Global and local grey matter reductions in boys with ADHD combined type and ADHD inattentive type
Introduction
Attention-deficit hyperactivity disorder (ADHD) is a common childhood developmental disorder defined by age-inappropriate levels of inattention, impulsivity and hyperactivity (American Psychiatric Association (APA), 2013). It is commonly associated with impairments in social, cognitive, educational and emotional domains (e.g., Ek et al., 2011, Martel et al., 2007, Nijmeijer et al., 2008, Shaw et al., 2014, Willcutt et al., 2012).
Neuroimaging studies of children and adolescents with ADHD have reported anomalous brain structure including global and local reductions in brain volume (Frodl and Skokauskas, 2012, Nakao et al., 2011). Meta-analyses of regional volumetric differences have implicated smaller basal ganglia structures including the right globus pallidus, putamen and bilateral caudate in children and the anterior cingulate cortex (ACC) in adults with ADHD (Frodl and Skokauskas, 2012, Nakao et al., 2011). However, the studies included in the meta-analyses were based on small, often underpowered samples. A recent investigation with a relatively large sample (n=131) of adults with ADHD only found subtle differences in global volumetric measures but no differences in local grey matter volumes (Maier et al., in press). Investigations in paediatric ADHD with larger samples (n >20) have reported grey matter reductions in the bilateral caudate and cerebellum (Yang et al., 2008), predominantly right-sided frontal–pallidal–parietal regions (McAlonan et al., 2007), bilateral frontal and cerebellar regions (Carmona et al., 2005), left dorsolateral/precentral prefrontal cortex (PFC) (Stevens and Haney-Caron, 2012) as well as no differences compared to typically developing control participants (Villemonteix et al., 2015). Inconsistencies across studies may be explained by differences in sample characteristics (medication status, age, gender ratios, comorbid conditions) or the structural neuroimaging methodology used. ADHD is heterogeneous in nature with inattentive symptoms accounting for varying levels of disorgor dysexecutive function and hyp/or dysexecutive function and hyperactive/impulsive symptoms relating to varying levels of abnormal reward discounting, social disinhibition and/or emotional dysregulation (Frick and Nigg, 2012). Therefore, most ADHD samples are likely to consist of differing individual neuropsychological and/or neurobiological profiles.
Despite the heterogeneity, several previous studies and subsequent meta-analyses have reported volume reductions of the caudate nucleus in children with ADHD (Frodl and Skokauskas, 2012, Nakao et al., 2011), which seem to normalise with increasing age (Carrey et al., 2012, Nakao et al., 2011). Caudate asymmetry may also be different in individuals with ADHD (Castellanos et al., 1994) with abnormalities more often observed on the right (Almeida Montes et al., 2010, Filipek et al., 1997, Tremols et al., 2008, Valera et al., 2007). Relative greater right than left caudate nucleus volume has been associated with higher attentional impulsiveness and higher ADHD symptom ratings in healthy young adults (Dang et al., 2016) as well as parent-rated symptoms of inattention in children without an ADHD diagnosis (Schrimsher et al., 2002).
The caudate nucleus plays a major role in relaying information from the prefrontal cortex to the basal ganglia and thalamus and back to the PFC (Arnsten and Rubia, 2012). Evidence from lesion studies in humans and animals and functional neuroimaging studies suggests that the caudate nucleus is crucial for attentional control (Crofts et al., 2001) and goal-directed action (Grahn et al., 2008). Tasks that probe attentional and executive function processes such as response inhibition and working memory during functional magnetic resonance imaging elicit less activation of the caudate nucleus in individuals with ADHD compared to control participants (e.g., Cubillo et al., 2011, Silk et al., 2005, Vance et al., 2007).
ADHD according to DSM-IV (APA, 1994) has been divided into three subtypes: a combined type (ADHD-C), which shares symptoms of hyperactivity and inattention, an inattentive type (ADHD-I), which exhibits primarily symptoms of inattention with no or few hyperactive/impulsive symptoms and a less common hyperactive type (ADHD-H), which shows hyperactive/impulsive symptoms but no or few difficulties in the domain of attention. These subtypes show limited stability over time, in contrast to the general diagnosis (Willcutt et al., 2012) suggesting subtypes may add little extra information to diagnosis and treatment. In recognition of the lack of evidence for concrete subcategories of ADHD, DSM5 denominates varying levels of hyperactive/impulsive and inattentive symptoms no longer subtypes but presentations (APA, 2013). The ICD10 equivalent of ADHD, hyperkinetic disorder does not distinguish between subtypes and/or presentations.
There is considerable debate as to whether ADHD subtypes have common or distinct underlying neurobiology. Neuroimaging studies have often failed to detect differences between the ADHD-C and ADHD-I subtypes but many of these studies were underpowered (Willcutt et al., 2012). A recent study in adults with ADHD (Maier et al., in press) comprising a relatively large sample of 66 individuals with a diagnosis of ADHD-C and 60 individuals with a diagnosis of ADHD-I only reported a trend for reduced grey matter in the left dorsolateral PFC (dlPFC) in the inattentive compared to the combined type. Few studies to date have examined volume differences between ADHD subtypes in children and adolescents with ADHD. Carmona et al. (2005) found no differences in grey matter volume between the two subtypes albeit in a very small sample and Pineda et al. (2002) also failed to detect significant volumetric differences of the caudate nucleus between children with ADHD-C and ADHD-I.
In this study we aimed to compare local and global grey matter volumetric differences between children with ADHD and typically developing children (TD). We expected to find reductions in both global and regional grey matter volumes in the ADHD group compared to TD. Due to inconsistent results of previous studies we did not make predictions as to the specific regions showing volume loss in ADHD. However, given meta-analytic findings of reduced caudate volume in ADHD we decided to test caudate volume differences hypothesising that the ADHD group would exhibit reductions in the volume of right caudate nucleus compared to TD. As it has previously been suggested that caudate volume shows a differential developmental trajectory in children with ADHD we were interested in the relationship between caudate volume and age and whether these would differ for each group. Given uncertainties with regard to structural differences between ADHD subtypes we further aimed to address the question of whether there are global and local volumetric differences in grey matter in boys with ADHD-C and ADHD-I compared to each other.
Section snippets
Participants
A total of 79 male participants took part in the study (age range 8.0–17.5 years). 48 boys meeting DSM-IV criteria for ADHD were recruited through an outpatient child psychiatry unit. Of these 33 met diagnostic criteria for ADHD-C and 15 met diagnostic criteria for ADHD-I. The Anxiety Disorders Child and Parent Interview Schedule (ADIS) (Silverman and Nelles, 1988) was used to ascertain diagnosis including comorbid conditions of oppositional defiant disorder and/or conduct disorder. In addition
Demographic information
Groups did not differ in age but significant differences in full-scale IQ were found (Table 2).
Global measures
The ADHD group had a significantly lower ICV compared to TD with a reduction of around 6%. This reduction is likely driven by the reduction in overall grey matter volume by around 8% in the clinical group as group differences in ICV are no longer significant when controlling for total grey matter (F(1,76)=0.729, p=0.396). Global white matter volume also showed a small but significant reduction. No
Discussion
This study found global reductions in total brain, grey and white matter volumes in children with ADHD compared to TD. Regional grey matter differences comprised clusters within the medial, middle and superior frontal gyri as well as the right superior parietal and the right middle temporal gyri. The study failed to find volume differences in the caudate nucleus between children with ADHD and TD; but a significant age by group interaction was found for the right caudate. Caudate volume showed a
Conflict of interest
All authors are declare that they have no conflict of interest.
Acknowledgements
This research was conducted within the Academic Child Psychiatry Unit, University of Melbourne, Royal Children's Hospital (clinical research assessments and scans) and the Developmental Imaging research group, Murdoch Childrens Research Institute and the Children's MRI Centre, Royal Children’s Hospital, Melbourne, Victoria (imaging analyses). NHMRC project grants 384419 and 569533 provided funds for the data collection. It was also supported by the Murdoch Childrens Research Institute, the
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