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Objective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits, Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition. [ABSTRACT FROM AUTHOR]

Objective: Bipolar I disorder is highly heritable, but endophenotypes of the disorder mediating genetic risk are only beginning to be defined. The authors investigate state- and trait-related neural mechanisms related to motivation in euthymic bipolar patients and unaffected first-degree relatives of bipolar patients to define the status of motivational processing as a neural systems-level endophenotype. Method: Our study comprised two samples; the first consisted of 19 euthymic bipolar patients and 19 matched comparison subjects, and the second included 22 relatives and 22 matched comparison subjects. Motivational processing was assessed with a probabilistic reversal learning task during event-related functional MRI. Data were analyzed using a region-of-interest approach restricting analysis to the medial and lateral orbitofrontal cortex, the amygdala, the anterior cingulate cortex, and the striatum. Results: The authors observed increased activation in response to reward and reward reversal contingencies in the left medial orbitofrontal cortex in patients with bipolar disorder and in the right medial orbitofrontal cortex in their relatives. Activation of the amygdala in response to reward reversal was increased in patients and relatives. In response to reward, activation of the amygdala was greater only in relatives, but there was a significant negative correlation between medication and amygdala activation in patients. Conclusions: These results identify increased activity of the orbitofrontal cortex and the amygdala, related to heightened sensitivity to reward and deficient prediction error signal, as a candidate endophenotype of bipolar disorder. The results support a role of motivational processing in the risk architecture of bipolar disorder and identify a new systems-level therapeutic target for the illness. [ABSTRACT FROM AUTHOR]