Distinct Brain Structure and Behavior Related to ADHD and Conduct Disorder Traits
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Molecular Psychiatry https://doi.org/10.1038/s41380-018-0202-6 ARTICLE Distinct brain structure and behavior related to ADHD and conduct disorder traits 1 1 1 2 3 Frida Bayard ● Charlotte Nymberg Thunell ● Christoph Abé ● Rita Almeida ● Tobias Banaschewski ● 4 5 6 6 7 Gareth Barker ● Arun L. W. Bokde ● Uli Bromberg ● Christian Büchel ● Erin Burke Quinlan ● 7 8,9 10 11 12 13 Sylvane Desrivières ● Herta Flor ● Vincent Frouin ● Hugh Garavan ● Penny Gowland ● Andreas Heinz ● 14 15 16 3,8 Bernd Ittermann ● Jean-Luc Martinot ● Marie-Laure Paillère Martinot ● Frauke Nees ● 10 17 18,19 20 21 Dimitri Papadopoulos Orfanos ● Tomáš Paus ● Luise Poustka ● Patricia Conrod ● Argyris Stringaris ● 3 22 23 3 6 24 Maren Struve ● Jani Penttilä ● Viola Kappel ● Yvonne Grimmer ● Tahmine Fadai ● Betteke van Noort ● 25 25 13 26 7 Michael N. Smolka ● Nora C. Vetter ● Henrik Walter ● Robert Whelan ● Gunter Schumann ● 1 Predrag Petrovic ● the IMAGEN Consortium Received: 16 April 2017 / Revised: 22 March 2018 / Accepted: 5 April 2018 © Springer Nature Limited 2018 Abstract fi 1234567890();,: 1234567890();,: Attention-De cit/Hyperactivity Disorder (ADHD) and conduct disorder (CD) exemplify top-down dysregulation conditions that show a large comorbidity and shared genetics. At the same time, they entail two different types of symptomology involving mainly non-emotional or emotional dysregulation. Few studies have tried to separate the specific biology underlying these two dimensions. It has also been suggested that both types of conditions consist of extreme cases in the general population where the symptoms are widely distributed. Here we test whether brain structure is specifically associated to ADHD or CD symptoms in a general population of adolescents (n = 1093) being part of the IMAGEN project. Both ADHD symptoms and CD symptoms were related to similar and overlapping MRI findings of a smaller structure in prefrontal and anterior cingulate cortex. However, our regions of interest (ROI) approach indicated that gray matter volume (GMV) and surface area (SA) in dorsolateral/dorsomedial prefrontal cortex and caudal anterior cingulate cortex were negatively associated to ADHD symptoms when controlling for CD symptoms while rostral anterior cingulate cortex GMV was negatively associated to CD symptoms when controlling for ADHD symptoms. The structural findings were mirrored in performance of neuropsychological tests dependent on prefrontal and anterior cingulate regions, showing that while performance on the Stop Signal test was specifically related to the ADHD trait, delayed discounting and working memory were related to both ADHD and CD traits. These results point towards a partially domain specific and dimensional capacity in different top-down regulatory systems associated with ADHD and CD symptoms. Introduction example, in Attention-Deficit/Hyperactivity Disorder (ADHD)–defined mainly by non-emotional symptoms Top-down dysregulation of information processing is a core including impulsivity, hyperactivity, and inattention–a core mechanism underlying many psychiatric disorders. For theory has evolved around deficits in executive functions (EF) [1, 2]. EF consists of a set of cognitive control pro- cesses associated with top-down regulatory systems in the brain [1, 2]. In line with this hypothesis, reported ADHD- These authors contributed equally: Frida Bayard, Charlotte Nymberg. symptoms have been associated with poor results in EF tests Electronic supplementary material The online version of this article although the relation has been surprisingly weak and (https://doi.org/10.1038/s41380-018-0202-6) contains supplementary unspecific[3]. material, which is available to authorized users. In addition to ADHD, there are also a set of psychiatric * Predrag Petrovic disorders which are characterized by top-down dysregula- [email protected] tion in emotional processing. These include Borderline Extended author information available on the last page of the article. Personality Disorder (BPD) and Antisocial Personality F. Bayard et al. Disorder (ASPD) in adults, and Conduct Disorder (CD) in systems of non-emotional processes [2, 17, 18, 23]. Espe- children and adolescents [2, 4–7]. They all comprise emo- cially EF tests that measure inhibition, switching, set- tional instability symptoms (partially overlapping with the shifting, updating, and sustained attention (including Stop concept of emotional lability) such as rapidly shifting Signal test, Stroop test, Wisconsin Card Sorting Test and emotional states and affective behavior. Also, altered Continuous Performance Test) have been shown to be emotional processing and regulation have been noted in altered in ADHD [3]. Further, working memory (WM), these states [2]. Collectively, these disorders may thus serve which partially consists of several EF components, has as valuable models for studying emotional dysregulation. shown to be significantly affected in ADHD [3]. Functional ADHD and emotional instability disorders show substantial imaging studies have consistently revealed networks symptom overlap and are highly comorbid [8–11]. A shared underlying non-emotional or “cool” EF processes involving genetic contribution [12] has also been suggested. The dorsolateral and dorsomedial prefrontal cortex (dl/dmPFC), overlapping relation between ADHD and emotional ventrolateral PFC (vlPFC), and caudal anterior cingulate instability disorders has made it problematic to isolate cortex (cACC), which work in conjunction with parietal and behaviors and mechanisms specific to each condition. subcortical regions such as the striatum [24, 25]. These A model encompassing both ADHD and emotional networks interact with the dopamine system and other instability disorders has recently been proposed [2]. The specific neuromodulatory systems [2]. The aforementioned model builds conceptually on the research domain criteria brain regions (including dl/dmPFC, vlPFC, and cACC) are (RDoC) approach [2, 13] and suggests that both forms of known to be less activated during EF tasks in ADHD disorders include similar top-down dysregulation—with the patients vs. controls [26–29]. On a brain structure level it difference being whether non-emotional or emotional reg- has been shown that the “ADHD-brain” matures sig- ulatory processes are predominantly affected. An important nificantly slower than for healthy individuals–especially in aspect of the model is that both non-emotional and emo- the prefrontal and anterior cingulate areas–with an delay of tional regulatory capacities are likely to be dimensional approximately three years (when medians for the two and vary among individuals even on a subclinical level groups were comapred) [30]. Although some of these within a healthy population [14–16]. In addition, some structural differences seem to disappear in adulthood [31], forms of ADHD may show a strong degree of subclinical some studies indicate smaller dl/dmPFC and cACC volume emotional dysregulation in the absence of other comorbid- also in adults with ADHD [32]. Recent meta-analyses ities [2, 17–19]. [29, 33, 34] have also shown decreased gray matter volume In children and adolescents, a clinical relation between (GMV) in insula, ventromedial prefrontal/medial orbito- ADHD and CD has been noted [6]. Although CD involves frontal cortex, rostral anterior cingulate cortex (rACC), and antisocial behaviors, which are not observed in pure occipital lobe and deep structures such as amygdala, basal ADHD, both disorders share common symptomatology ganglia (including nucleus accumbens), and hippocampus including problems with sustained attention, cognitive in individuals with ADHD. A major drawback in most switching, and inhibition [6]. The fact that these two dis- previous brain imaging studies on ADHD (including the orders are highly comorbid [11] has often not been con- above mentioned meta-analyses) is that they have often not sidered and might have confounded the findings of previous controlled for other sub-clinical symptoms such as traits of studies. Thus, it is still not entirely clear which of the fea- CD. tures are specific to each disorder. Some studies have In analogy with ADHD, it has been suggested that compared patients with pure ADHD and CD (without co- emotional instability disorders show a lack of regulatory morbidities), proposing the presence of a few disorder- capacity for emotional processes including emotional specific behaviors and brain functional characteristics [6]. aspects of EF, i.e., “hot” EF [2, 4–7]. Although there is a However, it has been suggested that the degree of ADHD large overlap between emotional and non-emotional reg- symptoms is related to the degree of CD symptoms even on ulatory processes, there seems to be some specificity, and it a sub-clinical level [2]. It is thus possible that studies on has been suggested that lateral orbitofrontal cortex (lOFC) ADHD still may be confounded by CD features and vice and rACC are more involved in the emotional sub- versa. It is therefore of importance to consider both symp- components of top-down regulation [2]. In line with this, tom dimensions simultaneously even on a sub-clinical level it has been observed that these brain regions are less acti- in relation to behavioral and neurobiological features. An vated in emotional regulation and “hot” EF tasks in emo- effective approach to better understand the specific beha- tional instability disorders as compared to controls [35–41]. vioral and neurobiological features in these two dimensions Moreover, several well-powered studies