Specific relationship between prefrontal neuronal N-acetylaspartate and activation of the working memory cortical network in schizophrenia

Objective: Abnormal activation of the dorsolateral prefrontal cortex and a related cortical network during working memory tasks has been demonstrated in patients with schizophrenia, but the responsible mechanism has not been identified. The present study was performed to determine whether neuronal p athology of the dorsolateral prefrontal cortex is linked to the activation of the working memory cortical network in patients with schizophrenia. Meth od: The brains of 13 patients with schizophrenia and 13 comparison subjects were studied with proton magnetic resonance spectroscopic (H-1-MRS) imagin g (to measure N-acetylaspartate as a marker of neuronal pathology) and with [O-15]water positron emission tomography (PET) during performance of the W isconsin Card Sorting Test (to measure activation of the working memory cor tical network). An independent cohort of patients (N=7) was also studied in a post hoc experiment with H-1-MRS imaging and with the same PET technique during performance of another working memory task (the "N-back" task). Res ults: Measures of N-acetylaspartate in the dorsolateral prefrontal cortex s trongly correlated with activation of the distributed working memory networ k, including the dorsolateral prefrontal, temporal, and inferior parietal c ortices, during both working memory tasks in the two independent groups of patients with schizophrenia. In contrast, N-acetylaspartate in other cortic al regions and in comparison subjects did not show these relationships. Con clusions: These findings directly implicate a population of dorsolateral pr efrontal cortex neurons as selectively accounting for the activity of the d istributed working memory cortical network in schizophrenia and complement other evidence that dorsolateral prefrontal cortex connectivity is fundamen tal to the pathophysiology of the disorder.