Acute effects of modafinil on brain resting state networks in young healthy subjects

Abstract

Background: There is growing debate on the use of drugs that promote cognitive enhancement. Amphetamine-like drugs have been employed as cognitive enhancers, but they show important side effects and induce addiction. In this study, we investigated the use of modafinil which appears to have less side effects compared to other amphetamine-like drugs. We analyzed effects on cognitive performances and brain resting state network activity of 26 healthy young subjects.

Methodology: A single dose (100 mg) of modafinil was administered in a double-blind and placebo-controlled study. Both groups were tested for neuropsychological performances with the Raven's Advanced Progressive Matrices II set (APM) before and three hours after administration of drug or placebo. Resting state functional magnetic resonance (rs-FMRI) was also used, before and after three hours, to investigate changes in the activity of resting state brain networks. Diffusion Tensor Imaging (DTI) was employed to evaluate differences in structural connectivity between the two groups. Protocol ID: Modrest_2011; NCT01684306; https://ichgcp.net/clinical-trials-registry/NCT01684306.

Principal findings: Results indicate that a single dose of modafinil improves cognitive performance as assessed by APM. Rs-fMRI showed that the drug produces a statistically significant increased activation of Frontal Parietal Control (FPC; p<0.04) and Dorsal Attention (DAN; p<0.04) networks. No modifications in structural connectivity were observed.

Conclusions and significance: Overall, our findings support the notion that modafinil has cognitive enhancing properties and provide functional connectivity data to support these effects.

Trial registration: ClinicalTrials.gov NCT01684306 https://ichgcp.net/clinical-trials-registry/NCT01684306.

Conflict of interest statement

Competing Interests: SLS is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT Diagram.

Flow diagram graphically describes the design of the study: enrollment, intervention, follow-up and data analysis.

Figure 2. Effects of modafinil on Raven’s advanced progressive matrices II set (APM) performances.

Dispersion diagrams for placebo and modafinil. Graphs depict degrees of improvement (expressed as Δ = xpost-xpre; xpost =  post test score, xpre =  pre-test score) against pre-test scores (xpre) for each level of APM difficulty (low, medium, and high). Segments indicate calculated linear regressions and geometric symbols depict levels of difficulty (low: diamonds; medium: squares; high: triangles).

Figure 3. Resting state networks obtained from ICA.

Resting state networks obtained with ICA when pooling together groups (modafinil and placebo) and conditions (pre and post treatments). Statistical maps are threshold at p

Figure 4. Effects of modafinil on functional connectivity of the left Fronto Parietal Control (lFPC) network.

Panel A depicts modafinil-induced changes in connectivity (voxel-by-voxel contrast between pre and post-drug conditions; p

Figure 5. Effects of modafinil on functional connectivity of the Extra striate Visual (EsV) network.

Panel A depicts modafinil-induced changes in connectivity (voxel-by-voxel contrast between pre and post-drug conditions, p

Figure 6. Effects of modafinil on functional connectivity of the Dorsal Attention Network (DAN).

Panel A depicts modafinil-induced changes in connectivity (voxel-by-voxel contrast between pre and post-drug conditions, p

Figure 7. Structural connectivity analysis.

TBSS analysis between the two groups (modafinil and placebo) shown on the MNI152 template. The FA skeleton (green) is used to extract data and compare areas of high anisotropy. No significant differences are observed between the two groups or between the pre-post drug/placebo conditions.