The biological basis of schizotypal personality disorder (SPD) is of intrinsic interest and also important because it bears closely on the nature of schizophrenia (SZ) and """"""""SZ spectrum disorders"""""""". SPD and SZ are genetically linked, but SPD may offer a clearer picture of the SZ spectrum, since SPD does not have the potentially confounding features of SZ, including chronic illness, medication, and hospitalization. This 5-year study will evaluate 80 right-handed, DSM-IV diagnosed SPD subjects, half males and half females, who will be unmedicated, neuroleptic-naive and drawn from the community, but not from clinical treatment settings. They will be contrasted with 80 age-, sex-, handedness- and parental SES-matched normal controls. We are fortunate to be able to use the same common core methodology for SPD evaluation that we use for our separately funded evaluation of SZ, including neuropsychological, Event-Related Potential (ERP), structural and functional magnetic resonance imaging (MRI), and Diffusion Tensor Imaging (DTI), thereby making valid comparisons possible. We believe that this systematic approach will enable us to discover which features are common to SPD and SZ, thereby defining the core deficits of the SZ spectrum, as well as determining which are found only in SZ. Those features found only in SZ may underlie the more severe, psychotic aspects of SZ, while features abnormal in SZ, but normal in SPD, may be protective. 2 major novel findings have emerged from our previous funding period: 1) overall, there are marked gender differences, with abnormalities generally less prominent in women; 2) abnormalities in SPD are likely to be primarily referable to temporal lobe systems {auditory & language processing) and to the frontal-striato-thalamic system (FST, working memory, set shifting), where structural abnormalities are present in the caudate but not in prefrontal cortex. Our proposed functional measures are specifically tailored to these 2 systems, with each system also having MRI & DTI anatomic measures. For example, temporal lobe systems will be studied with: Dichotic listening to complex tones, sentences, & emotion-laden words; ERP measures spanning early to late auditory/language processing; and Mismatch and Level of Processing fMRI tasks. The FST system will be studied with: delayed alternation and auditory working memory tasks, and the fMRI 2-back task. More generally, we expect negative symptom/working memory deficits to be associated with abnormalities in the FST and positive symptoms with the temporal lobe systems. For example, we expect a smaller Heschl's gyrus MRI volume will be associated with poorer performance on dichotic sentence tasks & complex tones, as well as abnormalities in the mismatch protocol (ERP and fMRI). As a FST system example, we expect decreased caudate volume/abnormal shape to be associated with perseveration, abnormal verbal working memory, & increased prefrontal activation in the 2-back fMRI test. Preliminary Data indicate DTI abnormalities -""""""""system disconnections""""""""- of the uncinate fasciculus (UF) white matter links between frontal & temporal lobes, which we predict will show strong associations with cognitive/clinical SPD features, i.e., left UF abnormalities will be associated with impaired cognitive performance while right UF abnormalities will be associated with increased psychopathological SPD symptoms. We believe the feasibility of our ambitious goal of linking biology with cognitive and clinical symptoms is validated by our group's extensive experience with these methods in schizophrenia and in SPD.
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