Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder.

S Bollmann,E Martin,J Ball,D Brandeis,L Michels,C Ghisleni,D Eich-Höchli,S-S Poil,R A E Edden,P Klaver,R L O'Gorman

doi:10.1038/tp.2015.79

Abstract

While the neurobiological basis and developmental course of attention-deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P=0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P>0.1), resulting in a significant age by disorder interaction (P=0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P=0.06). Glutamine levels were increased in children with ADHD (P=0.041), but there was no significant difference in adults (P>0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P<0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is a common developmental psychiatric disorder characterized by inattention, hyperactivity and impulsivity with a prevalence of about 5%.1 traditionally considered a disorder of childhood, mounting evidence suggests that ADHD often persists into adulthood.[2]
For the ADHD adults, we examined a left frontal region centered on the dorsolateral prefrontal cortex in addition to the subcortical voxel
The present study examined GABA+, Glu and Gln concentrations in a subcortical voxel centered on the basal ganglia for the first time in a developmental group of children and adults with and without ADHD, demonstrating a developmental alteration in GABA+ levels in ADHD patients

Summary

Introduction

Traditionally considered a disorder of childhood, mounting evidence suggests that ADHD often persists into adulthood.[2] While the neurobiological basis and developmental course of ADHD have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD.[3]. GABA, the main inhibitory neurotransmitter in the human cerebral cortex is synthesized from neuronal glutamate (Glu), and converted back into Glu in astrocytes. The astrocytic Glu is catalyzed into glutamine (Gln) and transported to the presynaptic neuron, where it is cycled back into Glu, some of which is converted into GABA.[4] GABA has been shown to be implicated in dopaminergic neurotransmission in the striatum[5] suggesting an important role in ADHD. The major excitatory neurotransmitter, modulates the release of dopamine,[3] and imbalances in Glu are believed to interfere with the gating of sensory information in striato-frontal pathways in patients with ADHD.[3]

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