TY - JOUR
T1 - Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia
AU - Smucny, Jason
AU - Dienel, Samuel J.
AU - Lewis, David A.
AU - Carter, Cameron S.
N1 - Funding Information:
This work was supported by grants MH124329 (SJD), MH043784 (DAL), MH106438 (CSC), MH119546 (CSC), and MH122139 (CSC) from the National Institute of Mental Health. DAL currently receives investigator-initiated research support from Merck. The remaining authors have nothing to disclose.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.
PY - 2021
Y1 - 2021
N2 - Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
AB - Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.
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U2 - 10.1038/s41386-021-01089-0
DO - 10.1038/s41386-021-01089-0
M3 - Review article
C2 - 34285373
AN - SCOPUS:85110809876
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
ER -