Activation In Attention Deficit Hyperactivity Disorder Research Articles

Sleep Spindle-Related EEG Connectivity in Children with Attention-Deficit/Hyperactivity Disorder: An Exploratory Study.

Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder with known brain abnormalities but no biomarkers to support clinical diagnosis. Recently, EEG analysis methods such as functional connectivity have rekindled interest in using EEG for ADHD diagnosis. Most studies have focused on resting-state EEG, while connectivity during sleep and spindle activity has been underexplored. Here we present the results of a preliminary study exploring spindle-related connectivity as a possible biomarker for ADHD. We compared sensor-space connectivity parameters in eight children with ADHD and nine age/sex-matched healthy controls during sleep, before, during, and after spindle activity in various frequency bands. All connectivity parameters were significantly different between the two groups in the delta and gamma bands, and Principal Component Analysis (PCA) in the gamma band distinguished ADHD from healthy subjects. Cluster coefficient and path length values in the sigma band were also significantly different between epochs, indicating different spindle-related brain activity in ADHD.

Reduced thalamic activity in ADHD under ABR forward masking conditions

Attention-deficit hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder characterized by symptoms of inattention, overactivity, and/or impulsiveness. The prevalence of ADHD varies in different settings and there have been voices raised to call for more objective measures in order to avoid over- and underdiagnosing of ADHD. Auditory Brainstem Response (ABR) is a method where click shaped sounds evoke potentials that are recorder from electrodes on the skull of a patient. The aim of this study was to explore possible alterations in the ABR of 29 patients with ADHD compared to 39 healthy controls. We used a forward masked sound. We found differences in ABR that correspond to the thalamic area. The thalamus seems to play an active role in regulation of activity level in ADHD. More research is needed to draw any further conclusions on using ABR as an objective measurement to detect ADHD.

Error-Related Brain Activity in ADHD: A Systematic Review and Meta-Analysis of Electroencephalography Markers of Cognitive Control Performance

Deviant cognitive control performance is implicated in Attention-Deficit-Hyperactivity-Disorder (ADHD). It is also conjectured to be a potential diagnoser and differentiator between the Inattentive and Hyperactive-Impulsive ADHD types. Reliable measures have not been established due to the variation in published results. We performed a systematic review and meta-analysis of the literature published up to May 2021 with data on electrophysiological correlates, that is, EEG correlates of cognitive control monitoring (error-related negativity, ERN; error positivity, Pe; correct-response negativity, CRN) in ADHD patients and the efficiency of EEG recordings in differentiating between ADHD types. Multiple databases including PubMed, Scopus, Google Scholar, bioRxiv, and medRxiv were searched for eligible literature. Meta-Analyses were performed through statistical tools provided by the open-source metafor package and separately using the Hedge's g standardized mean differences. Meta-Analyses were performed on a shortlisted set of 125 studies involving 7248 participants. To avoid extraneous variables, the sex ratio was maintained at 50:50, and the age groups of participants were equally varied between early teenagers (12-15years), late teenagers (15-18years), young adults (21-25), and middle-aged adults (29-37). The ADHD-afflicted group showed reduced ERN (Hedge's g=-0.58 [CIs: -0.76, -0.35]) and reduced Pe (Hedge's g=-0.65 [CIs: -0.79, -0.44). The Hyperactive-Impulsive ADHD types (2574/7248 participants) showed an increased CRN (Hedge's g=0.68 [CIs: 0.71, 0.29]), while the Inattentive ADHD Types (4674/7248 participants) showed a slightly reduced CRN (Hedge's g=-0.25 [CIs: -0.31, -0.28]. The prevalence of counted task errors was higher in the teenagers' group (12-18years) than the adults' group (21-37years). Results suggest that EEG Pattern Markers (especially Pe and CRN) can act as strong differentiators/diagnosers between the Hyperactive-Impulsive and Inattentive ADHD types. In further development, deep learning classifiers can be built for ADHD types using EEG Markers as Features and statistical values as weights. Pranjali Awasthi is a 14-year-old researcher working on the overlap of neuroimaging and machine learning at the Neural Dynamics of Control Lab, FIU. She is an avid speaker on topics of AI Awareness and Ethics. Here is a recent feature by the Analytics India Magazine: https://analyticsindiamag.com/how-this-15-year-old-created-a-research-career-in-machine-learning. New York Institute of Technology MRGA Committee.

Functional near-infrared spectroscopy in developmental psychiatry: a review of attention deficit hyperactivity disorder.

Research has linked executive function (EF) deficits to many of the behavioral symptoms of attention deficit hyperactivity disorder (ADHD). Evidence of the involvement of EF impairment in ADHD is corroborated by accumulating neuroimaging studies, specifically functional magnetic resonance imaging (fMRI) studies. However, in recent years, functional near-infrared spectroscopy (fNIRS) has become increasingly popular in ADHD research due to its portability, high ecological validity, resistance to motion artifacts, and cost-effectiveness. While numerous studies throughout the past decade have used fNIRS to examine alterations in neural correlates of EF in ADHD, a qualitative review of the reliability of these findings compared with those reported using gold-standard fMRI measurements does not yet exist. The current review aims to fill this gap in the literature by comparing the results generated from a qualitative review of fNIRS studies (children and adolescents ages 6-16years old) to a meta-analysis of comparable fMRI studies and examining the extent to which the results of these studies align in the context of EF impairment in ADHD. The qualitative analysis of fNIRS studies of ADHD shows a consistent hypoactivity in the right prefrontal cortex in multiple EF tasks. The meta-analysis of fMRI data corroborates altered activity in this region and surrounding areas during EF tasks in ADHD compared with typically developing controls. These findings indicate that fNIRS is a promising functional brain imaging technology for examining alterations in cortical activity in ADHD. We also address the disadvantages of fNIRS, including limited spatial resolution compared with fMRI.

P19. Vigilance regulation pattern in children with attention-deficit/hyperactivity disorder (ADHD) and depression measured by electroencephalography (EEG)

Objective Disturbed regulation of vigilance in wake state seems to play a key role in the development of mental disorders. In an actual model by Hegerl et al. (2014) hyperactivity in ADHD is assumed to be an attempt to increase a general low vigilance level via external stimulation. For depression the avoidance of stimulation is interpreted as a reaction to a tonic increased vigilance state. Although ADHD is assumed to start during childhood, this vigilance model has only been tested in a pilot study with children diagnosed for ADHD so far and was not compared to children with diagnosis of depression. Routine or assisted EEGs are not recommended for assessing vigilance (Sander et al., 2015) but the question remains if brain arousal can still be measured with it. If yes, it might be useful for clinical praxis, if relevant diagnostic conclusions can be drawn sufficiently from routine EEG measures. Methods 137 reting state EEG (10 min) measures from two groups of psychiatric patients (age: 13 ± 3.7 years) diagnosed with either ADHD or depression were analyzed. Vigilance classifications are compared between both groups via two-sample t-tests and chi-square tests. We used n-mean cluster analysis to detect EEG-patterns of vigilance regulation. In an ANOVA model, the relation between vigilance regulation and mental health symptoms (child behaviour check list, CBCL/6-18) was analyzed. Results We found more classification of low arousing stage B2/3 in ADHD compared to depression (50–20%) p Conclusion This study revealed that vigilance classification based on MTA assisted routine EEG of children showed results which are in accordance to the assumptions of hypo-aroused brain activity in ADHD and a more hyper-aroused brain state in depression. Therefore similar brain arousal states in children in these diagnostic groups can be assumed as has been showed for adults before. Interestingly, we could assign these different brain arousal states directly to attentional problems in our study sample. In order to analyze the validity of vigilance regulation analysis from a routine EEG in more detail a further direct comparison to EEG assessment according to the VIGALL protocol is still needed.

Inconsistency in Abnormal Brain Activity across Cohorts of ADHD-200 in Children with Attention Deficit Hyperactivity Disorder.

Many papers have shown results from the multi-site dataset of resting-state fMRI (rs-fMRI) in attention deficit hyperactivity disorder (ADHD), a data-sharing project named ADHD-200. However, few studies have illustrated that to what extent the pooled findings were consistent across cohorts. The present study analyzed three voxel-wise whole-brain metrics, i.e., amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC) based on the pooled dataset as well as individual cohort of ADHD-200. In addition to the conventional frequency band of 0.01–0.08 Hz, sub-frequency bands of 0–0.01, 0.01–0.027, 0.027–0.073, 0.073–0.198, and 0.198–0.25 Hz, were assessed. While the pooled dataset showed abnormal activity in some brain regions, e.g., the bilateral sensorimotor cortices, bilateral cerebellum, and the bilateral lingual gyrus, these results were highly inconsistent across cohorts, even across the three cohorts from the same research center. The standardized effect size was rather small. These findings suggested a high heterogeneity of spontaneous brain activity in ADHD. Future studies based on multi-site large-sample dataset should be performed on pooled data and single cohort data, respectively and the effect size must be shown.

Evidence of Altered Brain Responses to Nicotine in an Animal Model of Attention Deficit/Hyperactivity Disorder

Individuals with attention deficit/hyperactivity disorder (ADHD) are susceptible to earlier and more severe nicotine addiction. To shed light on the relationship between nicotine and ADHD, we examined nicotine's effects on functional brain networks in an animal model of ADHD. Awake magnetic resonance imaging was used to compare functional connectivity in adolescent (post-natal day 44 ± 2) males of the spontaneously hypertensive rat (SHR) strain and two control strains, Wistar-Kyoto and Sprague-Dawley (n = 16 each). We analyzed functional connectivity immediately before and after nicotine exposure (0.4 mg/kg base) in naïve animals, using a region-of-interest approach focussing on 16 regions previously implicated in reward and addiction. Relative to the control groups, the SHR strain demonstrated increased functional connectivity between the ventral tegmental area (VTA) and retrosplenial cortex in response to nicotine, suggesting an aberrant response to nicotine. In contrast, increased VTA-substantia nigra connectivity in response to a saline injection in the SHR was absent following a nicotine injection, suggesting that nicotine normalized function in this circuit. In the SHR, nicotine triggered an atypical response in one VTA circuit while normalizing activity in another. The VTA has been widely implicated in drug reward. Our data suggest that increased susceptibility to nicotine addiction in individuals with ADHD may involve altered responses to nicotine involving VTA circuits. Nicotine addiction is more common among individuals with ADHD. We found that two circuits involving the VTA responded differently to nicotine in animals that model ADHD in comparison to two control strains. In one circuit, nicotine normalized activity that was abnormal in the ADHD animals, while in the other circuit nicotine caused an atypical brain response in the ADHD animals. The VTA has been implicated in drug reward. Our results would be consistent with an interpretation that nicotine may normalize abnormal brain activity in ADHD, and that nicotine may be more rewarding for individuals with ADHD.

Diminished modulation of preparatory sensorimotor mu rhythm predicts attention-deficit/hyperactivity disorder severity.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by problems in regulating attention and in suppressing disruptive motor activity, i.e. hyperactivity and impulsivity. We recently found evidence that aberrant distribution of posterior α band oscillations (8-12 Hz) is associated with attentional problems in ADHD. The sensorimotor cortex also produces strong 8-12 Hz band oscillations, namely the μ rhythm, and is thought to have a similar inhibitory function. Here, we now investigate whether problems in distributing α band oscillations in ADHD generalize to the μ rhythm in the sensorimotor domain. In a group of adult ADHD (n = 17) and healthy control subjects (n = 18; aged 21-40 years) oscillatory brain activity was recorded using magnetoencephalography during a visuo-spatial attention task. Subjects had to anticipate a target with unpredictable timing and respond by pressing a button. Preparing a motor response, the ADHD group failed to increase hemispheric μ lateralization with relatively higher μ power in sensorimotor regions not engaged in the task, as the controls did (F 1,33 = 8.70, p = 0.006). Moreover, the ADHD group pre-response μ lateralization not only correlated positively with accuracy (r s = 0.64, p = 0.0052) and negatively with intra-individual reaction time variability (r s = -0.52, p = 0.033), but it also correlated negatively with the score on an ADHD rating scale (r s = -0.53, p = 0.028). We suggest that ADHD is associated with an inability to sufficiently inhibit task-irrelevant sensorimotor areas by means of modulating μ oscillatory activity. This could explain disruptive motor activity in ADHD. These results provide further evidence that impaired modulation of α band oscillations is involved in the pathogenesis of ADHD.

Hyperactivity in motor response inhibition networks in unmedicated children with attention deficit-hyperactivity disorder

Objectives: Hypo/reduced activity in motor response inhibition (RI) cerebral networks was recently proposed as a promising specific neurobiological marker of attention deficit-hyperactivity disorder (ADHD). Before adopting such a pattern as a key diagnosis tool, we aim to replicate in an independent study the mechanisms underlying reduced RI-related activity in ADHD, after controlling for potentially confounding effects.Methods: In this fMRI study, we investigated the neural networks mediating successful and failed motor RI in children with ADHD and typically developing children (TDC) using the stop-signal task (SST) paradigm.Results: In contrast to hypofrontality predictions, children with ADHD exhibit increased neural activity during successful response inhibition in an RI-related brain network encompassing the indirect and/or hyperdirect pathways between the basal ganglia and cortex. Voxel-based morphometry analyses have further evidenced reduced grey matter volume in the left caudate in children with ADHD, which paralleled higher functional responses. Finally, connectivity analyses disclosed tighter coupling between a set of cortical regions and the right caudate as well as the right IFG, networks involved in successful RI.Conclusions: Hypo/reduced activity in RI cerebral networks in children with ADHD cannot at this time be considered as a systematic biomarker for ADHD.

Neurofeedback Training Effects on Inhibitory Brain Activation in ADHD: A Matter of Learning?

Neurofeedback training (NF) is a promising non-pharmacological treatment for ADHD that has been associated with improvement of attention-deficit/hyperactivity disorder (ADHD)-related symptoms as well as changes in electrophysiological measures. However, the functional localization of neural changes following NF compared to an active control condition, and of successful learning during training (considered to be the critical mechanism for improvement), remains largely unstudied. Children with ADHD (N=16, mean age: 11.81, SD: 1.47) were randomly assigned to either slow cortical potential (SCP, n=8) based NF or biofeedback control training (electromyogram feedback, n=8) and performed a combined Flanker/NoGo task pre- and post-training. Effects of NF, compared to the active control, and of learning in transfer trials (approximating successful transfer to everyday life) were examined with respect to clinical outcome and functional magnetic resonance imaging (fMRI) changes during inhibitory control. After 20 sessions of training, children in the NF group presented reduced ADHD symptoms and increased activation in areas associated with inhibitory control compared to baseline. Subjects who were successful learners (n=9) also showed increased activation in an extensive inhibitory network irrespective of the type of training. Activation increased in an extensive inhibitory network following NF training, and following successful learning through NF and control biofeedback. Although this study was only powered to detect large effects and clearly requires replication in larger samples, the results suggest a crucial role for learning effects in biofeedback trainings.

Interplay between stress response genes associated with attention-deficit hyperactivity disorder and brain volume.

The glucocorticoid receptor plays a pivotal role in the brain's response to stress; a haplotype of functional polymorphisms in the NR3C1 gene encoding this receptor has been associated with attention-deficit hyperactivity disorder (ADHD). The serotonin transporter (5-HTT) gene polymorphism 5-HTTLPR is known to influence the relation between stress exposure and ADHD severity, which may be partly because of its reported effects on glucocorticoid levels. We therefore investigated if NR3C1 moderates the relation of stress exposure with ADHD severity and brain structure, and the potential role of 5-HTTLPR. Neuroimaging, genetic and stress exposure questionnaire data were available for 539 adolescents and young adults participating in the multicenter ADHD cohort study NeuroIMAGE (average age: 17.2 years). We estimated the effects of genetic variation in NR3C1 and 5-HTT, stress exposure and their interactions on ADHD symptom count and gray matter volume. We found that individuals carrying the ADHD risk haplotype of NR3C1 showed significantly more positive relation between stress exposure and ADHD severity than non-carriers. This gene-environment interaction was significantly stronger for 5-HTTLPR L-allele homozygotes than for S-allele carriers. These two- and three-way interactions were reflected in the gray matter volume of the cerebellum, parahippocampal gyrus, intracalcarine cortex and angular gyrus. Our findings illustrate how genetic variation in the stress response pathway may influence the effects of stress exposure on ADHD severity and brain structure. The reported interplay between NR3C1 and 5-HTT may further explain some of the heterogeneity between studies regarding the role of these genes and hypothalamic-pituitary-adrenal axis activity in ADHD.

Effects of d-Methylphenidate, Guanfacine, and Their Combination on Electroencephalogram Resting State Spectral Power in Attention-Deficit/Hyperactivity Disorder

Psychostimulant medications are the gold standard of treatment for attention-deficit/hyperactivity disorder (ADHD); however, a significant minority (∼30%) of individuals with ADHD fail to respond favorably. Noradrenergic agents are increasingly used as ADHD monotherapies or adjuncts for suboptimal stimulant response, yet knowledge of their cortical effects is limited. This study is the first to examine comparative effects of guanfacine (an α adrenergic 2A agonist), psychostimulant, and their combination on resting state cortical activity in ADHD. The sample comprised 179 participants aged 7 to 14 years old with ADHD (113 boys, 55 girls). Participants were randomized to 1 of 3 blinded conditions: guanfacine (GUAN), d-methylphenidate (DMPH), or the combination (COMB). Electroencephalography (EEG) was performed pre-, mid-, and post-medication titration, with concomitant assessment of behavioral and cognitive functioning. Analyses of spectral power measures during resting EEG suggested that each medication condition displayed a distinct profile of effects on cortical activity. Significant time effects suggested that GUAN decreased global alpha band (8-12 hertz [Hz]) power, DMPH and COMB increased centro-parietal beta band (13-21 Hz) power, and COMB resulted in decreased theta band (4-7 Hz) power. Relative to other medication groups, COMB was associated with significantly lower theta band power and DMPH with higher beta band power compared with those in the GUAN group. Medication-related changes in theta power were correlated with improvements in behavioral and cognitive functioning. These data reveal distinct underlying medication-related effects on neural mechanisms. The COMB condition uniquely exhibited an EEG profile that was associated with improved behavioral and cognitive functioning. Clinical trial registration information-Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273.

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD

Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.

The clinical utility of the continuous performance test and objective measures of activity for diagnosing and monitoring ADHD in children: a systematic review.

Attention-deficit hyperactivity disorder (ADHD) is typically diagnosed using clinical observation and subjective informant reports. Once children commence ADHD medication, robust monitoring is required to detect partial or non-responses. The extent to which neuropsychological continuous performance tests (CPTs) and objective measures of activity can clinically aid the assessment and titration process in ADHD is not fully understood. This review describes the current evidence base for the use of CPTs and objectively measured activity to support the diagnostic procedure and medication management for children with ADHD. Four databases (PsycINFO, Medline, Allied and Complementary Medicine (AMED), and PsycARTICLES) were systematically searched to understand the current evidence base for (1) the use of CPTs to aid clinical assessment of ADHD; (2) the use of CPTs to aid medication management; and (3) the clinical utility of objective measures of activity in ADHD. Sixty relevant articles were identified. The search revealed six commercially available CPTs that had been reported on for their clinical use. There were mixed findings with regard to the use of CPTs to assess and manage medication, with contrasting evidence on their ability to support clinical decision-making. There was a strong evidence base for the use of objective measures of activity to aid ADHD/non-ADHD group differentiation, which appears sensitive to medication effects and would also benefit from further research on their clinical utility. The findings suggest that combining CPTs and an objective measure of activity may be particularly useful as a clinical tool and worthy of further pursuit.

Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.

Background and ObjectivesDasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes.MethodsDasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout).ResultsDasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid Emax time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes.ConclusionThese results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms.Clinicaltrials.gov identifier: NCT01692782.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-015-0358-7) contains supplementary material, which is available to authorized users.

Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): a case-control study.

BackgroundThe essential amino acid tryptophan is catabolised mainly through the kynurenine pathway. Altered circulating levels of kynurenines have been reported in chronic inflammatory conditions and in several neuropsychiatric disorders, including depression and schizophrenia. Candidate gene studies suggest that genes related to the kynurenine catabolism may be associated with attention-deficit hyperactivity disorder (ADHD). Additionally, ADHD patients often report comorbid depression or anxiety. In this study we investigated serum levels of kynurenines in Norwegian adult ADHD patients and adult controls.MethodsWe compared serum levels of tryptophan and the seven tryptophan metabolites kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid in 133 adult patients with ADHD and 131 adult controls (18–40 years). Riboflavin (vitamin B2), total vitamin B6 and the nicotine metabolite cotinine were also measured. Serum samples were analysed using mass spectrometry. Patients and controls reported comorbid disorders and past (childhood) and current ADHD symptoms using the Wender Utah Rating Scale (WURS) and the Adult ADHD Self-report Scale (ASRS). Logistic regression was used to calculate odds ratios for having an ADHD diagnosis for different serum levels of each metabolite. In addition, we used Spearman’s correlation analysis to investigate the correlation between serum levels of tryptophan and kynurenines and ADHD symptom scores.ResultsLower serum concentrations of tryptophan [odds ratio 0.61 (95 % confidence interval 0.45–0.83)], kynurenic acid [0.73 (0.53–0.99)], xanthurenic acid [0.65 (0.48–0.89)] and 3-hydroxyanthranilic acid [0.63 (0.46–0.85)], and higher levels of cotinine [7.17 (4.37–12.58)], were significantly associated with ADHD. After adjusting for tryptophan levels, only 3-hydroxyanthranilic acid and cotinine remained significant. Lower levels of tryptophan and kynurenine were also found to be correlated with higher total ASRS score and higher total WURS score, when adjusting for smoking and age.ConclusionsOur results suggest that there may be differences in serum levels of tryptophan and kynurenines between adult ADHD patients and adult controls. Although our findings do not suggest a chronic immune activation in ADHD, the underlying mechanisms and possible clinical implications of the differences should be further explored.

Dysfunctional modulation of default mode network activity in attention-deficit/hyperactivity disorder.

The state regulation deficit model posits that individuals with attention-deficit/hyperactivity disorder (ADHD) have difficulty applying mental effort effectively under suboptimal conditions such as very fast and very slow event rates (ERs). ADHD is also associated with diminished suppression of default mode network (DMN) activity and related performance deficits on tasks requiring effortful engagement. The current study builds on these 2 literatures to test the hypothesis that failure to modulate DMN activity in ADHD might be especially pronounced at ER extremes. Nineteen adults with ADHD and 20 individuals without any neuropsychiatric condition successfully completed a simple target detection task under 3 ER conditions (2-, 4-, and 8-s interstimulus intervals) inside the scanner. Task-related DMN deactivations were compared between 2 groups. There was a differential effect of ER on DMN activity for individuals with ADHD compared to controls. Individuals with ADHD displayed excessive DMN activity at the fast and slow, but not at the moderate ER. The results indicate that DMN attenuation in ADHD is disrupted in suboptimal energetic states where additional effort is required to optimize task engagement. DMN dysregulation may be an important element of the neurobiological underpinnings of state regulation deficits in ADHD.

Hyperactivity and Motoric Activity in ADHD: Characterization, Assessment, and Intervention.

The aim of the present literature review is threefold. (1) We will review theories, models, and studies on symptomatic hyperactivity and motoric activity in attention-deficit/hyperactivity disorder (ADHD). (2) Another focus will be on assessment methods that have been proven to be effective in the detection of hyperactivity and motoric activity in children, adolescents, and adults with and without ADHD and emerging areas of research in the field of ADHD. We will compare subjective methods (i.e., rating scales) and objective methods (i.e., accelerometers). (3) Finally, physical activity intervention studies aiming at a modification of activity and overactive behavior will be summarized that seem to be promising candidates for alleviating hyperactivity symptoms in children, adolescents, and adults with ADHD.

Pattern classification of response inhibition in ADHD: Toward the development of neurobiological markers for ADHD

The diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) is based on subjective measures despite evidence for multisystemic structural and functional deficits. ADHD patients have consistent neurofunctional deficits in motor response inhibition. The aim of this study was to apply pattern classification to task‐based functional magnetic resonance imaging (fMRI) of inhibition, to accurately predict the diagnostic status of ADHD. Thirty adolescent ADHD and thirty age‐matched healthy boys underwent fMRI while performing a Stop task. fMRI data were analyzed with Gaussian process classifiers (GPC), a machine learning approach, to predict individual ADHD diagnosis based on task‐based activation patterns. Traditional univariate case‐control analyses were also performed to replicate previous findings in a relatively large dataset. The pattern of brain activation correctly classified up to 90% of patients and 63% of controls, achieving an overall classification accuracy of 77%. The regions of the discriminative network most predictive of controls included later developing lateral prefrontal, striatal, and temporo‐parietal areas that mediate inhibition, while regions most predictive of ADHD were in earlier developing ventromedial fronto‐limbic regions, which furthermore correlated with symptom severity. Univariate analysis showed reduced activation in ADHD in bilateral ventrolateral prefrontal, striatal, and temporo‐parietal regions that overlapped with areas predictive of controls, suggesting the latter are dysfunctional areas in ADHD. We show that significant individual classification of ADHD patients of 77% can be achieved using whole brain pattern analysis of task‐based fMRI inhibition data, suggesting that multivariate pattern recognition analyses of inhibition networks can provide objective diagnostic neuroimaging biomarkers of ADHD. Hum Brain Mapp 35:3083–3094, 2014. © 2013 Wiley Periodicals, Inc.

An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD

Spontaneous fluctuations can be measured in the brain that reflect dissociable functional networks oscillating at synchronized frequencies, such as the default mode network (DMN). In contrast to its diametrically opposed task-positive counterpart, the DMN predominantly signals during a state of rest, and inappropriate regulation of this network has been associated with inattention, a core characteristic of attention-deficit/hyperactivity disorder (ADHD). To examine whether abnormalities can be identified in the DMN component of patients with ADHD, we applied an independent components analysis to resting state functional magnetic resonance imaging data acquired from 22 male medication-naïve adults with ADHD and 23 neurotypical individuals. We observed a stronger coherence of the left dorsolateral prefrontal cortex (dlPFC) with the DMN component in patients with ADHD which correlated with measures of selective attention. The increased left dlPFC-DMN coherence also surfaced in a whole-brain replication analysis involving an independent sample of 9 medication-naïve adult patients and 9 controls. In addition, a post hoc seed-to-voxel functional connectivity analysis using the dlPFC as a seed region to further examine this region's suggested connectivity differences uncovered a higher temporal coherence with various other neural networks and confirmed a reduced anticorrelation with the DMN. These results point to a more diffuse connectivity between functional networks in patients with ADHD. Moreover, our findings suggest that state-inappropriate neural activity in ADHD is not confined to DMN intrusion during attention-demanding contexts, but also surfaces as an insufficient suppression of dlPFC signaling in relation to DMN activity during rest. Together with previous findings, these results point to a general dysfunction in the orthogonality of functional networks.