Impaired Hierarchical Control Within the Lateral Prefrontal Cortex in Schizophrenia

Abstract

In schizophrenia, disturbances of cognitive control have been associated with impaired functional specialization within the lateral prefrontal cortex (LPFC), but little is known about the functional interactions between specialized LPFC subregions. Here, we addressed this question with a recent model that describes the LPFC functioning as a cascade of control processes along a rostrocaudal axis, whereby anterior frontal regions influence the processing in posterior frontal regions to guide action selection on the basis of the temporal structure of information. We assessed effective connectivity within the rostrocaudal axis of the LPFC by means of functional magnetic resonance imaging in 15 schizophrenic patients and 14 matched healthy control subjects with structural equation modeling and psychophysiological interactions. In healthy subjects, activity in the left caudal LPFC regions was under the influence of left rostral LPFC regions when controlling information conveyed by past events. By contrast, schizophrenic patients failed to demonstrate significant effective connectivity from rostral to caudal LPFC regions in both hemispheres. The hierarchical control along the rostrocaudal axis of the LPFC is impaired in schizophrenia. This provides the first evidence of a top-down functional disconnection within the LPFC in this disorder. This disruption of top-down connectivity from rostral to caudal LPFC regions observed in patients might affect their ability to select the appropriate sets of stimulus-response associations in the caudal LPFC on the basis of information conveyed by past events. This impaired hierarchical control within the LPFC could result from poorly encoded contextual information due to abnormal computations in the caudal LPFC.