Dysfunctional Prefrontal Regional Specialization and Compensation in Schizophrenia

Abstract

The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.

Epistasis between catechol- O -methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function

“…2). Normal or increased engagement of more ventral prefrontal regions during executive tasks taxing DLPFC have also previously been observed in relatively highperforming schizophrenia patients (41,(43)(44)(45)59). These results suggest that physiological inefficiency relevant to schizophrenia could be influenced by prefrontal dopaminergic and glutamatergic states to involve first, a relative loss of function at higher-order processing regions in the DLPFC, despite intact cognitive performance and increased activation that is inefficient, and second, compensatory activation from the VLPFC.…”

“…As we sought to examine how the prefrontal functional organization might be altered with genetic variation during executive aspects of working memory, we focused on the differential activation between 1-back and 2-back tasks. This activation reflected incremental working memory load (number of target items stored) and information updating (the executive process of continuous selection and updating of target items), and putatively regions that tend to engage more DLPFC than VLPFC (22,28,41,46). Here, the higher-order working memory task engaged by 2-back Ͼ 1-back was associated with bilateral prefrontal cortical activation ( Fig.…”

“…Here, we investigated the prediction that, if indeed prefrontal cortical functions critically involve at least in part dopaminergic and glutamatergic interactions, then higher-order working memory processes assumed to tax DLPFC would be especially vulnerable to the combined effect of suboptimal dopaminergic and glutamatergic influence at the DLPFC during such an executive task. In addition to examining the prefrontal cortex, we extended our observations to the frontoparietal working memory network, with the prediction that DLPFC activation, if inefficient, would be accompanied by relatively reduced functional connectivity (41,42). Finally, apart from hypotheses driven by fundamental models of neural function, we also examined an empirical observation that additional VLPFC engagement occurred in the background of relatively deleterious COMT alleles (33) and in patients with schizophrenia (41,(43)(44)(45).…”

“…In addition to examining the prefrontal cortex, we extended our observations to the frontoparietal working memory network, with the prediction that DLPFC activation, if inefficient, would be accompanied by relatively reduced functional connectivity (41,42). Finally, apart from hypotheses driven by fundamental models of neural function, we also examined an empirical observation that additional VLPFC engagement occurred in the background of relatively deleterious COMT alleles (33) and in patients with schizophrenia (41,(43)(44)(45). This VLPFC engagement apparently diverges from DLPFC models of optimal executive function, possibly signifying a systems-level response to deficits at the DLPFC (41).…”

“…Finally, apart from hypotheses driven by fundamental models of neural function, we also examined an empirical observation that additional VLPFC engagement occurred in the background of relatively deleterious COMT alleles (33) and in patients with schizophrenia (41,(43)(44)(45). This VLPFC engagement apparently diverges from DLPFC models of optimal executive function, possibly signifying a systems-level response to deficits at the DLPFC (41). We explored how this VLPFC response could be related to combined variation in COMT and GRM3.…”