Moving towards causality in attention-deficit hyperactivity disorder: overview of neural and genetic mechanisms

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by developmentally inappropriate levels of inattention and hyperactivity or impulsivity. The heterogeneity of its clinical manifestations and the differential responses to treatment and varied prognoses have long suggested myriad underlying causes. Over the past decade, clinical and basic research efforts have uncovered many behavioural and neurobiological alterations associated with ADHD, from genes to higher order neural networks. Here, we review the neurobiology of ADHD by focusing on neural circuits implicated in the disorder and discuss how abnormalities in circuitry relate to symptom presentation and treatment. We summarise the literature on genetic variants that are potentially related to the development of ADHD, and how these, in turn, might affect circuit function and relevant behaviours. Whether these underlying neurobiological factors are causally related to symptom presentation remains unresolved. Therefore, we assess efforts aimed at disentangling issues of causality, and showcase the shifting research landscape towards endophenotype refinement in clinical and preclinical settings. Furthermore, we review approaches being developed to understand the neurobiological underpinnings of this complex disorder, including the use of animal models, neuromodulation, and pharmacoimaging studies.

Figure 1. Neural circuits implicated in attention-deficit hyperactivity disorder

Frontoparietal circuits encompass the frontal lobes (front), including the supplemental motor area and frontal eye fields (FEF), and the temporal parietal junction and inferior parietal sulcus (TPJ/IPS). These circuits underlie attentional processes including the altering and orienting of attentional resources. Dorsal frontostriatal circuits encompass the dorsolateral prefrontal cortex (PFC), dorsal striatum (DS), and the thalamus. These circuits underlie inhibitory control including response inhibition and interference control. Mesocorticolimbic circuits encompass the orbitofrontal cortex (OFC), ventral striatum and nucleus accumbens (NAcc), ventral tegmental area (VTA), and anterior hippocampus. These circuits underlie reward and emotional processes including motivation, frustration tolerance, and reward anticipation.

Figure 2. Functional connectivity within the default mode network (DMN) and the cognitive control network (CCN)

(A) Resting state functional connectivity maps of the DMN. Red shows positively correlated functional magnetic resonance imaging (fMRI) signal, or positive connectivity, within regions of the DMN including the medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and lateral parietal cortex (LPC). (B) Resting state functional connectivity maps of the CCN. Purple shows positively correlated fMRI signal within regions of the CCN including the dorsolateral prefrontal cortex (DLPFC), anterior insular cortex (AIC), and supramarginal gyrus (SMG). (C) Time series data extracted from the DMN (red) and the CCN (blue) show inversely correlated fMRI signal intensity between the DMN and CCN.