Daniel R. Weinberger, MD; Karen Faith Berman, MD; Ronald F. Zec, PhDAt the Archives of General Psychiatry
: To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while peforming a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.
This is a study from 1986 that appears to go to the core of examining the role of the dlPFC in schizophrenia. Physiological Dysfunction of the Dorsolateral Prefrontal Cortex in Schizophrenia Revisited
Joseph H. Callicott, Alessandro Bertolino, Venkata S. Mattay, Frederick J.P. Langheim, Jeffrey Duyn, Richard Coppola, Terry E. Goldberg and Daniel R. WeinbergerAt Cerebral Cortex
: Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC) in schizophrenia, but how this pathology is reflected in physiological neuroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a parametric version of the n-back working memory (WM) task. In a group of patients who performed relatively well on this task, there were three fundamental deviations from the ‘healthy’ pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMRI activation in the context of slightly impaired WM performance (i.e. physiological inefficiency). The second was that the significant correlations between behavioral WM performance and dorsal PFC fMRI activation were in opposite directions in the two groups. Third, the magnitude of the abnormal dorsal PFC fMRI response was predicted by an assay of N-acetylaspartate concentrations (NAA) in dorsal PFC, a measure of neuronal pathology obtained using proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMRI response in dorsal PFC (areas 9, 46) to varying WM difficulty — supporting the assumption that abnormal PFC responses arose from abnormal PFC neurons. These data suggest that under certain conditions the physiological ramifications of dorsal PFC neuronal pathology in schizophrenia includes exaggerated and inefficient cortical activity, especially of dorsal PFC.