Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited

Evidence implicates subtle neuronal pathology of the prefrontal cortex (PFC ) in schizophrenia, but how this pathology is reflected in physiological ne uroimaging experiments remains controversial. We investigated PFC function in schizophrenia using functional magnetic resonance imaging (fMRI) and a p arametric version of the n-back working memory (WM) task. In a group of pat ients who performed relatively well on this task, there were three fundamen tal deviations from the 'healthy' pattern of PFC fMRI activation to varying WM difficulty. The first characteristic was a greater magnitude of PFC fMR I activation in the context of slightly impaired WM performance (i.e. physi ological inefficiency). The second was that the significant correlations be tween behavioral WM performance and dorsal PFC fMRI activation were in oppo site directions in the two groups. Third, the magnitude of the abnormal dor sal PFC fMRI response was predicted by an assay of N-acetylaspartate concen trations (NAA) in dorsal PFC, a measure of neuronal pathology obtained usin g proton magnetic resonance spectroscopy. Patients had significantly lower dorsal PFC NAA than controls and dorsal PFC NAA inversely predicted the fMR I response in dorsal PFC (areas 9, 46) to varying WM difficulty - supportin g the assumption that abnormal PFC responses arose from abnormal PFC neuron s. These data suggest that under certain conditions the physiological ramif ications of dorsal PFC neuronal pathology in schizophrenia includes exagger ated and inefficient cortical activity, especially of dorsal PFC.