Editorial: Irritable Imaging: Interpreting Null Results in Psychiatric Neuroimaging.

There is a growing appreciation that clinically impairing irritability is an important transdiagnostic symptom among children and adolescents with mental illness. Severe irritability, defined by frequent, developmentally inappropriate temper outbursts and low frustration tolerance, is one of the most common reasons that youths are referred for psychiatric evaluation and care.1 Although chronic irritability is the primary symptom in disruptive mood dysregulation disorder, the symptom is common in a diverse set of DSM-5 diagnoses, including major depressive disorder, autism spectrum disorder, oppositional defiant disorder, bipolar disorder, and generalized anxiety disorder.1 Given that clinically impairing irritability is often predictive of poor outcomes in childhood and worse clinical course in adulthood, a concerted effort is being made to refine the definition of this symptom and determine if severe irritability could be better understood and treated as an independent diagnosis.1.

Reward Processing in Children With Disruptive Behavior Disorders and Callous-Unemotional Traits in the ABCD Study.

OBJECTIVE: Disrupted reward processing is implicated in the etiology of disruptive behavior disorders (DBDs) and callous-unemotional traits. However, neuroimaging investigations of reward processing underlying these phenotypes remain sparse. The authors examined neural sensitivity in response to reward anticipation and receipt among youths with DBDs, with and without callous-unemotional traits. METHODS: Data were obtained from the Adolescent Brain and Cognitive Development Study (mean age=9.51 years [SD=0.50]; 49% female). Reward-related activation during the monetary incentive delay task was examined across 16 brain regions, including the amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAcc), and orbitofrontal cortex (OFC). Latent variable modeling was used to examine network-level coactivation. The following diagnostic groups were compared: typically developing youths (N=693) and youths with DBDs (N=995), subdivided into those with callous-unemotional traits (DBD+CU, N=198) and without callous-unemotional traits (DBD only, N=276). RESULTS: During reward anticipation, youths in the overall DBD group (with and without callous-unemotional traits) showed decreased dorsal ACC activation compared with typically developing youths. The DBD-only group exhibited reduced ventral and dorsal striatal activity compared with the DBD+CU and typically developing groups. During reward receipt, youths with DBDs showed increased cortical (e.g., OFC) and subcortical (e.g., NAcc) regional activation compared with typically developing youths. The DBD+CU group demonstrated greater activation in several regions compared with those in the typically developing (e.g., amygdala) and DBD-only (e.g., dorsal ACC) groups. At the network level, the DBD-only group showed reduced anticipatory reward activation compared with the typically developing and DBD+CU groups, whereas youths in the DBD+CU group showed increased activation during reward receipt compared with those in the typically developing group. CONCLUSIONS: These findings advance our understanding of unique neuroetiologic pathways to DBDs and callous-unemotional traits.

Actionable and incidental neuroradiological findings in twins with neurodevelopmental disorders.

While previous research has investigated neuroradiological findings in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), the entire range of neurodevelopmental disorders (NDDs) has not yet been well-studied using magnetic resonance imaging (MRI). Considering the overlap among NDDs and simultaneous development of the brain and face, guided by molecular signaling, we examined the relationship of actionable and incidental (non-actionable) MRI findings and NDD diagnoses together with facial morphological variants and genetic copy number variants (CNVs). A cross-sectional study was conducted with a twin cohort 8-36 years of age (57% monozygotic, 40% dizygotic), including 372 subjects (46% with NDDs; 47% female) imaged by MRI, 280 with data for facial morphological variants, and 183 for CNVs. Fifty-one percent of participants had MRI findings. Males had a statistically significantly higher percentage of MRI findings (57.7%) compared with females (43.8%, p = 0.03). Twin zygosity was not statistically significantly correlated with incidence or severity of specific MRI findings. No statistically significant association was found between MRI findings and any NDD diagnosis or facial morphological variants; however, MRI findings were statistically significantly associated with the number of CNVs (OR 1.20, 95% CI 1.00-1.44, p = 0.05, adjusted OR for sex 1.24, 95% CI 1.03-1.50, p = 0.02). When combining the presence of MRI findings, facial morphological variants, and CNVs, statistically significant relationships were found with ASD and ADHD diagnoses (p = 0.0006 and p = 0.002, respectively). The results of this study demonstrate that the ability to identify NDDs from combined radiology, morphology, and CNV assessments may be possible. Additionally, twins do not appear to be at increased risk for neuroradiological variants.

Neural Correlates of Adolescent Irritability and Its Comorbidity With Psychiatric Disorders.

OBJECTIVE: Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries. METHOD: The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. RESULTS: Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p < .05). Structural equation models suggested that part of the observed smaller gray matter volume was exclusively driven by irritability separate from direct relationships between generalized anxiety disorder (or attention-deficit/hyperactivity disorder, major depressive disorder, or oppositional defiant disorder) and gray matter volume. CONCLUSION: This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.

Specific cortical and subcortical alterations for reactive and proactive aggression in children and adolescents with disruptive behavior.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice.

Looming Threats and Animacy: Reduced Responsiveness in Youth with Disrupted Behavior Disorders.

Theoretical models have implicated amygdala dysfunction in the development of Disruptive Behavior Disorders (DBDs; Conduct Disorder/Oppositional Defiant Disorder). Amygdala dysfunction impacts valence evaluation/response selection and emotion attention in youth with DBDs, particularly in those with elevated callous-unemotional (CU) traits. However, amygdala responsiveness during social cognition and the responsiveness of the acute threat circuitry (amygdala/periaqueductal gray) in youth with DBDs have been less well-examined, particularly with reference to CU traits. 31 youth with DBDs and 27 typically developing youth (IQ, age and gender-matched) completed a threat paradigm during fMRI where animate and inanimate, threatening and neutral stimuli appeared to loom towards or recede from participants. Reduced responsiveness to threat variables, including visual threats and encroaching stimuli, was observed within acute threat circuitry and temporal, lateral frontal and parietal cortices in youth with DBDs. This reduced responsiveness, at least with respect to the looming variable, was modulated by CU traits. Reduced responsiveness to animacy information was also observed within temporal, lateral frontal and parietal cortices, but not within amygdala. Reduced responsiveness to animacy information as a function of CU traits was observed in PCC, though not within the amygdala. Reduced threat responsiveness may contribute to risk taking and impulsivity in youth with DBDs, particularly those with high levels of CU traits. Future work will need to examine the degree to which this reduced response to animacy is independent of amygdala dysfunction in youth with DBDs and what role PCC might play in the dysfunctional social cognition observed in youth with high levels of CU traits.

Structural Brain Abnormalities of Attention-Deficit/Hyperactivity Disorder With Oppositional Defiant Disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia, and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of comorbid oppositional defiant disorder (ODD) (comorbidity rates up to 60%) on these neuroanatomical differences is scarcely studied, while ODD (in combination with conduct disorder) has been associated with structural abnormalities of the frontal lobe, amygdala, and insula. The aim of this study was to investigate the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD. METHODS: Three groups, 16 ± 3.5 years of age (mean ± SD; range 7-29 years), were studied on volumetric and cortical thickness characteristics using structural magnetic resonance imaging (surface-based morphometry): ADHD+ODD (n = 67), ADHD-only (n = 243), and control subjects (n = 233). Analyses included the moderators age, gender, IQ, and scan site. RESULTS: ADHD+ODD and ADHD-only showed volumetric reductions in total gray matter and (mainly) frontal brain areas. Stepwise volumetric reductions (ADHD+ODD < ADHD-only < control subjects) were found for mainly frontal regions, and ADHD+ODD was uniquely associated with reductions in several structures (e.g., the precuneus). In general, findings remained significant after accounting for ADHD symptom severity. There were no group differences in cortical thickness. Exploratory voxelwise analyses showed no group differences. CONCLUSIONS: ADHD+ODD and ADHD-only were associated with volumetric reductions in brain areas crucial for attention, (working) memory, and decision-making. Volumetric reductions of frontal lobes were largest in the ADHD+ODD group, possibly underlying observed larger impairments in neurocognitive functions. Previously reported striatal abnormalities in ADHD may be caused by comorbid conduct disorder rather than ODD.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD), characterized by severe irritability, and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid. This is the first study to characterize neural and behavioral similarities and differences in attentional functioning across these disorders. METHOD: Twenty-seven healthy volunteers, 31 patients with DMDD, and 25 patients with ADHD (8 to 18 years old) completed a functional magnetic resonance imaging attention task. Group differences in intra-subject variability in reaction time (RT) were examined. The present functional magnetic resonance imaging analytic approach precisely quantified trial-wise associations between RT and brain activity. RESULTS: Group differences manifested in the relation between RT and brain activity (all regions: p < .01, F > 2.54, partial eta-squared [ηp2] > 0.06). Patients with DMDD showed specific alterations in the right paracentral lobule, superior parietal lobule, fusiform gyrus, and cerebellar culmen. In contrast, patients with DMDD and those with ADHD exhibited blunted compensatory increases in activity on long RT trials. In addition, youth with DMDD exhibited increased activity in the postcentral gyrus, medial frontal gyrus, and cerebellar tonsil and declive (all regions: p < .05, F > 2.46, ηp2 > 0.06). Groups in the imaging sample did not differ significantly in intra-subject variability in RT (F2,79 = 2.664, p = .076, ηp2 = 0.063), although intra-subject variability in RT was significantly increased in youth with DMDD and ADHD when including those not meeting strict motion and accuracy criteria for imaging analysis (F2,96 = 4.283, p = .017, ηp2 = 0.083). CONCLUSION: Patients with DMDD exhibited specific alterations in the relation between pre-stimulus brain activity and RT. Patients with DMDD and those with ADHD exhibited similar blunting of compensatory neural activity in frontal, parietal, and other regions. In addition, patients with DMDD showed increased RT variability compared with healthy youth. This work is the first to identify common and unique behavioral and neural signatures of DMDD and ADHD.

Comparing Brain Morphometry Across Multiple Childhood Psychiatric Disorders.

OBJECTIVE: In both children and adults, psychiatric illness is associated with structural brain alterations, particularly in the prefrontal cortex (PFC). However, most studies compare gray matter volume (GMV) in healthy volunteers (HVs) to one psychiatric group. We compared GMV among youth with anxiety disorders, bipolar disorder (BD), disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), and HVs. METHOD: 3-Tesla T1-weighted magnetic resonance imaging scans were acquired in 184 youths (39 anxious, 20 BD, 52 DMDD, 20 ADHD, and 53 HV). Voxel-based morphometry analyses were conducted. One-way analysis of variance tested GMV differences with whole-brain familywise error (p < .05) correction; secondary, exploratory whole-brain analyses used a threshold of p < .001, ≥200 voxels. Given recent frameworks advocating dimensional approaches in psychopathology research, we also tested GMV associations with continuous anxiety, irritability, and inattention symptoms. RESULTS: Specificity emerged in the left dorsolateral PFC (dlPFC), which differed among youth with BD, anxiety, and HVs; GMV was increased in youth with anxiety, but decreased in BD, relative to HVs. Secondary analyses revealed BD-specific GMV decreases in the right lateral PFC, right dlPFC, and dorsomedial PFC, and also anxiety-specific GMV increases in the left dlPFC, right ventrolateral PFC, frontal pole, and right parahippocampal gyrus/lingual gyrus. Both BD and DMDD showed decreased GMV relative to HVs in the right dlPFC/superior frontal gyrus. GMV was not associated with dimensional measures of anxiety, irritability, or ADHD symptoms. CONCLUSION: Both disorder-specific and shared GMV differences manifest in pediatric psychopathology. Some differences were specific to anxiety disorders, others specific to BD, and others shared between BD and DMDD. Further developmental research might map commonalities and differences of structure and function in diverse pediatric psychopathologies.

The influence of comorbid oppositional defiant disorder on white matter microstructure in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid disorders. ADHD has been associated with altered white matter (WM) microstructure, though the literature is inconsistent, which may be due to differences in the in- or exclusion of participants with comorbid ODD. WM abnormalities in ODD are still poorly understood, and it is unclear whether comorbid ODD in ADHD may have confounded the current ADHD literature. Diffusion Tensor Imaging (DTI) was used to compare fractional anisotropy (FA) and mean diffusivity (MD) between ADHD patients with (n = 42) and without (n = 117) comorbid ODD. All participants were between 8-25 years and groups did not differ in mean age or gender. Follow-up analyses were conducted to examine the role of antisocial behaviour (conduct problems) on FA and MD values in both groups. Comorbid ODD in ADHD was associated with lower FA in left frontotemporal WM, which appeared independent of ADHD symptoms. FA was negatively associated with antisocial behaviour in ADHD + ODD, but not in ADHD-only. Comorbid ODD is associated with WM abnormalities in individuals with ADHD, which appears to be independent of ADHD symptoms. Altered WM microstructure in comorbid ODD may play a role in inconsistencies in the current DTI literature in ADHD. Altered development of these tracts may contribute to social-emotional and cognitive problems in children with oppositional and antisocial behaviour.

Neural correlates of reactive aggression in children with attention-deficit/hyperactivity disorder and comorbid disruptive behaviour disorders.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is often linked with impulsive and aggressive behaviour, indexed by high comorbidity rates between ADHD and disruptive behaviour disorders (DBD). The present study aimed to investigate underlying neural activity of reactive aggression in children with ADHD and comorbid DBD using functional neuroimaging techniques (fMRI). METHOD: Eighteen boys with ADHD (age 9-14 years, 10 subjects with comorbid DBD) and 18 healthy controls were administered a modified fMRI-based version of the 'Point Subtraction Aggression Game' to elicit reactive aggressive behaviour. Trials consisted of an 'aggression phase' (punishment for a fictitious opponent) and an 'outcome phase' (presentation of the trial outcome). RESULTS: During the aggression phase, higher aggressive responses of control children were accompanied by higher activation of the ventral anterior cingulate cortex and the temporoparietal junction. Patients displayed inverted results. During the outcome phase, comparison between groups and conditions showed differential activation in the dorsal striatum and bilateral insular when subjects gained points. Losing points was accompanied by differential activation of regions belonging to the insula and the middle temporal sulcus. CONCLUSION: Data support the hypothesis that deficient inhibitory control mechanisms are related to increased impulsive aggressive behaviour in young people with ADHD and comorbid DBD.