Abstract
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.
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Data availability
All data and Matlab code to re-create these analyses are available at OpenNeuro.org, accession #[WILL BE COMPLETED UPON ACCEPTANCE].
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Acknowledgements
We would like to thank Dr. Mark A. Geyer and Ms. Mahalah R. Buell for their support and Ms. Maria Bongiovanni for assistance with preparation of manuscript.
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The current project was funded by NIMH UH3 MH109168 and R01DA043535.
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SGB: conceptualization, methodology, writing—original draft, investigation, data curation, supervision, project administration, funding acquisition. JFC: conceptualization, methodology, software, formal analysis, writing—original draft, funding acquisition. GAL: conceptualization, methodology, resources, writing—review and editing, funding acquisition. NRS: conceptualization, methodology, writing—review and editing, investigation, data curation, supervision, project administration, funding acquisition. LB, JAT, JEK, BZR, and JAN: investigation, data curation, supervision, project administration. JLB and JWY: conceptualization, methodology, writing—review and editing, funding acquisition.
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JWY has received pharmaceutical funding from Sunovion Pharmaceuticals, Gilgamesh, and Heptares unrelated to the current work. All other authors report no biomedical financial interests of potential conflicts of interest.
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Bhakta, S.G., Cavanagh, J.F., Talledo, J.A. et al. EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants. Neuropsychopharmacol. 47, 1029–1036 (2022). https://doi.org/10.1038/s41386-021-01257-2
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DOI: https://doi.org/10.1038/s41386-021-01257-2
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