Modafinil Reverses Phencyclidine-Induced Deficits in Cognitive Flexibility, Cerebral Metabolism, and Functional Brain Connectivity

Abstract

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.

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

“…Acute ketamine treatment disrupts brain networks N Dawson et al hypofrontality characteristic of the disorder (Cochran et al, 2003;Dawson et al, 2012Dawson et al, , 2014, whereas acute ketamine treatment induces a contrasting hyperfrontality, a paradox that is yet to be resolved given the schizophrenia-like symptoms induced by acute ketamine treatment. It may be the case that ketamine-induced alterations in functional brain network structure have the greatest translational relevance to those symptoms present during acute psychotic episodes rather than those that remain present in chronic schizophrenia patients treated with antipsychotics.…”

A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia

“…In conclusion, four animal model studies of cognitive deficits showed significant improvements with modafinil [Dawson et al 2010;Goetghebeur and Dias, 2009;Pedersen et al 2009;Redrobe et al 2010]. In humans, four single-dose crossover RCTs showed significant positive effects of modafinil on executive functioning, verbal memory span, visual and working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition Scoriels et al 2011;Spence et al 2005;Turner et al 2004].…”

“…Administration of subchronic phencyclidine (PCP) to rats is used as an animal model for executive functioning deficits in schizophrenia. When PCP was administrated to rats an ID/ED shift deficit was induced and when these rats were treated with modafinil, the ID/ED shift deficit improved significantly [Dawson et al 2010;Goetghebeur and Dias, 2009;Pedersen et al 2009]. Neuroimaging showed that acute modafinil treatment effectively reversed distinct PCPinduced alterations in overt cerebral metabolism in the anterior prelimbic cortex, the retrosplenial cortex and the medial prelimbic cortex (layer 1).…”

“…In the latter region, modafinil caused hypermetabolism [Dawson et al 2010]. Redrobe and colleagues used the same animal model for executive functioning deficits [Redrobe et al 2010].…”

“…Modafinil is studied in schizophrenia, since on theoretical and preclinical grounds modafinil could have the potential to relieve negative and cognitive symptoms [Dawson et al 2010;Pedersen et al 2009]. Modafinil is registered for the treatment of several sleep disorders associated with excessive daytime sleepiness, including narcolepsy, obstructive sleep apnoea and shift work sleep disorder [Valentino and Foldvary-Schaefer, 2007].…”