Modafinil reverses phencyclidine-induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity.
OBJECTIVE
In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil.


METHODS
We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia.


RESULTS
We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity.


CONCLUSIONS
These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction.
Dawson
Neil
N
Psychiatric Research Institute of Neuroscience in Glasgow (PsyRING), University of Glasgow, G12 8QQ, UK. Neil.Dawson@strath.ac.uk
Thompson
Rhiannon J
RJ
McVie
Allan
A
Thomson
David M
DM
Morris
Brian J
BJ
Pratt
Judith A
JA
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D006213:Hallucinogens / Q000633:toxicity*; D008297:Male; D000077408:Modafinil; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010622:Phencyclidine / Q000633:toxicity*; D051381:Rats
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D006213:Hallucinogens; D010622:Phencyclidine; D000077408:Modafinil
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