A Network Approach to Understanding the Role of Executive Functioning and Alpha Oscillations in Inattention and Hyperactivity-Impulsivity Symptoms of ADHD.

OBJECTIVE: ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of inattention and hyperactivity-impulsivity. Impairments in executive functioning (EF) are central to models of ADHD, while alpha-band spectral power event-related decreases (ERD) have emerged as a putative electroencephalography (EEG) biomarker of EF in ADHD. Little is known about the roles of EF and alpha ERD and their interactions with symptoms of ADHD. METHOD: We estimated network models of ADHD symptoms and integrated alpha ERD measures into the symptom network. RESULTS: EF emerges as a bridge network node connecting alpha ERD and the hyperactivity/impulsivity and inattention symptoms. We found that EF most closely relates to a subset of symptoms, namely the motoric symptoms, "seat" (difficulty staying seated), and "runs" (running or climbing excessively). CONCLUSIONS: EF functions as a bridge node connecting alpha ERD and the ADHD symptom network. Motoric-type symptoms and EF deficits may constitute important nodes in the interplay between behavior/symptoms, cognition, and neurophysiological markers of ADHD.

Alpha event-related decreases during encoding in adults with ADHD - An investigation of sustained attention and working memory processes.

BACKGROUND: Executive functioning deficits are central to established neuropsychological models of ADHD. Oscillatory activity, particularly the alpha rhythm (8-12 Hz) has been associated with cognitive impairments in ADHD. However, most studies to date examined such neural mechanisms underlying executive dysfunction in children and adolescents with ADHD, raising the question of whether and to what extent those ADHD-related working memory impairments are still present in adults. To this end, the current study aimed to investigate the role of alpha event-related decreases (ERD) during working memory processes in adults with and without ADHD. METHODS: We collected electroencephalographic (EEG) data from 85 adults with a lifetime diagnosis of ADHD and 105 controls (aged 32-64), while they performed a continuous performance (CPT) and a spatial delayed response working memory task (SDRT). Time-frequency and independent component analysis (ICA) was used to identify alpha (8-12 Hz) clusters to examine group and condition effects during the temporal profile of sustained attention and working memory processes (encoding, maintenance, retrieval), loads (low and high) and trial type (go and nogo). RESULTS: Individuals with ADHD exhibited higher reaction time-variability in SDRT, and slower response times in SDRT and CPT, despite no differences in task accuracy. Although working memory load was associated with stronger alpha ERD in both tasks and both groups (ADHD, controls), we found no consistent evidence for attenuated alpha ERD in adults with ADHD, failing to replicate effects reported in children. In contrast, when looking at the whole sample, the correlations of alpha power during encoding with inattention and hyperactivity-impulsivity symptoms were significant, replicating prior findings in children with ADHD, but suggesting an alternate source for these effects in adults. CONCLUSIONS: Our results corroborate the robustness of alpha as a marker of visual attention and suggest that occipital alpha ERD normalizes in adulthood, but with unique contributions of centro-occipital alpha ERD, suggesting a secondary source. This implies that deviations in processes other than previously reported visuospatial cortex engagement may account for the persistent symptoms and cognitive deficits in adults with a history of ADHD.

From Consensus Statement to Pills to Pixels: New Innovations in Attention-Deficit/Hyperactivity Disorder Care.

Objectives: This review aims to present recent innovations and advancements in attention-deficit/hyperactivity disorder (ADHD) care, encompassing international consensus statement, new medication formulations, digital therapeutics, and neurostimulation devices. Methods: A comprehensive literature search of relevant articles published in the past five years was conducted, emphasizing the evidence base, efficacy, safety, and practical implications of these advancements. Results: The World Federation of ADHD Consensus Statement offers an updated diagnostic and treatment framework rooted in global scientific evidence. There are several newer ADHD medication formulations, including a nonstimulant (Viloxazine extended release) and the first transdermal amphetamine patch approved to treat ADHD. These options offer some unique benefits to personalize treatment based on symptom profile, lifestyle, preferences, and response. Digital tools offer additional means to restructure environments for individuals with ADHD, reducing impairment and reliance on others. In addition, digital therapeutics enhance access, affordability, personalization, and feasibility of ADHD care, complementing or augmenting existing interventions. Trigeminal nerve stimulation emerges as a well-tolerated nonpharmacological, device-based treatment for pediatric ADHD, with initial trials indicating effect sizes comparable to nonstimulant medications. Conclusions: These innovations in ADHD care represent clinically significant new treatment options and opportunities for personalized care. Health care professionals should integrate these developments into clinical practice, mindful of individual patient and family needs and preferences. Future research should assess long-term outcomes, cost-effectiveness, and acceptability of these innovations.

Additive and Interactive Effects of Attention-Deficit/Hyperactivity Disorder and Tic Disorder on Brain Connectivity.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and persistent tic disorder (PTD) are two neurodevelopmental disorders that frequently co-occur. Contributions of each disorder to cognitive and behavioral deficits have been reported. In this paper, we tested 3 models of pathophysiology for the two disorders (additive, interactive, and phenotypic) using resting-state connectivity associated with each disorder separately and together. METHODS: Participants were 148 children (55 with ADHD only, 33 with ADHD and PTD, 27 with PTD only, and 33 healthy control subjects) at ages 8 to 12 years. Following diagnostic interviews and behavioral assessment, participants underwent a 128-channel electroencephalography recording. Resting-state, cortical source-level effective connectivity was analyzed across the 4 groups using a 2 × 2 factorial design with factors of ADHD (with/without) and PTD (with/without). RESULTS: ADHD diagnosis was the primary driver of cognitive and behavioral deficits, while deficits associated with PTD were primarily with thought problems and internalizing problems when compared with controls. Subadditive effects were observed in co-occurring ADHD+PTD for parent-rated behavioral problems and cognitive functions. Aberrant effective connectivity was primarily associated with ADHD, more specifically with lower posterior and occipital-frontal connectivity, while children with PTD exhibited greater left postcentral to precuneus connectivity. Weaker ADHD-related connectivity was associated with more severe behavioral problems, including internalizing behaviors, thought problems, and working memory deficits. CONCLUSIONS: Similar to general behavioral deficits, aberrant resting-state neural connectivity in pediatric ADHD and PTD combines additively in co-occurring cases. The findings of this study support ADHD as a focus of treatment in comorbid cases, given the driving role of ADHD in both behavioral and neurophysiological deficits.

Brainmarker-I Differentially Predicts Remission to Various Attention-Deficit/Hyperactivity Disorder Treatments: A Discovery, Transfer, and Blinded Validation Study.

BACKGROUND: Attention-deficit/hyperactivity disorder is characterized by neurobiological heterogeneity, possibly explaining why not all patients benefit from a given treatment. As a means to select the right treatment (stratification), biomarkers may aid in personalizing treatment prescription, thereby increasing remission rates. METHODS: The biomarker in this study was developed in a heterogeneous clinical sample (N = 4249) and first applied to two large transfer datasets, a priori stratifying young males (<18 years) with a higher individual alpha peak frequency (iAPF) to methylphenidate (N = 336) and those with a lower iAPF to multimodal neurofeedback complemented with sleep coaching (N = 136). Blinded, out-of-sample validations were conducted in two independent samples. In addition, the association between iAPF and response to guanfacine and atomoxetine was explored. RESULTS: Retrospective stratification in the transfer datasets resulted in a predicted gain in normalized remission of 17% to 30%. Blinded out-of-sample validations for methylphenidate (n = 41) and multimodal neurofeedback (n = 71) corroborated these findings, yielding a predicted gain in stratified normalized remission of 36% and 29%, respectively. CONCLUSIONS: This study introduces a clinically interpretable and actionable biomarker based on the iAPF assessed during resting-state electroencephalography. Our findings suggest that acknowledging neurobiological heterogeneity can inform stratification of patients to their individual best treatment and enhance remission rates.

Methylphenidate, Guanfacine, and Combined Treatment Effects on Electroencephalography Correlates of Spatial Working Memory in Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The combination of d-methylphenidate and guanfacine (an α-2A adrenergic agonist) may be an effective alternative to either agent as monotherapy in children with attention-deficit/hyperactivity disorder (ADHD). This study investigated the neural mechanisms underlying medication effects using cortical source analysis of electroencephalography (EEG) data. METHOD: A total of 172 children with ADHD (aged 7-14; 118 boys) completed an 8-week randomized, double-blind, comparative study with 3 treatment arms: d-methylphenidate, guanfacine, or their combination. EEG modulations of brain oscillations at baseline and end point were measured during a spatial working memory task from cortical sources localized within the anterior cingulate (midfrontal) and primary visual cortex (midoccipital), based on previously reported ADHD and control differences. Linear mixed models examined treatment effects on EEG and performance measures. RESULTS: Combined treatment decreased midoccipital EEG power across most frequency bands and task phases. Several midoccipital EEG measures also showed significantly greater changes with combined treatment than with monotherapies. D-methylphenidate significantly increased midoccipital theta during retrieval, while guanfacine produced only trend-level reductions in midoccipital alpha during maintenance and retrieval. Task accuracy improved with combined treatment, was unchanged with d-methylphenidate, and worsened with guanfacine. Treatment-related changes in midoccipital power correlated with improvement in ADHD severity. CONCLUSION: These findings show that combined treatment ameliorates midoccipital neural activity associated with treatment-related behavioral improvements and previously implicated in visuo-attentional deficits in ADHD. Both monotherapies had limited effects on EEG measures, with guanfacine further showing detrimental effects on performance. The identified midoccipital EEG profile may aid future treatment monitoring for children with ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder (Project1); https://clinicaltrials.gov/; NCT00429273. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. We actively worked to promote sex and gender balance in our author group.

Electrophysiological and Clinical Predictors of Methylphenidate, Guanfacine, and Combined Treatment Outcomes in Children With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The combination of d-methylphenidate and guanfacine (an α-2A agonist) has emerged as a potential alternative to either monotherapy in children with attention-deficit/hyperactivity disorder (ADHD), but it is unclear what predicts response to these treatments. This study is the first to investigate pretreatment clinical and electroencephalography (EEG) profiles as predictors of treatment outcome in children randomized to these different medications. METHOD: A total of 181 children with ADHD (aged 7-14 years; 123 boys) completed an 8-week randomized, double-blind, comparative study with d-methylphenidate, guanfacine, or combined treatments. Pretreatment assessments included ratings on ADHD, anxiety, and oppositional behavior. EEG activity from cortical sources localized within midfrontal and midoccipital regions was measured during a spatial working memory task with encoding, maintenance, and retrieval phases. Analyses tested whether pretreatment clinical and EEG measures predicted treatment-related change in ADHD severity. RESULTS: Higher pretreatment hyperactivity-impulsivity and oppositional symptoms and lower anxiety predicted greater ADHD improvements across all medication groups. Pretreatment event-related midfrontal beta power predicted treatment outcome with combined and monotherapy treatments, albeit in different directions. Weaker beta modulations predicted improvements with combined treatment, whereas stronger modulation during encoding and retrieval predicted improvements with d-methylphenidate and guanfacine, respectively. A multivariate model including EEG and clinical measures explained twice as much variance in ADHD improvement with guanfacine and combined treatment (R2= 0.34-0.41) as clinical measures alone (R2 = 0.14-.21). CONCLUSION: We identified treatment-specific and shared predictors of response to different pharmacotherapies in children with ADHD. If replicated, these findings would suggest that aggregating information from clinical and brain measures may aid personalized treatment decisions in ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; https://clinicaltrials.gov; NCT00429273.

Preliminary evidence for a lower brain age in children with attention-deficit/hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a debilitating disorder with apparent roots in abnormal brain development. Here, we quantified the level of individual brain maturation in children with ADHD using structural neuroimaging and a recently developed machine learning algorithm. More specifically, we compared the BrainAGE index between three groups matched for chronological age (mean ± SD: 11.86 ± 3.25 years): 89 children diagnosed with ADHD, 34 asymptomatic siblings of those children with ADHD, and 21 unrelated healthy control children. Brains of children with ADHD were estimated significantly younger (-0.85 years) than brains of healthy controls (Cohen's d = -0.33; p = 0.028, one-tailed), while there were no significant differences between unaffected siblings and healthy controls. In addition, more severe ADHD symptoms were significantly associated with younger appearing brains. Altogether, these results are in line with the proposed delay of individual brain maturation in children with ADHD. However, given the relatively small sample size (N = 144), the findings should be considered preliminary and need to be confirmed in future studies.

Treatment biomarkers for ADHD: Taking stock and moving forward.

The development of treatment biomarkers for psychiatric disorders has been challenging, particularly for heterogeneous neurodevelopmental conditions such as attention-deficit/hyperactivity disorder (ADHD). Promising findings are also rarely translated into clinical practice, especially with regard to treatment decisions and development of novel treatments. Despite this slow progress, the available neuroimaging, electrophysiological (EEG) and genetic literature provides a solid foundation for biomarker discovery. This article gives an updated review of promising treatment biomarkers for ADHD which may enhance personalized medicine and novel treatment development. The available literature points to promising pre-treatment profiles predicting efficacy of various pharmacological and non-pharmacological treatments for ADHD. These candidate predictive biomarkers, particularly those based on low-cost and non-invasive EEG assessments, show promise for the future stratification of patients to specific treatments. Studies with repeated biomarker assessments further show that different treatments produce distinct changes in brain profiles, which track treatment-related clinical improvements. These candidate monitoring/response biomarkers may aid future monitoring of treatment effects and point to mechanistic targets for novel treatments, such as neurotherapies. Nevertheless, existing research does not support any immediate clinical applications of treatment biomarkers for ADHD. Key barriers are the paucity of replications and external validations, the use of small and homogeneous samples of predominantly White children, and practical limitations, including the cost and technical requirements of biomarker assessments and their unknown feasibility and acceptability for people with ADHD. We conclude with a discussion of future directions and methodological changes to promote clinical translation and enhance personalized treatment decisions for diverse groups of individuals with ADHD.

Cognitive control processes in behavior therapy for youth with Tourette's disorder.

BACKGROUND: Cognitive control processes are implicated in the behavioral treatment of Tourette's disorder (TD). However, the influence of these processes on treatment outcomes has received minimal attention. This study examined whether cognitive control processes and/or tic suppression predicted reductions in tic severity and treatment response to behavior therapy. METHOD: Fifty-three youth with TD or a pervasive tic disorder participated in a randomized wait list-controlled trial of behavior therapy. Following a baseline assessment to evaluate psychiatric diagnoses, tic severity, and cognitive control processes (e.g., response selection, inhibition, and suppression), youth were randomly assigned to receive eight sessions of behavior therapy (n = 23) or a wait list of equal duration (n = 28). Youth receiving immediate treatment completed a post-treatment assessment to determine improvement in tic severity. Meanwhile, youth in the wait list condition completed another assessment to re-evaluate tic severity and cognitive control processes, and subsequently received 8 sessions of behavior therapy followed by a post-treatment assessment to determine improvement. RESULTS: A multiple linear regression model found that pretreatment inhibition/switching on the Delis-Kaplan Executive Function System Color-Word Interference Test predicted reductions in tic severity after behavior therapy (ß = -.36, t = -2.35, p = .025, ƞ2 = .15). However, other cognitive control processes and tic suppression did not predict treatment response and/or reductions in tic severity. Small nonsignificant effects were observed in cognitive control processes after behavior therapy. CONCLUSION: Cognitive control processes may influence tic severity reductions in behavior therapy. Notably, even when other cognitive control processes are impaired and youth are initially unable to voluntarily suppress their tics, youth with TD can still benefit from behavior therapy. Findings offer implications for clinical practice and research for TD.

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.

Polygenic association between attention-deficit/hyperactivity disorder liability and cognitive impairments.

BACKGROUND: A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE). METHODS: The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8-40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses. RESULTS: When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, ß = 0.088, p = 0.02) but not for CE (R2 = 0.011, ß = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10). CONCLUSIONS: We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.

The ERN as a neural index of changes in performance monitoring following attention training in pediatric obsessive-compulsive disorder.

Evidence of associations between obsessive compulsive disorder (OCD) and alterations in neural indices of performance monitoring, i.e., elevated neural activity following errors, have accelerated interest in the error-related negativity (ERN) as a biomarker for pediatric OCD. The study investigates the degree to which attention bias training is linked to changes in neural measures of performance monitoring (ERN, correct response negativity or CRN) and whether pre-to-post training changes in these neural indices are associated with symptom changes in youth with OCD. The sample included 36 youth (8-17 years) diagnosed with OCD who completed a 12-session attention training program and pre- and post-training EEG assessment of performance monitoring using cognitive and emotional flanker tasks. The emotional flanker task was individualized to each participant's negative ratings of stimuli at pre-treatment to enhance salience of threat-related stimuli across youth. Results indicated that unlike participants who received attentional control protocol (CON), those who received attentional bias modification protocol (ABM) showed significant attenuations in neural activity following erroneous and correct responses in the emotional flanker task. The ERN amplitude during the cognitive flanker task was unchanged in both ABM and CON groups. Attenuations in the ERN were also linked to decreases in social anxiety and depressive symptoms. Findings highlight the relevance of including emotionally-salient tasks when investigating potential neural mechanisms of treatments and suggest that alterations in neural processes underlying performance monitoring can be targeted via attention training programs in pediatric OCD.

Emerging biomarkers for child & family intervention studies: A review of EEG studies of parenting.

Most interventions for childhood mental health problems require significant parental involvement, and treatment programs are increasingly incorporating components aimed at enhancing parents' own self-regulation in the context of potentially stressful parent-child interactions. This paper discusses the promise of EEG in examining the rapidly unfolding perceptual, cognitive, emotional, and regulatory processes that occur in parenting, in hopes of ultimately informing child and family interventions. First, we review two separate bodies of work that have used EEG with parents: one examining event-related potential (ERP) measures, and the other examining frontal alpha asymmetry (FAA). We discuss benefits of each within the study of parenting, and also suggest other EEG metrics (such as event-related time-frequency analyses) that can be leveraged to fill current gaps in our knowledge. Finally, we discuss the potential for these findings to inform clinical work with children and families, such as identifying biomarkers that could aid in assessment, treatment recommendations, and monitoring response to interventions.

Inhibitory control in youth with Tourette's Disorder, attention-deficit/hyperactivity disorder and their combination and predictors of objective tic suppressibility.

The present study investigated inhibitory control deficits in Tourette's Disorder (TD)-only, Attention Deficit/Hyperactivity Disorder (ADHD)-only, and TD+ADHD and explored the degree to which measures of inhibitory control, and tic and ADHD severity predicted objective tic suppressibility. Participants were youth ages 9 to 14 (M = 11.15) with TD-only (n = 24), TD+ADHD (n = 19), ADHD-only (n = 139), and typically-developing controls (n = 59) drawn from a larger study. Groups were compared on computer-based and paper and pencil neurocognitive inhibitory control tasks. Among youth with TD, neurocognitive measures of inhibitory control, subjective tic-suppressibility (Premonitory Urge for Tics Scale, item 10), and ADHD symptom severity were evaluated as predictors of objective tic suppressibility (i.e., laboratory-based tic suppression task), controlling for total tic severity. There were significant group differences on Color-Word inhibition/switching performance, though post-hoc comparisons yielded no significant pairwise group contrasts. Subjective tic suppressibility was the only significant predictor of objective tic suppressibility. The evident intact neurocognitive inhibitory control among youth with TD suggests that individuals with TD may use compensatory neural mechanisms to support typical speed and accuracy of response. The role of cognitive flexibility in mechanisms of tic suppression should also be further explored.

Neurocognitive subprocesses of working memory performance.

Working memory (WM) has been defined as the active maintenance and flexible updating of goal-relevant information in a form that has limited capacity and resists interference. Complex measures of WM recruit multiple subprocesses, making it difficult to isolate specific contributions of putatively independent subsystems. The present study was designed to determine whether neurophysiological indicators of proposed subprocesses of WM predict WM performance. We recruited 200 individuals defined by care-seeking status and measured neural responses using electroencephalography (EEG), while participants performed four WM tasks. We extracted spectral and time-domain EEG features from each task to quantify each of the hypothesized WM subprocesses: maintenance (storage of content), goal maintenance, and updating. We then used EEG measures of each subprocess as predictors of task performance to evaluate their contribution to WM. Significant predictors of WM capacity included contralateral delay activity and frontal theta, features typically associated with maintenance (storage of content) processes. In contrast, significant predictors of reaction time and its variability included contingent negative variation and the P3b, features typically associated with goal maintenance and updating. Broadly, these results suggest two principal dimensions that contribute to WM performance, tonic processes during maintenance contributing to capacity, and phasic processes during stimulus processing that contribute to response speed and variability. The analyses additionally highlight that reliability of features across tasks was greater (and comparable to that of WM performance) for features associated with stimulus processing (P3b and alpha), than with maintenance (gamma, theta and cross-frequency coupling).

Inhibitory control in children with tic disorder: aberrant fronto-parietal network activity and connectivity.

Chronic tic disorders, including Tourette syndrome, are typically thought to have deficits in cognitive inhibition and top down cognitive control due to the frequent and repetitive occurrence of tics, yet studies reporting task performance results have been equivocal. Despite similar behavioural performance, individuals with chronic tic disorder have exhibited aberrant patterns of neural activation in multiple frontal and parietal regions relative to healthy controls during inhibitory control paradigms. In addition to these top down attentional control regions, widespread alterations in brain activity across multiple neural networks have been reported. There is a dearth, however, of studies examining event-related connectivity during cognitive inhibitory paradigms among affected individuals. The goal of this study was to characterize neural oscillatory activity and effective connectivity, using a case-control design, among children with and without chronic tic disorder during performance of a cognitive inhibition task. Electroencephalogram data were recorded in a cohort of children aged 8-12 years old (60 with chronic tic disorder, 35 typically developing controls) while they performed a flanker task. While task accuracy did not differ by diagnosis, children with chronic tic disorder displayed significant cortical source-level, event-related spectral power differences during incongruent flanker trials, which required inhibitory control. Specifically, attenuated broad band oscillatory power modulation within the anterior cingulate cortex was observed relative to controls. Whole brain effective connectivity analyses indicated that children with chronic tic disorder exhibit greater information flow between the anterior cingulate and other fronto-parietal network hubs (midcingulate cortex and precuneus) relative to controls, who instead showed stronger connectivity between central and posterior nodes. Spectral power within the anterior cingulate was not significantly correlated with any connectivity edges, suggesting lower power and higher connectivity are independent (versus resultant) neural mechanisms. Significant correlations between clinical features, task performance and anterior cingulate spectral power and connectivity suggest this region is associated with tic impairment (r = -0.31, P = 0.03) and flanker task incongruent trial accuracy (r's = -0.27 to -0.42, P's = 0.0008-0.04). Attenuated activation of the anterior cingulate along with dysregulated information flow between and among nodes within the fronto-parietal attention network may be neural adaptations that result from frequent engagement of neural pathways needed for inhibitory control in chronic tic disorder.

Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.

Shared and unique neural mechanisms underlying pediatric trichotillomania and obsessive compulsive disorder.

BACKGROUND: Little is known about the neural underpinnings of pediatric trichotillomania (TTM). We examined error-related negativity (ERN)-amplitude and theta-EEG power differences among youth with TTM, OCD, and healthy controls (HC). METHODS: Forty channel EEG was recorded from 63 pediatric participants (22 with TTM, 22 with OCD, and 19 HC) during the Eriksen Flanker Task. EEG data from inhibitory control were used to derive estimates of ERN amplitude and event-related spectral power associated with motor inhibition. RESULTS: TTM and HC were similar in brain activity patterns in frontal and central regions and TTM and OCD were similar in the parietal region. Frontal ERN-amplitude was significantly larger in OCD relative to TTM and HC, who did not differ from each other. The TTM group had higher theta power compared to OCD in frontal and central regions, and higher theta than both comparison groups in right motor cortex and superior parietal regions. Within TTM, flanker task performance was correlated with EEG activity in frontal, central, and motor cortices whereas global functioning and impairment were associated with EEG power in bilateral motor and parietal cortices. CONCLUSIONS: Findings are discussed in terms of shared and unique neural mechanisms in TTM and OCD and treatment implications.

Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response.

OBJECTIVE: The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial. METHOD: Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of ≥25%, whereas nonresponders (NR) had <25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures. RESULTS: The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values <.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (ß = 0.65, p < .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p = .003), indicating moderate prediction of treatment response. CONCLUSION: Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction. CLINICAL TRIAL REGISTRATION INFORMATION: Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.