SKZ

1. SKZ

2. Hx ? • Ebefrenia • Catatonia • Demenza paranoide • paranoid • disorganized • catatonic • undifferentiated • residual • Demenza precox • Malattia maniaco-depressiva

3. Brain structures Nervous tissue architecture Cell properties ↓ Hypotheses models evidence

4. Background http://www.schizophrenia.com/research/schiz.brain.htm http://www.loni.ucla.edu/

5. Grey matter loss (red) n=96

11. SKZ • Interplay between biological and psychosocial factors • New conception of schizophrenia as a brain disorder (last 20 years) • Not to dismiss environmental stressors, but rather to put these in the perspective of a brain disorder in evolution

12. SKZ • Behavioral aberrations → diffuse abnormality in several brain systems • Frontal and temporal lobes • Reduced volume was reported in multiple regions including the superior temporal gyrus, hippocampus, and thalamus.

13. Preimaging era • Persistent negative symptoms have been observed as a neurobehavioral sequela of frontal lobe damage • Productive positive symptoms of hallucinations and delusions have been related to the temporolimbic system

14. SKZ • The exception is basal ganglia regions ↑ volume • → related to the effects of dopamine receptor antagonists ?

15. Blood flow • Patients did not show the normal pattern of more anterior than posterior flow. • Decreased frontal metabolic activity has been associated with duration of illness and negative symptoms • Improvement in clinical status correlated with a shift toward lower left hemispheric metabolism relative to that in the right hemisphere

16. Metabolism and blood flow • PET described abnormal cerebral blood flow in the parahippocampal gyrus, associated with positive symptoms. • SPECT blood flow changes in the hippocampus, parahippocampus, and amygdala → Hallucinations • Symmetrical temporal lobe perfusion (lower in the left than the right) in patients with auditory hallucinations (inconsistencies).

17. Activation studies • Healthy controls showed the expected greater left hemispheric increase for the verbal task and greater right hemispheric increase for the spatial task. • Patients with schizophrenia had a bilaterally symmetrical activation for the verbal task and greater left hemispheric activation for the spatial task.

18. Conclusion 1 • SKZ is a multifactorial brain disease • Neurodevelopment is crucial to the disease and sensitive to external stimula • Front lobes and the limbic system are central to SKZ but results from nimg did not yeald comprehensive results • Thus → go into into further details, propose and check models

19. Specificity of symptoms ?

21. Role of interneurons

22. Higher order cognitive processes → θ and γ oscillations (synchronized activity of networks of pyramidal neurons at 4–7 and 30–80 Hz) • Normal → Power of θ and γ synchrony ↑ when working memory load ↑ • SKZ → ↓cortical θ and γ band power and working memory performance • CCK-immunoreactive cell bodies → layers 2–superficial 3; axon terminals → layers 2, 4 and 6

23. Cortical θ and γ oscillations require strong inhibition provided by GABAergic inputs to the perisomatic region of pyramidal cells • Perisomatic inhibitory inputs to pyramidal neurons are furnished primarily by GABAergic basket cells that contain calcium-binding protein PV (PVb cells) or neuropeptide cholecystokinin (CCKb cells)

25. ↓ PV-immunoreactive axon might reflect fewer PVb terminals. • ∼50% of PV neurons lack detectable levels of GAD67 • ↑ μOR PFC → ↓ PV activity • ↓ GABAA receptor α1 subunit → ↑ activity of pyramidal cells

26. CB1R ↓ PFC statistically significant in layers deep 3–4 and 6 That results in ↓ GABAergic transmission

27. Is GABA that central ?

28. Cognitive deficits are present and progressive years before the onset of psychosis the degree of cognitive impairment is the best predictor of long-term functional outcome gamma frequency (30–80 Hz) oscillations in DLPFC neural networks are thought to be a key neural substrate for cognition ↓ GABA in DLPFC → ∆ gamma frequency

29. GAD65 and GAD67 drive the synthesis of GABA in the brain • GAD67 mRNA and protein have been found consistently to be lower in the DLPFC of subjects with schizophrenia • frontal lobe GABA levels tended to be correlated with working memory performance in subjects with early-stage schizophrenia

32. GABAergic transmission in the mPFC could be a main biological target for explaining the cognitive deficits in SKZ ▲ in the GABAergic transmission would result in ↓ efficacy of the mPFC functioning Thus → check in other regions, find common pathways Conclusion 2

33. SKZ KEY MAP POINTS • PFC • NACC • HIPPOCAMPUS/AMYGDALA

34. 1936 Jacobsen → monkeys with dlPFC lesions are example of “out of sight, out of mind” 1979 Brozoski → depletion of cathecolamines from dlPFC was detrimental as ablating the dlPFC itself 1992 Liddle → hyperactivity of the hippocampus in SKZ 2006 Lewis and Moghaddam → ↓ parvalbumin interneurons in SKZ 2010 Arnsten → neuromodulators ∆ dlPFC network firing (sec) through impacts on ion channels → dynamic network connectivity (DNC) PFC

36. 1987 Goldman Rakic → dlPFC receives visual feature, auditory feature or auditory spatial inputs, thus extending parallel sensory processing into the dlPFC • 1991 Goldman Rakic → dlPFC networks are already observed in utero and in very early life so they do not require experience to establish connections

38. Maier 2008 → A large portion of neurons in the principal sulcal dlPFC show spatially tuned, persistent firing across the delay period • Thus, neurons in dlPFC can represent visual space in the absence of sensory stimulation • Goldman Rakic, 1996 → behavioural inhibition and cognitive control depend on these mechanisms

39. Seo and lee, 2009 → emotions reward, changing rules and goals require the activation of the PFC

40. Nearby neurons with similar spatial tuning excite each other via connections on spines to maintain firing without the need for bottom-up regulatory stimulation • This persistent firing is highly dependent on NMDA receptors, including those with NR2B subunits (slow kinetics) • AMPA receptors are involved in the activity of GABA interneurons

41. Schizophrenia → ↓ GABAergic action, with loss of spines and neuropil in layer III • There is evidence of ↓ parvalbumin-containing neurons in schizophrenic patients • → profound working memory impairment and thought disorder • Layer III pyramidal cells are also an early target of neurofibrillary tangles and neurodegeneration in Alzheimer's disease

43. Layer V neurons also exhibit alterations in schizophrenia • They project to the striatum and engage in cortico-cortical connections • Lidow, 1998 → Some delay cells and most response cells reside in layer V, they are selectively influenced by D2 receptors and D2 receptor mRNA is enriched in layer V

44. Ford 2002 → alterations in discharge feedback from PFC may contribute to hallucinations • Corlett, 2007 → errors in feedback may also play a role in delusions

45. Long term memory It is associated with structural changes in synapses obtained through: Rapid ∆ n AMPA and NMDA receptors leading to structural changes of the spine • Working memory • A momentary ever changing pattern of recurrent activation of relative stable architectural networks

47. Long term memory • Requires Ca++ and cAMP which are facilitated by neuromodulators and lead to trascriptional events in the nucleus (Barco, 2003) • In this way the cortex is thought to accumulate a lifetime of experience in remote memory storage

48. Long term memory ↑ cAMP → ↑ long term memory ↑ NE stimulation of α1 receptors → ↑ long term memory • Working memory • ↑ cAMP → ↓ working memory • ↑ NE stimulation of α1 receptors → ↓ working memory • U shaped influence of catecolamines

50. PKA activation may uncouple the α2R that normally serve to inhibit cAMP signaling • Ca++ can build up in spines through a number of mechanisms: • NMDA • IP3 • NE α1R and mGluR This process is further increased through phosphorylation of IP3 receptors Ca++ opens a variety of channels, including the SK channels that provide negative feedback to NMDA receptors and reduce PFC firing thus impairing working memory