Modafinil Effects on Cognitive Control in Healthy Subjects and Schizophrenia Patients Measured by fMRI Michael J. Minze

1. Modafinil Effects on Cognitive Control in Healthy Subjects and Schizophrenia Patients Measured by fMRI Michael J. Minzenberg, Cameron S. Carter Psychiatry and Behavioral Sciences, University of California, Davis School of Medicine, Sacramento, CA • Introduction: • Prefrontal-dependent cognitive deficits are an important feature of Scz • These deficits include dysfunction of context processing and maintenance of information (supported by dorsolateral prefrontal cortex, DLPFC) and conflict monitoring (supported by anterior cingulate cortex, ACC), which support cognitive control • PFC-dependent cognition is modulated by catecholamines, in both animal models and in human neuroimaging studies • There is evidence for catecholamine dysfunction in schizophrenia • Antipsychotic medications generally do not remediate PFC functions • The functional neuroanatomy of effects of novel agents for cognitive dysfunction remains poorly-characterized in humans • Modafinil is a novel FDA-approved medication which elevates cortical DA and NE, is well-tolerated, and improves cognitive function in animal models, healthy adults and clinical populations • Hypothesis: Single-dose modafinil will be associated with improved PFC activity and related cognitive function in healthy adults and patients with schizophrenia 3) POP Task Performance 5) Conclusions Modafinil enhances DLPFC delay-period activity and related context- and maintenance-dependent performance Modafinil effects on ACC activity in conditions of response conflict may depend on underlying PFC/cognitive control ability Modafinil shows promise as an agent for remediation of these neural and cognitive dysfunctions in schizophrenia michael.minzenberg@ucdmc.ucdavis.edu 4) fMRI Results • Methods & Subjects: • Subjects: 8 adults with no personal or family psychiatric history or sig medical history (mean age 31.8 years; 5 female, 3 male); 4 patients with Schizophrenia (mean age 30.0 years, 1 female, 3 male; all on concurrent atypical antipsychotics) • Study design: Double-blind, placebo-controlled crossover (separate testing days): Modafinil 200 mg single oral dose vs Placebo; fMRI 3.5 hours post-dose • fMRI: Siemens Trio 3T; slow event-related, Preparing to Overcome Prepotency (POP) Task; TR 2000, TE 30, flip angle 90 deg, FOV 220 x 220, 36 contiguous slices 3.4 mm thick; Images motion-corrected, into MNI space, and spatial smoothing (with AIR); Signal derived (with NIS) in a priori ROIs (left DLPFC and midline ACC); inferential testing on ROI Signal Change with Subject as random factor, and within-subject factors Drug (Modafinil vs Placebo), Cue (Red vs Green) and Scan (1-4 for DLPFC; 5-10 for ACC). DLPFC: Main effect of Drug, F=3.75, p =.09; Drug X Scan, F=3.92, p =.023; Drug X Cue X Scan, F=2.15, p=.15 ACC: Main effect of Drug, F=3.24, p=.12; Drug X Cue, F=9.47, p=.02