Age-related brain deviations and aggression.

BACKGROUND: Disruptive behavior disorders (DBD) are heterogeneous at the clinical and the biological level. Therefore, the aims were to dissect the heterogeneous neurodevelopmental deviations of the affective brain circuitry and provide an integration of these differences across modalities. METHODS: We combined two novel approaches. First, normative modeling to map deviations from the typical age-related pattern at the level of the individual of (i) activity during emotion matching and (ii) of anatomical images derived from DBD cases (n = 77) and controls (n = 52) aged 8-18 years from the EU-funded Aggressotype and MATRICS consortia. Second, linked independent component analysis to integrate subject-specific deviations from both modalities. RESULTS: While cases exhibited on average a higher activity than would be expected for their age during face processing in regions such as the amygdala when compared to controls these positive deviations were widespread at the individual level. A multimodal integration of all functional and anatomical deviations explained 23% of the variance in the clinical DBD phenotype. Most notably, the top marker, encompassing the default mode network (DMN) and subcortical regions such as the amygdala and the striatum, was related to aggression across the whole sample. CONCLUSIONS: Overall increased age-related deviations in the amygdala in DBD suggest a maturational delay, which has to be further validated in future studies. Further, the integration of individual deviation patterns from multiple imaging modalities allowed to dissect some of the heterogeneity of DBD and identified the DMN, the striatum and the amygdala as neural signatures that were associated with aggression.

Emotion recognition profiles in clusters of youth based on levels of callous-unemotional traits and reactive and proactive aggression.

Youth with disruptive behavior showing high callous-unemotional (CU) traits and proactive aggression are often assumed to exhibit distinct impairments in emotion recognition from those showing mainly reactive aggression. Yet, reactive and proactive aggression and CU traits may co-occur to varying degrees across individuals. We aimed to investigate emotion recognition in more homogeneous clusters based on these three dimensions. In a sample of 243 youth (149 with disruptive behavior problems and 94 controls) aged 8-18 years, we used model-based clustering on self-report measures of CU traits and reactive and proactive aggression and compared the resulting clusters on emotion recognition (accuracy and response bias) and working memory. In addition to a Low and Low-Moderate symptom cluster, we identified two high CU clusters. The CU-Reactive cluster showed high reactive and low-to-medium proactive aggression; the CU-Mixed cluster showed high reactive and proactive aggression. Both CU clusters showed impaired fear recognition and working memory, whereas the CU-Reactive cluster also showed impaired recognition of disgust and sadness, partly explained by poor working memory, as well as a response bias for anger and happiness. Our results confirm the importance of CU traits as a core dimension along which youth with disruptive behavior may be characterized, yet challenge the view that high CU traits are closely linked to high proactive aggression per se. Notably, distinct neurocognitive processes may play a role in youth with high CU traits and reactive aggression with lower versus higher proactive aggression.

The effects of callous-unemotional traits and aggression subtypes on amygdala activity in response to negative faces.

BACKGROUND: Brain imaging studies have shown altered amygdala activity during emotion processing in children and adolescents with oppositional defiant disorder (ODD) and conduct disorder (CD) compared to typically developing children and adolescents (TD). Here we aimed to assess whether aggression-related subtypes (reactive and proactive aggression) and callous-unemotional (CU) traits predicted variation in amygdala activity and skin conductance (SC) response during emotion processing. METHODS: We included 177 participants (n = 108 cases with disruptive behaviour and/or ODD/CD and n = 69 TD), aged 8-18 years, across nine sites in Europe, as part of the EU Aggressotype and MATRICS projects. All participants performed an emotional face-matching functional magnetic resonance imaging task. RESULTS: Differences between cases and TD in affective processing, as well as specificity of activation patterns for aggression subtypes and CU traits, were assessed. Simultaneous SC recordings were acquired in a subsample (n = 63). Cases compared to TDs showed higher amygdala activity in response to negative faces (fearful and angry) v. shapes. Subtyping cases according to aggression-related subtypes did not significantly influence on amygdala activity; while stratification based on CU traits was more sensitive and revealed decreased amygdala activity in the high CU group. SC responses were significantly lower in cases and negatively correlated with CU traits, reactive and proactive aggression. CONCLUSIONS: Our results showed differences in amygdala activity and SC responses to emotional faces between cases with ODD/CD and TD, while CU traits moderate both central (amygdala) and peripheral (SC) responses. Our insights regarding subtypes and trait-specific aggression could be used for improved diagnostics and personalized treatment.

Amygdala reactivity and ventromedial prefrontal cortex coupling in the processing of emotional face stimuli in attention-deficit/hyperactivity disorder.

Impaired emotion recognition is common in individuals with attention-deficit/hyperactivity disorder (ADHD) and may, via deficient emotion self-regulation, relate to the frequently co-occurring affective and social problems. The present study used an emotional face-matching task and functional magnetic resonance imaging (fMRI) to investigate neural responses during the processing of angry and fearful faces and visuo-spatial control stimuli. Additionally, measures for emotion dysregulation, ADHD type, and age were investigated in relation to the behavioral and neural fMRI data. We utilized a sample of 61 adolescents/young adults with ADHD and 51 age-matched healthy controls (age range: 12-28 years). Participants with ADHD had higher emotion dysregulation scores than controls. They also reacted slower and less accurate in response to emotional but not visuo-spatial control stimuli. Neural response differences between emotional and visuo-spatial trials were significantly smaller in cases, particularly in the left amygdala. While coupling between the right amygdala and bilateral ventromedial prefrontal cortex was stronger for emotional than visuo-spatial stimuli in control subjects, levels of positive coupling between the trial types did not significantly differ in participants with ADHD. Neither emotion dysregulation scores, nor ADHD type or age were related to the behavioral and neural processing alterations during the emotional face-matching task. Results indicate that emotion recognition deficits in ADHD are particularly associated with lower amygdala activation to emotional stimuli and alterations in the functional connections of the amygdala to medial prefrontal areas. Emotion recognition deficits and associated neural alterations were unrelated to emotion dysregulation, ADHD type, or age.

Subgrouping children and adolescents with disruptive behaviors: symptom profiles and the role of callous-unemotional traits.

Disruptive behavior during childhood and adolescence is heterogeneous and associated with several psychiatric disorders. The identification of more homogeneous subgroups might help identify different underlying pathways and tailor treatment strategies. Children and adolescents (aged 8-18) with disruptive behaviors (N = 121) and healthy controls (N = 100) were included in a European multi-center cognition and brain imaging study. They were assessed via a battery of standardized semi-structured interviews and questionnaires. K-means cluster-model analysis was carried out to identify subgroups within the group with disruptive behaviors, based on clinical symptom profiles, callous-unemotional (CU) traits, and proactive and reactive aggression. The resulting subgroups were then compared to healthy controls with regard to these clinical variables. Three distinct subgroups were found within the group with disruptive behaviors. The High CU Traits subgroup presented elevated scores for CU traits, proactive aggression and conduct disorder (CD) symptoms, as well as a higher proportion of comorbidities (CD + oppositional defiant disorder + attention deficit hyperactivity disorder (ADHD). The ADHD and Affective Dysregulation subgroup showed elevated scores for internalizing and ADHD symptoms, as well as a higher proportion of females. The Low Severity subgroup had relatively low levels of psychopathology and aggressive behavior compared to the other two subgroups. The High CU Traits subgroup displayed more antisocial behaviors than the Low Severity subgroup, but did not differ when compared to the ADHD and Affective Dysregulation subgroup. All three subgroups differed significantly from the healthy controls in all the variables analyzed. The present study extends previous findings on subgrouping children and adolescents with disruptive behaviors using a multidimensional approach and describes levels of anxiety, affective problems, ADHD, proactive aggression and CU traits as key factors that differentiate conclusively between subgroups.

Emotion dysregulation and integration of emotion-related brain networks affect intraindividual change in ADHD severity throughout late adolescence.

The course of attention deficit hyperactivity disorder (ADHD) from adolescence into adulthood shows large variations between individuals; nonetheless determinants of interindividual differences in the course are not well understood. A frequent problem in ADHD, associated with worse outcomes, is emotion dysregulation. We investigated whether emotion dysregulation and integration of emotion-related functional brain networks affect interindividual differences in ADHD severity change. ADHD severity and resting state neuroimaging data were measured in ADHD and unaffected individuals at two points during adolescence and young adulthood. Bivariate latent change score models were applied to investigate whether emotion dysregulation and network integration affect ADHD severity changes. Emotion dysregulation was gauged from questionnaire subscales for conduct problems, emotional problems and emotional lability. Better emotion regulation was associated with a better course of ADHD (104 participants, 44 females, age range: 12-27). Using graph analysis, we determined network integration of emotion-related functional brain networks. Network integration was measured by nodal efficiency, i.e., the average inverse path distance from one node to all other nodes. A pattern of low nodal efficiency of cortical regions associated with emotion processing and high nodal efficiency in subcortical areas and cortical areas involved in implicit emotion regulation predicted a better ADHD course. Larger nodal efficiency of the right orbitofrontal cortex was related to a better course of ADHD (99 participants, 42 females, age range: 10-29). We demonstrated that neural and behavioral covariates associated with emotion regulation affect the course of ADHD severity throughout adolescence and early adulthood beyond baseline effects of ADHD severity.

Aggression subtypes relate to distinct resting state functional connectivity in children and adolescents with disruptive behavior.

There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggression-subtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.

Basal ganglia structure in Tourette's disorder and/or attention-deficit/hyperactivity disorder.

BACKGROUND: Tourette's disorder and attention-deficit/hyperactivity disorder often co-occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected. METHODS: T1-weighted magnetic resonance images from children (n = 141, 8 to 12 years) with Tourette's disorder and/or attention-deficit/hyperactivity disorder and controls were processed with the Oxford Centre for Functional MRI [Magnetic resonance imaging] of the Brain (FMRIB) integrated registration and segmentation tool to determine basal ganglia nuclei volume and shape. Across all participants, basal ganglia nuclei volume and shape were estimated in relation to Tourette's disorder (categorical), attention-deficit/hyperactivity disorder severity (continuous across all participants), and their interaction. RESULTS: The analysis revealed no differences in basal ganglia nuclei volumes or shape between children with and without Tourette's disorder, no association with attention-deficit/hyperactivity disorder severity, and no interaction between the two. CONCLUSION: We found no evidence that Tourette's disorder, attention-deficit/hyperactivity disorder severity, or a combination thereof are associated with structural variation of the basal ganglia in 8- to 12-year-old patients. © 2016 International Parkinson and Movement Disorder Society.

COMPULS: design of a multicenter phenotypic, cognitive, genetic, and magnetic resonance imaging study in children with compulsive syndromes.

BACKGROUND: Compulsivity, the closely linked trait impulsivity and addictive behaviour are associated with several neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive compulsive disorder (OCD). All three disorders show impaired fronto-striatal functioning, which may be related to altered glutamatergic signalling. Genetic factors are also thought to play an important role in the aetiology of compulsivity-related disorders. METHODS: The COMPULS study is a multi-center study designed to investigate the relationship between the traits compulsivity, impulsivity, and, to a lesser extent, addictive behaviour within and across the neurodevelopmental disorders ADHD, ASD, and OCD. This will be done at the phenotypic, cognitive, neural, and genetic level. In total, 240 participants will take part in COMPULS across four different sites in Europe. Data collection will include diagnostic interviews, behavioural questionnaires, cognitive measures, structural, functional and spectral neuroimaging, and genome-wide genetic information. DISCUSSION: The COMPULS study will offer the unique opportunity to investigate several key aspects of compulsivity across a large cohort of ADHD, ASD and OCD patients.

Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure.

The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods-combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6-30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.

Different whole-brain functional connectivity correlates of reactive-proactive aggression and callous-unemotional traits in children and adolescents with disruptive behaviors.

BACKGROUND: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. METHODS: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. RESULTS: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. CONCLUSIONS: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths.

Polygenic risk scores for antisocial behavior in relation to amygdala morphology across an attention deficit hyperactivity disorder case-control sample with and without disruptive behavior.

Antisocial and aggressive behaviors show considerable heritability and are central to disruptive behavior disorders (DBDs), but are also frequently observed in attention deficit hyperactivity disorder (ADHD). While the amygdala is implicated as a key neural structure, it remains unclear whether common genetic variants underlie this brain-behavior association. We hypothesized that polygenic (risk) scores for antisocial and aggressive behaviors (ASB-PRS) would be related to amygdala morphology. Using the Broad Antisocial Behavior Consortium genome-wide association study (GWAS; mostly population based cohorts), we calculated ASB-PRS in the NeuroIMAGE I ADHD case-control sample with varying levels of DBD symptomatology (n=679 from 379 families, aged 7 - 29). We first investigated associations of several ASB-PRS p value thresholds with the presence of DBD symptoms and self-reported antisocial behavior (ASB) to determine the threshold for further analyses. This PRS was then related to amygdala volume and shape using regression and vertex-wise analyses. Our results showed associations of ASB-PRS with the presence of DBD symptoms, self-reported ASB, and left basolateral amygdala shape, independent of ADHD symptom severity and ADHD-PRS, with a relative outward displacement of the vertices. No associations of ASB-PRS, DBD symptoms or self-reported ASB with amygdala volume were found. Our results indicate that genetic risk for antisocial and aggressive behaviors is related to amygdala shape alterations, and point to genetic sharing across different DBD and ASB and aggression-related phenotypes as a spectrum of genetically related quantitative traits. Additionally, our findings support the utility of vertex-based shape analyses in genetic studies of ASB, aggression, and DBDs.

Longitudinal changes of ADHD symptoms in association with white matter microstructure: A tract-specific fixel-based analysis.

BACKGROUND: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 - 34 years), and using the more physiologically informative fixel-based analysis (FBA). METHODS: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. RESULTS: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). CONCLUSIONS: Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory.

White Matter Microstructure in Attention-Deficit/Hyperactivity Disorder: A Systematic Tractography Study in 654 Individuals.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity. ADHD has been related to differences in white matter (WM) microstructure. However, much remains unclear regarding the nature of these WM differences and which clinical aspects of ADHD they reflect. We systematically investigated whether fractional anisotropy (FA) is associated with current and/or lifetime categorical diagnosis, impairment in daily life, and continuous ADHD symptom measures. METHODS: Diffusion-weighted imaging data were obtained from 654 participants (322 unaffected, 258 affected, 74 subthreshold; 7-29 years of age). We applied automated global probabilistic tractography on 18 major WM pathways. Linear mixed-effects regression models were used to examine associations of clinical measures with overall brain and tract-specific FA. RESULTS: There were significant interactions of tract with all ADHD variables on FA. There were no significant associations of FA with current or lifetime diagnosis, nor with impairment. Lower FA in the right cingulum angular bundle was associated with higher hyperactivity-impulsivity symptom severity (pfamilywise error = .045). There were no significant effects for other tracts. CONCLUSIONS: This is the first time global probabilistic tractography has been applied to an ADHD dataset of this size. We found no evidence for altered FA in association with ADHD diagnosis. Our findings indicate that associations of FA with ADHD are not uniformly distributed across WM tracts. Continuous symptom measures of ADHD may be more sensitive to FA than diagnostic categories. The right cingulum angular bundle in particular may play a role in symptoms of hyperactivity and impulsivity.

Developmental changes in fronto-striatal glutamate and their association with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder.

Autism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) show overlapping symptomatology and deficits in inhibitory control, which are associated with altered functioning and glutamatergic signaling in fronto-striatal circuitry. These parameters have never been examined together. The purpose of the current study was to investigate functioning during inhibitory control and its association with fronto-striatal glutamate concentrations across these disorders using a multi-center, longitudinal approach. Adolescents with ASD (n = 24), OCD (n = 15) and controls (n = 35) underwent two magnetic resonance imaging (MRI) sessions with a one-year interval. This included proton magnetic resonance spectroscopy (1H-MRS; n = 74) and functional MRI during an inhibitory control task (n = 53). We investigated 1H-MRS data and fMRI data separately as well as integrated in a multimodal analysis using linear models focusing on diagnosis and continuous measures of overlapping compulsivity symptoms. ACC glutamate was reduced over time in the ASD group compared with controls, while striatal glutamate decreased over time independent of diagnosis. Increased compulsive behavior seemed to be associated with increased striatal activity during failed inhibitory control. The integrated analyses showed differential involvement of increased striatal glutamate during failed but decreased striatal glutamate during successful inhibitory control in the OCD group compared to controls and ASD, suggesting different underlying mechanisms for OCD compared to ASD.

Correction: Szopinska-Tokov et al. Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms. Microorganisms 2020, 8, 406.

The authors wish to make the following correction to this paper [...].

Functional network topology of the right insula affects emotion dysregulation in hyperactive-impulsive attention-deficit/hyperactivity disorder.

Emotion dysregulation is common in attention-deficit/hyperactivity disorder (ADHD). It is highly prevalent in young adult ADHD and related to reduced well-being and social impairments. Neuroimaging studies reported neural activity changes in ADHD in brain regions associated with emotion processing and regulation. It is however unknown whether deficits in emotion regulation relate to changes in functional brain network topology in these regions. We used a combination of graph analysis and structural equation modelling (SEM) to analyze resting-state functional connectivity in 147 well-characterized young adults with ADHD and age-matched healthy controls from the NeuroIMAGE database. Emotion dysregulation was gauged with four scales obtained from questionnaires and operationalized through a latent variable derived from SEM. Graph analysis was applied to resting-state data and network topology measures were entered into SEM models to identify brain regions whose local network integration and connectedness differed between subjects and was associated with emotion dysregulation. The latent variable of emotion dysregulation was characterized by scales gauging emotional distress, emotional symptoms, conduct symptoms, and emotional lability. In individuals with ADHD characterized by prominent hyperactivity-impulsivity, the latent emotion dysregulation variable was related to an increased clustering and local efficiency of the right insula. Thus, in the presence of hyperactivity-impulsivity, clustered network formation of the right insula may underpin emotion dysregulation in young adult ADHD.

Impaired response inhibition during a stop-signal task in children with Tourette syndrome is related to ADHD symptoms: A functional magnetic resonance imaging study.

OBJECTIVES: Tourette syndrome (TS) is characterised by the presence of sudden, rapid movements and vocalizations (tics). The nature of tics suggests impairments in inhibitory control. However, findings of impaired inhibitory control have so far been inconsistent, possibly due to small sample sizes, wide age ranges, or not taking medication use or attention-deficit/hyperactivity disorder (ADHD) comorbidity into account. METHODS: We investigated group differences in response inhibition using an fMRI-based stop-signal task in 103 8 to 12-year-old children (n = 51 with TS, of whom n = 28 without comorbid ADHD [TS - ADHD] and n = 23 with comorbid ADHD [TS + ADHD]; and n = 52 healthy controls), and related these measures to tic and ADHD severity. RESULTS: We observed an impaired response inhibition performance in children with TS + ADHD, but not in those with TS - ADHD, relative to healthy controls, as evidenced by a slower stop-signal reaction time, slower mean reaction times, and larger variability of reaction times. Dimensional analyses implicated ADHD severity as the driving force in these findings. Neural activation during failed inhibition was stronger in the inferior frontal gyrus and temporal and parietal areas in TS + ADHD compared to healthy controls. CONCLUSIONS: Impaired inhibitory performance and increased neural activity in TS appear to manifest predominantly in relation to ADHD symptomatology.

Associations between attention-deficit hyperactivity disorder (ADHD) symptom remission and white matter microstructure: A longitudinal analysis.

Background: Attention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD. Methods: We obtained diffusion-weighted imaging (DWI) data from 99 participants at two timepoints (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time-points. Results: Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST; P FWE = 0.038 and P FWE = 0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (P FWE = 0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments. Conclusions: In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.