The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS).

BACKGROUND: Attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action. METHODS: A confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment. DISCUSSION: This multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD. TRIAL REGISTRATION: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .

Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review.

Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.

Profiles of autism characteristics in thirteen genetic syndromes: a machine learning approach.

BACKGROUND: Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. METHODS: Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader-Willi n = 278, Lowe n = 89, Smith-Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein-Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan-McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor. RESULTS: Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader-Willi, Rubinstein-Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith-Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. LIMITATIONS: The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. CONCLUSIONS: These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.

Event-related brain dynamics during mind wandering in attention-deficit/hyperactivity disorder: An experience-sampling approach.

Adults with attention-deficit/hyperactivity disorder (ADHD) report increased spontaneous mind wandering (MW) compared to control adults. Since MW is associated with ADHD severity and functional impairment, elucidating the brain mechanisms underlying MW may inform new interventions targeting MW and point to neural markers to monitor their efficacy. Population-based electroencephalographic (EEG) studies suggest that weaker event-related decreases in occipital alpha power characterise periods of MW, but no study has examined event-related brain oscillations during MW in individuals with ADHD. Using an experience-sampling method, we compared adults with ADHD (N = 23) and controls (N = 25) on event-related EEG measures of power modulations and phase consistency during two tasks with high and low demands on working memory and sustained attention, and during periods of MW and task focus. Compared to controls, individuals with ADHD showed weaker alpha power decreases during high working memory demands and across sustained attention demands, weaker theta power increases and phase consistency across working memory demands and during low sustained attention demands, and weaker beta power decreases during low working memory demands. These EEG patterns suggest broadly deficient attentional and motor response processes in ADHD. During MW episodes, adults with ADHD showed weaker alpha power decreases in the sustained attention task and lower theta phase consistency in the working memory task compared to controls. These findings suggest that atypical EEG patterns thought to reflect reduced inhibition of task-irrelevant processes and inconsistent stimulus processing underlie increased MW in adults with ADHD and may be useful for future real-time monitoring of treatment effects.

The effect of transcranial direct current stimulation (tDCS) combined with cognitive training on EEG spectral power in adolescent boys with ADHD: A double-blind, randomized, sham-controlled trial.

Transcranial direct current stimulation (tDCS) is a possible alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD), but its mechanisms of action in children and adolescents with ADHD are poorly understood. We conducted the first 15-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC) combined with cognitive training (CT) in 50 children/adolescents with ADHD. We investigated the mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD (n, sham = 10; anodal tDCS = 13). We failed to find a significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, a correlation between QEEG and Go/No-Go Task performance, and changes in clinical and cognitive measures. These findings extend the non-significant clinical and cognitive effects in our sample of 50 children/adolescents with ADHD. Given that the subgroup of 23 participants would have been underpowered, the interpretation of our findings is limited and should be used as a foundation for future investigations. Larger, adequately powered randomized controlled trials should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD.

Using e-diaries to investigate ADHD - State-of-the-art and the promising feature of just-in-time-adaptive interventions.

Attention-deficit/hyperactive disorder (ADHD) is characterized by symptoms which are dynamic in nature: states of hyperactivity, inattention and impulsivity as core symptoms, and emotion dysregulation as associated feature. Although tremendous work has been done to investigate between-subject differences (how patients with ADHD differ from healthy controls or patients with other disorders), little is known about the relationship between symptoms with triggers and contexts, that may allow us to better understand their causes and consequences. Understanding the temporal associations between symptoms and environmental triggers in an ecologically valid manner may be the basis to developing just-in-time adaptive interventions. Fortunately, recent years have seen advances in methodology, hardware and innovative statistical approaches to study dynamic processes in daily life. In this narrative review, we provide a description of the methodology (ambulatory assessment), summarize the existing literature in ADHD, and discuss future prospects for these methods, namely mobile sensing to assess contextual information, real-time analyses and just-in-time adaptive interventions.

Electrophysiological modulation of sensory and attentional processes during mind wandering in attention-deficit/hyperactivity disorder.

We recently reported increased mind wandering (MW) frequency in adults with attention-deficit/hyperactivity disorder (ADHD) relative to controls during high demands on sustained attention, reflecting deficient context regulation of MW. Studies on community samples previously linked context regulation of MW with attenuation in brain sensory processes, reflecting perceptual decoupling, and attentional processes during MW compared to task focus. However, the association between deficient context regulation of MW and these neural processes has not been studied in ADHD. We addressed this question by comparing adults with ADHD (N = 23) and controls (N = 25) on event-related potentials of early sensory processes (P1) and attention allocation (P3) during tasks manipulating cognitive demands (high vs low) on working memory and sustained attention, and during periods of MW and task focus measured through experience-sampling. Compared to controls, adults with ADHD showed reduced P1 during high sustained attention demands, as well as reduced P3 during high working memory demands. These group differences were no longer significant after adding MW frequency as a covariate. Across tasks, adults with ADHD showed no differences from controls on the P1 during MW episodes, but attenuated P1 during task focus. P3 was reduced in adults with ADHD compared to controls during MW, but not during task focus during the sustained attention task. These findings converge to indicate that impairments in early sensory processing in individuals with ADHD seem parallel to increased MW frequency and might reflect inefficient adjustments from periods of MW to task focus.

Context Regulation of Mind Wandering in ADHD.

OBJECTIVE: We aimed to understand the association between MW frequency and clinical measures, context regulation of MW and group differences in task performance. METHOD: 27 adults with ADHD and 29 controls performed tasks manipulating demand on working memory and sustained attention, and recorded their MW frequency using probes. RESULTS: A significant association between MW frequency and the clinical measures was demonstrated. Along with increased MW frequency, individuals with ADHD reported decreasing MW frequency during increasing demands on working memory (context regulation), but not on sustained attention (deficient context regulation). Controls, however, maintained continuous task focus across all conditions. Group differences in task performance were no longer significant after adding MW frequency as a covariate. CONCLUSION: Deficient context regulation during increasing demands on sustained attention suggests that sustained attention deficits may play a more important role in regulation of MW in ADHD. MW frequency might also underpin performance deficits in ADHD.

Wandering minds in attention-deficit/hyperactivity disorder and borderline personality disorder.

Attention-deficit/hyperactivity Disorder (ADHD) and borderline personality disorder (BPD) have overlapping symptoms. We proposed that excessive spontaneous mind wandering (MW-S) might reflect a component of psychopathology that distinguishes ADHD from BPD. Using a questionnaire measure of MW-S and an experience sampling method, we investigated MW-S in daily life, in 28 ADHD, 19 BPD, 22 comorbid ADHD+BPD, and 29 control females. The clinical groups reported heightened frequency and intensity of MW-S compared to controls, but no differences from each other. When controlling for depression and anxiety, significant differences only persisted between controls and ADHD, who also showed elevated intensity of MW-S compared to BPD and comorbid ADHD+BPD. We found no MW-S instability differences amongst clinical cases as well as cases versus controls. Negative content of MW-S was higher in BPD and comorbid ADHD+BPD compared to controls, with no differences between ADHD and controls. When controlling for depression/anxiety, the differences between BPD and comorbid ADHD+BPD and controls dissipated. MW-S is a trans-diagnostic process present in both ADHD and BPD. Yet, the underlying mechanisms of this experience may be driven by anxiety/depression in BPD but reflect a core process in ADHD.

Electrophysiological correlates of spontaneous mind wandering in attention-deficit/hyperactivity disorder.

We recently hypothesised that increased spontaneous mind wandering (MW-S) reflects a core process underlying attention-deficit/hyperactivity disorder (ADHD). Previous studies show that individuals with ADHD and neurotypical individuals with increased MW-S display similar cognitive-performance and electrophysiological (EEG) impairments in attentional processes. However, the cognitive-EEG markers associated with increased MW-S in ADHD remain poorly understood. We therefore investigated such markers in a sample of 69 sex- and age-matched adults with ADHD and 29 controls during the Sustained Attention to Response Task. We compared task performance and EEG measures (P3, time-frequency brain-oscillations) of attentional processes between groups, and examined their association with a validated self-report questionnaire of MW-S. Finally, we tested the hypothesis that MW-S and ADHD diagnosis relate to the same cognitive-EEG impairments using a hierarchical regression model. Compared to controls, adults with ADHD showed attenuations in P3, event-related alpha and beta suppression during response inhibition (No-Go trials), and theta power activations during response execution (Go trials), as well as increased reaction time variability and more commission/omission errors. MW-S was also continuously associated with most cognitive-EEG measures related to ADHD. The hierarchical regressions on measures associated with both ADHD diagnosis and MW-S showed that MW-S did not explain additional variance in the cognitive-EEG markers (except for beta suppression) beyond ADHD diagnosis, and vice versa. These findings are consistent with our hypothesis that ADHD diagnosis and MW-S share common neural deficits, and that MW-S may reflect a core symptom of the disorder.

The key role of daytime sleepiness in cognitive functioning of adults with attention deficit hyperactivity disorder.

BACKGROUND: Adults with attention deficit hyperactivity disorder (ADHD) frequently suffer from sleep problems and report high levels of daytime sleepiness compared to neurotypical controls, which has detrimental effect on quality of life. METHODS: We evaluated daytime sleepiness in adults with ADHD compared to neurotypical controls using an observer-rated sleepiness protocol during the Sustained Attention Response Task as well as electroencephalogram (EEG) slowing, a quantitative electroencephalographic measure collected during a short period of wakeful rest. RESULTS: We found that adults with ADHD were significantly sleepier than neurotypical controls during the cognitive task and that this on-task sleepiness contributed to cognitive performance deficits usually attributed to symptoms of ADHD. EEG slowing predicted severity of ADHD symptoms and diagnostic status, and was also related to daytime sleepiness. Frontal EEG slowing as well as increased frontal delta were especially prominent in adults with ADHD. We have validated and adapted an objective observer-rated measure for assessing on-task sleepiness that will contribute to future sleep research in psychology and psychiatry. CONCLUSIONS: These findings indicate that the cognitive performance deficits routinely attributed to ADHD and often conceptualized as cognitive endophenotypes of ADHD are largely due to on-task sleepiness and not exclusively due to ADHD symptom severity. Daytime sleepiness plays a major role in cognitive functioning of adults with ADHD.

The devil is in the detail: exploring the intrinsic neural mechanisms that link attention-deficit/hyperactivity disorder symptomatology to ongoing cognition.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental condition that profoundly affects quality of life. Although mounting evidence now suggests uncontrolled mind-wandering as a core aspect of the attentional problems associated with ADHD, the neural mechanisms underpinning this deficit remains unclear. To that extent, competing views argue for (i) excessive generation of task-unrelated mental content, or (ii) deficiency in the control of task-relevant cognition. METHODS: In a cross-sectional investigation of a large neurotypical cohort (n = 184), we examined alterations in the intrinsic brain functional connectivity architecture of the default mode (DMN) and frontoparietal (FPN) networks during resting state functional magnetic resonance imaging in relation to ADHD symptomatology, which could potentially underlie changes in ongoing thought within variable environmental contexts. RESULTS: The results illustrated that ADHD symptoms were linked to lower levels of detail in ongoing thought while the participants made more difficult, memory based decisions. Moreover, greater ADHD scores were associated with lower levels of connectivity between the DMN and right sensorimotor cortex, and between the FPN and right ventral visual cortex. Finally, a combination of high levels of ADHD symptomology with reduced FPN connectivity to the visual cortex was associated with reduced levels of detail in thought. CONCLUSIONS: The results of our study suggest that the frequent mind-wandering observed in ADHD may be an indirect consequence of the deficient control of ongoing cognition in response to increasing environmental demands, and that this may partly arise from dysfunctions in the intrinsic organisation of the FPN at rest.

The effects of emotional lability, mind wandering and sleep quality on ADHD symptom severity in adults with ADHD.

Mind wandering, emotional lability and sleep quality are currently mostly independently investigated but are all interlinked and play a major role is adult attention-deficit/ hyperactivity disorder (ADHD). Emotional lability is a core feature of the disorder, excessive mind wandering has recently been linked to symptoms and impairments of ADHD and poor sleep quality is experienced by a clear majority of adults with ADHD. All three phenomena lead to functional impairment in ADHD, however their relationship to each other and to ADHD symptom severity is not well understood. Here we used serial multiple mediation models to examine the influence of mind wandering, sleep quality and emotional lability on ADHD symptom severity. 81 adults diagnosed with ADHD participated in this study. We found that mind wandering and emotional lability predicted ADHD symptom severity and that mind wandering, emotional lability and sleep quality were all linked and significantly contributed to the symptomatology of adult ADHD. Mind wandering was found to lead to emotional lability which in turn lead to ADHD symptom severity; and poor sleep quality was found to exacerbate mind wandering leading to ADHD symptoms. Future research should employ objective on-task measures of mind wandering, sleepiness and emotional lability to investigate the neural basis of these impairing deficits in ADHD.

Mind wandering perspective on attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder associated with a range of mental health, neurocognitive and functional problems. Although the diagnosis is based on descriptions of behaviour, individuals with ADHD characteristically describe excessive spontaneous mind wandering (MW). MW in individuals with ADHD reflects constant mental activity which lacks topic stability and content consistency. Based on this review of the neural correlates of ADHD and MW, we outline a new perspective on ADHD: the MW hypothesis. We propose that altered deactivation of the default mode network, and dysfunctional interaction with the executive control network, leads to excessive and spontaneous MW, which underpins symptoms and impairments of ADHD. We highlight that processes linked to the normal neural regulation of MW (context regulation, sensory decoupling, salience thresholds) are deficient in ADHD. MW-related measures could serve as markers of the disease process, as MW can be experimentally manipulated, as well as measured using rating scales, and experience sampling during both cognitive tasks and daily life. MW may therefore be a potential endophenotype.

A Randomised Controlled Trial of Neuronavigated Repetitive Transcranial Magnetic Stimulation (rTMS) in Anorexia Nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with morbid fear of fatness, extreme food restriction and altered self-regulation. Neuroimaging data implicate fronto-striatal circuitry, including the dorsolateral prefrontal cortex (DLPFC). METHODS: In this double-blind parallel group study, we investigated the effects of one session of sham-controlled high-frequency repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC (l-DLPFC) in 60 individuals with AN. A food exposure task was administered before and after the procedure to elicit AN-related symptoms. OUTCOMES: The primary outcome measure was 'core AN symptoms', a variable which combined several subjective AN-related experiences. The effects of rTMS on other measures of psychopathology (e.g. mood), temporal discounting (TD; intertemporal choice behaviour) and on salivary cortisol concentrations were also investigated. Safety, tolerability and acceptability were assessed. RESULTS: Fourty-nine participants completed the study. Whilst there were no interaction effects of rTMS on core AN symptoms, there was a trend for group differences (p = 0.056): after controlling for pre-rTMS scores, individuals who received real rTMS had reduced symptoms post-rTMS and at 24-hour follow-up, relative to those who received sham stimulation. Other psychopathology was not altered differentially following real/sham rTMS. In relation to TD, there was an interaction trend (p = 0.060): real versus sham rTMS resulted in reduced rates of TD (more reflective choice behaviour). Salivary cortisol concentrations were unchanged by stimulation. rTMS was safe, well-tolerated and was considered an acceptable intervention. CONCLUSIONS: This study provides modest evidence that rTMS to the l-DLPFC transiently reduces core symptoms of AN and encourages prudent decision making. Importantly, individuals with AN considered rTMS to be a viable treatment option. These findings require replication in multiple-session studies to evaluate therapeutic efficacy. TRIAL REGISTRATION: www.Controlled-Trials.com ISRCTN22851337.

A systematic review of the effects of neuromodulation on eating and body weight: evidence from human and animal studies.

BACKGROUND: Eating disorders (ED) are chronic and sometimes deadly illnesses. Existing treatments have limited proven efficacy, especially in the case of adults with anorexia nervosa (AN). Emerging neural models of ED provide a rationale for more targeted, brain-directed interventions. AIMS: This systematic review has examined the effects of neuromodulation techniques on eating behaviours and body weight and assessed their potential for therapeutic use in ED. METHOD: All articles in PubMed, PsychInfo and Web of Knowledge were considered and screened against a priori inclusion/exclusion criteria. The effects of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, vagus nerve stimulation (VNS) and deep brain stimulation (DBS) were examined across studies in ED samples, other psychiatric and neurological disorders, and animal models. RESULTS: Sixty studies were identified. There is evidence for ED symptom reduction following rTMS and DBS in both AN and bulimia nervosa. Findings from studies of other psychiatric and neurological disorders and from animal studies demonstrate that increases in food intake and body weight can be achieved following DBS and that VNS has potential value as a means of controlling eating and inducing weight loss. CONCLUSIONS: Neuromodulation tools have potential for reducing ED symptomatology and related behaviours, and for altering food intake and body weight. In response to such findings, and emerging neural models of ED, treatment approaches are highly unlikely to remain 'brainless'. More research is required to evaluate the potential of neuromodulation procedures for improving long-term outcomes in ED.

Improvements in symptoms following neuronavigated repetitive transcranial magnetic stimulation (rTMS) in severe and enduring anorexia nervosa: findings from two case studies.

BACKGROUND: Advances in the treatment of anorexia nervosa (AN) are most likely to arise from targeted, brain-directed treatments, such as repetitive transcranial magnetic stimulation (rTMS). We describe findings from two individuals with treatment-resistant AN who received 19-20 sessions of neuronavigated, high frequency rTMS, applied to the left dorsolateral prefrontal cortex. METHOD: Within-session measures assessed changes pre-rTMS, post-rTMS in subjective eating disorder (ED) experiences. Weight, ED symptoms and mood were assessed pre-treatment, post-treatment and at 1 month follow-up. RESULTS: In both cases, there was improvement in ED symptomatology and mood after 19-20 sessions of neuronavigated rTMS, and these changes persisted or continued to improve at follow-up. Within sessions, Patient A demonstrated a consistent reduction in subjective ED experiences, and Patient B a reduction in some ED related experiences. CONCLUSIONS: These findings suggest that rTMS has potential as an adjunct to the treatment of AN and deserves further study.