Despite schizophrenia's (SZ) 1% prevalence, its all too evident devastating effects in the VA patient and world population, and the consequent intensive research, much is not known. This application is a competing renewal of a VA Merit Award which has been funded since 1998, and whose 35 peer-reviewed publications since the last submission indicate high productivity. This application strikes a new path in the inclusion of 3T proton magnetic resonance spectroscopy (MRS) of glutamatergic and GABAergic metabolites in a study of 40 VA SZ patients and of 40 community-recruited, non-patient, and never neuroleptic-medicated schizotypal personality disorder subjects (SPD), both compared with 48 healthy controls (HC), with HC oversampling allowing age-matching to SZ and SPD subject groups. This proposal follows the RDoC conceptualization in examining the neural circuit consisting of interactions between cortical GABA neurons containing parvalbumin and glutamatergic pyramidal neurons in the superior temporal gyrus (STG) across DSM categories of SZ and SPD. Using RDoC guidelines, we examine this neural circuit at both more basic levels in terms of its constituent molecules and neurons, and at higher levels, its relationship to physiology and to symptoms (illustrated in the Table in the Introduction Section). Accordingly, our MRS study provides key information on the molecular basis of this Neural Circuit in measures of GABA and glutamatergic metabolites. The overarching MRS hypothesis is of increased glutamatergic and decreased GABAergic neurotransmission in both SZ and SPD, compared with HC, resulting in neurophysiological and clinical abnormalities. Our PD suggest smaller glutamatergic and especially smaller GABAergic abnormalities in SPD compared with SZ. Going from the neural circuit to the higher level of physiology, extensive basic neuroscience work indicates that this neural circuit is responsible for generating Gamma Band Oscillations (GBO, about 40 Hz in scalp-recorded EEG). GBO are further advantageous since they provide a functional readout of both neurotransmission-relevant presynaptic (vesicular) and receptor components. Thus, we hypothesize, based on our preliminary data (PD), that the strength of the GBO furnishes a measure of the functional relevance of the GABAergic and Glutamatergic MRS values. The auditory steady state response (ASSR) provides a reliable experimental index of GBO strength; both SZ and SPD show an impaired response to 40 Hz. Since GBO play a role in information processing and transfer across brain regions, we conceptualize that their abnormalities lead to corruption of percepts and to the failure of veridical perceptual integration (including that of social cues) and in turn, lead to both positive and negative symptom components. Our main focus on the novel MRS region of interest, the STG, (especially on the left) is dictated by its role in generating ASSR GBO and our extensive preliminary data showing STG gray matter reduction and associated abnormal event- related potentials (ERPs) occurring in both SZ (Merit awards) and SPD (NIMH awards). Additionally, we evaluate the neural circuit consisting of anterior cingulate cortex (ACC) and STG interaction, formed by projections of pyramidal neurons from each nucleus to the other. At the molecular level we investigate the role of GABA and glutamate in circuit modulation. At the physiological level, ACC has a known role in decision making (oddball P300) and in the salience network (novel P300). We thus predict, and preliminary data confirm, that STG and ACC MRS glutamatergic and GABAergic metabolites modulate both oddball and novel P300 in both SZ and SPD. We further predict, based on our preliminary data, ERP-symptom associations.

Public Health Relevance

Despite schizophrenia's (SZ) 1% prevalence, its all too evident devastating effects in the VA patient and world population, and the consequent intensive research, much remains to be learned about its pathophysiology and thus the pathway toward rational treatment. This application focuses on VA patients with SZ, and a related but less severely affected schizotypal personality disorder group using a novel combination of magnetic resonance spectroscopy (MRS) to detect neurochemical abnormalities together with EEG measures of gamma band oscillations (GBO), which provide a functional measure of the impact of MRS abnormalities. GBO are responsible for communication between brain regions, and their abnormalities in SZ index deficient brain region integration in SZ. We thus suggest that GBO can serve as a translational biomarker whose use in animals will help define promising pharmacologic compounds and whose effectiveness in neurochemical alteration in SZ can be monitored using the same biomarker.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Mental Health and Behavioral Science A (MHBA)
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VA Boston Health Care System
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