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

Background:

Inhibitory dysfunction is a key behavioral and cognitive phenotype of attention‐deficit hyperactivity disorder (ADHD) and obsessive–compulsive disorder (OCD). Both disorders show neuropsychological deficits and fronto‐striatal dysfunction during tasks of motor response inhibition and cognitive flexibility. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder‐specific neurofunctional markers that distinguish these two inhibitory disorders.

Methods:

Event‐related fMRI was used to compare brain activation between 20 healthy boys, 18 (Stop task) or 12 boys (Switch task) with ADHD, and 10 boys with OCD during a tracking Stop task that measures inhibition and stopping failure and during a visual–spatial switching task measuring cognitive flexibility.

Results:

Both patient groups shared brain dysfunction compared to healthy controls in right orbitofrontal (successful inhibition) and left dorsolateral prefrontal cortices (failed inhibition). Right inferior prefrontal dysfunction, however, was disorder‐specific to ADHD during both tasks. Left inferior prefrontal dysfunction during the Switch task was significant in children with ADHD relative to controls, but only reached a trend in patients with OCD. Patients with ADHD furthermore showed disorder‐specific dysfunction in left basal ganglia and cingulate gyrus during the Switch task.

Conclusions:

Patients with ADHD compared to those with OCD have both common and distinct dysfunctions during inhibitory control. The most consistently reported functional abnormality in children with ADHD in right inferior prefrontal cortex during inhibitory control appears to be disorder‐specific when compared to patients with OCD and may be a specific neurofunctional biomarker of ADHD. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.

     

NOS1 ex1f-VNTR polymorphism affects prefrontal oxygenation during response inhibition tasks

Impulsivity is a trait shared by many psychiatric disorders and therefore a suitable intermediate phenotype for their underlying biological mechanisms. One of the molecular determinants involved is the NOS1 ex1f‐VNTR, whose short variants are associated with a variety of impulsive behaviors. Fifty‐six healthy controls were stratified into homozygous long (LL) (30 probands) and short (SS) (26 probands) allele groups. Subjects completed a combined stop‐signal go/nogo task, while the oxygenation in the prefrontal cortex was measured with functional near‐infrared spectroscopy. Electromyography was recorded to control for differences in muscle activity in the two inhibition tasks. Two questionnaires on impulsive traits were completed. Differences between the two tasks are shown by distinct activation patterns within the prefrontal cortex. The nogo task resulted mainly in the activation of the dorsolateral prefrontal cortex (dlPFC), whereas successful and unsuccessful inhibition in the stop‐signal task elicited the predicted activity in the inferior frontal cortex (IFC). Although significant differences were found in neither the scores obtained on impulsivity‐related questionnaires nor the behavioral data, the LL group displayed increased dlPFC activity during nogo trials and the predicted activation in the IFC during successful inhibition in the stop‐signal task, while no significant activation was found in the SS group. Our data confirm an influence of NOS1 ex1f‐VNTR on impulsivity, as carriers of the short risk allele exhibited diminished activity of (pre‐)frontal brain regions during the inhibition in a stop‐signal task. Impairment of prefrontal control with consecutive failure of inhibitory processes might underlie association findings reported previously. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Proactive response inhibition abnormalities in the sensorimotor cortex of patients with schizophrenia

BackgroundPrevious studies of response inhibition in patients with schizophrenia have focused on reactive inhibition tasks (e.g., stop-signal, go/no-go), primarily observing lateral prefrontal cortex abnormalities. However, recent studies suggest that purposeful and sustained (i.e., proactive) inhibition may also be affected in these patients.MethodsPatients with chronic schizophrenia and healthy controls underwent fMRI while inhibiting motor responses during multisensory (audiovisual) stimulation. Resting state data were also collected.ResultsWe included 37 patients with schizophrenia and 37 healthy controls in our study. Both controls and patients with schizophrenia successfully inhibited the majority of overt motor responses. Functional results indicated basic inhibitory failure in the lateral premotor and sensorimotor cortex, with opposing patterns of positive (schizophrenia) versus negative (control) activation. Abnormal activity was associated with independently assessed signs of psychomotor retardation. Patients with schizophrenia also exhibited unique activation of the pre–supplementary motor area (pre-SMA)/SMA and precuneus relative to baseline as well as a failure to deactivate anterior nodes of the default mode network. Independent resting-state connectivity analysis indicated reduced connectivity between anterior (task results) and posterior regions of the sensorimotor cortex for patients as well as abnormal connectivity between other regions (cerebellum, thalamus, posterior cingulate gyrus and visual cortex).LimitationsAside from rates of false-positive responses, true proactive response inhibition tasks do not provide behavioural metrics that can be independently used to quantify task performance.ConclusionOur results suggest that basic cortico-cortico and intracortical connections between the sensorimotor cortex and adjoining regions are impaired in patients with schizophrenia and that these impaired connections contribute to inhibitory failures (i.e., a positive rather than negative hemodynamic response).     

Cortical dopamine release during a behavioral response inhibition task

Dopamine (DA) dysregulation within fronto‐striatal circuitry may underlie impulsivity in alcohol and other substance use disorders. To date, no one has directly demonstrated DA release during a task requiring the control of impulsive behavior. The current study was conducted to determine whether a response inhibition task (stop signal task; SST) would elicit detectable extrastriatal DA release in healthy controls. We hypothesized that DA release would be detected in regions previously implicated in different aspects of inhibitory control. [¹⁸F]Fallypride (FAL) PET imaging was performed in nine healthy males (24.6 ± 4.1 y.o.) to assess changes in cortical DA during a SST relative to a baseline “Go” task. On separate days, subjects received one FAL scan during the SST, and one FAL scan during a “Go” control; task‐order was counter‐balanced across subjects. Parametric BP_ND images were generated and analyzed with SPM8. Voxel‐wise analysis indicated significant SST‐induced DA release in several cortical regions involved in inhibitory control, including the insula, cingulate cortex, orbitofrontal cortex, precuneus, and supplementary motor area. There was a significant positive correlation between stop signal reaction time and DA release in the left orbitofrontal cortex, right middle frontal gyrus, and right precentral gyrus. These data support the feasibility of using FAL PET to study DA release during response inhibition, enabling investigation of relationships between DA function and impulsive behavior. Synapse 68:266–274, 2014 . © 2014 Wiley Periodicals, Inc.     

Pretreatment Alterations and Acute Medication Treatment Effects on Brain Task–Related Functional Connectivity in Youth With Bipolar Disorder: A Neuroimaging Randomized Clinical Trial

ObjectiveDisruptions in cognition are a clinically significant feature of bipolar disorder (BD). The effects of different treatments on these deficits and the brain systems that support them remain to be established.MethodA continuous performance test was administered to 55 healthy controls and 71 acutely ill youths with mixed/manic BD to assess vigilance and working memory during task-based functional magnetic resonance imaging studies. Patients, who were untreated for at least 7 days at baseline, and controls were scanned at pretreatment baseline and at weeks 1 and 6. After baseline testing, patients (n = 71) were randomly assigned to 6-week double-blind treatment with lithium (n = 26; 1.0-1.2 mEq/L) or quetiapine (n = 45; 400-600 mg). Weighted seed-based connectivity (wSBC) was used to assess regional brain interactions during the attention task compared with the control condition.ResultsAt baseline, youths with BD showed reduced connectivity between bilateral anterior cingulate cortex and both left ventral lateral prefrontal cortex and left insula and increased connectivity between left ventral lateral prefrontal cortex and left temporal pole, left orbital frontal cortex and right postcentral gyrus, and right amygdala and right occipital pole compared with controls. At 1-week follow-up, quetiapine, but not lithium, treatment led to a significant shift of connectivity patterns toward those of the controls. At week 6, compared with baseline, there was no difference between treatment conditions, at which time both patient groups showed significant normalization of brain connectivity toward that of controls.ConclusionFunctional alterations in several brain regions associated with cognitive processing and the integration of cognitive and affective processing were demonstrated in untreated youths with BD before treatment. Treatment reduced several of these alterations, with significant effects at week 1 only in the quetiapine treatment group. Normalization of functional connectivity might represent a promising biomarker for early target engagement in youth with BD.Clinical trial registration informationMultimodal Neuroimaging of Treatment Effects in Adolescent Mania; https://clinicaltrials.gov/; NCT00893581.     

Neuroimaging of inhibitory control areas in children with attention deficit hyperactivity disorder who were treatment naive or in long-term treatment

OBJECTIVE: Difficulty with response inhibition is a cardinal symptom of attention deficit hyperactivity disorder (ADHD), combined type. Prefrontal and cingulate brain regions are known to be involved in inhibitory control. Event-related functional magnetic resonance imaging (fMRI) might establish if these regions differ in their activity in ADHD children relative to healthy comparison subjects. METHOD: Fifteen healthy comparison subjects and 17 children with ADHD, combined type, completed fMRI studies while performing the Stop Signal Task. Eight ADHD subjects were treatment naive; the remainder had a history of long-term treatment with stimulants, but they were medication free at the time of the fMRI. No subject had a learning disorder or a comorbid psychiatric condition (other than oppositional defiant disorder in the ADHD subjects). RESULTS: Both the ADHD and comparison subjects activated the right dorsolateral prefrontal cortex on "stop" trials relative to "go" trials; this increase was greater in ADHD subjects. When inhibition was unsuccessful (relative to successful inhibition), healthy comparison subjects strongly activated the anterior cingulate cortex and the left ventrolateral prefrontal cortex. In contrast, the ADHD subjects did not show these differences. Activations in treatment-naive and ADHD subjects treated in the long term did not differ significantly in any brain regions. CONCLUSIONS: In relation to comparison subjects, ADHD subjects failed to activate the anterior cingulate cortex and the left ventrolateral prefrontal cortex after unsuccessful inhibition. These findings appear in treatment-naive ADHD individuals and are unlikely to be an artifact of long-term treatment with stimulants or of abrupt termination of stimulants before imaging.     

Dissociation of response inhibition and performance monitoring in the stop signal task using event-related fMRI

We examined the neural substrate of motor response inhibition and performance monitoring in the stop signal task (SST) using event-related functional magnetic resonance imaging (fMRI). The SST involves a go task and the occasional requirement to stop the go response. We posit that both the go and the stop phases of the SST involve components of inhibition and performance monitoring. The goal of this study was to determine whether inhibition and performance monitoring during go and stop phases of the task activated different networks. We isolated go-phase activities underlying response withholding, monitoring, and sensorimotor processing and contrasted these with successful inhibition to identify the substrate of response inhibition. Error detection activity was isolated using trials in which a stop signal appeared but the response was executed. These trials were modeled as a hand-specific go trial followed by error processing. Cognitive go-phase processes included response withholding and monitoring and activated right prefrontal and midline networks. Response withdrawal additionally activated right inferior frontal gyrus and basal ganglia (caudate). Error detection invoked by failed inhibition activated dorsal anterior cingulate cortex (dACC) and right middle frontal Brodmann's area 9. Our results confirm that there are distinct aspects of inhibition and performance monitoring functions which come into play at various phases within a given trial of the SST, and that these are separable using fMRI.     

Self-referential processing influences functional activation during cognitive control: an fMRI study

Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task.     

Transcranial direct current stimulation facilitates response inhibition through dynamic modulation of the fronto-basal ganglia network

BackgroundResponse inhibition refers to the ability to stop an on-going action quickly when it is no longer appropriate. Previous studies showed that transcranial direct current stimulation (tDCS) applied with the anode over the right inferior frontal cortex (rIFC), a critical node of the fronto-basal ganglia inhibitory network, improved response inhibition. However, the tDCS effects on brain activity and network connectivity underlying this behavioral improvement are not known.ObjectiveThis study aimed to address the effects of tDCS applied with the anode over the rIFC on brain activity and network functional connectivity underlying the behavioral change in response inhibition.MethodsThirty participants performed a stop-signal task in a typical laboratory setting as a baseline during the first study visit (i.e., Session 1). In the second visit (at least 24 h after Session 1), all participants underwent resting-state functional magnetic resonance imaging (rsfMRI) scans before and after 1.5 mA tDCS (Anodal or Sham). Immediately following the post-tDCS rsfMRI, participants performed the same stop-signal task as in Session 1 during an event-related fMRI (efMRI) scan in a 3T scanner. Changes in task performance, i.e., the stop-signal response time (SSRT), a measure of response inhibition efficiency, was determined relative to the participants’ own baseline performance in Session 1.ResultsConsistent with previous findings, Anodal tDCS facilitated the SSRT. efMRI results showed that Anodal tDCS strengthened the functional connectivity between right pre-supplementary motor area (rPreSMA) and subthalamic nuclei during Stop responses. rsfMRI revealed changes in intrinsic connectivity between rIFC and caudate, and between rIFC, rPreSMA, right inferior parietal cortex (rIPC), and right dorsolateral prefrontal cortex (rDLPFC) after Anodal tDCS. In addition, corresponding to the regions of rsfMRI connectivity change, the efMRI BOLD signal in the rDLPFC and rIPC during Go responses accounted for 74% of the variance in SSRT after anodal tDCS, indicating an effect of tDCS on the Go-Stop process.ConclusionThese results indicate that tDCS with the anode over the rIFC facilitates response inhibition by modulating neural activity and functional connectivity in the fronto-basal ganglia as well as rDLPFC and rIPC as an integral part of the response inhibition network.     

Neural processes of preparatory control for stop signal inhibition

This study investigated the preparatory control of motor inhibition and motor execution using a stop signal task (SST) and functional magnetic resonance imaging (fMRI). In the SST, a frequent “go” signal triggered a prepotent response and a less frequent “stop” signal prompted the inhibition of this response. Preparatory control of motor inhibition and execution in the stop signal trials were examined by contrasting brain activation between stop success and stop error trials during the fore‐period, in which participants prepared to respond to go or to stop. Results from 91 healthy adults showed greater activation in the right prefrontal cortex and inferior parietal lobule during preparatory motor inhibition. Preparatory motor execution activated bilateral putamen, primary motor cortices, posterior cingulate cortex, ventromedial prefrontal cortex, and superior temporal/intraparietal sulci. Furthermore, the extents of these inhibition and execution activities were inversely correlated across subjects. On the basis of a median split of the stop signal reaction time (SSRT), subjects with short SSRT showed greater activity in the right orbital frontal cortex during preparatory inhibition. These new findings suggest that the go and stop processes interact prior to target presentation in the SST, in accord with recent computational models of stop signal inhibition. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Separate neural systems for behavioral change and for emotional responses to failure during behavioral inhibition

To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop‐signal task, in 1709 participants. First, areas activated more in stop‐success (SS) than stop‐failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10^?8). The results provide new evidence from this “big data” investigation consistent with the hypotheses that the lateral OFC is involved in the stop‐related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression. Hum Brain Mapp 38:3527–3537, 2017 . © 2017 Wiley Periodicals, Inc.     

Prefrontal Responses during Proactive and Reactive Inhibition Are Differentially Impacted by Stress in Anorexia and Bulimia Nervosa

Binge eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in frontostriatal regions implicated in self-regulatory control, and an influential theory posits that binge eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge eating in underweight individuals (i.e., anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (BN, 33 women; AN-BP, 22 women; 30 control participants). Participants underwent repeated functional MRI scanning during performance of the Stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses to induced stress and a control task were evaluated on 2 consecutive days. Women with BN had reduced proactive inhibition, while prefrontal responses were increased in both AN-BP and BN. Reactive inhibition was neurally and behaviorally intact in both diagnostic groups. Both AN-BP and BN groups showed distinct stress-induced changes in inferior and superior frontal activity during both proactive and reactive inhibition. However, task performance was unaffected by stress. These results offer novel evidence of reduced proactive inhibition in BN, yet inhibitory control deficits did not generalize to AN-BP. Our findings identify intriguing alterations of stress responses and inhibitory function associated with binge eating, but they counsel against stress-induced failures of inhibitory control as a comprehensive explanation for loss-of-control eating.SIGNIFICANCE STATEMENT Binge eating is a common psychiatric syndrome that feels uncontrollable to the sufferer. Theoretically, it has been related to reduced self-regulation under stress, but there remains no direct evidence for this link in binge-eating disorders. Here, we examined how experimentally induced stress affected response inhibition in control participants and women with anorexia nervosa and bulimia nervosa. Participants underwent repeated brain scanning under stressful and neutral conditions. Although patient groups had intact action cancellation, the slowing of motor responses was impaired in bulimia nervosa, even when the likelihood of having to stop increased. Stress altered brain responses for both forms of inhibition in both groups, yet performance remained unimpaired. These findings counsel against a simple model of stress-induced disinhibition as an adequate explanation for binge eating.     

Meta-analysis of the effects of transcranial direct current stimulation on inhibitory control

BackgroundInhibitory control refers to a central cognitive capacity involved in the interruption and correction of actions. Dysfunctions in these cognitive control processes have been identified as major maintaining mechanisms in a range of mental disorders such as ADHD, binge eating disorder, obesity, and addiction. Improving inhibitory control by transcranial direct current stimulation (tDCS) could ameliorate symptoms in a broad range of mental disorders.ObjectiveThe primary aim of this pre-registered meta-analysis was to investigate whether inhibitory control can be improved by tDCS in healthy and clinical samples. Additionally, several moderator variables were investigated.MethodsA comprehensive literature search was performed on PubMed/MEDLINE database, Web of Science, and Scopus. To achieve a homogenous sample, only studies that assessed inhibitory control in the go-/no-go (GNG) or stop-signal task (SST) were included, yielding a total of 75 effect sizes from 45 studies.ResultsResults of the meta-analysis indicate a small but significant overall effect of tDCS on inhibitory control (g = 0.21) which was moderated by target and return electrode placement as well as by the task. The small effect size was further reduced after correction for publication bias.ConclusionBased on the studies included, our meta-analytic approach substantiates previously observed differences between brain regions, i.e., involvement of the right inferior frontal gyrus (rIFG) vs. the right dorsolateral prefrontal cortex (rDLPFC) in inhibitory control. Results indicate a small moderating effect of tDCS on inhibitory control in single-session studies and highlight the relevance of technical and behavioral parameters.     

Overcoming the urge to splurge: influencing eating behavior by manipulating inhibitory control

Background and objectives

When inhibitory control is lacking, people are more prone to indulge in high calorie food. This research examined whether increasing or decreasing inhibitory control influences food intake in opposite directions.

Methods

In this study, baseline inhibitory control ability was measured with the Stop Signal Task. Next, participants performed a modified Stop Signal Task with three within-subjects conditions: One type of high calorie food was always paired with a stop signal (inhibition manipulation), while another type of high calorie food was never presented with a stop signal (impulsivity manipulation). In the control condition, high calorie food was presented with a stop signal on half the trials. Following the manipulation, intake of the three food products that were used in the manipulation was measured during a taste test.

Results

Participants with low inhibitory control abilities consumed more of the control food compared to participants with high inhibitory control abilities. However, the inhibition manipulation decreased food consumption in participants with low levels of inhibitory control to the same level of food intake as that of participants with high levels of inhibitory control. Conversely, the impulsivity manipulation increased food intake in participants with high levels of inhibitory control to the level of consumption of participants with low levels of inhibitory control.

Conclusions

These findings demonstrate the causal role of inhibition in eating behavior and suggest that strengthening inhibitory control can help people regain control over the consumption of high calorie food.     

fMRI of intrasubject variability in ADHD: anomalous premotor activity with prefrontal compensation

ObjectiveChildren with attention-deficit/hyperactivity disorder (ADHD) consistently display increased intrasubject variability (ISV) in response time across varying tasks, signifying inefficiency of response preparation compared to typically developing (TD) children. Children with ADHD also demonstrate impaired response inhibition; inhibitory deficits correlate with ISV, suggesting that similar brain circuits may underlie both processes. To better understand the neural mechanisms underlying increased ISV and inhibitory deficits in children with ADHD, functional magnetic resonance imaging was used to examine the neural correlates of ISV during Go/No-go task performance.MethodEvent-related functional magnetic resonance imaging was used to study 25 children with ADHD and 25 TD children ages 8 to 13 years performing a simplified Go/No-go task. Brain-behavior correlations were examined between functional magnetic resonance imaging activation and ISV within and between groups.ResultsFor TD children, increased rostral supplementary motor area (pre-supplementary motor area) activation during No-go events was associated with less ISV, whereas the reverse was true for children with ADHD for whom increased pre-supplementary motor area activation was associated with more ISV. In contrast, children with ADHD with less ISV showed greater prefrontal activation, whereas TD children with more prefrontal activation demonstrated more ISV.ConclusionsThese findings add to evidence that dysfunction of premotor systems may contribute to increased variability and impaired response inhibition in children with ADHD and that compensatory strategies eliciting increased cognitive control may improve function. However, recruitment of prefrontal resources as a compensatory mechanism for motor task performance may preclude the use of those prefrontal resources for higher order, more novel executive functions with which children with ADHD often struggle.     

Relationship between GABA levels and task-dependent cortical excitability in children with attention-deficit/hyperactivity disorder

ObjectiveCompared to typically developing (TD) peers, children with attention deficit hyperactivity disorder (ADHD) manifest reduced short interval cortical inhibition (SICI) in the dominant motor cortex measured with transcranial magnetic stimulation (TMS). This multimodal study investigates the inhibitory neurophysiology and neurochemistry by evaluating the relationship between SICI and γ-amino butyric acid (GABA+) levels, measured with magnetic resonance spectroscopy (MRS).MethodsAcross two sites, 37 children with ADHD and 45 TD children, ages 8–12 years, participated. Single and paired pulse TMS to left motor cortex quantified SICI during REST and at times of action selection (GO) and inhibition (STOP) during a modified Slater-Hammel stop signal reaction task. MRS quantified GABA+ levels in the left sensorimotor cortex. Relationships between SICI and GABA+, as well as stopping efficiency and clinical symptoms, were analyzed with correlations and repeated-measure, mixed-models.ResultsIn both groups, higher GABA+ levels correlated with less SICI. In TD children only, higher GABA+ levels correlated with larger TMS motor evoked potentials (MEPs) at REST. In GO and STOP trials, higher GABA+ was associated with smaller MEP amplitudes, for both groups. Overall, GABA+ levels did not differ between groups or correlate with ADHD clinical symptoms.ConclusionsIn children with higher motor cortex GABA+, motor cortex is less responsive to inhibitory TMS (SICI). Comparing the relationships between MRS-GABA+ levels and responses to TMS at REST vs. GO/STOP trials suggests differences in inhibitory neurophysiology and neurotransmitters in children with ADHD. These differences are more prominent at rest than during response inhibition task engagement.SignificanceEvaluating relationships between GABA+ and SICI may provide a biomarker useful for understanding behavioral diagnoses.     

Disorder-specific dysfunctions in patients with attention-deficit/hyperactivity disorder compared to patients with obsessive-compulsive disorder during interference inhibition and attention allocation

Background: Abnormalities in inhibitory control and underlying fronto‐striatal networks is common to both attention deficit hyperactivity disorder (ADHD) and obsessive‐compulsive‐disorder (OCD). The aim of this study was to investigate disorder‐specific abnormalities in neural networks mediating interference inhibition and selective attention. Method: Event‐related functional magnetic resonance imaging (fMRI) was used to compare brain activation of boys with ADHD (18), with OCD (10), and healthy boys during (20) during a Simon task that measures interference inhibition and controls for and therefore comeasures attention allocation. Results: During interference inhibition, both patient groups shared mesial frontal dysfunction compared to controls. Disorder‐specific dysfunctions were observed in OCD patients in dorsolateral prefrontal cortex during the oddball condition and in ADHD patients in inferior parietal lobe during interference inhibition and in caudate and posterior cingulate during the simpler oddball condition. The decreased activation in caudate and cingulate in ADHD was furthermore negatively correlated with ADHD symptoms and positively with OCD behavioral traits. Conclusions: The study shows that ADHD and OCD patients have shared but also disorder‐specific brain dysfunctions during interference inhibition and attention allocation. Both disorders shared dysfunction in mesial frontal cortex. Disorder‐specific dysfunctions, however, were observed in dorsolateral prefrontal cortex in OCD patients and in caudate, cingulate, and parietal brain regions in ADHD patients. The disorder‐specific dissociation of striato‐cingulate activation that was increased in OCD compared to ADHD patients, was furthermore inversely related to the symptomatology of the two disorders, and may potentially reflect differential dopamine modulation of striatal brain regions. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Neural correlates of cognitive flexibility in children at risk for bipolar disorder

BackgroundYouth with bipolar disorder (BD) show behavioral and neural deficits in cognitive flexibility; however, whether such deficits exist among youths at risk for BD has not been explored.MethodsThe current fMRI study examined the neural basis of cognitive flexibility in BD youth (n = 28), unaffected youth at risk for BD (AR; n = 13), and healthy volunteer youth (HV; n = 21) by comparing brain activation patterns while participants performed the change task. On change trials, subjects must inhibit a prepotent response and execute an alternate one.ResultsDuring successful change trials, both BD and AR youth had increased right ventrolateral prefrontal and inferior parietal activity, compared to HV youth. During failed change trials, both BD and AR youth exhibited increased caudate activation relative to HV youth, but BD youth showed increased activation in the subgenual anterior cingulate cortex (ACC) relative to the other two groups.ConclusionsAbnormal activity in ventrolateral prefrontal cortex, inferior parietal cortex, and striatum during a cognitive flexibility task may represent a potential BD endophenotype, but subgenual ACC dysfunction may represent a marker of BD illness itself.     

Linear age-correlated functional development of right inferior fronto-striato-cerebellar networks during response inhibition and anterior cingulate during error-related processes

Inhibitory and performance-monitoring functions have been shown to develop throughout adolescence. The developmental functional magnetic resonance imaging (fMRI) literature on inhibitory control, however, has been relatively inconsistent with respect to functional development of prefrontal cortex in the progression from childhood to adulthood. Age-related performance differences between adults and children have been shown to be a confound and may explain inconsistencies in findings. The development of error-related processes has not been studied so far using fMRI. The aim of this study was to investigate the neural substrates of the development of inhibitory control and error-related functions by use of an individually adjusted task design that forced subjects to fail on 50% of trials, and therefore controlled for differences in task difficulty and performance between different age groups. Event-related fMRI was used to compare brain activation between 21 adults and 26 children/adolescents during successful motor inhibition and inhibition failure. Adults compared with children/adolescents showed increased brain activation in right inferior prefrontal cortex during successful inhibition and in anterior cingulate during inhibition failure. A whole-brain age-regression analysis between 10 and 42 years showed progressive age-related changes in activation in these two brain regions, with additional changes in thalamus, striatum, and cerebellum. Age-correlated brain regions correlated with each other and with inhibitory performance, suggesting they form developing fronto-striato-thalamic and fronto-cerebellar neural pathways for inhibitory control. This study shows developmental specialization of the integrated function of right inferior prefrontal cortex, basal ganglia, thalamus, and cerebellum for inhibitory control and of anterior cingulate gyrus for error-related processes.     

Dissociations of cognitive inhibition,response inhibition,and emotional interference: Voxelwise ALE meta‐analyses of fMRI studies

Inhibitory control is the stopping of a mental process with or without intention, conceptualized as mental suppression of competing information because of limited cognitive capacity. Inhibitory control dysfunction is a core characteristic of many major psychiatric disorders. Inhibition is generally thought to involve the prefrontal cortex; however, a single inhibitory mechanism is insufficient for interpreting the heterogeneous nature of human cognition. It remains unclear whether different dimensions of inhibitory processes—specifically cognitive inhibition, response inhibition, and emotional interference—rely on dissociated neural systems. We conducted systematic meta‐analyses of fMRI studies in the BrainMap database supplemented by PubMed using whole‐brain activation likelihood estimation. A total of 66 study experiments including 1,447 participants and 987 foci revealed that while the left anterior insula was concordant in all inhibitory dimensions, cognitive inhibition reliably activated specific dorsal frontal inhibitory system, engaging dorsal anterior cingulate, dorsolateral prefrontal cortex, and parietal areas, whereas emotional interference reliably implicated a ventral inhibitory system, involving the ventral surface of the inferior frontal gyrus and the amygdala. Response inhibition showed concordant clusters in the fronto‐striatal system, including the dorsal anterior cingulate region and extended supplementary motor areas, the dorsal and ventral lateral prefrontal cortex, basal ganglia, midbrain regions, and parietal regions. We provide an empirically derived dimensional model of inhibition characterizing neural systems underlying different aspects of inhibitory mechanisms. This study offers a fundamental framework to advance current understanding of inhibition and provides new insights for future clinical research into disorders with different types of inhibition‐related dysfunctions.