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[Preprint]. 2025 May 22:2025.05.19.654915.
doi: 10.1101/2025.05.19.654915.

Stimulant medications affect arousal and reward, not attention

Benjamin P Kay  1 , Muriah D Wheelock  2 , Joshua S Siegel  3 , Ryan Raut  2   4   5 , Roselyne J Chauvin  1 , Athanasia Metoki  1 , Aishwarya Rajesh  2 , Andrew Eck  2 , Jim Pollaro  2 , Anxu Wang  1 , Vahdeta Suljic  1 , Babatunde Adeyemo  1 , Noah J Baden  1 , Kristen M Scheidter  1 , Julia Monk  1 , Nadeshka Ramirez-Perez  1   6 , Samuel R Krimmel  1 , Russel T Shinohara  7 , Brenden Tervo-Clemmens  8   9 , Robert J M Hermosillo  9   10 , Steven M Nelson  9   10 , Timothy J Hendrickson  9   10 , Thomas Madison  9   10 , Lucille A Moore  9   10 , Óscar Miranda-Domínguez  9   10 , Anita Randolph  9   10 , Eric Feczko  9   10 , Jarod L Roland  6 , Ginger E Nicol  11 , Timothy O Laumann  11 , Scott Marek  11 , Evan M Gordon  2 , Marcus E Raichle  1   2   12   13 , Deanna M Barch  11   12 , Damien A Fair  9   10   14 , Nico U F Dosenbach  1   2   12   13   15   16
Affiliations

Stimulant medications affect arousal and reward, not attention

Benjamin P Kay et al. bioRxiv. .

Update in

  • Stimulant medications affect arousal and reward, not attention networks.
    Kay BP, Wheelock MD, Siegel JS, Raut RV, Chauvin RJ, Metoki A, Rajesh A, Eck A, Pollaro J, Wang A, Suljic V, Adeyemo B, Baden NJ, Scheidter KM, Monk JS, Whiting FI, Ramirez-Perez N, Krimmel SR, Shinohara RT, Tervo-Clemmens B, Hermosillo RJM, Nelson SM, Hendrickson TJ, Madison T, Moore LA, Miranda-Domínguez Ó, Randolph A, Feczko E, Roland JL, Nicol GE, Laumann TO, Marek S, Gordon EM, Raichle ME, Barch DM, Fair DA, Dosenbach NUF. Kay BP, et al. Cell. 2025 Dec 24;188(26):7529-7546.e20. doi: 10.1016/j.cell.2025.11.039. Cell. 2025. PMID: 41448140 Free PMC article.

Abstract

Prescription stimulants such as methylphenidate are being used by an increasing portion of the population, primarily children. These potent norepinephrine and dopamine reuptake inhibitors promote wakefulness, suppress appetite, enhance physical performance, and are purported to increase attentional abilities. Prior functional magnetic resonance imaging (fMRI) studies have yielded conflicting results about the effects of stimulants on the brain's attention, action/motor, and salience regions that are difficult to reconcile with their proposed attentional effects. Here, we utilized resting-state fMRI (rs-fMRI) data from the large Adolescent Brain Cognitive Development (ABCD) Study to understand the effects of stimulants on brain functional connectivity (FC) in children (n = 11,875; 8-11 years old) using network level analysis (NLA). We validated these brain-wide association study (BWAS) findings in a controlled, precision imaging drug trial (PIDT) with highly-sampled (165-210 minutes) healthy adults receiving high-dose methylphenidate (Ritalin, 40 mg). In both studies, stimulants were associated with altered FC in action and motor regions, matching patterns of norepinephrine transporter expression. Connectivity was also changed in the salience (SAL) and parietal memory networks (PMN), which are important for reward-motivated learning and closely linked to dopamine, but not the brain's attention systems (e.g. dorsal attention network, DAN). Stimulant-related differences in FC closely matched the rs-fMRI pattern of getting enough sleep, as well as EEG- and respiration-derived brain maps of arousal. Taking stimulants rescued the effects of sleep deprivation on brain connectivity and school grades. The combined noradrenergic and dopaminergic effects of stimulants may drive brain organization towards a more wakeful and rewarded configuration, explaining improved task effort and persistence without direct effects on attention networks.

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Conflict of interest statement

Declaration of interest DAF and NUFD have a financial interest in Turing Medical and may financially benefit if the company is successful in marketing FIRMM motion-monitoring software products. DAF and NUFD may receive royalty income based on FIRMM technology developed at Washington University School of Medicine and Oregon Health and Sciences University and licensed to NOUS Imaging Inc. DAF and NUFD are co-founders of NOUS Imaging Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine, Oregon Health and Sciences University and the University of Minnesota. The other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Stimulant related functional connectivity differences.
ABCD Study data 5,795 children, 337 taking a stimulant. Stimulant-related findings are color coded red. (a) Magnitude (root mean square) of functional connectivity (FC) difference shown on the Gordon-Laumann cortical parcellation. (b) Differences in FC with an exemplar (most affected by stimulants) seed parcel in the motor-hand region (purple dot). (c,d) Significant (FWER p < 0.05) differences in FC between network pairs. (e) Magnitude (Welch’s t-statistic) of FC differences in whole networks relative to the whole connectome. Significant (FWER p < 0.05) differences are indicated by a *. DMN: default mode, VIS: visual, FPN: fronto-parietal, DAN: dorsal attention, VAN: ventral attention, SAL: salience, PMN: parietal memory, AMN: action-mode, SM: somato-cognitive action/motor, AUD: auditory, CAN: context association, HC: hippocampus, AMYG: amygdala, BG: basal ganglia, THAL: thalamus, CERB: cerebellum.
Figure 2:
Figure 2:. Stimulant effects validated in precision imaging drug trial.
(a) Magnitude (root mean square) of functional connectivity (FC) differences shown on the Gordon-Laumann cortical parcellation for 337 children taking stimulants in the ABCD Study (total n = 5,795). (b) Magnitude of acute FC differences in adult participants (n = 5) given methylphenidate 40 mg in a controlled study. The cortical maps are correlated at r = 0.36 (spin-test P < 0.001).
Figure 3:
Figure 3:. Sleep duration related functional connectivity differences.
ABCD Study data 5,795 children. Sleep-related findings are color coded blue. (a) Magnitude (root mean square) of functional connectivity (FC) differences shown on the Gordon-Laumann cortical parcellation. (b) Differences in FC with an exemplar seed parcel in the somatomotor hand region (purple dot). (c,d) Significant (FWER P < 0.05) differences in FC between network pairs. (e) Magnitude (Welch’s t-statistic) of FC difference in whole networks relative to the whole connectome. Significant (FWER P < 0.05) changes are indicated by a *. DMN: default mode, VIS: visual, FPN: fronto-parietal, DAN: dorsal attention, VAN: ventral attention, SAL: salience, PMN: parietal memory, AMN: action-mode, SM: somato-cognitive action/motor, AUD: auditory, CAN: context association, HC: hippocampus, AMYG: amygdala, BG: basal ganglia, THAL: thalamus, CERB: cerebellum.
Figure 4:
Figure 4:. Sleep duration effects validated against independent brain maps of arousal.
(a) Magnitude (root mean square) of functional connectivity (FC) differences related to sleep duration shown on the Gordon-Laumann cortical parcellation (ABCD Study, n = 5,795). (b) Arousal template obtained by correlating EEG alpha slow wave index (alpha/delta power ratio) with fMRI signal intensity (n = 10)., (c) Arousal map obtained from coherence between respiratory variation and fMRI signal intensity based on (Human Connectome Project, n = 190). (d) Non-displaceable binding potential for 11C-MRB (methylreboxetine) in a positron emission tomography (PET) study (n = 20)., Correlations between cortical maps are shown in gray arrows and summarized in Table 4. The correlation between the EEG- and respiration-derived arousal maps was r = 0.60 (spin test P < 0.0001).
Figure 5:
Figure 5:. Sleep duration and stimulant use’s interacting brain effects.
ABCD Study data 5,795 children, 337 taking a stimulant. (a) Functional connectivity (FC) difference magnitude (root mean square) for sleep shown on the Gordon-Laumann cortical parcellation in children not taking stimulants (n = 5,458) and (b) taking stimulants (n = 337). A more liberal t-value threshold was used in (b) to show detail. (c) Significant (FWER P < 0.05) differences in FC between network pairs in children not taking stimulants. (d) Magnitude (Welch’s t-statistic) of FC differences in whole networks, relative to the whole connectome, for sleep in children not taking stimulants and taking stimulants. Significant (FWER P < 0.05) changes are indicated by a *. (e) Significant (FWER P < 0.05) differences in FC between network pairs in children taking stimulants. DMN: default mode, VIS: visual, FPN: fronto-parietal, DAN: dorsal attention, VAN: ventral attention, SAL: salience, PMN: parietal memory, AMN: action-mode, SM: somato-cognitive action/motor, AUD: auditory, CAN: context association, HC: hippocampus, AMYG: amygdala, BG: basal ganglia, THAL: thalamus, CERB: cerebellum.
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