Training in cognitive reappraisal normalizes whole-brain indices of emotion regulation in borderline personality disorder.

BACKGROUND: Borderline personality disorder is the prototypical disorder of emotion dysregulation. We have previously shown that borderline personality disorder patients are impaired in their capacity to engage cognitive reappraisal, a frequently-employed adaptive emotion regulation strategy. METHODS: Here we report on the efficacy of longitudinal training in cognitive reappraisal to enhance emotion regulation in borderline patients. Specifically, the training targeted psychological distancing, a reappraisal tactic whereby negative stimuli are viewed dispassionately as though experienced by an objective, impartial observer. At each of 5 sessions over 2 weeks, 22 borderline (14 Female) and 22 healthy control (13 Female) participants received training in psychological distancing and then completed a widely-used picture-based reappraisal task. Self-reported negative affect ratings and functional magnetic resonance imaging (fMRI) data were acquired at the first and fifth sessions. In addition to behavioral analyses, we performed whole-brain pattern expression analyses using independently-defined patterns for negative affect and cognitive reappraisal implementation for each session. RESULTS: Borderline patients showed a decrease in negative affect pattern expression following reappraisal training, reflecting a normalization in neural activity. They did not, however, show significant change in behavioral self-reports. CONCLUSIONS: To our knowledge, this study represents the first longitudinal fMRI examination of task-based cognitive reappraisal training. Using a brief, proof-of-concept design, the results suggest a potential role for reappraisal training in the treatment of borderline patients.

Distinct Topological Properties of the Reward Anticipation Network in Preadolescent Children With Binge Eating Disorder Symptoms.

OBJECTIVE: Few studies have considered the neural underpinnings of binge eating disorder (BED) in children, despite clinical and subclinical symptom presentation occurring in this age group. Symptom presentation at this age is of clinical relevance, as early onset of binge eating is linked to negative health outcomes. Studies in adults have highlighted dysfunction in the frontostriatal reward system as a potential candidate for binge eating pathophysiology, although the exact nature of such dysfunction is currently unclear. METHOD: Data from 83 children (mean age 9.9 years, SD = 0.60) with symptoms of BED (57% girls) and 123 control participants (mean age 10.0 years, SD = 0.60) (52% girls) were acquired from the 4.0 baseline release of the Adolescent Brain Cognitive Development Study. Task-based graph theoretic techniques were used to analyze data from anticipation trials of the monetary incentive delay task. Network and nodal properties were compared between groups. RESULTS: The BED-S group showed alterations in topological properties associated with the frontostriatal subnetwork, such as reduced nodal efficiency in the superior frontal gyrus, nucleus accumbens, putamen, and in normal sex-difference patterns of these properties, such as diminished girls-greater-than-boys pattern of betweenness-centrality in nucleus accumbens observed in controls. CONCLUSION: Distinct network properties and sex-difference patterns in preadolescent children with BED-S suggest dysregulation in the reward system compared to those of matched controls. For the first time, these results quantify this dysregulation in terms of systems-level properties during anticipation of monetary reward and significantly inform the early and sex-related brain markers of BED symptoms.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Activation of the cognitive control network associated with information uncertainty.

The cognitive control network (CCN) that comprises regions of the frontoparietal network, the cingulo-opercular network, and other sub-cortical regions as core structures is commonly activated by events with an increase in information uncertainty. However, it is not clear whether this CCN activation is associated with both information entropy that represents the information conveyed by the context formed by a sequence of events and the surprise that quantifies the information conveyed by a specific type of event in the context. We manipulated entropy and surprise in this functional magnetic resonance imaging study by varying the probability of occurrence of two types of events in both the visual and auditory modalities and measured brain response as a function of entropy and surprise. We found that activation in regions of the CCN increased as a function of entropy and surprise in both the visual and auditory tasks. The frontoparietal network and additional structures in the CCN mediated the relationship between these information measures and behavioral response. These results suggest that the CCN is a high-level modality-general neural entity for the control of the processing of information conveyed by both context and event.

Temporal Dynamics of Functional Brain States Underlie Cognitive Performance.

The functional organization of the human brain adapts dynamically in response to a rapidly changing environment. However, the relation of these rapid changes in functional organization to cognitive functioning is not well understood. This study used a graph-based time-frame modularity analysis approach to identify temporally recurrent functional configuration patterns in neural responses to an n-back working memory task during fMRI. Working memory load was manipulated to investigate the functional relevance of the identified brain states. Four distinct brain states were defined by the predominant patterns of activation in the task-positive, default-mode, sensorimotor, and visual networks. Associated with escalating working memory load, the occurrence of the task-positive state and the probability of transitioning into this state increased. In contrast, the occurrence of the default-mode and sensorimotor states and the probability of these 2 states transitioning away from the task-positive state decreased. The task-positive state occurrence rate and the probability of transitioning from the default-mode state back to the task-positive state explained a significant and unique portion of the variance in task performance. The results demonstrate that dynamic brain activities support successful cognitive functioning and may have heuristic value for understanding abnormal cognitive functioning associated with multiple neuropsychiatric disorders.

Supramodal Mechanisms of the Cognitive Control Network in Uncertainty Processing.

Information processing under conditions of uncertainty requires the involvement of cognitive control. Despite behavioral evidence of the supramodal function (i.e., independent of sensory modality) of cognitive control, the underlying neural mechanism needs to be directly tested. This study used functional magnetic imaging together with visual and auditory perceptual decision-making tasks to examine brain activation as a function of uncertainty in the two stimulus modalities. The results revealed a monotonic increase in activation in the cortical regions of the cognitive control network (CCN) as a function of uncertainty in the visual and auditory modalities. The intrinsic connectivity between the CCN and sensory regions was similar for the visual and auditory modalities. Furthermore, multivariate patterns of activation in the CCN predicted the level of uncertainty within and across stimulus modalities. These findings suggest that the CCN implements cognitive control by processing uncertainty as abstract information independent of stimulus modality.

Distinct topological properties of cue-evoked attention processing network in persisters and remitters of childhood ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing neurodevelopmental disorder that persists into adulthood in a sizeable portion of afflicted children. The persistence of ADHD elevates the risk for adverse outcomes that result in substantial individual and societal burden. The objective of this study is to assess neurobiological substrates associated with variability of clinical outcomes in childhood ADHD, which has considerable value for the development of novel interventions that target mechanisms associated with recovery. A total of 36 young adults who were diagnosed with ADHD combined-type during childhood and 33 group-matched controls were involved in the study. Adults with childhood ADHD were further divided into 17 persisters and 19 remitters based on DSM-5 criteria. Functional magnetic resonance imaging data during a cue-evoked attention task were collected from each subject. The cue-evoked attention processing network was constructed using graph theoretic techniques. Network properties, including global-, local-, and nodal-efficiency, and network hubs were computed. Group comparisons of the network properties were conducted. Significantly lower nodal efficiency in right inferior frontal gyrus and reduced left side frontal-parietal functional interactions were observed in both remitters and persisters relative to the controls. The ADHD persisters showed a unique pattern of significantly lower nodal efficiency in right middle frontal gyrus (MFG) and hyper-interactions between bilateral MFG. This study suggests that right MFG functional impairments may relate to inactive fronto-parietal functional interactions for sensory and cognitive information processing and symptom persistence in young adults with childhood ADHD.

Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition. METHODS: Twenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity. RESULTS: Lisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD. CONCLUSIONS: Treatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance-resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.

Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine.

OBJECTIVE: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD). METHOD: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. RESULTS: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001). CONCLUSION: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. CLINICAL TRIAL REGISTRATION INFORMATION: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391.

Prefrontal and parietal correlates of cognitive control related to the adult outcome of attention-deficit/hyperactivity disorder diagnosed in childhood.

The protracted and highly variable development of prefrontal cortex regions that support cognitive control has been purported to shape the adult outcome of attention-deficit/hyperactivity disorder (ADHD). This neurodevelopmental model was tested in a prospectively followed sample of 27 adult probands who were diagnosed with ADHD in childhood and 28 carefully matched comparison subjects aged 21-28 years. Probands were classified with persistent ADHD or remitted ADHD. Behavioral and neural responses to the Stimulus and Response Conflict Task (SRCT) performed during functional magnetic resonance imaging (fMRI) were compared in probands and comparison subjects and in probands with persistent and remitted ADHD. Response speed and accuracy for stimulus, response, and combined conflicts did not differ across groups. Orbitofrontal, inferior frontal and parietal activation was lower in probands than comparison subjects, but only for combined conflicts, when demand for cognitive control was highest. Reduced activation for combined conflicts in probands was almost wholly attributable to the persistence of ADHD; orbitofrontal, inferior frontal, anterior cingulate and parietal activation was lower in probands with persistent ADHD than both probands with remitted ADHD and comparison subjects, but did not differ between probands with remitted ADHD and comparison subjects. These data provide the first evidence that prefrontal and parietal activation during cognitive control parallels the adult outcome of ADHD diagnosed in childhood, with persistence of symptoms linked to reduced activation and symptom recovery associated with activation indistinguishable from adults with no history of ADHD.

Neural correlates of emotional response inhibition in obsessive-compulsive disorder: A preliminary study.

Failure to inhibit recurrent anxiety-provoking thoughts is a central symptom of obsessive-compulsive disorder (OCD). Neuroimaging studies suggest inhibitory control and disgust processing abnormalities in patients with OCD. However, the emotional modulation of response inhibition deficits in OCD and their neural correlates remain to be elucidated. For this preliminary study we administered an adapted affective response inhibition paradigm, an emotional go/no-go task, during fMRI to characterize the neural systems underlying disgust-related and fear-related inhibition in nine adults with contamination-type OCD compared to ten matched healthy controls. Participants with OCD had significantly greater anterior insula cortex activation when inhibiting responses to both disgusting (bilateral), and fearful (right-sided) images, compared to healthy controls. They also had increased activation in several frontal, temporal, and parietal regions, but there was no evidence of amygdala activation in OCD or healthy participants and no significant between-group differences in performance on the emotion go/no-go task. The anterior insula appears to play a central role in the emotional modulation of response inhibition in contamination-type OCD to both fearful and disgusting images. The insula may serve as a potential treatment target for contamination-type OCD.

Neural mechanisms underlying the therapeutic actions of guanfacine treatment in youth with ADHD: a pilot fMRI study.

Twenty-five youth with attention-deficit/hyperactivity disorder (ADHD) were scanned with functional magnetic resonance imaging (fMRI) while performing a Go/No-go task before and after 6-8 weeks of randomized once-daily treatment with either the α2A-adrenergic receptor agonist guanfacine or placebo. Clinical improvement was greater for guanfacine than placebo and was differentially associated with reduced activation for guanfacine compared with placebo in the right midcingulate cortex/supplementary motor area and the left posterior cingulate cortex.

Reduced prefrontal efficiency for visuospatial working memory in attention-deficit/hyperactivity disorder.

OBJECTIVE: Visuospatial working memory impairments have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). However, most ADHD research has focused on the neural correlates of nonspatial mnemonic processes. This study examined brain activation and functional connectivity for visuospatial working memory in youth with and without ADHD. METHOD: Twenty-four youth with ADHD and 21 age- and sex-matched healthy controls were scanned with functional magnetic resonance imaging while performing an N-back test of working memory for spatial position. Block-design analyses contrasted activation and functional connectivity separately for high (2-back) and low (1-back) working memory load conditions versus the control condition (0-back). The effect of working memory load was modeled with linear contrasts. RESULTS: The 2 groups performed comparably on the task and demonstrated similar patterns of frontoparietal activation, with no differences in linear gains in activation as working memory load increased. However, youth with ADHD showed greater activation in the left dorsolateral prefrontal cortex (DLPFC) and left posterior cingulate cortex (PCC), greater functional connectivity between the left DLPFC and left intraparietal sulcus, and reduced left DLPFC connectivity with left midcingulate cortex and PCC for the high load contrast compared to controls (p < .01; k > 100 voxels). Reanalysis using a more conservative statistical approach (p < .001; k > 100 voxels) yielded group differences in PCC activation and DLPFC-midcingulate connectivity. CONCLUSION: Youth with ADHD show decreased efficiency of DLPFC for high-load visuospatial working memory and greater reliance on posterior spatial attention circuits to store and update spatial position than healthy control youth. Findings should be replicated in larger samples.

Guanfacine modulates the emotional biasing of amygdala-prefrontal connectivity for cognitive control.

Functional interactions between amygdala and prefrontal cortex provide a cortical entry point for emotional cues to bias cognitive control. Stimulation of α2 adrenoceptors enhances the prefrontal control functions and blocks the amygdala-dependent encoding of emotional cues. However, the impact of this stimulation on amygdala-prefrontal interactions and the emotional biasing of cognitive control have not been established. We tested the effect of the α2 adrenoceptor agonist guanfacine on psychophysiological interactions of amygdala with prefrontal cortex for the emotional biasing of response execution and inhibition. Fifteen healthy adults were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task following administration of oral guanfacine (1mg) and placebo in a double-blind, counterbalanced design. Happy, sad, and neutral faces served as trial cues. Guanfacine moderated the effect of face emotion on the task-related functional connectivity of left and right amygdala with left inferior frontal gyrus compared to placebo, by selectively reversing the functional co-activation of the two regions for response execution cued by sad faces. This shift from positively to negatively correlated activation for guanfacine was associated with selective improvements in the relatively low accuracy of responses to sad faces seen for placebo. These results demonstrate the importance of functional interactions between amygdala and inferior frontal gyrus to both bottom-up biasing of cognitive control and top-down control of emotional processing, as well as for the α2 adrenoceptor-mediated modulation of these processes. These mechanisms offer a possibile method to address the emotional reactivity that is common to several psychiatric disorders.

Emotional bias of cognitive control in adults with childhood attention-deficit/hyperactivity disorder.

Affect recognition deficits found in individuals with attention-deficit/hyperactivity disorder (ADHD) across the lifespan may bias the development of cognitive control processes implicated in the pathophysiology of the disorder. This study aimed to determine the mechanism through which facial expressions influence cognitive control in young adults diagnosed with ADHD in childhood. Fourteen probands with childhood ADHD and 14 comparison subjects with no history of ADHD were scanned with functional magnetic resonance imaging while performing a face emotion go/no-go task. Event-related analyses contrasted activation and functional connectivity for cognitive control collapsed over face valence and tested for variations in activation for response execution and inhibition as a function of face valence. Probands with childhood ADHD made fewer correct responses and inhibitions overall than comparison subjects, but demonstrated comparable effects of face emotion on response execution and inhibition. The two groups showed similar frontotemporal activation for cognitive control collapsed across face valence, but differed in the functional connectivity of the right dorsolateral prefrontal cortex, with fewer interactions with the subgenual cingulate cortex, inferior frontal gyrus, and putamen in probands than in comparison subjects. Further, valence-dependent activation for response execution was seen in the amygdala, ventral striatum, subgenual cingulate cortex, and orbitofrontal cortex in comparison subjects but not in probands. The findings point to functional anomalies in limbic networks for both the valence-dependent biasing of cognitive control and the valence-independent cognitive control of face emotion processing in probands with childhood ADHD. This limbic dysfunction could impact cognitive control in emotional contexts and may contribute to the social and emotional problems associated with ADHD.

Thalamo-cortical activation and connectivity during response preparation in adults with persistent and remitted ADHD.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control.

RATIONALE: Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α2 adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established. OBJECTIVES: This study tested the effect of the postsynaptic α2 adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex. METHODS: Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, cross-over design. RESULTS: Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions. CONCLUSIONS: These results provide evidence that guanfacine stimulation of postsynaptic α2 adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α2 adrenoceptor agonist treatment of attention-deficit hyperactivity disorder.

Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder.

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing psychiatric disorder that affects both children and adults. There are Food and Drug Administration-approved stimulant and nonstimulant medications for treating ADHD; however, little is known about the mechanisms by which these different treatments exert their therapeutic effects. OBJECTIVE To contrast changes in brain activation related to symptomatic improvement with use of the stimulant methylphenidate hydrochloride vs the nonstimulant atomoxetine hydrochloride. DESIGN Functional magnetic resonance imaging before and after 6 to 8 weeks of treatment with methylphenidate (n = 18) or atomoxetine (n = 18) using a parallel-groups design. SETTING Specialized ADHD clinical research program at Mount Sinai School of Medicine, New York, New York. PARTICIPANTS Thirty-six youth with ADHD (mean [SD] age, 11.2 [2.7] years; 27 boys) recruited from randomized clinical trials. MAIN OUTCOME MEASURES Changes in brain activation during a go/no-go test of response inhibition and investigator-completed ratings on the ADHD Rating Scale-IV-Parent Version. RESULTS Treatment with methylphenidate vs atomoxetine was associated with comparable improvements in both response inhibition on the go/no-go test and mean (SD) improvements in ratings of ADHD symptoms (55% [30%] vs 57% [25%]). Improvement in ADHD symptoms was associated with common reductions in bilateral motor cortex activation for both treatments. Symptomatic improvement was also differentially related to gains in task-related activation for atomoxetine and reductions in activation for methylphenidate in the right inferior frontal gyrus, left anterior cingulate/supplementary motor area, and bilateral posterior cingulate cortex. These findings were not attributable to baseline differences in activation. CONCLUSIONS Treatment with methylphenidate and atomoxetine produces symptomatic improvement via both common and divergent neurophysiologic actions in frontoparietal regions that have been implicated in the pathophysiology of ADHD. These results represent a first step in delineating the neurobiological basis of differential response to stimulant and nonstimulant medications for ADHD.

Preparatory activity and connectivity in dorsal anterior cingulate cortex for cognitive control.

Dorsal anterior cingulate cortex (dACC) is composed of functionally distinct subregions that may contribute to the top-down control of response selection and preparation. Multiple motor areas have been identified in dACC, including an anterior zone implicated in conflict monitoring and a caudal zone involved in movement execution. This study tested the involvement of a third cingulate area, the posterior zone of dACC, in the top-down control of response selection and preparation. Sixteen healthy young adults were scanned with event-related functional magnetic resonance imaging while performing a cued go/no-go task that was designed to minimize response conflicts. The activation and functional connectivity of dACC were tested with standard convolution models and psychophysiological interaction analyses, respectively. Ready cues that informed the direction of the impending response triggered preparatory neural activity in the posterior zone of dACC and strengthened functional connectivity with the anterior and caudal zones of dACC, as well as perigenual anterior cingulate cortex, frontal operculum, dorsolateral prefrontal cortex, sensory association cortices, and extra-pyramidal motor areas. The preparatory cues activated dACC above and beyond the general arousing effects common to cues despite negligible conflict in the go/no-go task. The integration of cognitive, sensorimotor, and incentive signals in dACC places the region in an ideal position to select and prepare appropriate behavioral responses to achieve higher-level goals.

Dopamine transporter gene variation modulates activation of striatum in youth with ADHD.

Polymorphisms in the 3'UTR variable number tandem repeat (VNTR) of exon 15 of the dopamine transporter gene (DAT1) have been linked to attention-deficit hyperactivity disorder (ADHD); moreover, variability in DAT1 3'UTR genotype may contribute to both heterogeneity of the ADHD phenotype and differences in response to stimulant medications. The impact of this VNTR on neuronal function in individuals with ADHD remains unclear despite evidence that the polymorphisms influence dopamine transporter expression. Thus, we used event-related functional magnetic resonance imaging to examine the impact of DAT1 3'UTR genotype on brain activation during response inhibition in unmedicated children and adolescents with ADHD. Twenty-one youth with ADHD who were homozygous for the 10-repeat (10R) allele of the DAT1 3'UTR and 12 youth who were carriers of the 9-repeat (9R) allele were scanned while they performed a Go/No-Go task. Response inhibition was modeled by contrasting activation during correct No-Go trials versus correct Go trials. Participants who were homozygous for the DAT1 3'UTR 10R allele and those who had a single 9R allele did not differ on percent of trials with successful inhibition, which was the primary measure of inhibitory control. Yet, youth with the DAT1 3'UTR 10R/10R genotype had significantly greater inhibitory control-related activation than those with one 9R allele in the left striatum, right dorsal premotor cortex, and bilaterally in the temporoparietal cortical junction. These findings provide preliminary evidence that neural activity related to inhibitory control may differ as a function of DAT1 3'UTR genotype in youth with ADHD.