Sensation‐to‐cognition cortical streams in attention‐deficit/hyperactivity disorder

We sought to determine whether functional connectivity streams that link sensory, attentional, and higher‐order cognitive circuits are atypical in attention‐deficit/hyperactivity disorder (ADHD). We applied a graph‐theory method to the resting‐state functional magnetic resonance imaging data of 120 children with ADHD and 120 age‐matched typically developing children (TDC). Starting in unimodal primary cortex—visual, auditory, and somatosensory—we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link‐step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher‐order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention‐regulatory areas is reduced. Third, at subsequent link‐step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication‐naïve children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. Hum Brain Mapp 36:2544–2557, 2015. © 2015 Wiley Periodicals, Inc .     

Disrupted brain functional networks in drug‐naïve children with attention deficit hyperactivity disorder assessed using graph theory analysis

Neuroimaging studies have revealed functional brain network abnormalities in attention deficit hyperactivity disorder (ADHD), but the results have been inconsistent, potentially related to confounding medication effects. Furthermore, specific topological alterations in functional networks and their role in behavioral inhibition dysfunction remain to be established. Resting‐state functional magnetic resonance imaging was performed on 51 drug‐naïve children with ADHD and 55 age‐matched healthy controls. Brain functional networks were constructed by thresholding the partial correlation matrices of 90 brain regions, and graph theory was used to analyze network topological properties. The Stroop test was used to assess cognitive inhibitory abilities. Nonparametric permutation tests were used to compare the topological architectures in the two groups. Compared with healthy subjects, brain networks in ADHD patients demonstrated altered topological characteristics, including lower global (FDR q = 0.01) and local efficiency (p = 0.032, uncorrected) and a longer path length (FDR q = 0.01). Lower nodal efficiencies were found in the left inferior frontal gyrus and anterior cingulate cortex in the ADHD group (FDR both q < 0.05). Altered global and nodal topological efficiencies were associated with the severity of inhibitory cognitive control deficits and hyperactivity symptoms in ADHD (p <0 .05). Alterations in network topologies in drug‐naïve ADHD patients indicate weaker small‐worldization with decreased segregation and integration of functional brain networks. Deficits in the cingulo‐fronto‐parietal attention network were associated with inhibitory control deficits.     

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

Spontaneous fluctuations can be measured in the brain that reflect dissociable functional networks oscillating at synchronized frequencies, such as the default mode network (DMN). In contrast to its diametrically opposed task‐positive counterpart, the DMN predominantly signals during a state of rest, and inappropriate regulation of this network has been associated with inattention, a core characteristic of attention‐deficit/hyperactivity disorder (ADHD). To examine whether abnormalities can be identified in the DMN component of patients with ADHD, we applied an independent components analysis to resting state functional magnetic resonance imaging data acquired from 22 male medication‐naïve adults with ADHD and 23 neurotypical individuals. We observed a stronger coherence of the left dorsolateral prefrontal cortex (dlPFC) with the DMN component in patients with ADHD which correlated with measures of selective attention. The increased left dlPFC‐DMN coherence also surfaced in a whole‐brain replication analysis involving an independent sample of 9 medication‐naïve adult patients and 9 controls. In addition, a post hoc seed‐to‐voxel functional connectivity analysis using the dlPFC as a seed region to further examine this region's suggested connectivity differences uncovered a higher temporal coherence with various other neural networks and confirmed a reduced anticorrelation with the DMN. These results point to a more diffuse connectivity between functional networks in patients with ADHD. Moreover, our findings suggest that state‐inappropriate neural activity in ADHD is not confined to DMN intrusion during attention‐demanding contexts, but also surfaces as an insufficient suppression of dlPFC signaling in relation to DMN activity during rest. Together with previous findings, these results point to a general dysfunction in the orthogonality of functional networks. Hum Brain Mapp 35:1261–1272, 2014. © 2013 Wiley Periodicals, Inc.     

Altered resting‐state connectivity during interictal generalized spike‐wave discharges in drug‐naïve childhood absence epilepsy

Purpose: To investigate the intrinsic brain connections at the time of interictal generalized spike‐wave discharges (GSWDs) to understand their mechanism of effect on brain function in untreated childhood absence epilepsy (CAE). Methods: The EEG‐functional MRI (fMRI) was used to measure the resting state functional connectivity during interictal GSWDs in drug‐naïve CAE, and three different brain networks—the default mode network (DMN), cognitive control network (CCN), and affective network (AN)—were investigated. Results: Cross‐correlation functional connectivity analysis with priori seed revealed decreased functional connectivity within each of these three networks in the CAE patients during interictal GSWDS. It included precuneus‐dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and inferior parietal lobule in the DMN; DLPFC‐inferior frontal junction (IFJ), and pre‐supplementary motor area (pre‐SMA) subregions connectivity disruption in CCN; ACC‐ventrolateral prefrontal cortex (VLPFC) and DMPFC in AN; There were also some regions, primarily the parahippcampus, paracentral in AN, and the left frontal mid orb in the CCN, which showed increased connectivity. Conclusions: The current findings demonstrate significant alterations of resting‐state networks in drug naïve CAE subjects during interictal GSWDs and interictal GSWDs can cause dysfunction in specific networks important for psychosocial function. Impairment of these networks may cause deficits both during and between seizures. Our study may contribute to the understanding of neuro‐pathophysiological mechanism of psychosocial function impairments in patients with CAE. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Response inhibition and reward anticipation in medication-naïve adults with attention-deficit/hyperactivity disorder: a within-subject case-control neuroimaging study

Background : Previous research suggests that ADHD patients are characterized by both reduced activity in the inferior frontal gyrus (IFG) during response inhibition tasks (such as the Go‐NoGo task), and reduced activity in the ventral striatum during reward anticipation tasks (such as the Monetary‐Incentive‐Delay [MID] task). However, no prior research has applied either of these paradigms in medication‐naïve adults with ADHD, nor have these been implemented in an intrasubject manner. Methods : The sample consisted of 19 medication‐naïve adults with ADHD and 19 control subjects. Main group analyses were based on individually defined regions of interest: the IFG and the VStr for the Go‐NoGo and the MID task respectively. In addition, we analyzed the correlation between the two measures, as well as between these measures and the clinical symptoms of ADHD. Results : We observed reduced bilateral VStr activity in adults with ADHD during reward anticipation. No differences were detected in IFG activation on the Go‐NoGo paradigm. Correlation analyses suggest that the two tasks are independent at a neural level, but are related behaviorally in terms of the variability of the performance reaction time. Activity in the bilateral VStr but not in the IFG was associated negatively with symptoms of hyperactivity/impulsivity. Conclusions : Results underline the implication of the reward system in ADHD adult pathophysiology and suggest that frontal abnormalities during response inhibition performance may not be such a pivotal aspect of the phenotype in adulthood. In addition, our findings point toward response variability as a core feature of the disorder. Hum Brain Mapp 33:2350–2361, 2012. © 2011 Wiley Periodicals, Inc.     

Local functional connectivity suggests functional immaturity in children with attention‐deficit/hyperactivity disorder

Previous studies have associated Attention‐Deficit/Hyperactivity Disorder (ADHD) with a maturational lag of brain functional networks. Functional connectivity of the human brain changes from primarily local to more distant connectivity patterns during typical development. Under the maturational lag hypothesis, we expect children with ADHD to exhibit increased local connectivity and decreased distant connectivity compared with neurotypically developing (ND) children. We applied a graph‐theory method to compute local and distant connectivity levels and cross‐sectionally compared them in a sample of 120 children with ADHD and 120 age‐matched ND children (age range = 7–17 years). In addition, we measured if potential group differences in local and distant connectivity were stable across the age range considered. Finally, we assessed the clinical relevance of observed group differences by correlating the connectivity levels and ADHD symptoms severity separately for each group. Children with ADHD exhibited more local connectivity than age‐matched ND children in multiple brain regions, mainly overlapping with default mode, fronto‐parietal and ventral attentional functional networks (p < .05‐ threshold free‐cluster enhancement–family‐wise error). We detected an atypical developmental pattern of local connectivity in somatomotor regions, that is, decreases with age in ND children, and increases with age in children with ADHD. Furthermore, local connectivity within somatomotor areas correlated positively with clinical severity of ADHD symptoms, both in ADHD and ND children. Results suggest an immature functional state of multiple brain networks in children with ADHD. Whereas the ADHD diagnosis is associated with the integrity of the system comprising the fronto‐parietal, default mode and ventral attentional networks, the severity of clinical symptoms is related to atypical functional connectivity within somatomotor areas. Additionally, our findings are in line with the view of ADHD as a disorder of deviated maturational trajectories, mainly affecting somatomotor areas, rather than delays that normalize with age.     

Differences between child and adult large‐scale functional brain networks for reading tasks

Reading is an important high‐level cognitive function of the human brain, requiring interaction among multiple brain regions. Revealing differences between children's large‐scale functional brain networks for reading tasks and those of adults helps us to understand how the functional network changes over reading development. Here we used functional magnetic resonance imaging data of 17 adults (19–28 years old) and 16 children (11–13 years old), and graph theoretical analyses to investigate age‐related changes in large‐scale functional networks during rhyming and meaning judgment tasks on pairs of visually presented Chinese characters. We found that: (1) adults had stronger inter‐regional connectivity and nodal degree in occipital regions, while children had stronger inter‐regional connectivity in temporal regions, suggesting that adults rely more on visual orthographic processing whereas children rely more on auditory phonological processing during reading. (2) Only adults showed between‐task differences in inter‐regional connectivity and nodal degree, whereas children showed no task differences, suggesting the topological organization of adults’ reading network is more specialized. (3) Children showed greater inter‐regional connectivity and nodal degree than adults in multiple subcortical regions; the hubs in children were more distributed in subcortical regions while the hubs in adults were more distributed in cortical regions. These findings suggest that reading development is manifested by a shift from reliance on subcortical to cortical regions. Taken together, our study suggests that Chinese reading development is supported by developmental changes in brain connectivity properties, and some of these changes may be domain‐general while others may be specific to the reading domain.     

Aberrant static and dynamic functional patterns of frontoparietal control network in antipsychotic‐naïve first‐episode psychosis subjects

Psychotic disorders are disabling clinical syndromes characterized by widespread alterations in cortical information processing. Disruption of frontoparietal network (FPN) connectivity has emerged as a common footprint across the psychosis spectrum. Our goal was to characterize the static and dynamic resting‐state functional connectivity (FC) of the FPN in antipsychotic‐naïve first‐episode psychosis (FEP) subjects. We compared the static FC of the FPN in 40 FEP and 40 healthy control (HC) subjects, matched on age, sex, and socioeconomic status. To study the dynamic FC, we measured quasiperiodic patterns (QPPs) that consist of infraslow spatioemporal patterns embedded in the blood oxygen level‐dependent signal that repeats over time, exhibiting alternation of high and low activity. Relative to HC, we found functional hypoconnectivity between the right middle frontal gyrus and the right middle temporal gyrus, as well as the left inferior temporal gyrus and the left inferior parietal gyrus in FEP (p < .05, false discovery rate corrected). The correlation of the QPP with all functional scans was significantly stronger for FEP compared to HC, suggesting a greater impact of the QPPs to intrinsic brain activity in psychotic population. Regressing the QPP from the functional scans erased all significant group differences in static FC, suggesting that abnormal connectivity in FEP could result from altered QPP. Our study supports that alterations of cortical information processing are not a function of psychotic chronicity or antipsychotic medication exposure and may be regarded as trait specific. In addition, static connectivity abnormality may be partly related to altered brain network temporal dynamics.     

Just‐in‐time response to reward as a function of ADHD symptom severity

Aim

Attention‐deficit hyperactivity disorder (ADHD) neuroimaging studies have identified substantial differences in reward‐related circuits on a trial‐by‐trial basis. However, no research to date has evaluated the effect of motivational context on neural activity in settings with intermittent reward in ADHD. The present study was designed to identify neural processes underlying both immediate effects of reward and sustained effects of reward associated with motivational context in adult ADHD patients.

Methods

We used a functional magnetic resonance imaging paradigm, including a time estimation task with constant versus intermittent reward conditions, in a sample of 21 medication‐naïve adults with combined ADHD and 24 healthy adults.

Results

Although no between‐group neural differences were detected, orbitofrontal activity dropped in association with high ADHD symptom severity during the transition from initial non‐reward context blocks to subsequent reward context blocks. In turn, ADHD symptom severity predicted higher orbitofrontal activity in response to immediate reward versus no reward within reward context blocks.

Conclusion

These results suggest that high ADHD symptom severity scorers adopted a ‘just‐in‐time’ strategy, involving the recruitment of reward processing brain areas in the face of immediate reward rather than a sustained response to motivational context.

     

Motor‐symptom laterality affects acquisition in Parkinson's disease: A cognitive and functional magnetic resonance imaging study

Background and Objectives : Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor‐symptom laterality could affect feedback‐based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients. Methods : We recruited 63 early‐stage medication‐naïve PD patients (29 left‐onset medication‐naïve patients, 34 right‐onset medication‐naïve patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting‐state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting‐state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum. Results : Left‐onset patients made significantly more errors in acquisition (feedback‐based associative learning) than right‐onset patients and normal controls, whereas right‐onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left‐onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right‐onset patients when compared to controls. Conclusions : Motor‐symptom laterality could affect feedback‐based associative learning in PD, with left‐onset medication‐naïve patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left‐sided onset.© 2016 International Parkinson and Movement Disorder Society     

Recent advances in structural and functional brain imaging studies of attention-deficit/hyperactivity disorder

The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naïve, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD.     

Parietal memory network and default mode network in first‐episode drug‐naïve schizophrenia: Associations with auditory hallucination

Atypical spontaneous activities in resting‐state networks may play a role in auditory hallucinations (AHs), but networks relevant to AHs are not apparent. Given the debating role of the default mode network (DMN) in AHs, a parietal memory network (PMN) may better echo cognitive theories of AHs in schizophrenia, because PMN is spatially adjacent to the DMN and more relevant to memory processing or information integration. To examine whether PMN is more relevant to AHs than DMN, we characterized these intrinsic networks in AHs with 59 first‐episode, drug‐naïve schizophrenics (26 AH+ and 33 AH?) and 60 healthy participants in resting‐state fMRI. We separated the PMN, DMN, and auditory network (AN) using independent component analysis, and compared their functional connectivity across the three groups. We found that only AH+ patients displayed dysconnectivity in PMN, both AH+ and AH? patients exhibited dysfunctions of AN, but neither patient group showed abnormal connectivity within DMN. The connectivity of PMN significantly correlated with memory performance of the patients. Further region‐of‐interest analyses confirmed that the connectivity between the core regions of PMN, the left posterior cingulate gyrus and the left precuneus, was significantly lower only in the AH+ group. In exploratory correlation analysis, this functional connectivity metric significantly correlated with the severity of AH symptoms. The results implicate that compared to the DMN, the PMN is more relevant to the AH symptoms in schizophrenia, and further provides a more precise potential brain modulation target for the intervention of AH symptoms.     

Dopaminergic modulation of resting‐state functional connectivity in de novo patients with Parkinson's disease

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014. © 2014 Wiley Periodicals, Inc .     

Broadband neurophysiological abnormalities in the medial prefrontal region of the default‐mode network in adults with ADHD

Previous investigations of the default‐mode network (DMN) in persons with attention‐deficit/hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and posterior aspects. This finding was originally demonstrated in adults with ADHD, then in youth with ADHD, and has been tentatively linked to ultra low frequency oscillations within the DMN. The current study evaluates the specificity of DMN abnormalities to neuronal oscillations in the ultra low frequency range, and examines the regional specificity of these DMN aberrations in medicated and unmedicated adults with, and those without ADHD. An individually matched sample of adults with and without ADHD completed 6‐minute sessions of resting‐state magnetoencephalography (MEG). Participants with ADHD were known responders to stimulant medications and completed two sessions (predrug/postdrug). MEG data were coregistered to the participant's MRI, corrected for head motion, fitted to a regional‐level source model, and subjected to spectral analyses to extract neuronal population activity in regions of the DMN. The unmedicated adults with ADHD exhibited broadband deficits in medial prefrontal cortices (MPFC), but not other DMN regions compared to adults without ADHD. Unmedicated patients also showed abnormal cross‐frequency coupling in the gamma range between the MPFC and posterior cingulate areas, and disturbed balance within the DMN as activity in posterior regions was stronger than frontal regions at beta and lower frequencies, which dissipated at higher γ‐frequencies. Administration of pharmacotherapy significantly increased prefrontal alpha activity (8–14 Hz) in adults with ADHD, and decreased the cross‐frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, and that they may be primarily attributable to abnormal broadband activity in the MPFC. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Disrupted functional connectivity of cerebellar default network areas in attention‐deficit/hyperactivity disorder

Attention‐deficit/hyperactivity disorder (ADHD) is increasingly understood as a disorder of spontaneous brain‐network interactions. The default mode network (DMN), implicated in ADHD‐linked behaviors including mind‐wandering and attentional fluctuations, has been shown to exhibit abnormal spontaneous functional connectivity (FC) within‐network and with other networks (salience, dorsal attention and frontoparietal) in ADHD. Although the cerebellum has been implicated in the pathophysiology of ADHD, it remains unknown whether cerebellar areas of the DMN (CerDMN) exhibit altered FC with cortical networks in ADHD. Here, 23 adults with ADHD and 23 age‐, IQ‐, and sex‐matched controls underwent resting state fMRI. The mean time series of CerDMN areas was extracted, and FC with the whole brain was calculated. Whole‐brain between‐group differences in FC were assessed. Additionally, relationships between inattention and individual differences in FC were assessed for between‐group interactions. In ADHD, CerDMN areas showed positive FC (in contrast to average FC in the negative direction in controls) with widespread regions of salience, dorsal attention and sensorimotor networks. ADHD individuals also exhibited higher FC (more positive correlation) of CerDMN areas with frontoparietal and visual network regions. Within the control group, but not in ADHD, participants with higher inattention had higher FC between CerDMN and regions in the visual and dorsal attention networks. This work provides novel evidence of impaired CerDMN coupling with cortical networks in ADHD and highlights a role of cerebro‐cerebellar interactions in cognitive function. These data provide support for the potential targeting of CerDMN areas for therapeutic interventions in ADHD. Hum Brain Mapp 36:3373–3386, 2015. © 2015 Wiley Periodicals, Inc.     

Adaptation of brain functional stream architecture in athletes with fast demands of sensorimotor integration

Training‐induced neuroplasticity has been described in athletes' population. However, it remains largely unknown how regular training and sports proficiency modifies neuronal circuits in the human brain. In this study, we used voxel‐based morphometry and stepwise functional connectivity (SFC) analyses to uncover connectivity changes in the functional stream architecture in student‐athletes at early stages of sensorimotor skill training. Thirty‐two second‐year student‐athletes whose major was little‐ball sports and thirty‐four nonathlete controls were recruited for the study. We found that athletes showed greater gray matter volume in the right sensorimotor area, the limbic lobe, and the anterior lobe of the cerebellum. Furthermore, SFC analysis demonstrated that athletes displayed significantly smaller optimal connectivity distance from those seed regions to the dorsal attention network (DAN) and larger optimal connectivity distance to the default mode network (DMN) compared to controls. The Attention Network Test showed that the reaction time of the orienting attention subnetwork was positively correlated with SFC between the seeds and the DAN, while negatively correlated with SFC between the seeds and the DMN. Our findings suggest that neuroplastic adaptations on functional connectivity streams after motor skill training may enable novel information flow from specific areas of the cortex toward distributed networks such as the DAN and the DMN. This could potentially regulate the focus of external and internal attention synchronously in athletes, and consequently accelerate the reaction time of orienting attention in athletes.     

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

Background. Problems with cognitive flexibility have been observed in patients with attention deficit hyperactivity disorder (ADHD) and in patients with conduct disorder (CD), characterized by the violation of societal rules and the rights of others. Functional magnetic resonance imaging (fMRI) of cognitive switching, however, has only been investigated in patients with ADHD, including comorbidity with CD, finding frontostriatal and temporoparietal underactivation. This study investigates disorder‐specific functional abnormalities during cognitive flexibility between medication‐naïve children and adolescents with noncomorbid CD and those with noncomorbid ADHD compared to healthy controls. Methods. Event‐related fMRI was used to compare brain activation of 14 boys with noncomorbid, childhood‐onset CD, 14 boys with noncomorbid ADHD, and 20 healthy comparison boys during a visual–spatial Switch task. Results. Behaviorally, children with ADHD compared to children with CD had significantly slower reaction times to switch compared to repeat trials. The fMRI comparison showed that the patients with ADHD compared to both controls and patients with CD showed underactivation in right and left inferior prefrontal cortex. No disorder‐specific brain underactivation was observed in patients with CD. Only when compared with controls alone, the disruptive behavior group showed reduced activation in bilateral temporoparietal and occipital brain regions. Conclusions. The findings extend previous evidence for disorder‐specific underactivation in patients with ADHD compared to patients with CD in inferior prefrontal cortex during tasks of inhibitory control to the domain of cognitive flexibility. Inferior prefrontal underactivation thus appears to be a disorder‐specific neurofunctional biomarker for ADHD when compared with patients with CD. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Network connectivity abnormality profile supports a categorical‐dimensional hybrid model of ADHD

Attention‐deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity, but there is no consensus regarding whether ADHD exists on the extreme end of a continuum of normal behavior or represents a discrete disorder. In this study, we sought to characterize both the categorical and dimensional variations in network functional connectivity in order to identify neural connectivity mechanisms of ADHD. Functional connectivity analyses of resting‐state fMRI data from 155 children with ADHD and 145 typically developing children (TDC) defined the dorsal attention network (DA), default mode network (DM), salience processing network (SAL) and executive control network (CON). Regional alterations in connectivity associated with categorical diagnoses and dimensional symptom measures (inattention and hyperactivity/impulsivity) as well as their interaction were systematically characterized. Dimensional relationships between symptom severity measures and functional connectivity that did not differ between TDC and children with ADHD were observed for each network, supporting a dimensional characterization of ADHD. However, categorical differences in functional connectivity magnitude between TDC and children with ADHD were detected after accounting for dimensional relationships, indicating the existence of categorical mechanisms independent of dimensional effects. Additionally, differential dimensional relationships for TDC versus ADHD children demonstrated categorical differences in brain–behavior relationships. The patterns of network functional organization associated with categorical versus dimensional measures of ADHD accentuate the complexity of this disorder and support a dual characterization of ADHD etiology featuring both dimensional and categorical mechanisms. Hum Brain Mapp 35:4531–4543, 2014. © 2014 Wiley Periodicals, Inc .     

White‐matter abnormalities in attention deficit hyperactivity disorder: A diffusion tensor imaging study

Current evidence suggests that attention deficit hyperactivity disorder (ADHD) involves dysfunction in wide functional networks of brain areas associated with attention and cognition. This study examines the structural integrity of white‐matter neural pathways, which underpin these functional networks, connecting fronto‐striatal and fronto‐parietal circuits, in children with ADHD. Fifteen right‐handed 8 to 18‐year‐old males with ADHD‐combined type and 15 right‐handed, age, verbal, and performance IQ‐matched, healthy males underwent diffusion tensor imaging. A recent method of tract‐based spatial statistics was used to examine fractional anisotropy (FA) and mean diffusivity within major white‐matter pathways throughout the whole‐brain. White‐matter abnormalities were found in several distinct clusters within left fronto‐temporal regions and right parietal‐occipital regions. Specifically, participants with ADHD showed greater FA in white‐matter regions underlying inferior parietal, occipito‐parietal, inferior frontal, and inferior temporal cortex. Secondly, eigenvalue analysis suggests that the difference in FA in ADHD may relate to a lesser degree of neural branching within key white‐matter pathways. Tractography methods showed these regions to generally form part of white‐matter pathways connecting prefrontal and parieto‐occipital areas with the striatum and the cerebellum. Our findings demonstrate anomalous white‐matter development in ADHD in distinct cortical regions that have previously been shown to be dysfunctional or hypoactive in fMRI studies of ADHD. These data add to an emerging picture of abnormal development within fronto‐parietal cortical networks that may underpin the cognitive and attentional disturbances associated with ADHD. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Antidepressant medication exposure and 5‐HT1A autoreceptor binding in major depressive disorder

Objective: We have previously reported higher brain serotonin 1A (5‐HT_1A) autoreceptor binding in antidepressant‐naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5‐HT_1A receptor binding after medication discontinuation. Methods: Positron emission tomography (PET) imaging with the 5‐HT_1A receptor radioligand [¹¹C]WAY‐100635 was performed in 66 individuals with current DSM‐IV MDD to examine relationships between 5‐HT_1A binding and time since most recent antidepressant treatment. All subjects were medication‐free for at least 2 weeks prior to scanning. Thirty‐two additional MDD comparison subjects were antidepressant naïve. Results: No differences in [¹¹C]WAY‐100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [¹¹C]WAY‐100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. Conclusion: These results indicate that any antidepressant‐associated downregulation of 5‐HT_1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness‐related binding levels.