Atypical functional connectivity in adolescents and adults with persistent and remitted ADHD during a cognitive control task

We previously provided initial evidence for cognitive and event-related potential markers of persistence/remission of attention-deficit/hyperactivity disorder (ADHD) from childhood to adolescence and adulthood. Here, using a novel brain-network connectivity approach, we aimed to examine whether task-based functional connectivity reflects a marker of ADHD remission or an enduring deficit unrelated to ADHD outcome. High-density EEG was recorded in a follow-up of 110 adolescents and young adults with childhood ADHD (87 persisters, 23 remitters) and 169 typically developing individuals during an arrow-flanker task, eliciting cognitive control. Functional connectivity was quantified with network-based graph-theory metrics before incongruent (high-conflict) target onset (pre-stimulus), during target processing (post-stimulus) and in the degree of change between pre-stimulus/post-stimulus. ADHD outcome was examined with parent-reported symptoms and impairment using both a categorical (DSM-IV) and a dimensional approach. Graph-theory measures converged in indicating that, compared to controls, ADHD persisters showed increased connectivity in pre-stimulus theta, alpha, and beta and in post-stimulus beta (all p < .01) and reduced pre-stimulus/post-stimulus change in theta connectivity (p < .01). In the majority of indices showing ADHD persister–control differences, ADHD remitters differed from controls (all p < .05) but not from persisters. Similarly, connectivity measures were unrelated to continuous outcome measures of ADHD symptoms and impairment in participants with childhood ADHD. These findings indicate that adolescents and young adults with persistent and remitted ADHD share atypical over-connectivity profiles and reduced ability to modulate connectivity patterns with task demands, compared to controls. Task-based functional connectivity impairments may represent enduring deficits in individuals with childhood ADHD irrespective of diagnostic status in adolescence/young adulthood.

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title: Atypical Default Network Connectivity in Youth with Attention-Deficit/Hyperactivity Disorder
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This study used the typical developmental context provided previously by Fair et al. (2008) to examine coherence of brain activity within the default network using rs-fcMRI in children with (n = 23) and without attention deficit/hyperactivity disorder (n = 23).



We found that functional connections previously shown as developmentally dynamic in the default network were atypical in children with attention deficit/hyperactivity disorder-consistent with perturbation or failure of the maturational processes.



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abstract: A previous study indicated that adults with attention deficit hyperactivity disorder (ADHD) had a decreased anti-correlation between the dorsal anterior cingulate cortex (dACC) and the default mode network (DMN). In this study, we investigated whether children with ADHD also show a decreased anti-correlation between the dACC and the DMN. We also explored the developmental characteristics of the resting-state functional connectivity (RSFC) of the dACC with the DMN in children with ADHD. Resting-state functional magnetic resonance imaging scans were obtained from a 3T scanner in 19 drug-naïve boys with ADHD and 23 controls. Compared with normal controls, the dACC in boys with ADHD showed a significantly decreased negative RSFC with the DMN, including the dorsomedial prefrontal cortex and the posterior cingulate cortex. The RSFC strength between the dACC and the posterior cingulate cortex showed a significantly negative correlation with age in normal controls, but not in boys with ADHD. This decreased anti-correlation may suggest an abnormal balance or interaction between attentional and intrinsic thoughts. Our age-related analysis suggested an abnormal development pattern of the dACC-DMN interaction in ADHD.

title: Cingulate-Precuneus Interactions: A New Locus of Dysfunction in Adult Attention-Deficit/Hyperactivity Disorder
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Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers.



Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and precuneus/posterior cingulate cortex regions (p < .0004, corrected). Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex (p < 3 x 10(-11), corrected) and portions of posterior cingulate (p < .02, corrected).



Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD.

title: Connectivity supporting attention in children with attention deficit hyperactivity disorder
abstract: Intra-subject variability (ISV) is the most consistent behavioral deficit in Attention Deficit Hyperactivity Disorder (ADHD). ISV may be associated with networks involved in sustaining task control (cingulo-opercular network: CON) and self-reflective lapses of attention (default mode network: DMN). The current study examined whether connectivity supporting attentional control is atypical in children with ADHD. Group differences in full-brain connection strength and brain–behavior associations with attentional control measures were examined for the late-developing CON and DMN in 50 children with ADHD and 50 typically-developing (TD) controls (ages 8–12 years). Children with ADHD had hyper-connectivity both within the CON and within the DMN. Full-brain behavioral associations were found for a number of between-network connections. Across both groups, more anti-correlation between DMN and occipital cortex supported better attentional control. However, in the TD group, this brain–behavior association was stronger and occurred for a more extensive set of DMN–occipital connections. Differential support for attentional control between the two groups occurred with a number of CON–DMN connections. For all CON–DMN connections identified, increased between-network anti-correlation was associated with better attentional control for the ADHD group, but worse attentional control in the TD group. A number of between-network connections with the medial frontal cortex, in particular, showed this relationship. Follow-up analyses revealed that these associations were specific to attentional control and were not due to individual differences in working memory, IQ, motor control, age, or scan motion. While CON–DMN anti-correlation is associated with improved attention in ADHD, other circuitry supports improved attention in TD children. Greater CON–DMN anti-correlation supported better attentional control in children with ADHD, but worse attentional control in TD children. On the other hand, greater DMN–occipital anti-correlation supported better attentional control in TD children.

title: An independent components and functional connectivity analysis of resting state fMRI data points to neural network dysregulation in adult ADHD
abstract: 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.  2014.

title: Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood.
abstract: The neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD) and particularly those associated with the persistence of ADHD into adulthood are not yet well understood. The correlation patterns in spontaneous neural fluctuations at rest are known as resting-state functional connectivity (RSFC) and could characterize ADHD-specific connectivity changes.



To determine the specific location of possible ADHD-related differences in RSFC between adults diagnosed as having ADHD in childhood and control subjects.  Using resting-state functional magnetic resonance imaging, we calculated and compared functional connectivity from attention, affective, default, and cognitive control networks involved in the psychopathology of ADHD between the ADHD and control groups.  University psychiatric service and magnetic resonance imaging research center.



Sixteen drug-free adults (5 women and 11 men; mean age, 24.5 years) diagnosed with combined-type ADHD in childhood and 16 healthy controls matched for age (mean age, 24.4 years), sex, handedness, and educational level recruited from the community.



Functional magnetic resonance imaging.



Connectivity data from ventral and dorsal attention, affective, default, and cognitive control networks and ADHD symptoms derived from ADHD-specific rating instruments.



Adults with ADHD showed significantly decreased RSFC within the attention networks and increased RSFC within the affective and default mode and the right lateralized cognitive control networks compared with healthy controls (P < .01, familywise error for whole-brain cluster correction). Lower RSFC in the ventral and dorsal attention network was significantly correlated with higher levels of ADHD symptoms (P < .001).



These RSFC findings might underpin a biological basis for adult ADHD and are functionally related to persistent inattention, disturbance in cognitive control, and emotional dysregulation in adults with ADHD. These findings need to be understood in the context of all aspects of brain function in ADHD.

title: Altered resting-state functional connectivity patterns of anterior cingulate cortex in adolescents with attention deficit hyperactivity disorder
abstract: Dorsal anterior cingulate cortex (dACC) has been found to function abnormally in attention deficit hyperactivity disorder (ADHD) patients in several former functional MRI (fMRI) studies. Resting-state low-frequency fluctuations (LFFs) of blood oxygen level-dependent (BOLD) fMRI signals have been proved to be quite informative. This study used resting-state LFFs to investigate the resting-state functional connectivity pattern differences of dACC in adolescents with and without ADHD. As compared to the controls, the ADHD patients exhibited more significant resting-state functional connectivities with the dACC in bilateral dACC, bilateral thalamus, bilateral cerebellum, bilateral insula and bilateral brainstem (pons). No brain region in the controls was found to exhibit more significant resting-state functional connectivity with the dACC. We suggest these abnormally more significant functional connectivities in the ADHD patients may indicate the abnormality of autonomic control functions in them.

title: Altered intrinsic organisation of brain networks implicated in attentional processes in adult attention-deficit/hyperactivity disorder: a resting-state study of attention, default mode and salience network connectivity
abstract: Deficits in task-related attentional engagement in attention-deficit/hyperactivity disorder (ADHD) have been hypothesised to be due to altered interrelationships between attention, default mode and salience networks. We examined the intrinsic connectivity during rest within and between these networks. Six-minute resting-state scans were obtained. Using a network-based approach, connectivity within and between the dorsal and ventral attention, the default mode and the salience networks was compared between the ADHD and control group. The ADHD group displayed hyperconnectivity between the two attention networks and within the default mode and ventral attention network. The salience network was hypoconnected to the dorsal attention network. There were trends towards hyperconnectivity within the dorsal attention network and between the salience and ventral attention network in ADHD. Connectivity within and between other networks was unrelated to ADHD. Our findings highlight the altered connectivity within and between attention networks, and between them and the salience network in ADHD. One hypothesis to be tested in future studies is that individuals with ADHD are affected by an imbalance between ventral and dorsal attention systems with the former playing a dominant role during task engagement, making individuals with ADHD highly susceptible to distraction by salient task-irrelevant stimuli.

title: Characterising resting-state functional connectivity in a large sample of adults with ADHD
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder that often persists into adulthood. While several studies have identified altered functional connectivity in brain networks during rest in children with ADHD, few studies have been performed on adults with ADHD. Existing studies have generally investigated small samples. We therefore investigated aberrant functional connectivity in a large sample of adult patients with childhood-onset ADHD, using a data-driven, whole-brain approach. Adults with a clinical ADHD diagnosis (N=99) and healthy, adult comparison subjects (N=113) underwent a 9-minute resting-state fMRI session in a 1.5T MRI scanner. After elaborate preprocessing including a thorough head-motion correction procedure, group independent component analysis (ICA) was applied from which we identified six networks of interest: cerebellum, executive control, left and right frontoparietal and two default-mode networks. Participant-level network maps were obtained using dual-regression and tested for differences between patients with ADHD and controls using permutation testing. Patients showed significantly stronger connectivity in the anterior cingulate gyrus of the executive control network. Trends were also observed for stronger connectivity in the cerebellum network in ADHD patients compared to controls. However, there was considerable overlap in connectivity values between patients and controls, leading to relatively low effect sizes despite the large sample size. These effect sizes were slightly larger when testing for correlations between hyperactivity/impulsivity symptoms and connectivity strength in the executive control and cerebellum networks. This study provides important insights for studies on the neurobiology of adult ADHD; it shows that resting-state functional connectivity differences between adult patients and controls exist, but have smaller effect sizes than existing literature suggested.

title: Large-scale brain functional network topology disruptions underlie symptom heterogeneity in children with attention-deficit/hyperactivity disorder
abstract: Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.

title: fMRI functional connectivity applied to adolescent neurodevelopment.
abstract: The exponential rise in the number of functional brain connectivity studies, particularly those examining intrinsic functional connectivity (iFC) at rest, and the promises of this work for unraveling the ontogeny of functional neural systems motivate this review. Shortly before this explosion in functional connectivity research, developmental neuroscientists had proposed theories based on neural systems models to explain behavioral changes, particularly in adolescence. The current review presents recent advances in imaging in brain connectivity research, which provides a unique tool for the study of neural systems. Understanding the potential of neuroimaging for refining neurodevelopmental models of brain function requires a description of various functional connectivity approaches. In this review, we describe task-based and resting-state functional magnetic resonance imaging (fMRI) analytic strategies, but we focus on iFC findings from resting-state data to describe general developmental trajectories of brain network organization. Finally, we use the example of drug addiction to frame a discussion of psychopathology that emerges in adolescence.

title: Can brain state be manipulated to emphasize individual differences in functional connectivity?
abstract: &NA; While neuroimaging studies typically collapse data from many subjects, brain functional organization varies between individuals, and characterizing this variability is crucial for relating brain activity to behavioral phenotypes. Rest has become the default state for probing individual differences, chiefly because it is easy to acquire and a supposed neutral backdrop. However, the assumption that rest is the optimal condition for individual differences research is largely untested. In fact, other brain states may afford a better ratio of within‐ to between‐subject variability, facilitating biomarker discovery. Depending on the trait or behavior under study, certain tasks may bring out meaningful idiosyncrasies across subjects, essentially enhancing the individual signal in networks of interest beyond what can be measured at rest. Here, we review theoretical considerations and existing work on how brain state influences individual differences in functional connectivity, present some preliminary analyses of within‐ and between‐subject variability across conditions using data from the Human Connectome Project, and outline questions for future study. HighlightsRest is the default for studying individual differences in functional connectivity.But certain tasks may improve the ratio of within‐ to between‐subject variability.We review work on how scan condition influences individual differences.Preliminary results using HCP data show individual differences change with task.Using certain tasks over rest may improve sensitivity of imaging‐based biomarkers.

title: Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naïve children with ADHD during a rewarded continuous performance task
abstract: Children with Attention Deficit Hyperactivity Disorder (ADHD) have deficits in motivation and attention that can be ameliorated with the indirect dopamine agonist Methylphenidate (MPH). We used functional magnetic resonance imaging (fMRI) to investigate the effects of MPH in medication-naïve children with ADHD on the activation and functional connectivity of "cool" attentional as well as "hot" motivation networks.



13 medication-naïve children with ADHD were scanned twice, under either an acute clinical dose of MPH or Placebo, in a randomised, double-blind design, while they performed a rewarded continuous performance task that measured vigilant selective attention and the effects of reward. Brain activation and functional connectivity was compared to that of 13 healthy age-matched controls to test for normalisation effects of MPH.



MPH normalised performance deficits that were observed in children with ADHD compared to controls. Under placebo, children with ADHD showed reduced activation and functional inter-connectivity in bilateral fronto-striato-parieto-cerebellar networks during the attention condition, but enhanced activation in the orbitofrontal and superior temporal cortices for reward. MPH within children with ADHD enhanced the activation of fronto-striato-cerebellar and parieto-temporal regions. Compared to controls, MPH normalised differences during vigilant attention in parieto-temporal activation and fronto-striatal and fronto-cerebellar connectivity; MPH also normalised the enhanced orbitofrontal activation in children with ADHD in response to reward.



MPH normalised attention differences between children with ADHD and controls by both up-regulation of dysfunctional fronto-striato-thalamo-cerebellar and parieto-temporal attention networks and down-regulation of hyper-sensitive orbitofrontal activation for reward processing. MPH thus shows context-dependent dissociative modulation of both motivational and attentional neuro-functional networks in children with ADHD.

title: Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings
abstract: Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.  Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).  Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.  Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.

title: Reduced activation and inter-regional functional connectivity of fronto-striatal networks in adults with childhood Attention-Deficit Hyperactivity Disorder (ADHD) and persisting symptoms during tasks of motor inhibition and cognitive switching.
abstract: Attention-Deficit Hyperactivity Disorder (ADHD) in children has been associated with fronto-striatal functional abnormalities during tasks of inhibitory control. In adults with ADHD, however, hardly any functional magnetic resonance imaging (fMRI) studies have investigated the neurofunctional correlates of the most compromised cognitive functions of motor response inhibition and no study has investigated cognitive flexibility. In this study we used fMRI to compare brain function and task-relevant inter-regional functional connectivity between 11 medication-naïve adults with persistent inattentive/hyperactive behaviours, followed up from childhood when they had been diagnosed with ADHD, and 14 age-matched healthy controls during a Stop and a cognitive Switch tasks. Whole-brain regression MR analyses were conducted within patients to correlate symptoms with brain activation. Despite comparable task performance, adults with childhood ADHD showed reduced activation compared to controls in bilateral inferior prefrontal cortex, caudate and thalamus during both tasks, as well as in left parietal lobe during the Switch task. Within patients, the severity of the behavioural symptoms was negatively correlated with more extensive activation of similar regions in fronto-striatal, parietal and cerebellar brain areas. In the Stop task, patients showed reduced inter-regional functional connectivity between right inferior fronto-frontal, fronto-striatal and fronto-parietal neural networks. The findings demonstrate that adults with childhood ADHD and persisting behavioural symptoms show strikingly similar patterns of fronto-striatal and parietal dysfunction to those observed in childhood ADHD during the same tasks of inhibitory control. This suggests that neuro-functional abnormalities in ADHD patients are likely to continue between childhood and early adulthood.

title: Ventral striatal hyperconnectivity during rewarded interference control in adolescents with ADHD
abstract: Attention-deficit/hyperactivity disorder (ADHD) is characterized by cognitive deficits (e.g., interference control) and altered reward processing. Cognitive control is influenced by incentive motivation and according to current theoretical models, ADHD is associated with abnormal interactions between incentive motivation and cognitive control. However, the neural mechanisms by which reward modulates cognitive control in individuals with ADHD are unknown.



We used event-related functional resonance imaging (fMRI) to study neural responses during a rewarded Stroop color-word task in adolescents (14-17 years) with ADHD (n = 25; 19 boys) and healthy controls (n = 33; 22 boys).



Adolescents with ADHD showed increased reward signaling within the superior frontal gyrus and ventral striatum (VS) relative to controls. Importantly, functional connectivity analyses revealed a hyperconnectivity between VS and motor control regions in the ADHD group, as a function of reward-cognitive control integration. Connectivity was associated with performance improvement in controls but not in the ADHD group, suggesting inefficient connectivity.



Adolescents with ADHD show increased neural sensitivity to rewards and its interactions with interference control in VS and motor regions, respectively. The findings support theoretical models of altered reward-cognitive control integration in individuals with ADHD.

title: Brain development in ADHD
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with underlying brain anatomical and functional measures, as well as familial/genetic factors that are major foci of neuropsychiatric research. Advances in imaging technology have shown structural and functional brain differences between individuals with and without ADHD. Longitudinal studies have enabled the elucidation of differences in developmental course. Studies comparing persisting and remitting cases of ADHD are particularly promising. Therapeutic doses of psychostimulants normalize many measures of brain anatomy and function.

title: Fast fMRI can detect oscillatory neural activity in humans
abstract: A major challenge in neuroscience is our limited ability to image neural signals noninvasively in humans. Oscillations in brain activity are important for perception, attention, and awareness, and progress in cognitive neuroscience depends on localizing these patterns. fMRI is thought to be too slow to measure brain oscillations because it depends on slow changes in blood flow. Here, we use recently developed imaging techniques to show that fMRI can measure faster neural oscillations than previously thought, and responses are 10 times larger than expected. With computational modeling and simultaneous electroencephalography we show that vascular responses are surprisingly fast when brain activity fluctuates rapidly. These results suggest that fMRI can be used to track oscillating brain activity directly during human cognition. Oscillatory neural dynamics play an important role in the coordination of large-scale brain networks. High-level cognitive processes depend on dynamics evolving over hundreds of milliseconds, so measuring neural activity in this frequency range is important for cognitive neuroscience. However, current noninvasive neuroimaging methods are not able to precisely localize oscillatory neural activity above 0.2 Hz. Electroencephalography and magnetoencephalography have limited spatial resolution, whereas fMRI has limited temporal resolution because it measures vascular responses rather than directly recording neural activity. We hypothesized that the recent development of fast fMRI techniques, combined with the extra sensitivity afforded by ultra-high-field systems, could enable precise localization of neural oscillations. We tested whether fMRI can detect neural oscillations using human visual cortex as a model system. We detected small oscillatory fMRI signals in response to stimuli oscillating at up to 0.75 Hz within single scan sessions, and these responses were an order of magnitude larger than predicted by canonical linear models. Simultaneous EEG–fMRI and simulations based on a biophysical model of the hemodynamic response to neuronal activity suggested that the blood oxygen level-dependent response becomes faster for rapidly varying stimuli, enabling the detection of higher frequencies than expected. Accounting for phase delays across voxels further improved detection, demonstrating that identifying vascular delays will be of increasing importance with higher-frequency activity. These results challenge the assumption that the hemodynamic response is slow, and demonstrate that fMRI has the potential to map neural oscillations directly throughout the brain.

title: Using quantitative and analytic EEG methods in the understanding of connectivity in autism spectrum disorders: a theory of mixed over- and under-connectivity
abstract: Neuroimaging technologies and research has shown that autism is largely a disorder of neuronal connectivity. While advanced work is being done with fMRI, MRI-DTI, SPECT and other forms of structural and functional connectivity analyses, the use of EEG for these purposes is of additional great utility. Cantor et al. (1986) were the first to examine the utility of pairwise coherence measures for depicting connectivity impairments in autism. Since that time research has shown a combination of mixed over and under-connectivity that is at the heart of the primary symptoms of this multifaceted disorder. Nevertheless, there is reason to believe that these simplistic pairwise measurements under represent the true and quite complicated picture of connectivity anomalies in these persons. We have presented three different forms of multivariate connectivity analysis with increasing levels of sophistication (including one based on principle components analysis, sLORETA source coherence, and Granger causality) to present a hypothesis that more advanced statistical approaches to EEG coherence analysis may provide more detailed and accurate information than pairwise measurements. A single case study is examined with findings from MR-DTI, pairwise and coherence and these three forms of multivariate coherence analysis. In this case pairwise coherences did not resemble structural connectivity, whereas multivariate measures did. The possible advantages and disadvantages of different techniques are discussed. Future work in this area will be important to determine the validity and utility of these techniques.

title: Brain functional connectivity abnormalities in attention‐deficit hyperactivity disorder
abstract: Recent evidence suggests that attention‐deficit hyperactivity disorder (ADHD) is associated with brain functional connectivity (FC) abnormalities.

title: Neuronal Oscillations in Cortical Networks
abstract: Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.

title: Neural Synchrony in Brain Disorders: Relevance for Cognitive Dysfunctions and Pathophysiology
abstract: Following the discovery of context-dependent synchronization of oscillatory neuronal responses in the visual system, novel methods of time series analysis have been developed for the examination of task- and performance-related oscillatory activity and its synchronization. Studies employing these advanced techniques revealed that synchronization of oscillatory responses in the beta- and gamma-band is involved in a variety of cognitive functions, such as perceptual grouping, attention-dependent stimulus selection, routing of signals across distributed cortical networks, sensory-motor integration, working memory, and perceptual awareness. Here, we review evidence that certain brain disorders, such as schizophrenia, epilepsy, autism, Alzheimer's disease, and Parkinson's are associated with abnormal neural synchronization. The data suggest close correlations between abnormalities in neuronal synchronization and cognitive dysfunctions, emphasizing the importance of temporal coordination. Thus, focused search for abnormalities in temporal patterning may be of considerable clinical relevance.

title: Segregated Systems of Human Brain Networks
abstract: The organization of the brain network enables its function. Evaluation of this organization has revealed that large-scale brain networks consist of multiple segregated subnetworks of interacting brain areas. Descriptions of resting-state network architecture have provided clues for understanding the functional significance of these segregated subnetworks, many of which correspond to distinct brain systems. The present report synthesizes accumulating evidence to reveal how maintaining segregated brain systems renders the human brain network functionally specialized, adaptable to task demands, and largely resilient following focal brain damage. The organizational properties that support system segregation are harmonious with the properties that promote integration across the network, but confer unique and important features to the brain network that are central to its function and behavior.

title: Human subthalamic nucleus–medial frontal cortex theta phase coherence is involved in conflict and error related cortical monitoring
abstract: The medial prefrontal cortex (mPFC) is thought to control the shift from automatic to controlled action selection when conflict is present or when mistakes have been recently committed. Growing evidence suggests that this process involves frequency specific communication in the theta (4–8 Hz) band between the mPFC and the subthalamic nucleus (STN), which is the main target of deep brain stimulation (DBS) for Parkinson's disease. Key in this hypothesis is the finding that DBS can lead to impulsivity by disrupting the correlation between higher mPFC oscillations and slower reaction times during conflict. In order to test whether theta band coherence between the mPFC and the STN underlies adjustments to conflict and to errors, we simultaneously recorded mPFC and STN electrophysiological activity while DBS patients performed an arrowed flanker task. These recordings revealed higher theta phase coherence between the two sites during the high conflict trials relative to the low conflict trials. These differences were observed soon after conflicting arrows were displayed, but before a response was executed. Furthermore, trials that occurred after an error was committed showed higher phase coherence relative to trials that followed a correct trial, suggesting that mPFC–STN connectivity may also play a role in error related adjustments in behavior. Interestingly, the phase coherence we observed occurred before increases in theta power, implying that the theta phase and power may influence behavior at separate times during cortical monitoring. Finally, we showed that pre-stimulus differences in STN theta power were related to the reaction time on a given trial, which may help adjust behavior based on the probability of observing conflict during a task.

title: An EEG coherence-based analysis approach for investigating response conflict processes in 7 and 9-year old children
abstract: Understanding the development of the brain's neural networks can reveal critical insights into the cognitive changes that occur from infancy to late childhood. Behavioural metrics including: task accuracy, stimuli recognition, and reaction time show dramatic changes over childhood. In this study we investigated response control using the Erikson Flanker task. In a dataset of 45 EEG recordings, we calculated spectral coherence to measure connectivity between all possible electrode pairs. Coherence measures were performed on two different trial conditions -congruent (where there is no response conflict) and incongruent (where response conflict is induced). The increase in incongruent coherence compared to the congruent was investigated for each electrode pair over 45 healthy subjects aged seven years. The same calculation was then performed on the same group of subjects two years later when they were aged nine years. The results revealed that at age seven years, increased coherence was detected in the left prefrontal to right and left parieto-occipital - i.e. an anatomical region located between the parietal and occipital lobes - within theta band. No increase was found for the older group-at age nine years- which may indicate cognitive development in conflict processing mechanism.

title: Occipital alpha power reveals fast attentional inhibition of incongruent distractors.
abstract: Recent associative models of cognitive control hypothesize that cognitive control can be learned (optimized) for task-specific settings via associations between perceptual, motor, and control representations, and, once learned, control can be implemented rapidly. Midfrontal brain areas signal the need for control, and control is subsequently implemented by biasing sensory representations, boosting or suppressing activity in brain areas processing task-relevant or task-irrelevant information. To assess the timescale of this process, we employed EEG. In order to pinpoint control implementation in specific sensory areas, we used a flanker task with incongruent flankers shown in only one hemifield (congruent flankers in the other hemifield) isolating their processing in the contralateral hemisphere. ERPs revealed fast modulations specifically in visual processing areas contralateral to the incongruent flankers. To test whether these modulations reflect increased or decreased processing of incongruent flankers, we investigated alpha power, a marker for attentional inhibition. Importantly, we show increased alpha power over visual areas processing incongruent flankers from 300 to 500 ms poststimulus onset. This suggests fast cognitive control by attentional inhibition for information disrupting goal-oriented actions. Additionally, we show that midfrontal theta earlier in the trial is also modulated by incongruency, and that theta power predicts subsequent alpha power modulations. This supports the hypothesis that midfrontal incongruency detection leads to control implementation, and reveals that these mechanisms take place on a fast, within-trial timescale.

title: Differential Oscillatory Electroencephalogram Between Attention-Deficit/Hyperactivity Disorder Subtypes and Typically Developing Adolescents
abstract: A neurobiological-based classification of attention-deficit/hyperactivity disorder (ADHD) subtypes has thus far remained elusive. The aim of this study was to use oscillatory changes in the electroencephalogram (EEG) related to informative cue processing, motor preparation, and top-down control to investigate neurophysiological differences between typically developing (TD) adolescents, and those diagnosed with predominantly inattentive (IA) or combined (CB) (associated with symptoms of inattention as well as impulsivity/hyperactivity) subtypes of ADHD.



The EEG was recorded from 57 rigorously screened adolescents (12 to 17 years of age; 23 TD, 17 IA, and 17 CB), while they performed a cued flanker task. We examined the oscillatory changes in theta (3-5 Hz), alpha (8-12 Hz), and beta (22-25 Hz) EEG bands after cues that informed participants with which hand they would subsequently be required to respond.



Relative to TD adolescents, the IA group showed significantly less postcue alpha suppression, suggesting diminished processing of the cue in the visual cortex, whereas the CB group showed significantly less beta suppression at the electrode contralateral to the cued response hand, suggesting poor motor planning. Finally, both ADHD subtypes showed weak functional connectivity between frontal theta and posterior alpha, suggesting common top-down control impairment.



We found both distinct and common task-related neurophysiological impairments in ADHD subtypes. Our results suggest that task-induced changes in EEG oscillations provide an objective measure, which in conjunction with other sources of information might help distinguish between ADHD subtypes and therefore aid in diagnoses and evaluation of treatment.

title: Coherence in children with Attention-Deficit/Hyperactivity Disorder and excess beta activity in their EEG
abstract: This study investigated differences in coherence measures between two groups of children with Attention-Deficit/Hyperactivity Disorder (ADHD) - with the typical EEG profile (increased theta and decreased beta activity), and with excess beta activity - and a normal control group.



Thirty-four children with ADHD were included in each of the typical and excess beta groups, and were age and sex matched with 34 control subjects. EEG was recorded from 21 sites during an eyes-closed resting condition. Wave-shape coherence was calculated for eight intrahemispheric and eight interhemispheric electrode pairs, for the delta, theta, alpha and beta bands.



In comparison to the controls, the typical ADHD group primarily had increased intrahemispheric theta and beta coherence at short-medium inter-electrode distances, and increased interhemispheric coherence for theta in the frontal and central/parietal/occipital regions. Their laterality effect for interhemispheric short-medium inter-electrode distances was reduced in the theta band. Differences between the excess beta group and the control group were primarily found in laterality of the intrahemispheric theta coherence at short-medium electrode distances, and increased interhemispheric theta coherence in the frontal regions. Reduced delta coherence in the temporal regions was also found.



These results suggest that ADHD children with excess beta power have an underlying brain dysfunction in the frontal lobes which is found in common with children with the typical EEG profile. However a number of qualitative differences exist which could be associated with other aspects of the ADHD diagnosis or another comorbid condition.



This is the first study to investigate EEG coherence in ADHD children who have increased beta power.

title: EEG coherence in girls with attention-deficit/hyperactivity disorder: stimulant effects in good responders.
abstract: This study investigated the effects of stimulants on EEG coherence in girls with Attention-Deficit/Hyperactivity Disorder (AD/HD). Twenty girls with AD/HD (aged 7-12) and 20 age- and sex-matched controls had an eyes-closed resting electroencephalogram (EEG) recorded from 21 electrode sites. Coherence was calculated from eight intrahemispheric electrode pairs (four in each hemisphere), and eight interhemispheric electrode pairs, for the delta, theta, alpha and beta frequency bands. AD/HD participants were tested twice: first, prior to medication being prescribed, and second, six months later on a therapeutic dose of a stimulant. With intrahemispheric coherences at short-medium inter-electrode distances, AD/HD girls off-medication had reduced lateralisation in the delta, theta and alpha bands. They also had reduced lateralisation in the theta band for longer inter-electrode distances, and increased frontal interhemispheric coherences in all frequency bands. Medication had no impact on the laterality anomalies, but produced novel increases in intrahemispheric coherences at short-medium inter-electrode distances, which reached significance in the delta band and approached significance in the alpha band. However, these increased coherences remained indistinguishable from control levels. Reduced hemispheric lateralisations found in these AD/HD participants illustrate cortical abnormalities consistent with maturational lag explanations. The widespread elevated frontal interhemispheric coherences found in these AD/HD girls could reflect the narrow profile of female medication responders identified in clinical settings. The lack of substantial coherence medication effects in good clinical responders supports a previous medication study with AD/HD boys, and suggests that these coherence anomalies reflect structural, rather than solely functional, differences in brain development in AD/HD.

title: EEG coherence adjusted for inter-electrode distance in children with attention-deficit/hyperactivity disorder.
abstract: Cognition and behaviour depend on the integration of activity in different brain regions, and hence study of the coupling between regions is useful in understanding dysfunctional processes involved in disorders such as attention-deficit/hyperactivity disorder (AD/HD). Such coupling can be estimated by the electroencephalographic (EEG) coherence between scalp electrodes. However, EEG coherence between two points is strongly affected by the distance between them, being inflated by volume conduction effects at short distances and reduced by signal phase differences at larger distances. These distance effects preclude simple comparison of coherence estimates involving different inter-electrode distances. Our group recently introduced a procedure for adjusting coherence measures to remove such distance effects, and explored its potential using normal children. In this study we applied that coherence adjustment procedure to groups of children with AD/HD of the combined (AD/HDcom) and predominantly inattentive (AD/HDin) subtypes, and compared them with a control group. All groups were age- and gender-matched. AD/HD children were found to have a reciprocal pattern of coherence disturbance in the cortico-cortical circuits involved in slow and fast wave activity-elevated slow-wave coherences and reduced fast-wave coherences. This disturbance was larger for inter-hemispheric than intra-hemispheric coherences, and varied markedly with region, suggesting a complex pattern of coherence anomalies with a substantial frontal focus. This complex pattern differed little between subtypes, suggesting that it may constitute the fundamental dysfunction underlying the inattention common to both groups. In contrast, coherence was globally elevated in children with AD/HDcom compared with both AD/HDin and control children. This elevation in coherence may be directly related to the hyperactivity and impulsivity unique to that subtype. Further research using the coherence adjustment procedure appears useful in elucidating the electrophysiological anomalies underlying AD/HD and other disorders.

title: Functional connectivity of frontal cortex in healthy and ADHD children reflected in EEG coherence.
abstract: Abnormal functional brain connectivity is a candidate factor in developmental brain disorders associated with cognitive dysfunction. We analyzed a substantial (10 min per subject) record of dense array electroencephalography with spectral power and coherence methods in attention-deficit hyperactivity disorder (ADHD) (n = 42) and control (n = 21) 10- to 13-year-old children. We found topographically distinct narrow band coherence differences between subject groups: ADHD subjects showed elevated coherence in the lower alpha (8 Hz) band and reduced coherence in the upper alpha (10-11 Hz) band. The 8-Hz ADHD elevation and a 2- to 6-Hz control group coherence elevation were independent of stimulus presentation. In response to visual stimulation, the ADHD group exhibited reduced evoked potential power and elevated frontal coherence. Only the upper alpha band control group coherence elevation discriminated according to ADHD group medication status. The findings suggest a static state of deficient connectivity in ADHD and a stimulus-induced state of overconnectivity within and between frontal hemispheres.

title: Identifying true brain interaction from EEG data using the imaginary part of coherency
abstract: The main obstacle in interpreting EEG/MEG data in terms of brain connectivity is the fact that because of volume conduction, the activity of a single brain source can be observed in many channels. Here, we present an approach which is insensitive to false connectivity arising from volume conduction.



We show that the (complex) coherency of non-interacting sources is necessarily real and, hence, the imaginary part of coherency provides an excellent candidate to study brain interactions. Although the usual magnitude and phase of coherency contain the same information as the real and imaginary parts, we argue that the Cartesian representation is far superior for studying brain interactions. The method is demonstrated for EEG measurements of voluntary finger movement.



We found: (a) from 5 s before to movement onset a relatively weak interaction around 20 Hz between left and right motor areas where the contralateral side leads the ipsilateral side; and (b) approximately 2-4 s after movement, a stronger interaction also at 20 Hz in the opposite direction.



It is possible to reliably detect brain interaction during movement from EEG data.



The method allows unambiguous detection of brain interaction from rhythmic EEG/MEG data.

title: EEG coherency. I: Statistics, reference electrode, volume conduction, Laplacians, cortical imaging, and interpretation at multiple scales.
abstract: Several methodological issues which impact experimental design and physiological interpretations in EEG coherence studies are considered, including reference electrode and volume conduction contributions to erroneous coherence estimates. A new measure, 'reduced coherency', is introduced as the difference between measured coherency and the coherency expected from uncorrelated neocortical sources, based on simulations and analytic-statistical studies with a volume conductor model. The concept of reduced coherency is shown to be in semi-quantitative agreement with experimental EEG data. The impact of volume conduction on statistical confidence intervals for coherence estimates is discussed. Conventional reference, average reference, bipolar, Laplacian, and cortical image coherencies are shown to be partly independent measures of neocortical dynamic function at different spatial scales, due to each method's unique spatial filtering of intracranial source activity.

title: Complex network measures of brain connectivity: Uses and interpretations
abstract: Brain connectivity datasets comprise networks of brain regions connected by anatomical tracts or by functional associations. Complex network analysis-a new multidisciplinary approach to the study of complex systems-aims to characterize these brain networks with a small number of neurobiologically meaningful and easily computable measures. In this article, we discuss construction of brain networks from connectivity data and describe the most commonly used network measures of structural and functional connectivity. We describe measures that variously detect functional integration and segregation, quantify centrality of individual brain regions or pathways, characterize patterns of local anatomical circuitry, and test resilience of networks to insult. We discuss the issues surrounding comparison of structural and functional network connectivity, as well as comparison of networks across subjects. Finally, we describe a Matlab toolbox (http://www.brain-connectivity-toolbox.net) accompanying this article and containing a collection of complex network measures and large-scale neuroanatomical connectivity datasets.

title: Small-World Brain Functional Networks in Children With Attention-Deficit/Hyperactivity Disorder Revealed by EEG Synchrony
abstract: We investigated the topologic properties of human brain attention-related functional networks associated with Multi-Source Interference Task (MSIT) performance using electroencephalography (EEG). Data were obtained from 13 children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and 13 normal control children. Functional connectivity between all pairwise combinations of EEG channels was established by calculating synchronization likelihood (SL). The cluster coefficients and path lengths were computed as a function of degree K. The results showed that brain attention functional networks of normal control subjects had efficient small-world topologic properties, whereas these topologic properties were altered in ADHD. In particular, increased local characteristics combined with decreased global characteristics in ADHD led to a disorder-related shift of the network topologic structure toward ordered networks. These findings are consistent with a hypothesis of dysfunctional segregation and integration of the brain in ADHD, and enhance our understanding of the underlying pathophysiologic mechanism of this illness.

title: The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies
abstract: This study examined the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood.  We analyzed data from published follow-up studies of ADHD. To be included in the analysis, these additional studies had to meet the following criteria: the study included a control group and it was clear from the methods if the diagnosis of ADHD included subjects who did not meet full criteria but showed residual and impairing signs of the disorder. We used a meta-analysis regression model to separately assess the syndromatic and symptomatic persistence of ADHD.  When we define only those meeting full criteria for ADHD as having ‘persistent ADHD’, the rate of persistence is low, ~15% at age 25 years. But when we include cases consistent with DSM-IV's definition of ADHD in partial remission, the rate of persistence is much higher, ~65%.  Our results show that estimates of ADHD's persistence rely heavily on how one defines persistence. Yet, regardless of definition, our analyses show that evidence for ADHD lessens with age. More work is needed to determine if this reflects true remission of ADHD symptoms or is due to the developmental insensitivity of diagnostic criteria for the disorder.

title: Defining ADHD symptom persistence in adulthood: optimizing sensitivity and specificity
abstract: Longitudinal studies of children diagnosed with ADHD report widely ranging ADHD persistence rates in adulthood (5-75%). This study documents how information source (parent vs. self-report), method (rating scale vs. interview), and symptom threshold (DSM vs. norm-based) influence reported ADHD persistence rates in adulthood.



Five hundred seventy-nine children were diagnosed with DSM-IV ADHD-Combined Type at baseline (ages 7.0-9.9 years) 289 classmates served as a local normative comparison group (LNCG), 476 and 241 of whom respectively were evaluated in adulthood (Mean Age = 24.7). Parent and self-reports of symptoms and impairment on rating scales and structured interviews were used to investigate ADHD persistence in adulthood.



Persistence rates were higher when using parent rather than self-reports, structured interviews rather than rating scales (for self-report but not parent report), and a norm-based (NB) threshold of 4 symptoms rather than DSM criteria. Receiver-Operating Characteristics (ROC) analyses revealed that sensitivity and specificity were optimized by combining parent and self-reports on a rating scale and applying a NB threshold.



The interview format optimizes young adult self-reporting when parent reports are not available. However, the combination of parent and self-reports from rating scales, using an 'or' rule and a NB threshold optimized the balance between sensitivity and specificity. With this definition, 60% of the ADHD group demonstrated symptom persistence and 41% met both symptom and impairment criteria in adulthood.

title: Growing out of attention deficit hyperactivity disorder: Insights from the ‘remitted’ brain
abstract: HighlightsWe review neuroimaging studies of adults who have remitted from childhood ADHD.Most studies find adult remitters show neural features indistinguishable from controls.Fewer studies find that remission arises due to compensatory neural re‐organization.Some deep brain anomalies may persist from childhood even in those who remit.  We consider developmental and cognitive models to explain why some children ‘grow out’ of attention deficit hyperactivity disorder (ADHD) by adulthood. The first model views remission as a convergence towards more typical brain function and structure. In support, some studies find that adult remitters are indistinguishable from those who were never affected in the neural substrates of ‘top‐down’ mechanisms of cognitive control, some ‘bottom‐up’ processes of vigilance/response preparation, prefrontal cortical morphology and intrinsic functional connectivity. A second model postulates that remission is driven by the recruitment of new brain systems that compensate for ADHD symptoms. It draws support from demonstrations of atypical, but possibly beneficial, patterns of connectivity within the cognitive control network in adult remitters. The final model holds that some childhood ADHD anomalies show lifelong persistence, regardless of adult outcome, supported by shared reports of anomalies in remitters and persisters in posterior cerebral and striato‐thalamic regions. The models are compatible: different processes driving remission might occur in different brain regions. These models provide a framework for future studies which might inform novel treatments to ‘accelerate’ remission.

title: Live fast, die young? A review on the developmental trajectories of ADHD across the lifespan
abstract: Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.

title: Trajectories of Cerebral Cortical Development in Childhood and Adolescence and Adult Attention-Deficit/Hyperactivity Disorder
abstract: Childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. Herein, we link the trajectories of cerebral cortical development during childhood and adolescence with the severity of adult ADHD.



Using a longitudinal study design, 92 participants with ADHD had childhood (mean 10.7 years, SD 3.3) and adult clinical assessments (mean 23.8 years, SD 4.3) with repeated neuroanatomic magnetic resonance imaging. Contrast was made against 184 matched typically developing volunteers.



Attention-deficit/hyperactivity disorder persisted in 37 (40%) subjects and adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm (SE = .0004, t = 4.2, p < .0001), representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning (greater than -.007 mm/year) was found exclusively among individuals who remitted.



Adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD.

title: Cognitive and neurophysiological markers of ADHD persistence and remission
abstract: Attention-deficit hyperactivity disorder (ADHD) persists in around two-thirds of individuals in adolescence and early adulthood.  To examine the cognitive and neurophysiological processes underlying the persistence or remission of ADHD.  Follow-up data were obtained from 110 young people with childhood ADHD and 169 controls on cognitive, electroencephalogram frequency, event-related potential (ERP) and actigraph movement measures after 6 years.  ADHD persisters differed from remitters on preparation-vigilance measures (contingent negative variation, delta activity, reaction time variability and omission errors), IQ and actigraph count, but not on executive control measures of inhibition or working memory (nogo-P3 amplitudes, commission errors and digit span backwards).  Preparation-vigilance measures were markers of remission, improving concurrently with ADHD symptoms, whereas executive control measures were not sensitive to ADHD persistence/remission. For IQ, the present and previous results combined suggest a role in moderating ADHD outcome. These findings fit with previously identified aetiological separation of the cognitive impairments in ADHD. The strongest candidates for the development of non-pharmacological interventions involving cognitive training and neurofeedback are the preparation-vigilance processes that were markers of ADHD remission.

title: White Matter Alterations at 33-Year Follow-Up in Adults with Childhood Attention-Deficit/Hyperactivity Disorder
abstract: Attention-deficit/hyperactivity disorder (ADHD) is increasingly conceived as reflecting altered functional and structural brain connectivity. The latter can be addressed with diffusion tensor imaging (DTI). We examined fractional anisotropy (FA), a DTI index related to white matter structural properties, in adult male subjects diagnosed with ADHD in childhood (probands) and matched control subjects without childhood ADHD. Additionally, we contrasted FA among probands with and without current ADHD in adulthood and control subjects.



Participants were from an original cohort of 207 boys and 178 male control subjects. At 33-year follow-up, analyzable DTI scans were obtained in 51 probands (41.3 ± 2.8 yrs) and 66 control subjects (41.2 ± 3.1 yrs). Voxel-based FA was computed with tract-based spatial statistics, controlling for multiple comparisons.



Probands with childhood ADHD exhibited significantly lower FA than control subjects without childhood ADHD in the right superior and posterior corona radiata, right superior longitudinal fasciculus, and in a left cluster including the posterior thalamic radiation, the retrolenticular part of the internal capsule, and the sagittal stratum (p<.05, corrected). Fractional anisotropy was significantly decreased relative to control subjects in several tracts in both probands with current and remitted ADHD, who did not differ significantly from each other. Fractional anisotropy was not significantly increased in probands in any region.



Decreased FA in adults with childhood ADHD regardless of current ADHD might be an enduring trait of ADHD. White matter tracts with decreased FA connect regions involved in high-level as well as sensorimotor functions, suggesting that both types of processes are involved in the pathophysiology of ADHD.

title: Neuropsychological Weaknesses in Adult ADHD; Cognitive Functions as Core Deficit and Roles of Them in Persistence to Adulthood
abstract: Prior investigations have shown that individuals with attention deficit hyperactivity disorder (ADHD) have impaired neuropsychological functions. This study had two aims, first to investigate weakened cognitive functions in adult ADHD (aADHD), and second, to investigate difference between persisters (those having persistently ongoing ADHD diagnosis in adulthood), and remitters (those having ADHD diagnosis only in childhood and not in adulthood), in terms of cognitive deficits. We evaluated performance on a comprehensive neuropsychological battery in three groups including 34 persisters, 35 remitters, and 35 healthy control group (absence of childhood and adulthood ADHD diagnosis). Our findings showed that adults with ADHD have inefficient attention, interference control and set-shifting functions, which may be revealed on neuropsychological tests that require greater cognitive demand. Given the finding that interference control deficit exists across the lifespan in people with ADHD, we suggest that interference control-associated functional weakness may be a core deficit for ADHD. (JINS, 2012, 18, 1–8)

title: Are cognitive deficits in attention deficit/hyperactivity disorder related to the course of the disorder? A prospective controlled follow-up study of grown up boys with persistent and remitting course
abstract: To investigate the longitudinal course of cognitive functions in boys with persistent and remittent attention deficit/hyperactivity disorder (ADHD) from childhood into young adult years. Males (n=217) 15-31 years with and without ADHD were assessed at 3 time points over 10 years into young adulthood. Subjects were stratified into Remittent ADHD, and Persistent ADHD based on the course of ADHD. Cognitive domains included: 1) overall IQ (overall IQ, block design IQ, vocabulary IQ); 2) achievement scores in reading and math and measures of executive function (Wechsler arithmetic, digit span, digit symbol, Rey-Osterrieth, Wisconsin Card Sorting Test, and the Stroop Test). Cognitive outcomes were modeled as a function of group (Controls, Remittent ADHD, and Persistent ADHD), age, group by age interaction, and any demographic confounders using linear growth-curve models. There were no significant interaction effects of group by time. Main group effects indicated that persistent and remittent ADHD groups both had significantly lower scores on all cognitive outcomes compared with controls, and these did not differ between the ADHD subgroups Psychometrically defined cognitive deficits are relatively stable into young adult years and appear to be independent of the course of ADHD. More work is needed to help define the implications of these deficits in individuals with a remitting course of ADHD.

title: The persistence of cognitive deficits in remitted and unremitted ADHD: a case for the state-independence of response inhibition
abstract: Response inhibition, working memory, and response variability are possible endophenotypes of ADHD based on their association with the disorder and evidence of heritability. One of the critical although rarely studied criteria for a valid endophenotype is that it persists despite waxing and waning of the overt manifestations of the disorder, a criterion known as state-independence. This study examined whether these aspects of cognition exhibit state-independence in ADHD.  One hundred and seventy-nine children diagnosed with ADHD in a rigorous baseline assessment were contacted for follow-up assessment in adolescence. Of this sample, 130 (73%) were reascertained. At follow-up, children previously diagnosed with ADHD were identified as remittent (n = 24), persistent (n = 64), or in partial remission (n = 42) based on symptoms and impairment of the disorder. Response inhibition, working memory, and response variability were assessed both in childhood (baseline) and adolescence (follow-up) and were compared with age-matched controls (40 children and 28 adolescents) seen at either time point.  Relative to controls, ADHD children showed baseline deficits in response inhibition, working memory, and response variability. Only the group difference in response inhibition remained significant in adolescence. In general, cognitive performance among ADHD participants improved with age and did so regardless of changes in ADHD symptoms and impairment. Within the ADHD group, however, cognitive performance in childhood and in adolescence did not differ amongst those with persistent, remittent, and partially remittent forms of the disorder.  Results demonstrate that response inhibition not only distinguishes ADHD children from their unaffected peers but is also state-independent, such that deficits remain present irrespective of changes in the disease phenotype. In other words, inhibitory deficits measured in childhood persist into adolescence even when the ADHD phenotype remits. These findings provide further evidence that the ability to stop prepotent actions is an endophenotype of ADHD.

title: Peripheral Hypoarousal but Not Preparation-Vigilance Impairment Endures in ADHD Remission
abstract: This study investigates whether impairments associated with persistent ADHD—impaired attention allocation (P3 amplitude), peripheral hypoarousal (skin conductance level [SCL]), and adjustment in preparatory state (contingent negative variation [CNV])—reflect enduring deficits unrelated to ADHD outcome or are markers of ADHD remission.  Young people with childhood ADHD (73 persisters and 18 remitters) and 144 controls were compared on neurophysiological measures during two conditions (baseline and fast-incentive) of a four-choice reaction time task.  ADHD remitters differed from persisters, and were indistinguishable from controls, on baseline P3 amplitude and fast-incentive CNV amplitude (p ≤ .05). ADHD remitters differed from controls (p ≤ .01), and were indistinguishable from persisters (p > .05), on baseline SCL.  Preparation-vigilance measures were markers of ADHD remission, confirming previous findings with other measures. Yet, SCL-measured peripheral hypoarousal emerges as an enduring deficit unrelated to ADHD improvement. Future studies should explore potential compensatory mechanisms that enable efficient preparation-vigilance processes in ADHD remitters.

title: Thalamo-cortical activation and connectivity during response preparation in adults with persistent and remitted ADHD.
abstract: The neural correlates of stimulus-driven processes, such as response preparation, have been posited to be associated with the onset of attention deficit hyperactivity disorder (ADHD) while being distinct from the neural mechanisms associated with recovery. The authors tested this hypothesis in adults with remitted and persistent ADHD.



Thirty-eight young adults who were diagnosed with combined-type ADHD in childhood (probands) and 32 carefully matched comparison subjects were followed longitudinally and scanned with functional MRI while performing an event-related cued reaction time task. Probands were characterized as individuals with persistent or remitted ADHD. Differences in thalamo-cortical activation and functional connectivity during response preparation between comparison subjects and probands and between individuals with persistent ADHD and those with remitted ADHD were assessed by contrasting neural activation and functional connectivity during cue or noncue events.



Probands exhibited less cue-related activation than comparison subjects in the thalamus, anterior cingulate cortex, supplementary motor area, inferior parietal lobe, and dorsolateral prefrontal cortex despite similar overall patterns of activation. There were no differences in activation between individuals in the remitted ADHD group and those in the persistent ADHD group in any hypothesized regions. However, cue-related functional connectivity between the right thalamus and brainstem was greater in comparison subjects relative to probands, and cue-related connectivity was greater between the right thalamus and prefrontal regions in individuals with remitted ADHD relative to those with persistent ADHD.



Decreased thalamo-cortical activation during response preparation was present in adults diagnosed with ADHD in childhood regardless of symptom remission in adulthood, and may be partly driven by less functional coordination between the brainstem and thalamus. Greater functional integration of the thalamo-cortical network might parallel symptom recovery.

title: Separation of cognitive impairments in attention-deficit/hyperactivity disorder into 2 familial factors.
abstract: Attention-deficit/hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots or separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations.



To determine, by using a multivariate familial factor analysis approach, whether 1 or more familial factors underlie the slow and variable reaction times, impaired response inhibition, and choice impulsivity associated with ADHD.



An ADHD and control sibling-pair design.



Belgium, Germany, Ireland, Israel, Spain, Switzerland, and the United Kingdom.



A total of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with combined-subtype ADHD), and 345 control participants.



Performance on a 4-choice reaction time task, a go/no-go inhibition task, and a choice-delay task.



The final model consisted of 2 familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98% to 100% of the familial influences on mean reaction time and reaction time variability. The second, smaller factor, reflecting 13% of the familial variance of ADHD, captured 62% to 82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model because of poor fit.



The findings suggest the existence of 2 familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the 2 cognitive impairments is consistent with recent theoretical models--a developmental model and an arousal-attention model--of 2 separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally sensitive interventions.

title: The Etiological Structure of Cognitive-Neurophysiological Impairments in ADHD in Adolescence and Young Adulthood
abstract: Previous studies in children with ADHD identified two partially separable familial factors underlying cognitive dysfunction, but evidence in adolescents and adults is lacking. Here, we investigate the etiological structure of cognitive-neurophysiological impairments in ADHD in adolescents and young adults.  Factor analyses and multivariate familial models were run in 356 participants from ADHD and control sibling pairs aged 11 to 27 years on data on IQ, digit span forward (DSF) and backward (DSB), and cognitive-performance and event-related potential (ERP) measures from three cognitive tasks.  Three familial factors (cF1-3), showing substantial familial overlap with ADHD, captured the familial covariation of ADHD with nine cognitive-ERP measures. cF1 loaded on IQ, mean reaction time (MRT), and reaction-time variability (RTV); cF2 on DSF and DSB; and cF3 on number of errors and ERPs of inhibition and error processing.  These results identify three partially separable etiological pathways leading to cognitive-neurophysiological impairments in adolescent and adult ADHD.

title: Childhood predictors of adolescent and young adult outcome in ADHD.
abstract: Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood, but it remains unclear which childhood factors predict future outcome.



To identify childhood predictors of ADHD outcome using both dimensional and categorical approaches.



116 adolescents and young adults with childhood ADHD were followed up on average 6.6 years later. ADHD outcome variables were interview-based parent-reported ADHD symptoms and impairment. Childhood predictors included parent- and teacher-rated ADHD symptoms and co-occurring behaviours; actigraph measures of activity level; socio-economic status (SES); and cognitive measures previously associated with ADHD.



Of the sample, 79% continued to meet clinical criteria of ADHD in adolescence and young adulthood. Higher parent-rated ADHD symptoms and movement intensity in childhood, but not teacher-rated symptoms, predicted ADHD symptoms at follow up. Co-occurring symptoms of oppositional behaviours, anxiety, social and emotional problems were also significant predictors, but these effects disappeared after controlling for ADHD symptoms. IQ and SES were significant predictors of both ADHD symptoms and impairment at follow up, but no other cognitive measures significantly predicted outcome.



SES and IQ emerge as potential moderators for the prognosis of ADHD. Childhood severity of ADHD symptoms, as measured by parent ratings and actigraph movement intensity, also predicts later ADHD outcome. These factors should be considered when identifying ADHD children at most risk of poor long-term outcomes and for the development of interventions to improve prognosis.

title: Criteria and concurrent validity of DIVA 2.0: A semi-structured diagnostic interview for adult ADHD
abstract: Attention Deficit Hyperactivity Disorder (ADHD) prevalence in the general adult population is estimated to be between 2–4%. Despite the high prevalence, until recently there was only one validated semi-structured interview available for the accurate diagnostic assessment of ADHD within the adult population: the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID).  To examine the concurrent validity of the DIVA 2.0 interview comparing the diagnostic rate with the CAADID interview. To analyse the criterion validity of the DIVA 2.0 in the Spanish language in an adult sample.  The aim of this is to study was to evaluate criterion validity of the DIVA 2.0 in an adult sample comparing with the CAADID and other ADHD severity scales.  A transversal study was performed to check the criteria and concurrent validity of the DIVA 2.0 compared to the CAADID.  Forty patients were recruited in an adult ADHD program at a university hospital. The DIVA 2.0 interview showed a diagnostic accuracy of 100% when compared with the diagnoses obtained with the CAADID interview and goods correlations with three self-reported rating scales: the WURS, the ADHD Rating Scale and Sheehan's’ Dysfunction Inventory.  The DIVA 2.0 has good psychometric properties and is a reliable tool for the assessment of ADHD in adults. Disclosure of interest The authors have not supplied their declaration of competing interest.

title: Attention-deficit hyperactivity disorder : a clinical workbook
abstract: ADHD fact sheet forms for use with children and adolescents forms for the evaluation of adults forms for use during medication treatment.

title: Self-report of ADHD shows limited agreement with objective markers of persistence and remittance
abstract: A controversial issue is whether self-report of symptoms and impairment is sufficient for diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adolescents and adults in the absence of other informants, such as parents. The present study investigated how well self-report is reflected by cognitive-neurophysiological and actigraph measures, which we have previously shown to discriminate between ADHD persisters, remitters and controls using parent-report (Cheung et al., 2015; ).  Parent- and self-reported ADHD symptoms and impairment, together with cognitive, electroencephalogram (EEG) frequency, event-related potential (ERP) and actigraph measures were obtained from 108 adolescents and young adults with childhood ADHD and 167 controls.  Participants reported lower levels of ADHD symptoms and impairments than parents (p < 0.05) and the ADHD persistence rate based on self-report was low at 44%, compared to the persistence rate of 79% previously reported based on parent-report. Regression analyses showed that the objective measures distinguished poorly between ADHD persistent and remittent groups based on self-report, in contrast to findings based on parent-report (Cheung et al., 2015), although the measures differentiated well between ADHD persisters and controls. Correlation analyses revealed that self-reported impairment significantly correlated with fewer of the objective measures, despite parent- and self-reported symptoms showing similar correlations with the measures.  The findings show that self-reported ADHD outcome is not as well reflected by cognitive-neurophysiological and movement correlates as we previously found for parent-reported ADHD.

title: Action Monitoring in Boys With Attention-Deficit/Hyperactivity Disorder, Their Nonaffected Siblings, and Normal Control Subjects: Evidence for an Endophenotype
abstract: Attention-deficit/hyperactivity disorder (ADHD) is a very common and highly heritable child psychiatric disorder associated with dysfunctions in fronto-striatal networks that control attention and response organization. The aim of this study was to investigate whether features of action monitoring related to dopaminergic functions represent endophenotypes that are brain functions on the pathway from genes and environmental risk factors to behavior.



Action monitoring and error processing as indicated by behavioral and electrophysiological parameters during a flanker task were examined in boys with ADHD combined type according to DSM-IV (n = 68), their nonaffected siblings (n = 18), and healthy control subjects with no known family history of ADHD (n = 22).



Boys with ADHD displayed slower and more variable reaction-times. Error negativity (Ne) was smaller in boys with ADHD compared with healthy control subjects, whereas nonaffected siblings displayed intermediate amplitudes following a linear model predicted by genetic concordance. The three groups did not differ on error positivity (Pe). The N2 amplitude enhancement due to conflict (incongruent flankers) was reduced in the ADHD group. Nonaffected siblings also displayed intermediate N2 enhancement.



Converging evidence from behavioral and event-related potential findings suggests that action monitoring and initial error processing, both related to dopaminergically modulated functions of anterior cingulate cortex, might be an endophenotype related to ADHD.

title: Performance monitoring is altered in adult ADHD: A familial event-related potential investigation
abstract: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. Electrophysiological studies in children with ADHD provide evidence for abnormal performance monitoring processes and familial association of these processes with ADHD. It is not yet known whether these processes show the same abnormalities and familial effects in adults.



We investigated event-related potential (ERP) indices of performance monitoring in adults with ADHD compared to age matched control participants. We subsequently investigated whether the ERP indices showed a familial association with ADHD by investigating these processes in first degree relatives of children with ADHD. This was achieved using an arrow flanker task presented to 21 adults with ADHD, 20 fathers of children with ADHD and 20 control participants.



Compared to the control group, both adults with ADHD and fathers of children with ADHD displayed significantly weaker error and conflict monitoring, as indexed by the smaller error negativity (Ne) and the N2 components. These two components were highly correlated within each of the three groups (r=0.53-0.65). The groups did not differ on the error positivity (Pe).



These findings closely resemble those previously found in children with ADHD, suggesting that conflict monitoring and early error processing are also abnormal in adults with ADHD; and share familial influences with ADHD throughout the lifespan. The relationship between different indices of performance monitoring may suggest partly common underlying mechanisms or modulators.

title: Removing electroencephalographic artifacts by blind source separation.
abstract: Eye movements, eye blinks, cardiac signals, muscle noise, and line noise present serious problems for electroencephalographic (EEG) interpretation and analysis when rejecting contaminated EEG segments results in an unacceptable data loss. Many methods have been proposed to remove artifacts from EEG recordings, especially those arising from eye movements and blinks. Often regression in the time or frequency domain is performed on parallel EEG and electrooculographic (EOG) recordings to derive parameters characterizing the appearance and spread of EOG artifacts in the EEG channels. Because EEG and ocular activity mix bidirectionally, regressing out eye artifacts inevitably involves subtracting relevant EEG signals from each record as well. Regression methods become even more problematic when a good regressing channel is not available for each artifact source, as in the case of muscle artifacts. Use of principal component analysis (PCA) has been proposed to remove eye artifacts from multichannel EEG. However, PCA cannot completely separate eye artifacts from brain signals, especially when they have comparable amplitudes. Here, we propose a new and generally applicable method for removing a wide variety of artifacts from EEG records based on blind source separation by independent component analysis (ICA). Our results on EEG data collected from normal and autistic subjects show that ICA can effectively detect, separate, and remove contamination from a wide variety of artifactual sources in EEG records with results comparing favorably with those obtained using regression and PCA methods. ICA can also be used to analyze blink-related brain activity.

title: Discovering oscillatory interaction networks with M/EEG: challenges and breakthroughs
abstract: The systems-level neuronal mechanisms that coordinate temporally, anatomically and functionally distributed neuronal activity into coherent cognitive operations in the human brain have remained poorly understood. Synchronization of neuronal oscillations may regulate network communication and could thus serve as such a mechanism. Evidence for this hypothesis, however, was until recently sparse, as methodological challenges limit the investigation of interareal interactions with non-invasive magneto- and electroencephalography (M/EEG) recordings. Nevertheless, recent advances in M/EEG source reconstruction and clustering methods support complete phase-interaction mappings that are essential for uncovering the large-scale neuronal assemblies and their functional roles. These data show that synchronization is a robust and behaviorally significant phenomenon in task-relevant cortical networks and could hence bind distributed neuronal processing to coherent cognitive states.

title: Information-based modeling of event-related brain dynamics.
abstract: We discuss the theory and practice of applying independent component analysis (ICA) to electroencephalographic (EEG) data. ICA blindly decomposes multi-channel EEG data into maximally independent component processes (ICs) that typically express either particularly brain generated EEG activities or some type of non-brain artifacts (line or other environmental noise, eye blinks and other eye movements, or scalp or heart muscle activity). Each brain and non-brain IC is identified with an activity time course (its 'activation') and a set of relative strengths of its projections (by volume conduction) to the recording electrodes (its 'scalp map'). Many non-articraft IC scalp maps strongly resemble the projection of a single dipole, allowing the location and orientation of the best-fitting equivalent dipole (or other source model) to be easily determined. In favorable circumstances, ICA decomposition of high-density scalp EEG data appears to allow concurrent monitoring, with high time resolution, of separate EEG activities in twenty or more separate cortical EEG source areas. We illustrate the differences between ICA and traditional approaches to EEG analysis by comparing time courses and mean event related spectral perturbations (ERSPs) of scalp channel and IC data. Comparing IC activities across subjects necessitates clustering of similar Ics based on common dynamic and/or spatial features. We discuss and illustrate such a component clustering strategy. In sum, continued application of ICA methods in EEG research should continue to yield new insights into the nature and role of the complex macroscopic cortical dynamics captured by scalp electrode recordings.

title: Mining event-related brain dynamics
abstract: This article provides a new, more comprehensive view of event-related brain dynamics founded on an information-based approach to modeling electroencephalographic (EEG) dynamics. Most EEG research focuses either on peaks 'evoked' in average event-related potentials (ERPs) or on changes 'induced' in the EEG power spectrum by experimental events. Although these measures are nearly complementary, they do not fully model the event-related dynamics in the data, and cannot isolate the signals of the contributing cortical areas. We propose that many ERPs and other EEG features are better viewed as time/frequency perturbations of underlying field potential processes. The new approach combines independent component analysis (ICA), time/frequency analysis, and trial-by-trial visualization that measures EEG source dynamics without requiring an explicit head model.

title: Oscillatory mechanisms of process binding in memory
abstract: A central topic in cognitive neuroscience is the question, which processes underlie large scale communication within and between different neural networks. The basic assumption is that oscillatory phase synchronization plays an important role for process binding--the transient linking of different cognitive processes--which may be considered a special type of large scale communication. We investigate this question for memory processes on the basis of different types of oscillatory synchronization mechanisms. The reviewed findings suggest that theta and alpha phase coupling (and phase reorganization) reflect control processes in two large memory systems, a working memory and a complex knowledge system that comprises semantic long-term memory. It is suggested that alpha phase synchronization may be interpreted in terms of processes that coordinate top-down control (a process guided by expectancy to focus on relevant search areas) and access to memory traces (a process leading to the activation of a memory trace). An analogous interpretation is suggested for theta oscillations and the controlled access to episodic memories.

title: EEG alpha oscillations: The inhibition–timing hypothesis
abstract: The traditional belief is that the event-related alpha response can solely be described in terms of suppression or event-related desynchronization (ERD). Recent research, however, has shown that under certain conditions alpha responds reliably with an increase in amplitudes (event-related synchronization or ERS). ERS is elicited in situations, where subjects withhold or control the execution of a response and is obtained over sites that probably are under, or exert top-down control. Thus, we assume that alpha ERS reflects top-down, inhibitory control processes. This assumption leads over to the timing aspect of our hypothesis. By the very nature of an oscillation, rhythmic amplitude changes reflect rhythmic changes in excitation of a population of neurons. Thus, the time and direction of a change - described by phase - is functionally related to the timing of neuronal activation processes. A variety of findings supports this view and shows, e.g., that alpha phase coherence increases between task-relevant sites and that phase lag lies within a time range that is consistent with neuronal transmission speed. Another implication is that phase reset will be a powerful mechanism for the event-related timing of cortical processes. Empirical evidence suggests that the extent of phase locking is a functionally sensitive measure that is related to cognitive performance. Our general conclusion is that alpha ERS plays an active role for the inhibitory control and timing of cortical processing whereas ERD reflects the gradual release of inhibition associated with the emergence of complex spreading activation processes.

title: Rapid distributed fronto-parieto-occipital processing stages during working memory in humans.
abstract: Cortical potentials were recorded from implanted electrodes during a difficult working memory task requiring rapid storage, modification and retrieval of multiple memoranda. Synchronous event-related potentials were generated in distributed occipital, parietal, Rolandic and prefrontal sites beginning approximately 130 ms after stimulus onset and continuing for >500 ms. Coherent phase-locked, event-related oscillations supported interaction between these dorsal stream structures throughout the task period. The Rolandic structures generated early as well as sustained potentials to sensory stimuli in the absence of movement. Activation peaks and phase lags between synaptic populations suggested that perceptual processing occurred exclusively in the visual association cortex from approximately 90 to 130 ms, with its results projected to fronto-parietal areas for interpretation from approximately 130 to 280 ms. The direction of interaction then appeared to reverse from approximately 300 to 400 ms, consistent with mental arithmetic being performed by fronto-parietal areas operating upon a visual scratch pad in the dorsolateral occipital cortex. A second reversal, from approximately 420 to 600 ms, may have represented an updating of memoranda stored in fronto-parietal sites. Lateralized perisylvian oscillations suggested an articulatory loop. Anterior cingulate activity was evoked by feedback signals indicating errors. These results indicate how a fronto-centro-parietal 'central executive' might interact with an occipital visual scratch pad, perisylvian articulatory loop and limbic monitor to implement the sequential stages of a complex mental operation.

title: Frontoparietal Cortex Controls Spatial Attention through Modulation of Anticipatory Alpha Rhythms
abstract: A dorsal frontoparietal network, including regions in intraparietal sulcus (IPS) and frontal eye field (FEF), has been hypothesized to control the allocation of spatial attention to environmental stimuli. One putative mechanism of control is the desynchronization of electroencephalography (EEG) alpha rhythms (∼8–12 Hz) in visual cortex in anticipation of a visual target. We show that brief interference by repetitive transcranial magnetic stimulation (rTMS) with preparatory activity in right IPS or right FEF while subjects attend to a spatial location impairs identification of target visual stimuli ∼2 s later. This behavioral effect is associated with the disruption of anticipatory (prestimulus) alpha desynchronization and its spatially selective topography in parieto-occipital cortex. Finally, the disruption of anticipatory alpha rhythms in occipital cortex after right IPS- or right FEF-rTMS correlates with deficits of visual identification. These results support the causal role of the dorsal frontoparietal network in the control of visuospatial attention, and suggest that this is partly exerted through the synchronization of occipital visual neurons.

title: Spectral fingerprints of large-scale neuronal interactions
abstract: Cognition results from interactions among functionally specialized but widely distributed brain regions; however, neuroscience has so far largely focused on characterizing the function of individual brain regions and neurons therein. Here we discuss recent studies that have instead investigated the interactions between brain regions during cognitive processes by assessing correlations between neuronal oscillations in different regions of the primate cerebral cortex. These studies have opened a new window onto the large-scale circuit mechanisms underlying sensorimotor decision-making and top-down attention. We propose that frequency-specific neuronal correlations in large-scale cortical networks may be 'fingerprints' of canonical neuronal computations underlying cognitive processes.

title: Structure and function of complex brain networks
abstract: An increasing number of theoretical and empirical studies approach the function of the human brain from a network perspective. The analysis of brain networks is made feasible by the development of new imaging acquisition methods as well as new tools from graph theory and dynamical systems. This review surveys some of these methodological advances and summarizes recent findings on the architecture of structural and functional brain networks. Studies of the structural connectome reveal several modules or network communities that are interlinked by hub regions mediating communication processes between modules. Recent network analyses have shown that network hubs form a densely linked collective called a “rich club,” centrally positioned for attracting and dispersing signal traffic. In parallel, recordings of resting and task-evoked neural activity have revealed distinct resting-state networks that contribute to functions in distinct cognitive domains. Network methods are increasingly applied in a clinical context, and their promise for elucidating neural substrates of brain and mental disorders is discussed.

title: Disrupted Functional Brain Networks in Autistic Toddlers
abstract: Communication and integration of information between brain regions plays a key role in healthy brain function. Conversely, disruption in brain communication may lead to cognitive and behavioral problems. Autism is a neurodevelopmental disorder that is characterized by impaired social interactions and aberrant basic information processing. Aberrant brain connectivity patterns have indeed been hypothesized to be a key neural underpinning of autism. In this study, graph analytical tools are used to explore the possible deviant functional brain network organization in autism at a very early stage of brain development. Electroencephalography (EEG) recordings in 12 toddlers with autism (mean age 3.5 years) and 19 control subjects were used to assess interregional functional brain connectivity, with functional brain networks constructed at the level of temporal synchronization between brain regions underlying the EEG electrodes. Children with autism showed a significantly increased normalized path length and reduced normalized clustering, suggesting a reduced global communication capacity already during early brain development. In addition, whole brain connectivity was found to be significantly reduced in these young patients suggesting an overall under-connectivity of functional brain networks in autism. Our findings support the hypothesis of abnormal neural communication in autism, with deviating effects already present at the early stages of brain development.

title: Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis
abstract: Brain regions are not independent. They are interconnected by white matter tracts, together forming one integrative complex network. The topology of this network is crucial for efficient information integration between brain regions. Here, we demonstrate that schizophrenia involves an aberrant topology of the structural infrastructure of the brain network. Using graph theoretical analysis, complex structural brain networks of 40 schizophrenia patients and 40 human healthy controls were examined. Diffusion tensor imaging was used to reconstruct the white matter connections of the brain network, with the strength of the connections defined as the level of myelination of the tracts as measured through means of magnetization transfer ratio magnetic resonance imaging. Patients displayed a preserved overall small-world network organization, but focusing on specific brain regions and their capacity to communicate with other regions of the brain revealed significantly longer node-specific path lengths (higher L) of frontal and temporal regions, especially of bilateral inferior/superior frontal cortex and temporal pole regions. These findings suggest that schizophrenia impacts global network connectivity of frontal and temporal brain regions. Furthermore, frontal hubs of patients showed a significant reduction of betweenness centrality, suggesting a less central hub role of these regions in the overall network structure. Together, our findings suggest that schizophrenia patients have a less strongly globally integrated structural brain network with a reduced central role for key frontal hubs, resulting in a limited structural capacity to integrate information across brain regions.

title: Graph Theoretical Analysis of Organization of Functional Brain Networks in ADHD
abstract: This article presents a new methodology for investigation of the organization of the overall and hemispheric brain network of patients with attention-deficit hyperactivity disorder (ADHD) using theoretical analysis of a weighted graph with the goal of discovering how the brain topology is affected in such patients. The synchronization measure used is the nonlinear fuzzy synchronization likelihood (FSL) developed by the authors recently. Recent evidence indicates a normal neocortex has a small-world (SW) network with a balance between local structure and global structure characteristics. Such a network results in optimal balance between segregation and integration which is essential for high synchronizabilty and fast information transmission in a complex network. The SW network is characterized by the coexistence of dense clustering of connections (C) and short path lengths (L) among the network units. The results of investigation of C show the local structure of functional left-hemisphere brain networks of ADHD diverges from that of non-ADHD which is recognizable in the delta electroencephalograph (EEG) sub-band. Also, the results of investigation for L show the global structure of functional left-hemisphere brain networks of ADHD diverges from that of non-ADHD which is observable in the delta EEG sub-band. It is concluded that the changes in left-hemisphere brain's structure of ADHD from that of the non-ADHD are so much that L and C can distinguish the ADHD brain from the non-ADHD brain in the delta EEG sub-band.

title: The architecture of complex weighted networks.
abstract: Networked structures arise in a wide array of different contexts such as technological and transportation infrastructures, social phenomena, and biological systems. These highly interconnected systems have recently been the focus of a great deal of attention that has uncovered and characterized their topological complexity. Along with a complex topological structure, real networks display a large heterogeneity in the capacity and intensity of the connections. These features, however, have mainly not been considered in past studies where links are usually represented as binary states, i.e., either present or absent. Here, we study the scientific collaboration network and the world-wide air-transportation network, which are representative examples of social and large infrastructure systems, respectively. In both cases it is possible to assign to each edge of the graph a weight proportional to the intensity or capacity of the connections among the various elements of the network. We define appropriate metrics combining weighted and topological observables that enable us to characterize the complex statistical properties and heterogeneity of the actual strength of edges and vertices. This information allows us to investigate the correlations among weighted quantities and the underlying topological structure of the network. These results provide a better description of the hierarchies and organizational principles at the basis of the architecture of weighted networks.

title: Contributions and challenges for network models in cognitive neuroscience
abstract: The confluence of new approaches in recording patterns of brain connectivity and quantitative analytic tools from network science has opened new avenues toward understanding the organization and function of brain networks. Descriptive network models of brain structural and functional connectivity have made several important contributions; for example, in the mapping of putative network hubs and network communities. Building on the importance of anatomical and functional interactions, network models have provided insight into the basic structures and mechanisms that enable integrative neural processes. Network models have also been instrumental in understanding the role of structural brain networks in generating spatially and temporally organized brain activity. Despite these contributions, network models are subject to limitations in methodology and interpretation, and they face many challenges as brain connectivity data sets continue to increase in detail and complexity.

title: Graph analysis of EEG resting state functional networks in dyslexic readers
abstract: Neuroimaging research suggested a mixed pattern of functional connectivity abnormalities in developmental dyslexia. We examined differences in the topological properties of functional networks between 29 dyslexics and 15 typically reading controls in 3rd grade using graph analysis. Graph metrics characterize brain networks in terms of integration and segregation.



We used EEG resting-state data and calculated weighted connectivity matrices for multiple frequency bands using the phase lag index (PLI). From the connectivity matrices we derived minimum spanning tree (MST) graphs representing the sub-networks with maximum connectivity. Statistical analyses were performed on graph-derived metrics as well as on the averaged PLI connectivity values.



We found group differences in the theta band for two graph metrics suggesting reduced network integration and communication between network nodes in dyslexics compared to controls.



Collectively, our findings point to a less efficient network configuration in dyslexics relative to the more proficient configuration in the control group.



Graph metrics relate to the intrinsic organization of functional brain networks. These metrics provide additional insights on the cognitive deficits underlying dyslexia and, thus, may advance our knowledge on reading development. Our findings add to the growing body literature suggesting compromised networks rather than specific dysfunctional brain regions in dyslexia.

title: An improved Bonferroni procedure for multiple tests of significance
abstract: A modification of the Bonferroni procedure for testing multiple hypotheses is presented. The method, based on the ordered p-values of the individual tests, is less conservative than the classical Bonferroni procedure but is still simple to apply. A simulation study shows that the probability of a type I error of the procedure does not exceed the nominal significance level, a, for a variety of multivariate normal and multivariate gamma test statistics. For independent tests the procedure has type I error probability equal to a. The method appears particularly advantageous over the classical Bonferroni procedure when several highly-correlated test statistics are involved.

title: A big-world network in ASD: Dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections
abstract: Over the last years, increasing evidence has fuelled the hypothesis that Autism Spectrum Disorder (ASD) is a condition of altered brain functional connectivity. The great majority of these empirical studies relies on functional magnetic resonance imaging (fMRI) which has a relatively poor temporal resolution. Only a handful of studies has examined networks emerging from dynamic coherence at the millisecond resolution and there are no investigations of coherence at the lowest frequencies in the power spectrum-which has recently been shown to reflect long-range cortico-cortical connections. Here we used electroencephalography (EEG) to assess dynamic brain connectivity in ASD focusing in the low-frequency (delta) range. We found that connectivity patterns were distinct in ASD and control populations and reflected a double dissociation: ASD subjects lacked long-range connections, with a most prominent deficit in fronto-occipital connections. Conversely, individuals with ASD showed increased short-range connections in lateral-frontal electrodes. This effect between categories showed a consistent parametric dependency: as ASD severity increased, short-range coherence was more pronounced and long-range coherence decreased. Theoretical arguments have been proposed arguing that distinct patterns of connectivity may result in networks with different efficiency in transmission of information. We show that the networks in ASD subjects have less Clustering coefficient, greater Characteristic Path Length than controls - indicating that the topology of the network departs from small-world behaviour - and greater modularity. Together these results show that delta-band coherence reveal qualitative and quantitative aspects associated with ASD pathology.

title: Fast reconfiguration of high-frequency brain networks in response to surprising changes in auditory input.
abstract: How do human brain networks react to dynamic changes in the sensory environment? We measured rapid changes in brain network organization in response to brief, discrete, salient auditory stimuli. We estimated network topology and distance parameters in the immediate central response period, <1 s following auditory presentation of standard tones interspersed with occasional deviant tones in a mismatch-negativity (MMN) paradigm, using magnetoencephalography (MEG) to measure synchronization of high-frequency (gamma band; 33-64 Hz) oscillations in healthy volunteers. We found that global small-world parameters of the networks were conserved between the standard and deviant stimuli. However, surprising or unexpected auditory changes were associated with local changes in clustering of connections between temporal and frontal cortical areas and with increased interlobar, long-distance synchronization during the 120- to 250-ms epoch (coinciding with the MMN-evoked response). Network analysis of human MEG data can resolve fast local topological reconfiguration and more long-range synchronization of high-frequency networks as a systems-level representation of the brain's immediate response to salient stimuli in the dynamically changing sensory environment.

title: Commonalities in EEG Spectral Power Abnormalities Between Women With ADHD and Women With Bipolar Disorder During Rest and Cognitive Performance
abstract: While attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BD) denote distinct psychiatric conditions, diagnostic delineation is impeded by considerable symptomatic overlap. Direct comparisons across ADHD and BD on neurophysiological measures are limited. They could inform us on impairments that are specific to or shared between the disorders and, therefore, potential biomarkers that may aid in the identification of the diagnostic boundaries. Our aim was to test whether quantitative EEG (QEEG) identifies differences or similarities between women with ADHD and women with BD during resting-state and task conditions. QEEG activity was directly compared between 20 ADHD, 20 BD and 20 control women during an eyes-open resting-state condition (EO) and a cued continuous performance task (CPT-OX). Both ADHD (t38 = 2.50, p = 0.017) and BD (t38 = 2.54, p = 0.018) participants showed higher absolute theta power during EO than controls. No significant differences emerged between the two clinical groups. While control participants showed a task-related increase in absolute theta power from EO to CPT-OX (t19 = −3.77, p = 0.001), no such change in absolute theta power was observed in the ADHD (t19 = −0.605, p = 0.553) or BD (t19 = 1.82, p = 0.084) groups. Our results provide evidence for commonalities in brain dysfunction between ADHD and BD. Absolute theta power may play a role as a marker of neurobiological processes in both disorders.

title: Normalisation of frontal theta activity following methylphenidate treatment in adult attention-deficit/hyperactivity disorder
abstract: Attention-deficit/hyperactivity disorder (ADHD) is associated with cognitive performance and functional brain changes that are sensitive to task conditions, indicating a role for dynamic impairments rather than stable cognitive deficits. Prominent hypotheses consistent with this observation are a failure to optimise brain arousal or activation states. Here we investigate cortical activation during different conditions. Using a sample of 41 non-comorbid adults with ADHD and 48 controls, we examine quantitative EEG activity during a resting state, a cued continuous performance test with flankers (CPT-OX) and the sustained attention to response task (SART). We further investigate the effects of methylphenidate in a subsample of 21 ADHD cases. Control participants showed a task-related increase in theta activity when engaged in cognitive tasks, primarily in frontal and parietal regions, which was absent in participants with ADHD. Treatment with methylphenidate resulted in normalisation of the resting state to task activation pattern. These findings suggest that ADHD in adults is associated with insufficient allocation of neuronal resources required for normal cortical activation commensurate with task demands. Further work is required to clarify the causal role of the deficit in cortical activation and provide a clearer understanding of the mechanisms involved.

title: Brain differences between persistent and remitted attention deficit hyperactivity disorder.
abstract: Previous resting state studies examining the brain basis of attention deficit hyperactivity disorder have not distinguished between patients who persist versus those who remit from the diagnosis as adults. To characterize the neurobiological differences and similarities of persistence and remittance, we performed resting state functional magnetic resonance imaging in individuals who had been longitudinally and uniformly characterized as having or not having attention deficit hyperactivity disorder in childhood and again in adulthood (16 years after baseline assessment). Intrinsic functional brain organization was measured in patients who had a persistent diagnosis in childhood and adulthood (n = 13), in patients who met diagnosis in childhood but not in adulthood (n = 22), and in control participants who never had attention deficit hyperactivity disorder (n = 17). A positive functional correlation between posterior cingulate and medial prefrontal cortices, major components of the default-mode network, was reduced only in patients whose diagnosis persisted into adulthood. A negative functional correlation between medial and dorsolateral prefrontal cortices was reduced in both persistent and remitted patients. The neurobiological dissociation between the persistence and remittance of attention deficit hyperactivity disorder may provide a framework for the relation between the clinical diagnosis, which indicates the need for treatment, and additional deficits that are common, such as executive dysfunctions.