Thalamic shape and connectivity abnormalities in children with attention- deficit/hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is characterized by widespread structural and functional abnormalities in the cortico-striato-thalmo-cortical (CSTC) loops that subserve attention and executive functions. In this study, we analyzed thalamic shape and its white matter connections using structural magnetic resonance imaging and diffusion (DTI) data acquired from children with ADHD (n=19) and controls (n=19). Shape morphology of the thalamus was assessed using shape-based analysis, while connectivity between the thalamus and other brain regions was determined using probabilistic diffusion tractography. Shape-based analysis indicated significant regional atrophy in the left thalamus in children with ADHD compared to controls. Group analyses of white matter connectivity measures showed significantly decreased mean fractional anisotropy (FA) and volume of the tracts between thalamus and striatum, hippocampus, and prefrontal lobe in children with ADHD compared to controls. The structural abnormalities within the thalamus and the reduced integrity of the white matter tracks between the thalamus and other brain regions, as shown from the results of this study, may be the anatomical bases of the impaired cognitive performances in the attention and executive function domains in ADHD.

Introduction

Attention-deficit/hyperactivity disorder (ADHD), one of the most commonly diagnosed childhood neurodevelopmental disorders, is characterized by inattention, impulsivity, and/or hyperactivity, which interfere with various aspects of the academic, home, and/or social lives of these children (American Psychiatric Association, 1994). Studies report that children with ADHD have deficits in executive function (Sergeant et al., 2002), working memory (Castellanos and Tannock, 2002), response inhibition (Barkley, 1997), selective attention (Booth et al., 2005), and delay of reward (Sonuga-Barke et al., 1992). Although the etiology of these conditions is not clear, converging evidence indicates that cortico-striato-thalamo-cortical (CSTC) loops likely subserve the functions of attention and cognition, and disturbances of CSTC loops may cause abnormal information processing leading to the hallmark of ADHD (Rowe et al., 2005, Bush et al., 2005, Dickstein et al., 2006, Schneider et al., 2006, Ivanov et al., 2010, Cubillo et al., 2011).

Structural and functional imaging studies in ADHD have predominantly reported abnormalities of fronto-striatal/ fronto-subcortical circuitry, which is a part of the CSTC loops, linking prefrontal cortex and the striatum (Schneider et al., 2006, Paloyelis et al., 2007). Structural and functional abnormalities in other cortical regions, including the anterior cingulate and the temporal, and posterior parietal cortices, have also been reported in ADHD (Cherkasova and Hechtman, 2009). These regions may contain efferents to and/or from fronto-striatal circuitry, and are partly mediated via the thalamus during attention and other cognitive performances. Disturbances of these regions may contribute to difficulty with attention in ADHD (Fan et al., 2005, Schneider et al., 2006).

The thalamus is an important component of the CSTC loops. It forms a crucial link between the basal ganglia (striatum) and cerebral cortices by relaying output to specific cortices and mediating the flow of information between cortical networks (McFarland and Haber, 2002, Smith et al., 2008). Studies have provided evidence of functional and structural abnormalities in the thalamus in individuals with ADHD. Biological studies have revealed an energy deficiency in the thalamus in children and adolescents with ADHD (Ferreira et al., 2009, Cortese et al., 2012). Task-based functional magnetic resonance imaging (fMRI) studies have demonstrated reduced blood–oxygen-level dependent (BOLD) activation in the thalamus during tasks of motor inhibition and cognitive switching in adults with ADHD, which are persistent from childhood (Cubillo et al., 2010), and reduced BOLD activation in the thalamus during task switching in adults with ADHD (Dibbets et al., 2011). Resting-state fMRI studies have reported abnormal functional connectivity between thalamus and striatum, hippocampus and amygdala within CSTC loops in children with ADHD (Cao et al., 2009, Qiu et al., 2011). Diffusion tensor imaging (DTI) studies have reported white matter abnormalities within the thalamus in children and adolescents with ADHD (Silk et al., 2009). Shape analyses of subcortical structures have been increasingly utilized to closely assess the locations and patterns of structural abnormalities within the subcortical structures in neurological and psychiatric disorders such as schizophrenia, Parkinson's disease, and Alzheimer's disease (McKeown et al., 2008, Kang et al., 2008, Shaw and Rabin, 2009, Coscia et al., 2009, Zarei et al., 2010, Smith et al., 2010). Rarely have shape analyses been applied to the studies of ADHD, but one such study examined thalamic morphology and reported regional deficits, especially at the pulvinar nuclei, in both hemispheres in the youth with ADHD, but there was no change in overall thalamic volume, compared to controls (Ivanov et al., 2010).

As reviewed above, imaging studies have indicated thalamus-related functional and structural abnormalities in patients with ADHD. Based on these findings, we hypothesized that regional structural anomalies of the thalamus and disrupted white matter connections between the thalamus and other brain regions could exist and may contribute to the pathophysiology of ADHD. In this study, we analyzed the structural MRI and DTI data acquired from children with combined-type ADHD and group-matched controls, to examine the thalamic shape features and its white matter connections with other brain regions. A Vertex-based method was applied to the structural MRI data to analyze shape characteristics of the thalamus. Fractional anisotropy (FA), which is an index of the directional selectivity of water diffusion, and probabilistic diffusion tensor tractography were applied to the DTI data, to evaluate the connectivity patterns of the white matter pathways between the thalamus and other brain areas.