Pharmacological fMRI on the effects of Fluoxetine on functions of Working Memory, Impulsiveness and Cognitive Flexibility in boys with Attention Deficit Hyperactivity Disorder and boys with Autism Spectrum Disorder

Student thesis: Doctoral ThesisDoctor of Philosophy


Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are highly comorbid and share deficits in working memory, motor inhibition and cognitive flexibility. Serotonin modulates these functions and Fluoxetine has positive clinical effects in these disorders.
Functional magnetic resonance imaging was used to scan 22 ADHD and 22 ASD boys, under placebo or an acute dose of Fluoxetine, in a double-blind, placebo-controlled, randomised design, while they performed N-Back, Stop and reversal learning tasks. Repeated measures analyses within patients assessed drug effects. Patients under each drug condition were compared to 20 controls to test for normalisation effects.
During the N-Back, under placebo, relative to controls, ADHD and ASD groups shared underactivation in right dorsolateral prefrontal cortex (DLPFC). ASD boys showed disorder-specific deactivation of posterior cingulate (PCC). Under Fluoxetine, DLPFC underactivation in ASD was significantly normalised and PCC deactivation was increased in ADHD, relative to controls.
During the Stop task, under placebo, relative to controls, ASD boys showed disorder-specific overactivation in bilateral inferior frontal cortex while ADHD boys showed disorder-specific underactivation in ventrolateral prefrontal cortex. Under Fluoxetine, prefrontal dysfunctions were significantly normalised in both disorders, due to inverse up and downregulation effects of Fluoxetine in these regions, in each disorder.
During reversal learning, under placebo, ASD boys exhibited disorder-specific underactivation in medial prefrontal cortex (mPFC), compared to controls and ADHD, while patients shared decreased activation in precuneus. Under Fluoxetine, mPFC activation was upregulated and normalised in ASD boys, but down-regulated in ADHD boys.
Fluoxetine had disorder-dissociated, inverse effects on frontal brain function in ADHD and ASD during inhibition and reversal learning. During working memory Fluoxetine improved task-positive frontal activation in ASD and task-negative activation in ADHD. These inverse effects of Fluoxetine on frontal brain activation in the two disorders potentially reflect inverse baseline serotonin levels and may underlie its clinical effect.
Date of Award1 Jul 2013
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorKatya Rubia (Supervisor) & Declan Murphy (Supervisor)

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