Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement

J Psychiatr Res. 2024 Feb:170:19-26. doi: 10.1016/j.jpsychires.2023.11.037. Epub 2023 Dec 3.


Background: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation.

Methods: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels.

Results: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri).

Conclusions: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial Identifier: NCT01924429.

Keywords: ADHD; Computational modeling; Lisdexamphetamine; Reward processing; fMRI.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Attention Deficit Disorder with Hyperactivity* / diagnostic imaging
  • Attention Deficit Disorder with Hyperactivity* / drug therapy
  • Central Nervous System Stimulants* / pharmacology
  • Central Nervous System Stimulants* / therapeutic use
  • Decision Making
  • Dextroamphetamine / pharmacology
  • Dextroamphetamine / therapeutic use
  • Double-Blind Method
  • Humans
  • Lisdexamfetamine Dimesylate / pharmacology
  • Lisdexamfetamine Dimesylate / therapeutic use
  • Treatment Outcome


  • Lisdexamfetamine Dimesylate
  • Dextroamphetamine
  • Central Nervous System Stimulants

Associated data