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Andreas S. Meyer-Lindenberg, MD, PhD; Rosanna K. Olsen; Philip D. Kohn; Timothy Brown; Michael F. Egan, MD; Daniel R. Weinberger, MD; Karen Faith Berman, MD

Arch Gen Psychiatry. 2005;62:379-386.

Background  Two brain regions often implicated in schizophrenia are the dorsolateral prefrontal cortex (DLPFC) and the hippocampal formation (HF). It has been hypothesized that the pathophysiology of the disorder might involve an alteration of functional interactions between medial temporal and prefrontal areas.

Methods  We used neuroimaging data acquired during a working memory challenge and a sensorimotor control task in 22 medication-free schizophrenic patients and 22 performance-, age-, and sex-matched healthy subjects to investigate "functional connectivity" between HF and DLPFC in schizophrenia. The HF blood flow, measured with positron emission tomography, was assessed within a probabilistic template. Brain areas whose activity was positively or negatively coupled to HF were identified using voxelwise analysis of covariance throughout the entire brain and analyzed using a random effects model.

Results  During working memory, patients showed reduced activation of the right DLPFC and left cerebellum. In both groups, inverse correlations were observed between the HF and the contralateral DLPFC and inferior parietal lobule. While these did not differ between diagnostic groups during the control task, the working memory challenge revealed a specific abnormality in DLPFC-HF functional connectivity—while the right DLPFC was significantly coupled to the left HF in both groups during the control task, this correlation was not seen in healthy subjects during working memory but persisted undiminished in patients, resulting in a significant task-by-group interaction.

Conclusions  Our results suggest a regionally specific alteration of HF-DLPFC functional connectivity in schizophrenia that manifests as an unmodulated persistence of an HF-DLPFC linkage during working memory activation. Thus, a mechanism by which HF dysfunction may manifest in schizophrenia is by inappropriate reciprocal modulatory interaction with the DLPFC.

Author Affiliations: Unit on Integrative Neuroimaging (Drs Meyer-Lindenberg and Berman, Ms Olsen, and Messrs Kohn and Brown) and Genes, Cognition, and Psychosis Program (Drs Meyer-Lindenberg, Egan, Weinberger, and Berman; Ms Olsen; and Messrs Kohn and Brown), National Institute of Mental Health, Bethesda, Md.

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