EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 47; no. 5; pp. 1029 - 1036
• Main Authors: Bhakta, Savita G., Cavanagh, James F., Talledo, Jo A., Kotz, Juliana E., Benster, Lindsay, Roberts, Benjamin Z., Nungaray, John A., Brigman, Jonathan L., Light, Gregory A., Swerdlow, Neal R., Young, Jared W.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2022; Springer International Publishing
• Subjects: Adult; Biomarkers; Clinical trials; Cognition; Cognitive ability; Dextroamphetamine - pharmacology; EEG; Electroencephalography; Healthy Volunteers; Humans; Mental disorders; Reaction time task; Schizophrenia; Visual evoked potentials
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-021-01257-2

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.