Schizophrenia and Gamma Oscillations

1. Schizophrenia and Gamma Oscillations

2. Shizophrenia-General Overview • Most often occurs at 17-35 years of age and affects roughly 1% of the population • Schizophrenia presents in a vast variety of ways and is characterized by 4 major categories of symptoms: i) Positive symptoms - Hearing voices, suspiciousness, feeling under constant surveillance, delusions, or making up words without a meaning (neologisms). ii) Negative (or deficit) symptoms - Social withdrawal, difficulty in expressing emotions (in extreme cases called blunted affect), difficulty in taking care of themselves, inability to feel pleasure (These symptoms cause severe impairment and are often mistaken for laziness.) iii) Cognitive symptoms - Difficulties attending to and processing of information, in understanding the environment, and in remembering simple tasks iv) Affective (or mood) symptoms - Most notably depression, accounting for a very high rate of attempted suicide in people suffering from schizophrenia • Schizophrenia seems to be caused by an interaction between genetics and environment and is highly heritable with twin studies yielding concordance rates of 50%

3. Theories on Schizophrenia Disconnection Hypothesis Disconnectivity Hypothesis Aberrant Connectivity Hypothesis

4. Disconnectivity Hypothesis &Aberrant Connectivity Hypothesis • Genetic Factors • NMDAR (N-methyl-D-aspartate receptor) • Spectrum Disease • Specific impairments of synaptic plasticity • Corollary discharge • NMDA antagonists (ketamine) • Hypo and hyper activity in brain regions • Schizophrenia in relation to gamma

5. Genetic Factors • Brain development and genetics seem to be a key factor leading to schizophrenia • Studies have found abnormalities in the genes leading to synaptic plasticity development in schizophrenics especially in NMDARs and its regulation by DA and ACh • Schizophrenics have decreased scripts for pre-synaptic secretory machinery involved in glutamatergic and GABAergic neurotransmission • DISC1 effects dendritic growth and maintenance in those with schizophrenia both are reduced implicating this gene as the culprit • NRG1: is heavily implicated in regulation of oligodendrocyte maturation and myelin production • Reelin has been implicated in cortical layer formation and in the renewal and maintenance of dendritic spine in interneurons

6. Genetic Factors Cont. “Collectively, the experimental evidence summarized above indicates that schizophrenia is a spectrum disease that may be caused by different genetic mechanisms and pathophysiological processes; these processes, however, appear to converge onto the same functional pathway, ie, the regulation of NMDAR-controlled plasticity of glutamatergic synapses by neuromodulatory transmitters like DA, 5-HT, and Ach.”(Stephan, Klaas., et al. 2009)

7. Corollary Discharge • Corollary discharges are self monitoring mechanisms which are supposed to be malfunctioning in schizophrenics • When movements are self-generated, the sensory areas receive a signal from motor areas, informing them about the intended movement and thus allowing them to predict the proprioceptive input they should be receiving. This signal has been called a ‘‘corollary discharge,’’ or ‘‘efference copy.’’ (Stephan, Klaas., et al. 2009) • This goes back to the presentation we had on perrisaccadic eye movements and is the same kind of concept but has to do with all somatosensory movements that are self-generated • In people with schizophrenia the motor movement and the sensory movement may fail to coordinate

8. Corollary Discharge Cont. • Frontotemporal delta and theta band coherence that is enhanced during talking (compared with listening) in healthy volunteers is diminished in schizophrenic patients; the deficit is particularly pronounced in patients with auditory hallucinations. (Ford et al., year 2008) • A problem in communication between brain areas in schizophrenics could distinguish between their self generated speech and external speech • The disconnectivity leading to incongruence between different bands of oscillations may show how different neuronal assemblies fail to communicate leading to these hallucinations and actually studies have shown that the larger the disconnectivity between brain regions the more symptoms of hallucinations in the patients there are Synchrony Dysynchrony

9. Neural Synchrony Indexes Disordered Perception and Cognition in SchizophreniaSpencer, K. M., et al. 2004 • Hypothesized that a clearer relationship between neural synchrony and schizophrenic symptoms might be found if we examined oscillations that were phase-locked to reaction time rather than stimulus onset • They decided to do this because single unit recording studies have found that the processes are more correlated with reaction time than stimulus onset time • In order to test this theory they got two groups of 20 people each one group being schizophrenics and the other a control group • Subjects watched a central cross and pushed a button according to whether an illusory square was present or absent

10. Neural Synchrony Indexes Disordered Perception and Cognition in Schizophrenia • When presented with these Gestalt stimuli a gamma oscillation was elicited in both healthy subjects and schizophrenics, however the frequency of the oscillation in schizophrenics was lower • This may mean that schizophrenics are unable to support high frequency oscillations as well as healthy individuals • The occipital response locked oscillation was different in two ways from that in healthy people: i) the lower frequency and ii) the increases in symptoms were associated with increased phase-locking effects

11. Stimulus Locked

12. Response Time locked

13. Gamma Oscillations in Schizophrenics • Impaired cortical circuitry would not synchronize properly and lead to the perceptual distortions and failures of cognitive integration that characterize schizophrenia • Post mortem brain studies have found decreased density of inhibitory interneurons as well as decreased somal size and spine density of pyramidal cells • This is evidence towards cortical hyperexcitability in schizophrenics because of a lack of inhibition • The abnormalities in the interneurons contribute to neural dysynchrony with their decreased inhibitory output by increasing pyramidal excitability while decreasing spike outbursts

14. Ketamine & Schizophrenia • Ketamine is an NMDA antagonist and produces schizophrenia like symptoms in users • Ketamine produces aberrant gamma oscillations in rodents as well as hyperlocomotion • These aberrant gamma oscillations were not caused by sensorimotor processing and occurred all over the cerebral cortex and in subcortical structures related to sensory, motor and associative/cognitive systems • These oscillations were not conscious and gamma hyperactivity was a generalized phenomenon not limited to sensorimotor systems • Plateaus 1-4 • Due to similarities in the symptoms of taking ketamine including neural dysynchrony and the antagonism of nmda to schizophrenia it may provide researchers with the abillity to do research on animals that is as close to the mind of a schizophrenic individual as we can get

15. Gamma Oscillations in Schizophrenics Summary • Most contemporary views on schizophrenia believe that it is a result of dysfunctional neural synchronization more specifically in regards to gamma oscillations and somewhat in beta oscillations • The dysfunctional neural synchronization seems to be due to hyperexcitation in some brain areas and hypoexcitation in others leading to difficulty in communication and phase-locking • Schizophrenics have varied presentation and varied brain abnormalities leading to varied problems in synaptic plasticity which is why it is believed in the future it will be a spectrum disease with different types of schizophrenia diagnosed depending on which abnormalities are present • There is still a long way to go in the research on schizophrenia and it will continue to help us better understand the brains global functioning from both a top-down and bottom-up perspective

16. Works Cited • Stephan, K. E., et al. (2009). Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring. Schizophrenia Bulletin, vol. 35 no. 3 pp. 509–527. • Gaspar, P.A., et al. (2009). The Aberrant Connectivity Hypothesis in Schizophrenia, Ch15. • Spencer, K.M., et al. (2004). Neural synchrony indexes disordered perception and cognition in schizophrenia. PNAS, vol. 101, no. 49. www.pnas.orgcgidoi10.1073pnas.0406074101. • Hakami T, Jones NC, Tolmacheva EA, Gaudias J, Chaumont J, et al. (2009). NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant Gamma Oscillations Independent of Hyperlocomotion and the State of Consciousness. PLoS ONE 4(8): e6755. doi:10.1371/journal.pone.0006755 • Williams, L.M., et al. (2009). Journal of Psychiatry Neuroscience. Neural synchrony in patients with a first episode of schizophrenia: tracking relations with grey matter and symptom profile34(1):21-9. • Celia J., et al. (2008). Society for the Study of Addiction. Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex-users with polydrug and non-using controls. 104, 77–87