The broad aim of this 5-year multidisciplinary research study is to advance our understanding of the biological basis of schizotypal personality disorder (SPD), using neuropsychological, electrophysiological, and magnetic resonance imaging (MRI) studies on DSM IV-diagnosed patients and age-, sex-, and parental socioeconomic status-matched normal controls (NC). SPD is on intrinsic interest, and is also important to study because it is shares a common heritability with schizophrenia (SZ). SPD thus affords a unique opportunity to investigate the biological substrate and markers of SZ spectrum disorders without the complicating and perhaps confounding factors of SZ, e.g., chronic illness, chronic medication, and chronic hospitalization. We propose to study 150 SPD and 150 NCs recruited from the community, equally balanced for males and females, all right-handed and with no history of neuroleptic medication or current psychotropic medication. We will develop clinical syndrome measures from the Schizotypal Personality Questionnaire and Structured Interview for Schizotypy. Based on data collected in our laboratory, as well as studies reported in the literature, we predict an association of """"""""positive clinical symptoms"""""""" with structural and functional measures referable to the temporal lobe (and, specifically, the left temporal lobe for language-related functions), as well as an association of """"""""negative clinical symptoms"""""""" with structural and functional measures referable to the frontal lobe. In SPD, we thus predict conjoint associations among positive symptoms (including thought disorder), left temporal P300 ERP amplitude reduction, and MRI cortical gray matter volume reductions, especially of the left Planum Temporale and Superior Temporal Gyrus, as well as deficits in dichotic shadowing (implying deficits in cognitive inhibition) and the Continuous Performance Task (CPT) with Interference (high verbal load). We further predict, based on intracranial recording localization, that N400 abnormalities, indicating deficiencies in semantic inhibition and activation, will be associated with inferior temporal and fusiform gyri MRI gray matter volume reduction. Similarly, we predict conjoint associations among negative symptoms, poor performance on the Wisconsin Card Sorting Test (perseverative errors), a Delayed Alternation test, CPT-interference and -memory tasks, and the presence of MRI developmental abnormalities (Cavum Septi Pellucidum and sulco-gyral pattern), prefrontal gray matter volume reductions and MR diffusion tensor abnormalities in fronto-temporal white matter tracts. We further predict the SZ abnormalities of early neurophysiological processing (e.g., gamma frequency following and mismatch negativity) will not be present in SPD, but that both SPD and SZ will show qualitatively similar deficits on later, cognitively more complex processing (e.g., P300 and N400). Finally, we predict less severe abnormalities in female than male SPD subjects. Our long-term goal is to link the clinical manifestations of SPD to brain structural and functional abnormalities.
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