Rethinking the external globus pallidus and information flow in cortico-basal ganglia-thalamic circuits.

For decades, the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here, we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity and functional role of the GPe in behaviour. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behaviour.

Persistent avoidance of virtual food in anorexia nervosa-restrictive type: Results from motion tracking in a virtual stopping task.

OBJECTIVE: Food avoidance is central to patients with anorexia nervosa-restrictive type (AN-R). Competing accounts in experimental psychopathology research suggest that food avoidance may result from automatic, habitual responses or from elevated inhibitory control abilities. This study investigated behavioral trajectories of food avoidance in a novel virtual reality stopping task. METHOD: Sixty patients with AN-R and 29 healthy controls with normal weight were investigated using a novel, kinematic task in virtual reality. We recorded spatial displacement in stop- and go-trials to virtual food and control objects. Inhibitory control abilities were operationalized by the VR task in stopping performance (i.e., interrupted movement in stop-trials), whereas we also measured habitual avoidance of virtual food across both go- and stop-trials (i.e., delayed movement relative to nonfood objects). RESULTS: In patients with AN-R, hand displacements were shorter to food versus nonfood across stop- and go-trials, reflected in a Stimulus × Group interaction. Healthy controls showed no differences. Importantly, the food-specific effect in AN-R was identical across stop- and go-trials, indicating habitual food avoidance. Moreover, stop error rates (i.e., stop-trials with response) were lower in patients with AN-R. DISCUSSION: The findings suggest food-specific habitual avoidance and heightened generalized inhibitory control in AN-R. The continuously delayed displacements during active hand movements across stop- and go-trials indicated the persistence of patients' avoidance of food. PUBLIC SIGNIFICANCE: Experimental research investigates the mechanisms underlying mental disorders such as anorexia nervosa. In this study, we measured interrupted hand movements in response to food pictures or neutral pictures (shoes) in patients with anorexia nervosa and healthy controls. A virtual reality scenario was used. Findings indicated that patients were slower at approaching food, interrupted or not. Key mechanisms of food avoidance can be translated into habit-based treatment options in future research.

Real-time fMRI neurofeedback in adolescents with attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is associated with poor self-control, underpinned by inferior fronto-striatal deficits. Real-time functional magnetic resonance neurofeedback (rtfMRI-NF) allows participants to gain self-control over dysregulated brain regions. Despite evidence for beneficial effects of electrophysiological-NF on ADHD symptoms, no study has applied the spatially superior rtfMRI-NF neurotherapy to ADHD. A randomized controlled trial tested the efficacy of rtfMRI-NF of right inferior prefrontal cortex (rIFG), a key region that is compromised in ADHD and upregulated with psychostimulants, on improvement of ADHD symptoms, cognition, and inhibitory fMRI activation. To control for region-specificity, an active control group received rtfMRI-NF of the left parahippocampal gyrus (lPHG). Thirty-one ADHD boys were randomly allocated and had to learn to upregulate their target brain region in an average of 11 rtfMRI-NF runs over 2 weeks. Feedback was provided through a video-clip of a rocket that had to be moved up into space. A transfer session without feedback tested learning retention as a proximal measure of transfer to everyday life. Both NF groups showed significant linear activation increases with increasing number of runs in their respective target regions and significant reduction in ADHD symptoms after neurotherapy and at 11-month follow-up. Only the group targeting rIFG, however, showed a transfer effect, which correlated with ADHD symptom reductions, improved at trend level in sustained attention, and showed increased IFG activation during an inhibitory fMRI task. This proof-of-concept study demonstrates for the first time feasibility, safety, and shorter- and longer-term efficacy of rtfMRI-NF of rIFG in adolescents with ADHD. Hum Brain Mapp 38:3190-3209, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Shared and drug-specific effects of atomoxetine and methylphenidate on inhibitory brain dysfunction in medication-naive ADHD boys.

The stimulant methylphenidate (MPX) and the nonstimulant atomoxetine (ATX) are the most commonly prescribed medications for attention deficit hyperactivity disorder (ADHD). However, no functional magnetic resonance imaging (fMRI) study has as yet investigated the effects of ATX on inhibitory or any other brain function in ADHD patients or compared its effects with those of MPX. A randomized, double-blind, placebo-controlled, crossover pharmacological design was used to compare the neurofunctional effects of single doses of MPX, ATX, and placebo during a stop task, combined with fMRI within 19 medication-naive ADHD boys, and their potential normalization effects relative to 29 age-matched healthy boys. Compared with controls, ADHD boys under placebo showed bilateral ventrolateral prefrontal, middle temporal, and cerebellar underactivation. Within patients, MPX relative to ATX and placebo significantly upregulated right ventrolateral prefrontal activation, which correlated with enhanced inhibitory capacity. Relative to controls, both drugs significantly normalized the left ventrolateral prefrontal underactivation observed under placebo, while MPX had a drug-specific effect of normalizing right ventrolateral prefrontal and cerebellar underactivation observed under both placebo and ATX. The findings show shared and drug-specific effects of MPX and ATX on performance and brain activation during inhibitory control in ADHD patients with superior upregulation and normalization effects of MPX.

Effects of age and gender on neural networks of motor response inhibition: from adolescence to mid-adulthood.

Functional inhibitory neural networks mature progressively with age. However, nothing is known about the impact of gender on their development. This study employed functional magnetic resonance imaging (fMRI) to investigate the effects of age, sex, and sex by age interactions on the brain activation of 63 healthy males and females, between 13 and 38 years, performing a Stop task. Increasing age was associated with progressively increased activation in typical response inhibition areas of right inferior and dorsolateral prefrontal and temporo-parietal regions. Females showed significantly enhanced activation in left inferior and superior frontal and striatal regions relative to males, while males showed increased activation relative to females in right inferior and superior parietal areas. Importantly, left frontal and striatal areas that showed increased activation in females, also showed significantly increased functional maturation in females relative to males, while the right inferior parietal activation that was increased in males showed significantly increased functional maturation relative to females. The findings demonstrate for the first time that sex-dimorphic activation patterns of enhanced left fronto-striatal activation in females and enhanced right parietal activation in males during motor inhibition appear to be the result of underlying gender differences in the functional maturation of these brain regions.

The ABCD stop signal data: Response to Bissett et al.

This paper responds to a recent critique by Bissett et al. of the fMRI Stop task used in the Adolescent Brain Cognitive Development℠ Study (ABCD Study®). The critique focuses primarily on a task design feature related to race model assumptions (i.e., that the Go and Stop processes are fully independent). In response, we note that the race model is quite robust against violations of its assumptions. Most importantly, while Bissett raises conceptual concerns with the task we focus here on analyzes of the task data and conclude that the concerns appear to have minimal impact on the neuroimaging data (the validity of which do not rely on race model assumptions) and have far less of an impact on the performance data than the critique suggests. We note that Bissett did not apply any performance-based exclusions to the data they analyzed, a number of the trial coding errors they flagged were already identified and corrected in ABCD annual data releases, a number of their secondary concerns reflect sensible design decisions and, indeed, their own computational modeling of the ABCD Stop task suggests the problems they identify have just a modest impact on the rank ordering of individual differences in subject performance.

Neurofunctional and behavioural measures associated with fMRI-neurofeedback learning in adolescents with Attention-Deficit/Hyperactivity Disorder.

Functional Magnetic Resonance Imaging Neurofeedback (fMRI-NF) targeting brain areas/networks shown to be dysfunctional by previous fMRI research is a promising novel neurotherapy for ADHD. Our pioneering study in 31 adolescents with ADHD showed that fMRI-NF of the right inferior frontal cortex (rIFC) and of the left parahippocampal gyrus (lPHG) was associated with clinical improvements. Previous studies using electro-encephalography-NF have shown, however, that not all ADHD patients learn to self-regulate, and the predictors of fMRI-NF self-regulation learning are not presently known. The aim of the current study was therefore to elucidate the potential predictors of fMRI-NF learning by investigating the relationship between fMRI-NF learning and baseline inhibitory brain function during an fMRI stop task, along with clinical and cognitive measures. fMRI-NF learning capacity was calculated for each participant by correlating the number of completed fMRI-NF runs with brain activation in their respective target regions from each run (rIFC or lPHG); higher correlation values were taken as a marker of better (linear) fMRI-NF learning. Linear correlations were then conducted between baseline measures and the participants' capacity for fMRI-NF learning. Better fMRI-NF learning was related to increased activation in left inferior fronto-striatal regions during the fMRI stop task. Poorer self-regulation during fMRI-NF training was associated with enhanced activation in posterior temporo-occipital and cerebellar regions. Cognitive and clinical measures were not associated with general fMRI-NF learning across all participants. A categorical analysis showed that 48% of adolescents with ADHD successfully learned fMRI-NF and this was also not associated with any baseline clinical or cognitive measures except that faster processing speed during inhibition and attention tasks predicted learning. Taken together, the findings suggest that imaging data are more predictive of fMRI-NF self-regulation skills in ADHD than behavioural data. Stronger baseline activation in fronto-striatal cognitive control regions predicts better fMRI-NF learning in ADHD.

Interaction of task-related learning and transcranial direct current stimulation of the prefrontal cortex in modulating executive functions.

The effects of transcranial direct-current stimulation (tDCS) on cognitive functions, such as response inhibition, might be mediated through plastic changes within the prefrontal cortex. Previous studies have also confirmed learning-related plasticity in prefrontal neurocircuitry. The susceptibility of prefrontal neurocircuitry for tDCS-induced plastic changes and consequent behavioural modulations might depend on the level of learning in a particular task. Variabilities in the cognitive outcome of tDCS might be related to the interaction of tDCS and task-relevant learning. 73 participants completed the Stop Task before and after tDCS over the dorsolateral prefrontal cortex. Participants had to deliver a speeded response upon the onset of a visual go-cue and inhibit the response when the go-cue was replaced by a stop signal. We measured response time (RT) in Go trials, and stop signal reaction time (SSRT) as an index of inhibition ability. A shorter SSRT indicates a better inhibition ability. Participants received either anodal or sham stimulation in two separate sessions (one week apart). RT was increased and SSRT became shorter from pre-stimulation to post-stimulation testing, indicating within-session learning. Furthermore, compared to the first week of testing, RT was increased and SSRT became shorter in the second week, indicating across-session learning. Within-session learning was significantly higher if anodal stimulation was given in the first week rather than the second week indicating that the behavioural effects of tDCS were dependent on the level of learning. Our findings indicate that tDCS effects on executive functions are dependent on the level of experience (learning) in the cognitive task.

Dynamic elastic response prostheses alter approach angles and ground reaction forces but not leg stiffness during a start-stop task.

In a dynamic elastic response prosthesis (DERP), spring-like properties aim to replace the loss of musculature and soft tissues and optimise dynamic movement biomechanics, yet higher intact limb (IL) loading exists. It is unknown how amputees wearing a DERP will perform in start-stop movements and how altering the prosthetic stiffness will influence the performance and loading. This study assessed movement dynamics through comparisons in spatiotemporal, kinematic and kinetic variables and leg stiffness of intact, prosthetic and control limbs. The effect of prosthetic stiffness on movement dynamics was also determined. Eleven male unilateral transtibial amputees performed a start-stop task with one DERP set at two different stiffness - Prescribed and Stiffer. Eleven control participants performed the movement with the dominant limb. Kinematic and kinetic data were collected by a twelve-camera motion capture system synchronised with a Kistler force platform. Selected variables were compared between intact, prosthetic and control limbs, and against prosthetic stiffness using ANOVA and effect size. Pearson's Correlation was used to analyse relationship between leg stiffness and prosthetic deflection. Amputees showed a more horizontal approach to the bound during the start-stop movement, with lower horizontal velocities and a longer stance time on the IL compared to controls. In both stiffness conditions, the IL showed selected higher anteroposterior and vertical forces and impulses when compared to the controls. Leg stiffness was not significantly different between limbs as a result of the interplay between angle swept and magnitude of force, even with the change in prosthetic stiffness. A main effect for prosthetic stiffness was found only in higher impact forces of the prosthetic limb and more horizontal touchdown angles of the IL when using the prescribed DERP. In conclusion, amputees achieve the movement with a horizontal approach when compared to controls which may reflect difficulty of movement initiation with a DERP and a difficulty in performing the movement dynamically. The forces and impulses of the IL were high compared to control limbs. The consistent leg stiffness implies compensation strategies through other joints.

Associations between regional brain physiology and trait impulsivity, motor inhibition, and impaired control over drinking.

Trait impulsivity and poor inhibitory control are well-established risk factors for alcohol misuse, yet little is known about the associated neurobiological endophenotypes. Here we examined correlations among brain physiology and self-reported trait impulsive behavior, impaired control over drinking, and a behavioral measure of response inhibition. A sample of healthy drinkers (n = 117) completed a pulsed arterial spin labeling (PASL) scan to quantify resting regional cerebral blood flow (rCBF), as well as measures of self-reported impulsivity (Eysenck I7 Impulsivity scale) and impaired control over drinking. A subset of subjects (n = 40) performed a stop signal task during blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess brain regions involved in response inhibition. Eysenck I7 scores were inversely related to blood flow in the right precentral gyrus. Significant BOLD activation during response inhibition occurred in an overlapping right frontal motor/premotor region. Moreover, impaired control over drinking was associated with reduced BOLD response in the same region. These findings suggest that impulsive personality and impaired control over drinking are associated with brain physiology in areas implicated in response inhibition. This is consistent with the idea that difficulty controlling behavior is due in part to impairment in motor restraint systems.

Differential neural control in early bilinguals and monolinguals during response inhibition.

We tested the hypothesis that early bilinguals and monolinguals use different brain areas when performing nonlinguistic executive control tasks. For this, we explored brain activity of early bilinguals and monolinguals during a manual stop-signal paradigm. Behaviorally, bilinguals and monolinguals did not show significant differences in the task, which led us to compare brain activation that cannot be attributed to differences in performance. Analyses demonstrated that monolinguals activated the anterior cingulate cortex more than bilinguals when performing the stop-signal task. These results offer direct support for the notion that early bilingualism exerts an effect on neural circuitry responsible for executive control. Consistent with recent reports, we found that bilinguals used the anterior cingulate more efficiently than monolinguals to monitor nonlinguistic cognitive conflicts.

Investigating a race model account of executive control in rats with the countermanding paradigm.

The countermanding paradigm investigates the ability to withhold a response when a stop signal is presented occasionally. The race model (Logan and Cowan, 1984) was developed to account for performance in humans and to estimate the stop signal response time (SSRT). This model has yet to be fully validated for countermanding performance in rats. Furthermore, response adjustments observed in human performance of the task have not been examined in rodents. Male Wistar rats were trained to respond to a visual stimulus (go signal) by pressing a lever below that stimulus, but to countermand the lever press (25% of trials) subsequent to an auditory tone (stop signal) presented after a variable delay. We found decreased inhibitory success as stop signal delay (SSD) increased and estimated a SSRT of 157ms. As expected by the race model, response time (RT) of movements that escaped inhibition: (1) were faster than responses made in the absence of a stop signal; (2) lengthened with increasing SSD; and (3) were predictable by the race model. In addition, responses were slower after stop trial errors, suggestive of error monitoring. Amphetamine (AMPH) (0.25, 0.5mg/kg) resulted in faster go trial RTs, baseline-dependent changes in SSRT and attenuated response adjustments. These findings demonstrate that the race model of countermanding performance, applied successfully in human and nonhuman primate models, can be employed in the countermanding performance of rodents. This is the first study to reveal response adjustments and AMPH-induced alterations of response adjustments in rodent countermanding.

Alpha- and beta-band oscillations subserve different processes in reactive control of limb movements.

The capacity to rapidly suppress a behavioral act in response to sudden instruction to stop is a key cognitive function. This function, called reactive control, is tested in experimental settings using the stop signal task, which requires subjects to generate a movement in response to a go signal or suppress it when a stop signal appears. The ability to inhibit this movement fluctuates over time: sometimes, subjects can stop their response, and at other times, they can not. To determine the neural basis of this fluctuation, we recorded local field potentials (LFPs) in the alpha (6-12 Hz) and beta (13-35 Hz) bands from the dorsal premotor cortex of two nonhuman primates that were performing the task. The ability to countermand a movement after a stop signal was predicted by the activity of both bands, each purportedly representing a distinct neural process. The beta band represents the level of movement preparation; higher beta power corresponds to a lower level of movement preparation, whereas the alpha band supports a proper phasic, reactive inhibitory response: movements are inhibited when alpha band power increases immediately after a stop signal. Our findings support the function of LFP bands in generating the signatures of various neural computations that are multiplexed in the brain.

Kindergarten children's attachment security, inhibitory control, and the internalization of rules of conduct.

Starting from research on relations between attachment and the development of self-regulation, the present study aimed to investigate research questions on relations among inhibitory control, internalization of rules of conduct (i.e., behavior regulation, concern occasioned by others transgressions, confession, reparation after wrongdoing), and attachment security. Attachment security and internalization of rules of conduct of German kindergarten children (N = 82) were assessed by maternal reports. Children's inhibitory control was measured with the Stop-task. Regression analyses revealed that inhibitory control was positively related to attachment security and to internalization of rules of conduct. Mediational analysis using a bootstrapping approach indicated an indirect effect of attachment security on internalization processes via inhibitory control. Implications for further research on the development of inhibitory control and internalization of rules of conduct are discussed.

STOP TALKING! Inhibition of Speech is Affected by Word Frequency and Dysfunctional Impulsivity.

Speaking is a complex natural behavior that most people master very well. Nevertheless, systematic investigation of the factors that affect adaptive control over speech production is relatively scarce. The present experiments quantified and compared inhibitory control over manual and verbal responses using the stop-signal paradigm. In tasks with only two response alternatives, verbal expressions were slower than manual responses, but the stopping latencies of hand and verbal actions were comparable. When engaged in a standard picture-naming task using a large set of pictures, verbal stopping latencies were considerably prolonged. Interestingly, stopping was slower for naming words that are less frequently used compared to words that are used more frequently. These results indicate that adaptive action control over speech production is affected by lexical processing. This notion is compatible with current theories on speech self-monitoring. Finally, stopping latencies varied with individual differences in impulsivity, indicating that specifically dysfunctional impulsivity, and not functional impulsivity, is associated with slower verbal stopping.