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Objective: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phasesynchronization (i.e., an increased stimulus-related variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Method: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. Results: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a 'fractionized' and unfocussed pattern of activation in patients. Conclusions: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia. (Am J Psychiatry 2006; 163:1960-1968)

Objective: It has been suggested that increased variability of prefrontal physiological responses may represent a fundamental mechanism underlying frontal lobe deficits in schizophrenia. Increased response variability ('noise') is thought to result from impaired phase resetting of stimulus-induced dynamic changes of ongoing rhythmic oscillations (field potentials) generated in the apical dendrites of pyramidal neurons. In the present study, the authors explored whether this particular physiological abnormality predicts working memory performance and is related to the genetic risk for schizophrenia. Method: Prefrontal response variability of discrete frequency components was investigated across a broad frequency range (0.5-45.0 Hz) during processing of an oddball paradigm in patients with schizophrenia (N=66), their clinically unaffected siblings (N=115), and healthy comparison subjects (N=89). Results: AS hypothesized, prefrontal noise was negatively correlated with working memory performance across all subjects. In addition, it was observed that prefrontal noise possesses trait characteristics and is strongly associated with genetic risk for schizophrenia. Conclusions: Frontal lobe-related cognitive function depends on the ability to synchronize cortical pyramidal neurons, which is in part genetically controlled. Increased prefrontal 'noise' is an intermediate phenotype related to genetic susceptibility for schizophrenia.

Objective: Postmortem studies have implicated the central muscarinic acetylcholine system in schizophrenia. However, central muscarinic receptor availability has not previously been studied in vivo. Using [I-123]iodoquinuclidinyl benzilate ([[sup.123]I] IQNB) single photon emission computed tomography (SPECT), the authors sought to compare the muscarinic receptor availability in vivo in unmedicated patients with schizophrenia and normal subjects. Method: Twelve medication-free patients with schizophrenia underwent an [[sup.123]I]IQNB SPECT scan during approximate-equilibrium conditions. A group of 10 age- and gender-matched normal comparison subjects were given the same kind of scan under similar conditions. Regions of interest were analyzed in the cortex, basal ganglia, thalamus, and pons. Binding data were analyzed as nCi/ml tissue per mci injected dose. Results: Muscarinic receptor availability was significantly less in patients with schizophrenia than in normal subjects in all regions of interest except the pons. Reductions ranged from -33% in the caudate to -20% in the occipital cortex. Positive symptoms of schizophrenia correlated negatively with muscarinic receptor availability in the striatum and the frontal cortex. Conclusions: These results indicate a reduction in muscarinic acetylcholine receptor availability in vivo in unmedicated patients with schizophrenia, confirming results from postmortem studies and adding further evidence that the muscarinic system is involved in the pathophysiology of schizophrenia.