-32 (Post synaptic pruning events during puberty - brain maturation) GENETIC Susceptibility genes Birth Adolescence Schizophrenia obstetric complications adverse life events prenatal infection substance abuse nutritional deficiency (cannabis use - 6x risk) ENVIRONMENTAL 6 Neuropathology Structural changes: • Ventricular enlargement • Reduced brain volume (less gray matter) (temporal lobes, frontal lobes, subcortical structures) • Cytoarchitectural differences in cortex and hippocampus Healthy Schizophrenic Healthy Schizophrenic 7 Neuropathology Structural changes: • Ventricular enlargement • Reduced brain volume (less gray matter) (temporal lobes, frontal lobes, subcortical structures) • Cytoarchitectural differences in cortex and hippocampus Healthy Schizophrenic Healthy Schizophrenic 8 Neuropathology Paracingulate sulcus morphology associated with hallucinations: J.R. Garrison et al. 2015, Nature communications Source: http://www.memlab.psychol.cam.ac.uk/pubs/Garrison2015%20NatureComms.pdf Reality monitoring 9 Neurodevelopmental model of schizophrenia During adolescence grey matter is lost (pink), which may speed up in early-onset schizophrenia Dobbs, Nature, 2010 Age at first admissio n 10 Neurodevelopmental model of schizophrenia Thompson PM et al., PNAS, 2001 measure used: gray matter density 12 patients vs. 12 controls MRI scanned repeatedly over 5 years 11 (aged ~14 years at first scan) Wisconsin Card Sorting Task Wisconsin Card Sorting Task Neurophysiology Functional changes: Hypofrontality during periods of high cognitive load (e.g. Wisconsin Card Sorting Test - test of cognitive flexibility) MacDonald et al., Am J Psychiatry, 2005 Increases in activity in dlPFC seen in healthy volunteers absent in schizophrenics. Negative and cognitive symptoms. 14 Neurodevelopmental model of schizophrenia Thompson PM et al., PNAS, 2001 15 Neurodevelopmental model of schizophrenia Insel, Nature, 2010 Neurophysiology Functional changes: Auditory cortex activation during hallucinations (fMRI evidence) a. Patients press a button during auditory verbal hallucinations – Correlation with BOLD signal b. Patients listen to binaural Acoustic stimuli Dierks et al., Neuron, 1999 17 Neurophysiology Oscillations: important organizers of brain activity, plasticity and connectivity (*maturation) Neuronal synchrony: well-timed coordination and communication between neural populations Theta rhythm Alpha rhythm Beta rhythm Gamma rhythm (4-8 Hz, 250-125 (~10 ms) Hz, ~100ms) (15-30 Hz, 67-33(30-80 ms) Hz, 17-13 ms) Attention Perception Working Memory Wang, Physiol Rev, 2010 Nachev et al., Nat Rev Neurosci, 2008 (from Bear, Connors & Paradiso) 18 Neurophysiology High frequency oscillations and synchrony emerge during the transition from adolescence to adulthood. Differences in neural oscillations and synchrony between controls and patients with schizophrenia. Ulhaas & Singer, Nat Rev Neurosci, 2010 19 Neurophysiology summary Hypofrontality Hyper-excitable sensory cortex Abnormal neural oscillations 20 Psychopharmacology Dopamine neurons - cell bodies in the midbrain - project into the forebrain Nigrostriatal system Mesolimbic system Mesocorticolimbic pathway Mesocortical system (reward & reinforcement, provides stimulus salience) (from Bear, Connors & Paradiso) 21 Psychopharmacology Dopamine hypothesis – evidence 1) Typical Antipsychotic (neuroleptic) Drugs D2 receptor antagonists Prevent positive symptoms First antipsychotic (discovered in 1950s): Chlorpromazine Haloperidol: more potent than Chlorpromazine Parkinsonian-like side effects: - dopamine mechanism? Antipsychotic dosage correlates with their potency as D2 receptor antagonists 2) DA agonists e.g. cocaine, amphetamine, L-DOPA can (in large doses) cause positive symptoms of schizophrenia (e.g. psychosis) These drug-induced psychoses can be treated with the D2 antagonist antipsychotic drugs. 22 Psychopharmacology Correlation of drug effective dose in controlling schizophrenia and drug binding affinity for D2 receptors (from Bear, Connors & Paradiso) 23 Dopamine hypothesis contd. Dopamine receptors D1 receptor family (Gs coupled) D2 receptor family (Gi coupled) D1 D2 caudateputamen NAcc olfactory tubercule D5 hippocampus hypothalamus NAcc olfactory tubercule D3 D4 caudate- olfactory frontal putamen tubercule cortex hypothalamus medulla NAcc amygdala cerebellum midbrain Extrapyramidal side effects caused by typical antipsychotics Parkinsonian-like symptoms (inhibition of DA action in Caudate) (slow movement, lack of facial expression) followed by Tardive dyskinesia (slow, faulty movements) (upregulation of D2 receptorssupersensitivity - need to keep upping the dose) Atypical antipsychotics (e.g. clozapine - more selective to D4 - beneficial effects without EPS (plus actions at other receptors - 5HT receptors) 24 Psychopharmacology Typical vs. atypical antipsychotics • Atypical antipsychotics can work in patients resistant to typicals • Atypicals do not have same extra-pyramidal side effects (lower activity at D2 receptor) Clozapine activity mainly at D4 receptors (also binds D3, D1, D2, D5) 5HT receptors improves positive and negative symptoms side effects - weight gain, sedation, hypersalivation, tachycardia, hypotension, neutropenia (needs to be watched - blood tests) Other atypicals: Risperidone, Olanzapine - differing affinities for receptor subtypes, varying levels of side effects. 25 Psychopharmacology Glutamate Hypothesis – evidence 1) PCP (phencyclidine, angel dust) • Causes many positive, negative and cognitive symptoms of schizophrenia • NMDA receptor antagonist http://journals.prous.com/journals/dnp/20021504/html/dn150226/images/Smith_f4.jpg 26 Psychopharmacology Glutamate Hypothesis – evidence 2) Genetically engineered mice with fewer NMDA receptors. Mohn et al, Cell, 1999 27 Psychopharmacology (from Carlson, 9th Ed) PCP treatment used to model schizophrenia in animal studies: 1) NMDA antagonism in PFC - less glutamatergic firing to VTA GABA neurons 2) Less GABAergic inhibition of VTA-NAcc DA neurons 3) Greater DA release in NAcc 4) Less activation of VTA-PFC DA neurons - less Glu - hypofrontality 28 Psychopharmacology Dopamine antagonists - antipsychotic Dopamine agonists or boosting drugs - cause psychosis Action in Nucleus accumbens (and amygdala) Glutamate antagonists(PCP) - positive + negative + cognitive symptoms Action in PFC (feedback to DA system - hyperactive in NAcc - hypoactive in PFC) HYPOactive PCP/schizophrenic PFC Normal PFC PFC VTA NAcc VTA Glutamate GABA Dopamine NAcc HYPERactive NAcc 29 Psychopharmacology Atypical antipsychotic drugs seem to: •Increase DA activity in PFC and •Decrease DA in NAcc 30 Effects of a Partial agonist High concentration of DA (black) in the NAcc Partial agonist (atypical antipsychotic) acts as an antagonist Partial agonist (atypical antipsychotic) acts as an agonist Low concentration of DA (black) in the PFC 31 Effects of a Partial agonist High concentration of DA (black) in the NAcc Partial agonist (atypical antipsychotic) acts as an antagonist Partial agonist (atypical antipsychotic) acts as an agonist Low concentration of DA (black) in the PFC 32 Neurocognitive Deficits Enduring symptom of the disease typical antipsychotics - no effect on these symptoms atypicals - some improvement, e.g. increase verbal fluency Lower IQ Attentional deficits (e.g. Stroop Test) Working memory (e.g. Wisconsin Card Sorting Test) Planning and information processing deficits 33 Stroop task What colour are the following: RED YELLOW BLUE BROWN GREEN ORANGE And these: YELLOW RED GREEN BROWN BLUE ORANGE Patients with schizophrenia are slower and less accurate (hard time inhibiting the other contextual information and attending to the colours) 34 Summary • Aetiology : Genes and Environment •Structural changes: Ventricular enlargement Less gray matter Cytoarchitectural differences in cortex and hippocampus • Neurodevelopmental model • Neurophysiology: Hypofrontality Hyper-excitable sensory cortex Abnormal neural oscillations • Psychopharmacology: DA and Glu • Cognitive impairments 35 Reading materials Carlson, Physiology of Behaviour: Chapter 16 Bear, Connors, Paradiso: Chapter 22 http://www.nature.com/news/specials/schizophrenia/index.html 36