Inverse fluoxetine effects on inhibitory brain activation in non-comorbid boys with ADHD and with ASD

Abstract

RationaleAttention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often comorbid and have both performance and brain dysfunctions during motor response inhibition. Serotonin agonists modulate motor response inhibition and have shown positive behavioural effects in both disorders.AimsWe therefore used functional magnetic resonance imaging (fMRI) to investigate the so far unknown shared and disorder-specific inhibitory brain dysfunctions in these two disorders, as well as the effects of a single dose of the selective serotonin reuptake inhibitor fluoxetine.MethodsAge-matched boys with ADHD (18), ASD (19) and healthy controls (25) were compared with fMRI during a stop task measuring motor inhibition. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomised design. Repeated measures analyses within patients assessed drug effects. To test for potential normalisation effects of brain dysfunctions, patients under each drug condition were compared to controls.ResultsUnder placebo, relative to controls, ASD boys showed overactivation in left and right inferior frontal cortex (IFC), while ADHD boys showed disorder-specific underactivation in orbitofrontal cortex (OFC) and basal ganglia. Under fluoxetine, the prefrontal dysfunctions were no longer observed, due to inverse effects of fluoxetine on these activations: fluoxetine downregulated IFC and OFC activation in ASD but upregulated them in ADHD.ConclusionsThe findings show that fluoxetine normalises frontal lobe dysfunctions in both disorders via inverse effects, downregulating abnormally increased frontal activation in ASD and upregulating abnormally decreased frontal activation in ADHD, potentially reflecting inverse baseline serotonin levels in both disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-014-3837-2) contains supplementary material, which is available to authorized users.

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD

“…Based on previous findings, we hypothesized that ADHD adolescents under placebo would show steeper TD rates (Noreika et al, 2013) and reduced IFC-insular-striatal activation during TD (Chantiluke et al, 2014d, Plichta et al, 2009. Furthermore, based on our fMRI studies showing upregulation and normalisation with fluoxetine in task-relevant regions during related tasks of cognitive control in ADHD (Chantiluke et al, 2014a, Chantiluke et al, 2014b, Chantiluke et al, 2014c, and evidence for 5-HT modulation of IFC-striatal regions in healthy adults (Lamar et al, 2009, Rubia et al, 2005, we hypothesized that fluoxetine would upregulate IFC-insulastriato-parietal activation within patients and normalise regional underactivation relative to controls.…”

Real‐time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder

“…An fMRI version of an individually adjusted visual tracking Stop task [Chantiluke et al, 2015;Rubia et al, 2003Rubia et al, , 2005Rubia et al, , 2007bRubia et al, , 2011Rubia et al, , 2014b, measuring motor response inhibition, was administered immediately before and after the rtfMRI-NF training. The contrast of successful Stop-Go trials assessed inhibitory activation.…”

“…rIFG in particular is a key hub region mediating functions that are compromised in ADHD like attention, inhibition, and timing [Hugdahl et al, 2015;Kim, 2014;Radua et al, 2014], and its activation correlates with behavioral impulsiveness [Rubia et al, 1999[Rubia et al, , 2005. rIFG underactivation in ADHD is furthermore disorder-specific relative to other childhood disorders such as conduct, obsessive-compulsive and autism spectrum disorder [Chantiluke et al, 2015;Norman et al, 2016;Rubia, 2011Rubia, , 2017Rubia et al, 2008Rubia et al, , 2009b and is the region most consistently upregulated with single and chronic stimulant medication doses [Norman et al, 2016;Rubia et al, 2014b].…”

Longitudinal alterations in fronto-striatal glutamate are associated with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder

“…We found no whole-brain differences during inhibitory control in participants with ASD and OCD, which is also in concordance with the main findings from Gooskens and colleagues (58). However, other studies with similar behavioral results still found altered brain activation during inhibitory control (17,25,27).…”

“…In studies using the stop signal task in ASD and OCD, there has been inconsistent results. Some studies have found no behavioral differences in ASD nor in OCD (17)(18)(19), while others have found worse performance in participants with OCD (5,6,(20)(21)(22), demonstrating deficits in inhibitory control. However, these differences are more commonly found in adults with OCD than children (23).…”