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Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivothe relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = − 0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.

Functional magnetic resonance imaging (fMRI) is a potential paradigm shift in psychiatric neuroimaging. The technique provides individual, rather than group-averaged, functional neuroimaging data, but subtle methodological confounds represent unique challenges for psychiatric research. As an exemplar of the unique potential and problems of fMRI, we present a study of 10 inpatients with schizophrenia and 10 controls performing a novel “n back” working memory (WM) task. We emphasize two key design steps: (1) the use of an internal activation standard (i.e., a physiological control region) to address activation validity, and (2) the assessment of signal stability to control for “activation” artifacts arising from unequal signal variance across groups. In the initial analysis, all but one of the patients failed to activate dorsolateral prefrontal cortex (DLPFC) during the working memory task. However, some patients (and one control) also tended to show sparse control region activation in spite of normal motor performance, a result that raises doubts about the validity of the initial analysis and concerns about unequal subject motion. Subjects were then matched for signal variance (voxel stability), producing a subset of six patients and six controls. In this comparison, the internal activation standard (i.e., motor activation) was similar in both groups, and five of six patients, including two whom were neuroleptic-naive, failed to activate DLPFC. In addition, a tendency for overactivation of parietal cortex was seen. These results illustrate some of the promise and pitfalls of fMRI. Although fMRI generates individual brain maps, a specialized survey of the data is necessary to avoid spurious or unreliable findings, related to artifacts such as motion, which are likely to be frequent in psychiatric patients. © 1998 American College of Neuropsychopharmacology

Using proton magnetic resonance spectroscopic imaging (1H-MRSI) we found in a previous study a specific pattern of neuronal pathology in patients with schizophrenia as determined by relative loss of signal from N-acetyl-containing compounds (NAA). The purpose of the present study was to assess the reproducibility of the results of 1H-MRSI both in patients with schizophrenia and in normal controls. We studied twice 10 patients and 10 controls on 2 days separated by, on average, 3 months. Reproducibility was assessed with several statistical procedures including ANOVA, coefficients of variation (CVs) and intra-class correlation coefficients (ICC). Patients showed significant reductions of NAA/creatine-phosphocreatine (CRE) and NAA/choline-containing compounds (CHO) selectively in the hippocampal region (HIPPO) and in the dorsolateral prefrontal cortex (DLPFC) on both experimental days. A repeated measures ANOVA showed no effect of time on metabolite ratios in all subjects. CVs were fairly low (especially for NAA/CRE and CHO/CRE) and did not differ significantly between patients and controls. The ICCs of the ROIs reached statistical significance only in a few instances. The present multislice 1H-MRSI study shows that: (1) patients with schizophrenia, when compared as a group to normal controls, show a consistent 1H-MRSI pattern of group differences, i.e., bilateral reductions of NAA/CRE and NAA/CHO in HIPPO and DLPFC; (2) 1H-MRSI data in both patients and controls do not show significant changes over this 90-day period; however, absolute metabolite ratios in individuals show low predictability over this time interval; (3) 1H-MRSI data show relatively low variability (as measured by the CVs) both in patients and normal controls, especially for NAA/CRE and CHO/CRE.Neuropsychopharmacology (1998) 18 1–9.10.1016/S0893-133X(97)00090-0