Biomarker Of Attention-deficit/hyperactivity Disorder Research Articles

Neurobiology of Adult ADHD: Emerging Evidence for Network Dysfunctions.

FIGURE 1. Changes in cortical thickness provide one measure of brain maturation. A large longitudinal study found that for most areas of cortex, children with attention deficit hyperactivity disorder (ADHD) reach peak cortical thickness several years later than typically developing children, supporting presence of developmental delay. The rate of cortical thinning also differed between the group who continued to meet diagnostic criteria into adulthood (persistent ADHD) and those who did not (remitted ADHD). Areas of cortex in which the rate of thinning correlated with adult symptom level (green, more symptoms associated with more thinning) are approximated on medial and lateral simplified representations of cortex. An earlier study also identified multiple areas in which cortex was thinner in adults with persistent ADHD compared with controls (orange). In addition, this study noted some areas of thicker cortex in remitted ADHD when compared with persistent ADHD (blue).

Underarousal in Adult ADHD: How Are Peripheral and Cortical Arousal Related?

In children and adults with attention deficit/hyperactivity disorder (ADHD), a general slowing of spontaneous electroencephalographic (EEG) brain activity and a decrease of event-related potential amplitudes such as the contingent negative variation (CNV) are observed. Additionally, some studies have reported decreased skin conductance level (SCL) in this clinical population leading to the hypothesis of a peripheral hypoarousal, which may be a target of biofeedback treatment in addition to or instead of neurofeedback. To our knowledge, the relationship between SCL and CNV has not been simultaneously investigated in one experiment. Using the theoretical background of the hypoarousal model, this article aims to gain more insight into the differences and correlations of cortical (CNV) and peripheral (SCL) arousal in adults with ADHD. A sample of 23 adults with ADHD and 22 healthy controls underwent an auditory Go-NoGo task with simultaneous 22-channel EEG and SCL recordings. Reaction time (RT) and reaction time variability (RTV) were also measured to assess task performance. Significantly decreased CNV amplitude and significantly higher RTV were observed in the ADHD group, reflecting cortical underarousal and problems with sustained attention. No significant correlation between peripheral underarousal and cortical underarousal was observed in the ADHD group or the control group. The observed cortical underarousal reflected in the decreased CNV supports the notion of a reduced CNV amplitude as a possible biomarker for ADHD. However, the connection between cortical and peripheral arousal is not as clear as is suggested in previous research investigating both separately. Implications of these results for new treatment options for ADHD such as biofeedback are discussed.

Functional dysconnectivity of corticostriatal circuitry and differential response to methylphenidate in youth with attention-deficit/hyperactivity disorder.

Brain frontostriatal circuits have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, effects of methylphenidate on circuit-level functional connectivity are as yet unclear. The aim of the present study was to comprehensively investigate the functional connectivity of major striatal subregions in children with ADHD, including subanalyses directed at mapping cognitive and treatment response characteristics. Using a comprehensive seeding strategy, we examined resting-state functional connectivity of dorsal and ventral subdivisions of the caudate nucleus and putamen in children and adolescents with ADHD and in age- and sex-matched healthy controls. We enrolled 83 patients with ADHD and 22 controls in our study. Patients showed significantly reduced dorsal caudate functional connectivity with the superior and middle prefrontal cortices as well as reduced dorsal putamen connectivity with the parahippocampal cortex. These connectivity measures were correlated in opposite directions in patients and controls with attentional performance, as assessed using the Continuous Performance Test. Patients showing a good response to methylphenidate had significantly reduced ventral caudate/nucleus accumbens connectivity with the inferior frontal cortices compared with poor responders. Possible confounding effects of age-related functional connectivity change were not excluded owing to the wide age range of participants. We observed a region-specific effect of methylphenidate on resting-state functional connectivity, suggesting the pretreatment level of ventral frontostriatal functional connectivity as a possible methylphenidate response biomarker of ADHD.

Variability of kinematic graphomotor fluency in adults with ADHD

Although graphomotor differences and variability of performance have been observed in children with attention deficit hyperactivity disorder (ADHD), no study has investigated whether this variability manifests in the kinematic graphomotor domain in adults with ADHD. Fourteen ADHD and 20 control participants wrote a novel grapheme and common word on a digitizing tablet 30 times each, with ADHD participants counterbalanced on and off stimulant medication. Variability of graphomotor fluency was significantly greater in ADHD versus control participants only in the novel writing task, both on, F(1,31)=5.988, p=.020, and off stimulant medication, F(1,32)=8.789, p=.006. Results suggest that motor control differences in ADHD are not limited to childhood and extend into adulthood. Given sufficient additional research, variability of kinematic graphomotor fluency may increase the sensitivity/specificity of differential diagnoses and/or represent a biomarker for ADHD.

Electroencephalographic activity before and after cognitive effort in children with attention deficit/hyperactivity disorder.

Numerous studies have detected elevated electroencephalographic (EEG) theta/beta ratio (TBR) or theta power in children with attention deficit/hyperactivity disorder (ADHD) and therefore TBR has been suggested to be a promising biomarker of ADHD. At the same time, recent theoretical models have emphasized the heterogeneity of ADHD and the notion that cognitive deficits in ADHD are not fixed but fluctuate according to contextual and state factors. Surprisingly, so far the context- or state-dependency of EEG abnormalities in ADHD has hardly been addressed. Therefore, in the current study, 3 minutes eyes closed resting EEG before and after execution of 3 n-back tasks were compared between 21 children with ADHD and 22 typically developing children. No difference between groups was found for TBR or theta power (or other frequency bands), neither before nor after task execution, indicating that enhanced TBR or theta power is not to be considered universal for the disorder. Hence, cautiousness is warranted in using these indices for diagnostic purposes in ADHD. Across groups, posterior theta power, as well as central and posterior beta power was attenuated after task execution, which was interpreted as the children experiencing a more alert state after cognitive effort. Yet, this EEG modulation was similar in both groups, providing no support for a context-or state-dependency of EEG abnormalities in ADHD. However, in light of the absence of any group differences in EEG parameters, further research is warranted.

Predictive Neurofunctional Markers of Attention-Deficit/Hyperactivity Disorder Based on Pattern Classification of Temporal Processing

Attention-deficit/hyperactivity disorder (ADHD) is currently diagnosed on the basis of subjective measures, despite evidence for multi-systemic structural and neurofunctional deficits. A consistently observed neurofunctional deficit is in fine-temporal discrimination (TD). The aim of this proof-of-concept study was to examine the feasibility of distinguishing patients with ADHD from controls using multivariate pattern recognition analyses of functional magnetic resonance imaging (fMRI) data of TD. A total of 20 medication-naive adolescent male patients with ADHD and 20 age-matched healthy controls underwent fMRI while performing a TD task. The fMRI data were analyzed with Gaussian process classifiers to predict individual ADHD diagnosis based on brain activation patterns. The pattern of brain activation correctly classified up to 80% of patients and 70% of controls, achieving an overall classification accuracy of 75%. The distributed activation networks with the highest delineation between patients and controls corresponded to a distributed network of brain regions involved in TD and typically compromised in ADHD, including inferior and dorsolateral prefrontal, insula, and parietal cortices, and the basal ganglia, anterior cingulate, and cerebellum. These regions overlapped with areas of reduced activation in patients with ADHD relative to controls in a univariate analysis, suggesting that these are dysfunctional regions. We show evidence that pattern recognition analyses combined with fMRI using a disorder-sensitive task such as timing have potential in providing objective diagnostic neuroimaging biomarkers of ADHD.

Global and local brain network reorganization in attention-deficit/hyperactivity disorder

Brain is a complex network with an anatomical and functional organization. The differences in brain organization of those with attention-deficit/hyperactivity disorder (ADHD) are still not well understood. Here, we study brain organization in ADHD subjects using a complex network derived from resting-state functional magnetic resonance imaging (fMRI) data of ADHD and normal subjects. Our results reveal that the brain networks of ADHD subjects are reorganized compared to those without ADHD in global and local brain functional networks. We find that the ADHD subjects show decreasing brain network integration and increasing brain network segregation. More interestingly, we find similarities of brain topology properties between local and global brain networks. Our finding indicates that cognitive dysfunction in ADHD is probably associated with disrupted global and local brain network topological properties. Our results can help us understand the pathophysiological mechanism of ADHD and serve as a sensitive and specific biomarker of 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.

Decreased binding capacity (B max) of muscarinic acetylcholine receptors in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD)

Monoaminergic dysregulation is implicated in attention-deficit/hyperactivity disorder (ADHD), and methylphenidate and amphetamines are the most frequently prescribed pharmacological agents for treating ADHD. However, it has recently been proposed that the core symptoms of the disorder might be due to an imbalance between monoaminergic and cholinergic systems. In this study, we used fibroblast cell homogenates from boys with and without ADHD as an extraneural cell model to examine the cholinergic receptor density, that is, muscarinic acetylcholine receptors (mAChRs). We found that the binding capacity (B max) of [3H] Quinuclidinyl benzilate (3H-QNB) to mAChRs was decreased by almost 50 % in the children with ADHD (mean = 30.6 fmol/mg protein, SD = 25.6) in comparison with controls [mean = 63.1 fmol/mg protein, SD = 20.5, p ≤ 0.01 (Student’s unpaired t test)]. The decreased B max indicates a reduced cholinergic receptor density, which might constitute a biomarker for ADHD. However, these preliminary findings need to be replicated in larger ADHD and comparison cohorts.

Biomarkers for attention-deficit/hyperactivity disorder (ADHD). A consensus report of the WFSBP task force on biological markers and the World Federation of ADHD

Objective. Psychiatric “nosology” is largely based on clinical phenomenology using convention-based diagnostic systems not necessarily reflecting neurobiological pathomechanisms. While progress has been made regarding its molecular biology and neuropathology, the phenotypic characterization of ADHD has not improved. Thus, validated biomarkers, more directly linked to the underlying pathology, could constitute an objective measure for the condition. Method. The task force on biological markers of the World Federation of Societies of Biological Psychiatry (WFSBP) and the World Federation of ADHD commissioned this paper to develop a consensus report on potential biomarkers of ADHD. The criteria for biomarker-candidate evaluation were: (1) sensitivity > 80%, (2) specificity > 80%, (3) the candidate is reliable, reproducible, inexpensive, non-invasive, easy to use, and (4) confirmed by at least two independent studies in peer-reviewed journals conducted by qualified investigators. Results. No reliable ADHD biomarker has been described to date, but some promising candidates (e.g., olfactory sensitivity, substantial echogenicity) exist. A problem in the development of ADHD markers is sample heterogeneity due to aetiological and phenotypic complexity and age-dependent co-morbidities. Conclusions. Most likely, no single ADHD biomarker can be identified. However, the use of a combination of markers may help to reduce heterogeneity and to identify homogeneous subtypes of ADHD.

Decreased Regional Cortical Thickness and Thinning Rate Are Associated With Inattention Symptoms in Healthy Children

Children with attention-deficit/hyperactivity disorder (ADHD) have delayed cortical maturation, evidenced by regionally specific slower cortical thinning. However, the relationship between cortical maturation and attention capacities in typically developing children is unknown. This study examines cortical thickness correlates of inattention symptoms in a large sample of healthy children. Data from 357 healthy subjects (6.0-18.4 years of age) were obtained from the NIH MRI Study of Normal Brain Development. In cross-sectional analysis (first visit, n = 257), Child Behavior Checklist Attention Problems (AP) scores were linearly regressed against cortical thickness, controlling for age, gender, total brain volume, and site. For longitudinal data (up to three visits, n = 357/672 scans), similar analyses were performed using mixed-effects linear regressions. Interactions of AP with age and gender were tested. A cross-sectional "AP by age" interaction was found in bilateral orbito-frontal cortex, right inferior frontal cortex, bilateral ventromedial prefrontal cortex, bilateral dorsolateral prefrontal cortex, and several additional attention network regions. The interaction was due to negative associations between AP and thickness in younger subjects (6-10 years of age) that gradually disappeared over time secondary to slower cortical thinning. Similar trends were present in longitudinal analyses. Higher AP scores were associated with thinner cortex at baseline and slower cortical thinning with aging in multiple areas involved in attention processes. Similar patterns have been identified in ADHD, suggesting a dimensional component to the link between attention and cortical maturation. The identified association between cortical maturation and attention in healthy development will help to inform studies of neuroimaging biomarkers of ADHD.

Thinning of the Cerebral Cortex During Development: A Dimension of ADHD

Thinning of the Cerebral Cortex During Development: A Dimension of ADHD

Disorder‐specific inferior prefrontal hypofunction in boys with pure attention‐deficit/hyperactivity disorder compared to boys with pure conduct disorder during cognitive flexibility

Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder-specific functional abnormalities during cognitive flexibility between medication-naïve children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. Event-related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood-onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual-spatial Switch task. Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder-specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. The findings extend previous evidence for disorder-specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder-specific neurofunctional biomarker for ADHD when compared with patients with CD.

Disorder‐specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention‐deficit hyperactivity disorder compared to boys with obsessive–compulsive disorder

Inhibitory dysfunction is a key behavioral and cognitive phenotype of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Both disorders show neuropsychological deficits and fronto-striatal dysfunction during tasks of motor response inhibition and cognitive flexibility. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder-specific neurofunctional markers that distinguish these two inhibitory disorders. Event-related fMRI was used to compare brain activation between 20 healthy boys, 18 (Stop task) or 12 boys (Switch task) with ADHD, and 10 boys with OCD during a tracking Stop task that measures inhibition and stopping failure and during a visual-spatial switching task measuring cognitive flexibility. Both patient groups shared brain dysfunction compared to healthy controls in right orbitofrontal (successful inhibition) and left dorsolateral prefrontal cortices (failed inhibition). Right inferior prefrontal dysfunction, however, was disorder-specific to ADHD during both tasks. Left inferior prefrontal dysfunction during the Switch task was significant in children with ADHD relative to controls, but only reached a trend in patients with OCD. Patients with ADHD furthermore showed disorder-specific dysfunction in left basal ganglia and cingulate gyrus during the Switch task. Patients with ADHD compared to those with OCD have both common and distinct dysfunctions during inhibitory control. The most consistently reported functional abnormality in children with ADHD in right inferior prefrontal cortex during inhibitory control appears to be disorder-specific when compared to patients with OCD and may be a specific neurofunctional biomarker of ADHD.

P01-04 Disorder-specific right inferior prefrontal dysfunction during two tasks of inhibitory control in pediatric attention-deficit/hyperactivity disorder compared to pediatric obsessive-compulsive disorder

Inhibitory dysfunction is the key behavioural and cognitive phenotype of Attention Deficit Hyperactivity Disorder (ADHD) and of obsessive-compulsive-disorder (OCD). Both disorders show deficits in tasks of response inhibition and cognitive flexibility as well as fronto-striatal brain dysfunctions during task performance. The goal of this research was to investigate differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder-specific neurofunctional biomarkers.Event-related functional magnetic resonance imaging (fMRI) was used to compare brain activation of 18/12 boys (Stop/Switch task) with clinical ADHD, 10 boys with clinical OCD and 20 healthy comparison boys during a tracking Stop task measuring motor response inhibition and its failure and a switching task measuring cognitive flexibility. Non-parametric permutation analyses were used for fMRI analysis (XBAM). Functional connectivity analyses investigating group differences in fronto-striatal connections will be presented at the conference.Both patient groups shared brain dysfunction compared to controls in right orbitofrontal, left dorsolateral (Stop task) and left inferior prefrontal cortices (Switch task). Right inferior prefrontal under-activation, however, was specific to ADHD during both tasks. Under-activation in left caudate and anterior cingulate was also specific to ADHD during the Switch task.Patients with ADHD appear to have both common and distinct dysfunctions during inhibitory control compared to OCD patients. The most consistent fMRI finding in ADHD of a dysfunction in right inferior prefrontal cortex during inhibitory control appears to be disorder-specific when compared to OCD, and may be a specific neurofunctional biomarker of ADHD.