Physiological Dysfunction of the Dorsolateral Prefrontal Cortex in Schizophrenia Revisited

TLDR

Subtle neuronal pathology of the prefrontal cortex is implicated in schizophrenia, yet its physiological neuroimaging signature remains controversial. The study examined PFC function in schizophrenia with fMRI during a parametric n‑back working memory task. Functional MRI was used to assess PFC activation while participants performed a parametric n‑back working memory task. Patients showed exaggerated, inefficient dorsal PFC activation that correlated oppositely with working‑memory performance and was predicted by reduced N‑acetylaspartate levels, indicating that neuronal pathology drives abnormal PFC responses.

Abstract

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.