Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in Attention-Deficit/Hyperactivity Disorder

Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Aug;3(8):686-693. doi: 10.1016/j.bpsc.2018.03.004. Epub 2018 Mar 19.


Background: Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition.

Methods: Twenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity.

Results: Lisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD.

Conclusions: Treatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance-resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.

Trial registration: NCT01924429.

Keywords: ADHD; Adults; Amygdala; Emotion go/no-go; Psychostimulant; fMRI.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amygdala* / diagnostic imaging
  • Amygdala* / drug effects
  • Amygdala* / physiopathology
  • Attention Deficit Disorder with Hyperactivity* / diagnostic imaging
  • Attention Deficit Disorder with Hyperactivity* / drug therapy
  • Attention Deficit Disorder with Hyperactivity* / physiopathology
  • Central Nervous System Stimulants / pharmacology*
  • Cross-Over Studies
  • Emotions* / drug effects
  • Emotions* / physiology
  • Executive Function* / drug effects
  • Executive Function* / physiology
  • Facial Expression
  • Female
  • Functional Neuroimaging / methods*
  • Humans
  • Inhibition, Psychological
  • Lisdexamfetamine Dimesylate / pharmacology*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Prefrontal Cortex* / diagnostic imaging
  • Prefrontal Cortex* / drug effects
  • Prefrontal Cortex* / physiopathology
  • Young Adult


  • Central Nervous System Stimulants
  • Lisdexamfetamine Dimesylate

Associated data