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.

Relations between hemispheric asymmetries of grey matter and auditory processing of spoken syllables in 281 healthy adults.

Most people have a right-ear advantage for the perception of spoken syllables, consistent with left hemisphere dominance for speech processing. However, there is considerable variation, with some people showing left-ear advantage. The extent to which this variation is reflected in brain structure remains unclear. We tested for relations between hemispheric asymmetries of auditory processing and of grey matter in 281 adults, using dichotic listening and voxel-based morphometry. This was the largest study of this issue to date. Per-voxel asymmetry indexes were derived for each participant following registration of brain magnetic resonance images to a template that was symmetrized. The asymmetry index derived from dichotic listening was related to grey matter asymmetry in clusters of voxels corresponding to the amygdala and cerebellum lobule VI. There was also a smaller, non-significant cluster in the posterior superior temporal gyrus, a region of auditory cortex. These findings contribute to the mapping of asymmetrical structure-function links in the human brain and suggest that subcortical structures should be investigated in relation to hemispheric dominance for speech processing, in addition to auditory cortex.

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.

A graph theory study of resting-state functional connectivity in children with Tourette syndrome.

Little is known about the brain's functional organization during resting-state in children with Tourette syndrome (TS). We aimed to investigate this with a specific focus on the role of comorbid attention-deficit/hyperactivity disorder (ADHD). We applied graph theoretical analysis to resting-state functional magnetic resonance imaging data of 109 8-to-12-year-old children with TS (n = 46), ADHD without tics (n = 23), and healthy controls (n = 40). First, we compared these three groups, and in a second comparison four groups, distinguishing TS with (TS + ADHD, n = 19) and without comorbid ADHD (TS-ADHD, n = 27). Weighted brain graphs were constructed for both comparisons to investigate global efficiency, local efficiency, and clustering coefficient per acquired network. Local efficiency and clustering coefficient were significantly lower in children with TS-ADHD in the default mode network compared with healthy controls, and in the frontoparietal network compared with ADHD; we also found associations with higher tic severity. Our study supports a different functional brain network organization in children with TS-ADHD, compared with healthy controls and children with ADHD.

Executive function in children with Tourette syndrome and attention-deficit/hyperactivity disorder: Cross-disorder or unique impairments?

Findings of executive functioning deficits in Tourette syndrome (TS) have so far been inconsistent, possibly due to methodological challenges of previous studies, such as the use of small sample sizes and not accounting for comorbid attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or medication use. We aimed to address these issues by examining several areas of executive functioning (response inhibition, attentional flexibility, cognitive control, and working memory) and psychomotor speed in 174 8-to-12-year-old children with TS [n = 34 without (TS-ADHD) and n = 26 with comorbid ADHD (TS+ADHD)], ADHD without tics (ADHD-TS; n = 54), and healthy controls (n = 60). We compared executive functioning measures and psychomotor speed between these groups and related these to ADHD severity across the whole sample, and tic severity across the TS groups. Children with TS+ADHD, but not TS-ADHD, made more errors on the cognitive control task than healthy children, while TS-ADHD had a slower psychomotor speed compared to healthy controls. The ADHD group showed impairment in cognitive control and working memory versus healthy controls. Moreover, higher ADHD severity was associated with poorer cognitive control and working memory across all groups; there was no relation between any of the executive functioning measures and tic severity. OCD severity or medication use did not influence our results. In conclusion, we found little evidence for executive function impairments inherent to TS. Executive function problems appear to manifest predominantly in relation to ADHD symptomatology, with both cross-disorder and unique features of neuropsychological functioning when cross-comparing TS and ADHD.

Neural reward processing in paediatric Tourette syndrome and/or attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common comorbidity in individuals with Tourette syndrome (TS). Yet, it is unclear to what extent TS and ADHD show overlapping or distinct neural abnormalities. ADHD has been associated with altered reward processing, but there are very few studies on reward processing in TS. This study assessed neural activation of basal ganglia and thalamus during reward anticipation and receipt in children with TS and/or ADHD. We analysed mean activations of a priori specified regions of interest during an fMRI monetary incentive delay task. Data was used from 124 children aged 8-12 years (TS n = 47, of which 29 had comorbid ADHD; ADHD n = 29; healthy controls n = 48). ADHD severity across ADHD and TS groups and healthy controls was marginally related to hypoactivation of the right nucleus accumbens during reward anticipation; this effect was not moderated by TS diagnosis. We detected no associations of neural activation with TS. The association between ADHD severity and hypoactivation of the right nucleus accumbens during reward anticipation, independent of the presence or absence of TS, is in line with the view of nucleus accumbens hypoactivation as a dimensional, neurofunctional marker of ADHD severity, transcending the boundaries of primary diagnosis.

Frontostriatal functional connectivity correlates with repetitive behaviour across autism spectrum disorder and obsessive-compulsive disorder.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are neurodevelopmental disorders with considerable overlap in terms of their defining symptoms of compulsivity/repetitive behaviour. Little is known about the extent to which ASD and OCD have common versus distinct neural correlates of compulsivity. Previous research points to potentially common dysfunction in frontostriatal connectivity, but direct comparisons in one study are lacking. Here, we assessed frontostriatal resting-state functional connectivity in youth with ASD or OCD, and healthy controls. In addition, we applied a cross-disorder approach to examine whether repetitive behaviour across ASD and OCD has common neural substrates. METHODS: A sample of 78 children and adolescents aged 8-16 years was used (ASD n = 24; OCD n = 25; healthy controls n = 29), originating from the multicentre study COMPULS. We tested whether diagnostic group, repetitive behaviour (measured with the Repetitive Behavior Scale-Revised) or their interaction was associated with resting-state functional connectivity of striatal seed regions. RESULTS: No diagnosis-specific differences were detected. The cross-disorder analysis, on the other hand, showed that increased functional connectivity between the left nucleus accumbens (NAcc) and a cluster in the right premotor cortex/middle frontal gyrus was related to more severe symptoms of repetitive behaviour. CONCLUSIONS: We demonstrate the fruitfulness of applying a cross-disorder approach to investigate the neural underpinnings of compulsivity/repetitive behaviour, by revealing a shared alteration in functional connectivity in ASD and OCD. We argue that this alteration might reflect aberrant reward or motivational processing of the NAcc with excessive connectivity to the premotor cortex implementing learned action patterns.

Putamen functional connectivity during inhibitory control in smokers and non-smokers.

The putamen has been shown to play a key role in inhibitory control and addiction, and consists of distinct subregions associated with distinct functions. The anterior putamen is thought to be specialized in goal-directed control or response-monitoring in connection with frontal regions, whereas the posterior part is specialized in habitual or automatic responding in connection with sensorimotor regions. The present study is the first to delineate functional networks of the anterior and posterior putamen in a Go-NoGo response inhibition task, and to examine differences between smokers (n = 25) and non-smokers (n = 23) within these networks. Functional connectivity analyses were conducted on fMRI data from a Go-NoGo study, using the generalized form of psychophysiological interaction with anterior and posterior putamen seed regions. In the context of inhibition, the anterior putamen exhibited connectivity with the anterior cingulate cortex (ACC) and precuneus (pFWE < .05), which was in line with previous literature. Conversely, the posterior putamen showed connectivity with regions implicated in sensorimotor processing. When we compared smokers to non-smokers, we did not observe the expected weaker connectivity between the anterior putamen and ACC during inhibition in smokers. Instead, our study revealed stronger inhibition-related connectivity between the anterior putamen and right insula in smokers. This finding highlights the involvement of putamen - insula interactions in addiction and impulse control.

Multi-modal imaging investigation of anterior cingulate cortex cytoarchitecture in neurodevelopment.

Multi-modal imaging may improve our understanding of the relationship between cortical morphology and cytoarchitecture. To this end we integrated the analyses of several magnetic resonance imaging (MRI) and spectroscopy (MRS) metrics within the anterior cingulate cortex (ACC). Considering the ACCs role in neurodevelopmental disorders, we also investigated the association between neuropsychiatric symptoms and the various metrics. T1 and diffusion-weighted MRI and 1H-MRS (ACC voxel) data along with phenotypic information were acquired from children (8-12 years) with various neurodevelopmental disorders (n=95) and healthy controls (n=50). From within the MRS voxel mean diffusivity (MD) of the grey matter fraction, intrinsic curvature (IC) of the surface and concentrations of creatine, choline, glutamate, N-acetylaspartate and myo-inositol were extracted. Linear models were used to investigate if the neurochemicals predicted MD and IC or if MD predicted IC. Finally, measures of various symptom severities were included to determine the influence of symptoms of neurodevelopmental disorders. All five neurochemicals inversely predicted MD (all puncorrected<0.04, ß=0.23-0.36). There was no association between IC and MD or IC and the neurochemicals (all p>0.05). Severity of autism symptoms related positively to MD (puncorrected=0.002, ß=0.39). Our findings support the notion that the neurochemicals relate to cytoarchitecture within the cortex. Additionally, we showed that autism symptoms across participants relate to the ACC cytoarchitecture.

Effect of tobacco smoking on frontal cortical thickness development: A longitudinal study in a mixed cohort of ADHD-affected and -unaffected youth.

Smoking rates are particularly high during adolescence and young adulthood, when the brain is still undergoing significant developmental changes. Cross-sectional studies have revealed altered brain structure in smokers, such as thinner frontal cortical areas. Attention-deficit/hyperactivity disorder (ADHD) increases the risk of becoming nicotine-dependent, and has also been associated with abnormalities in frontal gray matter structure. The present study examines the relationships between smoking, cortical thickness and ADHD symptoms in a longitudinal design that compares adolescent and young adult smokers (n=44; 35 ADHD-affected) and non-smokers (n=45; 32 ADHD-affected) on frontal cortical thickness. Average frontal cortical thickness was estimated through structural magnetic resonance imaging (MRI) at two time points (mean ages 17.7 and 21.1 years), on average 3.4 years apart. Smokers had a 2.6% thinner frontal cortex than non-smokers and this difference was not explained by ADHD or other confounding factors. The rate of cortical thinning across the 3.4-year MRI measurement interval was similar in the total group of smokers compared to non-smokers. However, speeded thinning did occur in smokers who had started regular smoking more recently, in between the two measurements. These novel regular smokers did not differ significantly from the non-smokers at baseline. This suggests that the thinner frontal cortex was not a predisposing factor but rather a consequence of smoking. Although smokers had more ADHD symptoms overall, smoking did not influence the developmental course of ADHD symptoms.

Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies. METHOD: We used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12 years of age (TD n = 15, ADHD n = 39, TD + ADHD n = 29, and healthy controls n = 53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3 Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations. RESULTS: We did not find any group differences in glutamate concentrations in either the ACC (F(3132) = 0.97, p = 0.41) or striatum (F(3121) = 0.59, p = 0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive-compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho = 0.35, puncorrected  = 0.02). CONCLUSION: We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

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.

Dorsomedial Prefrontal Cortex Mediates the Impact of Serotonin Transporter Linked Polymorphic Region Genotype on Anticipatory Threat Reactions.

BACKGROUND: Excessive anticipatory reactions to potential future adversity are observed across a range of anxiety disorders, but the neurogenetic mechanisms driving interindividual differences are largely unknown. We aimed to discover and validate a gene-brain-behavior pathway by linking presumed genetic risk for anxiety-related psychopathology, key neural activity involved in anxious anticipation, and resulting aversive emotional states. METHODS: The functional neuroanatomy of aversive anticipation was probed through functional magnetic resonance imaging in two independent samples of healthy subjects (n = 99 and n = 69), and we studied the influence of genetic variance in the serotonin transporter linked polymorphic region (5-HTTLPR). Skin conductance and startle data served as objective psychophysiological indices of the intensity of individuals' anticipatory responses to potential threat. RESULTS: Threat cues signaling risk of future electrical shock activated the dorsomedial prefrontal cortex (dmPFC), anterior insula, bed nucleus of the stria terminalis, thalamus, and midbrain consistently across both samples. Threat-related dmPFC activation was enhanced in 5-HTTLPR short allele carriers in sample 1 and this effect was validated in sample 2. Critically, we show that this region mediates the increase in anticipatory psychophysiological reactions in short allele carriers indexed by skin conductance (experiment 1) and startle reactions (experiment 2). CONCLUSIONS: The converging results from these experiments demonstrate that innate 5-HTTLPR linked variation in dmPFC activity predicts psychophysiological responsivity to pending threats. Our results reveal a neurogenetic pathway mediating interindividual variability in anticipatory responses to threat and yield a novel mechanistic account for previously reported associations between genetic variability in serotonin transporter function and stress-related psychopathology.