Assessing Inhibitory Control Deficits in Adult ADHD: A Systematic Review and Meta-analysis of the Stop-signal Task.

In recent years, there has been an increasing quest in improving our understanding of the neurocognitive deficits underlying adult attention-deficit/hyperactivity disorder (ADHD). Current statistical manuals of psychiatric disorders emphasize inattention and hyperactivity-impulsivity symptoms, but empirical studies have also shown consistent alterations in inhibitory control. To date, there is no established neuropsychological test to assess inhibitory control deficits in adult ADHD. A common paradigm for assessing response inhibition is the stop-signal task (SST). Following PRISMA-selection criteria, our systematic review and meta-analysis integrated the findings of 26 publications with 27 studies examining the SST in adult ADHD. The meta-analysis, which included 883 patients with adult ADHD and 916 control participants, revealed reliable inhibitory control deficits, as expressed in prolonged SST response times, with a moderate effect size [Formula: see text] = 0.51 (95% CI: 0.376-0.644,[Formula: see text] < 0.0001). The deficits were not moderated by study quality, sample characteristics or clinical parameters, suggesting that they may be a phenotype in this disorder. The analyses of secondary outcome measures revealed greater SST omission errors and reduced go accuracy in patients, indicative of altered sustained attention. However, only few (N < 10) studies were available for these measures. Our meta-analysis suggests that the SST, in conjunction with other tests and questionnaires, could become a valuable tool for assessing inhibitory control deficits in adult ADHD.

User experience of applying AMSTAR 2 to appraise systematic reviews of healthcare interventions: a commentary.

BACKGROUND: 'A Measurement Tool to Assess Systematic Reviews, version 2' (AMSTAR 2) is a validated 16-item scale designed to appraise systematic reviews (SRs) of healthcare interventions and to rate the overall confidence in their results. This commentary aims to describe the challenges with rating of the individual items and the application of AMSTAR 2 from the user perspective. DISCUSSION: A group of six experienced users (methodologists working in different clinical fields for at least 10 years) identified and discussed the challenges in rating of each item and the general use of AMSTAR 2 to appraise SRs. A group discussion was used to develop recommendations on how users could deal with the identified challenges. We identified various challenges with the content of items 2-16 and with the derivation of the overall confidence ratings on AMSTAR 2. These challenges include the need (1) to provide additional definitions (e.g., what constitutes major deviations from SR protocol on item 2), (2) to choose a rating strategy for multiple conditions on single items (e.g., how to rate item 5 if studies were selected in duplicate, but consensus between two authors was not reported), and (3) to determine rules for deriving the confidence ratings (e.g., what items are critical for such ratings). Based on these challenges we formulated specific recommendations for items 2-16 that AMSTAR 2 users could consider before applying the tool. Our commentary adds to the existing literature by providing the first in-depth examination of the AMSTAR 2 tool from the user perspective. The identified challenges could be addressed by additional decision rules including definitions for ambiguous items and guidance for rating of complex items and derivation of confidence ratings. We recommend that a team consensus regarding such decision rules is required before appraisal procedure begins. TRIAL REGISTRATION: Not applicable.

Adolescents' neural reactivity to acute psychosocial stress: dysfunctional regulation habits are linked to temporal gyrus response.

Mid-adolescence is a critical time for the development of stress-related disorders and it is associated with significant social vulnerability. However, little is known about normative neural processes accompanying psychosocial stress at this time. Previous research found that emotion regulation strategies critically influence the relationship between stress and the development of psychiatric symptoms during adolescence. Using functional magnetic resonance imaging (fMRI), we examined neural responses to acute stress and analyzed whether the tendency to use adaptive or maladaptive emotion regulation strategies is related to neural and autonomic stress responses. Results show large linear activation increases from low to medium to high stress levels mainly in medial prefrontal, insulae and temporal areas. Caudate and subgenual anterior cingulate cortex, neural areas related to reward and affective valuations, showed linearly decreasing activation. In line with our hypothesis, the current adolescent neural stress profile resembled social rejection and was characterized by pronounced activation in insula, angular and temporal cortices. Moreover, results point to an intriguing role of the anterior temporal gyrus. Stress-related activity in the anterior temporal gyrus was positively related to maladaptive regulation strategies and stress-induced autonomic activity. Maladaptive coping might increase the social threat and reappraisal load of a stressor, relating to higher stress sensitivity of anterior temporal cortices.

Do Belonging and Social Exclusion at School Affect Structural Brain Development During Adolescence?

Students' sense of belonging presents an essential resource for academic and health outcomes, whereas social exclusion at school negatively impacts students' well-being and academic performance. Aiming to understand how feelings of school-related belonging and exclusion shape the structural brain development, this study applied longitudinal questionnaire-based data and MRI data from 71 adolescent students (37 females, Mage at t1 = 15.0; t2 = 16.1 years). All were white participants from Germany. Voxel-based morphometry revealed only an association of social exclusion (and not of belonging) and gray matter volume in the left anterior insula: From t1 to t2, there was less gray matter decrease, the more social exclusion students perceived. School-related social exclusion and disturbed neurodevelopment are thus significantly associated.

Loneliness and Adolescents' Neural Processing of Self, Friends, and Teachers: Consequences for the School Self-Concept.

The present interdisciplinary study explored whether perceived loneliness is associated with ventromedial prefrontal cortex (vMPFC) activation during self- and social judgments (friends and teachers) in adolescents. Moreover, we examined how vMPFC activity is related to the academic self-concept (ASC). Results of manifest path analysis indicated that high perceived loneliness was related to lower neural response to self-judgments. In turn, high neural response to self-judgments was positively associated with the ASC, whereas there was a trendwise negative association between high neural response to teacher-related judgments and ASC. This study reveals associations between perceived loneliness and neural processing of the self, underlining the idea that feeling isolated from others may hinder self-insight and, by extension, the formation of a stable academic self-concept.

Functional changes in the reward circuit in response to gaming-related cues after training with a commercial video game.

In the present longitudinal study, we aimed to investigate video game training associated neuronal changes in reward processing using functional magnetic resonance imaging (fMRI). We recruited 48 healthy young participants which were assigned to one of 2 groups: A group in which participants were instructed to play a commercial video game ("Super Mario 64 DS") on a portable Nintendo DS handheld console at least 30minutes a day over a period of two months (video gaming group; VG) or to a matched passive control group (CG). Before and after the training phase, in both groups, fMRI imaging was conducted during passively viewing reward and punishment-related videos sequences recorded from the trained video game. The results show that video game training may lead to reward related decrease in neuronal activation in the dorsolateral prefrontal cortex (DLPFC) and increase in the hippocampus. Additionally, the decrease in DLPFC activation was associated with gaming related parameters experienced during playing. Specifically, we found that in the VG, gaming related parameters like performance, experienced fun and frustration (assessed during the training period) were correlated to decrease in reward related DLPFC activity. Thus, neuronal changes in terms of video game training seem to be highly related to the appetitive character and reinforcement schedule of the game. Those neuronal changes may also be related to the often reported video game associated improvements in cognitive functions.

Taking control! Structural and behavioural plasticity in response to game-based inhibition training in older adults.

While previous attempts to train self-control in humans have frequently failed, we set out to train response inhibition using computer-game elements. We trained older adults with a newly developed game-based inhibition training on a tablet for two months and compared them to an active and passive control group. Behavioural effects reflected in shorter stop signal response times that were observed only in the inhibition-training group. This was accompanied by structural growth in cortical thickness of right inferior frontal gyrus (rIFG) triangularis, a brain region that has been associated with response inhibition. The structural plasticity effect was positively associated with time spent on the training-task and predicted the final percentage of successful inhibition trials in the stop task. The data provide evidence for successful trainability of inhibition when game-based training is employed. The results extend our knowledge on game-based cognitive training effects in older age and may foster treatment research in psychiatric diseases related to impulse control.

Reversal learning strategy in adolescence is associated with prefrontal cortex activation.

Adolescence is a critical maturation period for human cognitive control and executive function. In this study, a large sample of adolescents (n = 85) performed a reversal learning task during functional magnetic resonance imaging. We analyzed behavioral data using a reinforcement learning model to provide individually fitted parameters and imaging data with regard to reward prediction errors (PE). Following a model-based approach, we formed two groups depending on whether individuals tended to update expectations predominantly for the chosen stimulus or also for the unchosen one. These groups significantly differed in their problem behavior score obtained using the child behavior checklist (CBCL) and in a measure of their developmental stage. Imaging results showed that dorsolateral striatal areas covaried with PE. Participants who relied less on learning based on task structure showed less prefrontal activation compared with participants who relied more on task structure. An exploratory analysis revealed that PE-related activity was associated with pubertal development in prefrontal areas, insula and anterior cingulate. These findings support the hypothesis that the prefrontal cortex is implicated in mediating flexible goal-directed behavioral control.

Neural correlates of the self-concept in adolescence-A focus on the significance of friends.

The formation of a coherent and unified self-concept represents a key developmental stage during adolescence. Imaging studies on self-referential processing in adolescents are rare, and it is not clear whether neural structures involved in self-reflection are also involved in reflections of familiar others. In the current study, 41 adolescents were asked to make judgments about trait adjectives during functional magnetic resonance imaging (fMRI): they had to indicate whether the word describes themselves, their friends, their teachers or politicians. Findings indicate a greater overlap in neural networks for responses to self- and friend-related judgments compared to teachers and politicians. In particular, classic self-reference structures such as the ventromedial prefrontal cortex and medial posterior parietal cortex also exhibited higher activation to judgments about friends. In contrast, brain responses towards judgments of teachers (familiar others) compared to politicians (unfamiliar others) did not significantly differ. Results support behavioral findings of a greater relevance of friends for the development of a self-concept during adolescence and indicate underlying functional brain processes. Hum Brain Mapp 38:987-996, 2017. © 2016 Wiley Periodicals, Inc.

Neural correlates of training and transfer effects in working memory in older adults.

As indicated by previous research, aging is associated with a decline in working memory (WM) functioning, related to alterations in fronto-parietal neural activations. At the same time, previous studies showed that WM training in older adults may improve the performance in the trained task (training effect), and more importantly, also in untrained WM tasks (transfer effects). However, neural correlates of these transfer effects that would improve understanding of its underlying mechanisms, have not been shown in older participants as yet. In this study, we investigated blood-oxygen-level-dependent (BOLD) signal changes during n-back performance and an untrained delayed recognition (Sternberg) task following 12sessions (45min each) of adaptive n-back training in older adults. The Sternberg task used in this study allowed to test for neural training effects independent of specific task affordances of the trained task and to separate maintenance from updating processes. Thirty-two healthy older participants (60-75years) were assigned either to an n-back training or a no-contact control group. Before (t1) and after (t2) training/waiting period, both the n-back task and the Sternberg task were conducted while BOLD signal was measured using functional Magnetic Resonance Imaging (fMRI) in all participants. In addition, neuropsychological tests were performed outside the scanner. WM performance improved with training and behavioral transfer to tests measuring executive functions, processing speed, and fluid intelligence was found. In the training group, BOLD signal in the right lateral middle frontal gyrus/caudal superior frontal sulcus (Brodmann area, BA 6/8) decreased in both the trained n-back and the updating condition of the untrained Sternberg task at t2, compared to the control group. fMRI findings indicate a training-related increase in processing efficiency of WM networks, potentially related to the process of WM updating. Performance gains in untrained tasks suggest that transfer to other cognitive tasks remains possible in aging.

Adolescents' Socio-Motivational Relationships With Teachers, Amygdala Response to Teacher's Negative Facial Expressions, and Test Anxiety.

The amygdala is essential for processing emotions, including the processing of aversive faces. The aim of this multimethodological study was to relate the amygdala reactivity of students (N = 88) toward teachers' fearful and angry faces, to students' relationship with their teachers. Furthermore, students' neural responses during the perception of teachers' faces were tested as predictors of test anxiety (controlling for neuroticism as a potential trait anxiety effect). Multiple regression analysis revealed that students reporting high-quality teacher-student relationships showed stronger amygdala activity toward fearful faces, which was related to worry. Furthermore, students with high levels of neuroticism tended to perceive their teachers as motivators and showed higher amygdala activity toward angry faces, which was related to the measures of emotionality.

Working memory load-dependent brain response predicts behavioral training gains in older adults.

In the domain of working memory (WM), a sigmoid-shaped relationship between WM load and brain activation patterns has been demonstrated in younger adults. It has been suggested that age-related alterations of this pattern are associated with changes in neural efficiency and capacity. At the same time, WM training studies have shown that some older adults are able to increase their WM performance through training. In this study, functional magnetic resonance imaging during an n-back WM task at different WM load levels was applied to compare blood oxygen level-dependent (BOLD) responses between younger and older participants and to predict gains in WM performance after a subsequent 12-session WM training procedure in older adults. We show that increased neural efficiency and capacity, as reflected by more "youth-like" brain response patterns in regions of interest of the frontoparietal WM network, were associated with better behavioral training outcome beyond the effects of age, sex, education, gray matter volume, and baseline WM performance. Furthermore, at low difficulty levels, decreases in BOLD response were found after WM training. Results indicate that both neural efficiency (i.e., decreased activation at comparable performance levels) and capacity (i.e., increasing activation with increasing WM load) of a WM-related network predict plasticity of the WM system, whereas WM training may specifically increase neural efficiency in older adults.

Subjective illusion of control modulates striatal reward anticipation in adolescence.

The perception of control over the environment constitutes a fundamental biological adaptive mechanism, especially during development. Previous studies comparing an active choice condition with a passive no-choice condition showed that the neural basis of this mechanism is associated with increased activity within the striatum and the prefrontal cortex. In the current study, we aimed to investigate whether subjective belief of control in an uncertain gambling situation induces elevated activation in a cortico-striatal network. We investigated 79 adolescents (age range: 13-16years) during reward anticipation with a slot machine task using functional magnetic resonance imaging. We assessed post-experimentally whether the participants experienced a subjective illusion of control on winning or losing in this task that was objectively not given. Nineteen adolescents experienced an illusion of control during slot machine gambling. This illusion of control group showed an increased neural activity during reward anticipation within a cortico-striatal network including ventral striatum (VS) as well as right inferior frontal gyrus (rIFG) relative to the group reporting no illusion of control. The rIFG activity was inversely associated with impulsivity in the no illusion of control group. The subjective belief about control led to an elevated ventral striatal activity, which is known to be involved in the processing of reward. This finding strengthens the notion that subjectively perceived control, not necessarily the objective presence of control, affects striatal reward-related processing.

Chronic alcohol intake abolishes the relationship between dopamine synthesis capacity and learning signals in the ventral striatum.

Drugs of abuse elicit dopamine release in the ventral striatum, possibly biasing dopamine-driven reinforcement learning towards drug-related reward at the expense of non-drug-related reward. Indeed, in alcohol-dependent patients, reactivity in dopaminergic target areas is shifted from non-drug-related stimuli towards drug-related stimuli. Such 'hijacked' dopamine signals may impair flexible learning from non-drug-related rewards, and thus promote craving for the drug of abuse. Here, we used functional magnetic resonance imaging to measure ventral striatal activation by reward prediction errors (RPEs) during a probabilistic reversal learning task in recently detoxified alcohol-dependent patients and healthy controls (N = 27). All participants also underwent 6-[(18) F]fluoro-DOPA positron emission tomography to assess ventral striatal dopamine synthesis capacity. Neither ventral striatal activation by RPEs nor striatal dopamine synthesis capacity differed between groups. However, ventral striatal coding of RPEs correlated inversely with craving in patients. Furthermore, we found a negative correlation between ventral striatal coding of RPEs and dopamine synthesis capacity in healthy controls, but not in alcohol-dependent patients. Moderator analyses showed that the magnitude of the association between dopamine synthesis capacity and RPE coding depended on the amount of chronic, habitual alcohol intake. Despite the relatively small sample size, a power analysis supports the reported results. Using a multimodal imaging approach, this study suggests that dopaminergic modulation of neural learning signals is disrupted in alcohol dependence in proportion to long-term alcohol intake of patients. Alcohol intake may perpetuate itself by interfering with dopaminergic modulation of neural learning signals in the ventral striatum, thus increasing craving for habitual drug intake.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum.

Response inhibition is a basic mechanism in cognitive control and dysfunctional in major psychiatric disorders. The neuronal mechanisms are in part driven by dopamine in the striatum. Animal data suggest a regulatory role of glutamate on the level of the striatum. We used a trimodal imaging procedure of the human striatum including F18-DOPA positron emission tomography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging of a stop signal task. We investigated dopamine synthesis capacity and glutamate concentration in vivo and their relation to functional properties of response inhibition. A mediation analysis revealed a significant positive association between dopamine synthesis capacity and inhibition-related neural activity in the caudate nucleus. This relationship was significantly mediated by striatal glutamate concentration. Furthermore, stop signal reaction time was inversely related to striatal activity during inhibition. The data show, for the first time in humans, an interaction between dopamine, glutamate, and the neural signature of response inhibition in the striatum. This finding stresses the importance of the dopamine-glutamate interaction for behavior and may facilitate the understanding of psychiatric disorders characterized by impaired response inhibition.

Reward anticipation in the adolescent and aging brain.

Processing of reward is the basis of adaptive behavior of the human being. Neural correlates of reward processing seem to be influenced by developmental changes from adolescence to late adulthood. The aim of this study is to uncover these neural correlates during a slot machine gambling task across the lifespan. Therefore, we used functional magnetic resonance imaging to investigate 102 volunteers in three different age groups: 34 adolescents, 34 younger adults, and 34 older adults. We focused on the core reward areas ventral striatum (VS) and ventromedial prefrontal cortex (VMPFC), the valence processing associated areas, anterior cingulate cortex (ACC) and insula, as well as information integration associated areas, dorsolateral prefrontal cortex (DLPFC), and inferior parietal lobule (IPL). Results showed that VS and VMPFC were characterized by a hyperactivation in adolescents compared with younger adults. Furthermore, the ACC and insula were characterized by a U-shape pattern (hypoactivation in younger adults compared with adolescents and older adults), whereas the DLPFC and IPL were characterized by a J-shaped form (hyperactivation in older adults compared with younger groups). Furthermore, a functional connectivity analysis revealed an elevated negative functional coupling between the inhibition-related area rIFG and VS in younger adults compared with adolescents. Results indicate that lifespan-related changes during reward anticipation are characterized by different trajectories in different reward network modules and support the hypothesis of an imbalance in maturation of striatal and prefrontal cortex in adolescents. Furthermore, these results suggest compensatory age-specific effects in fronto-parietal regions.

Fast-and-frugal decision tree for the rapid critical appraisal of systematic reviews.

Conducting high-quality overviews of reviews (OoR) is time-consuming. Because the quality of systematic reviews (SRs) varies, it is necessary to critically appraise SRs when conducting an OoR. A well-established appraisal tool is A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2, which takes about 15-32 min per application. To save time, we developed two fast-and-frugal decision trees (FFTs) for assessing the methodological quality of SR for OoR either during the full-text screening stage (Screening FFT) or to the resulting pool of SRs (Rapid Appraisal FFT). To build a data set for developing the FFT, we identified published AMSTAR 2 appraisals. Overall confidence ratings of the AMSTAR 2 were used as a criterion and the 16 items as cues. One thousand five hundred and nineteen appraisals were obtained from 24 publications and divided into training and test data sets. The resulting Screening FFT consists of three items and correctly identifies all non-critically low-quality SRs (sensitivity of 100%), but has a positive predictive value of 59%. The three-item Rapid Appraisal FFT correctly identifies 80% of the high-quality SRs and correctly identifies 97% of the low-quality SRs, resulting in an accuracy of 95%. The FFTs require about 10% of the 16 AMSTAR 2 items. The Screening FFT may be applied during full-text screening to exclude SRs with critically low quality. The Rapid Appraisal FFT may be applied to the final SR pool to identify SR that might be of high methodological quality.

CID: a valid incentive delay paradigm for children.

Despite several modifications and the wide use of the monetary incentive delay paradigm (MID; Knutson et al. in J Neurosci 21(16):RC159, 2001a) for assessing reward processing, evidence concerning its application in children is scarce. A first child-friendly MID modification has been introduced by Gotlib et al. (Arch Gen Psychiatry 67(4): 380-387, 2010); however, comparability in the results of different tasks and validity across different age groups remains unclear. We investigated the validity of a newly modified MID task for children (CID) using functional magnetic resonance imaging. The CID comprises the integration of a more age appropriate feedback phase. We focused on reward anticipation and their neural correlates. Twenty healthy young adults completed the MID and the CID. Additionally, 10 healthy children completed the CID. As expected, both paradigms elicited significant ventral and dorsal striatal activity in young adults during reward anticipation. No differential effects of the tasks on reaction times, accuracy rates or on the total amount of gain were observed. Furthermore, the CID elicited significant ventral striatal activity in healthy children. In conclusion, these findings demonstrate evidence for the validity of the CID paradigm. The CID can be recommended for the application in future studies on reward processing in children, adolescents, and in adults.

Cue reactivity and its inhibition in pathological computer game players.

Despite a rising social relevance of pathological computer game playing, it remains unclear whether the neurobiological basis of this addiction-like behavioral disorder and substance-related addiction are comparable. In substance-related addiction, attentional bias and cue reactivity are often observed. We conducted a functional magnetic resonance study using a dot probe paradigm with short-presentation (attentional bias) and long-presentation (cue reactivity) trials in eight male pathological computer game players (PCGPs) and nine healthy controls (HCs). Computer game-related and neutral computer-generated pictures, as well as pictures from the International Affective Picture System with positive and neutral valence, served as stimuli. PCGPs showed an attentional bias toward both game-related and affective stimuli with positive valence. In contrast, HCs showed no attentional bias effect at all. PCGPs showed stronger brain responses in short-presentation trials compared with HCs in medial prefrontal cortex (MPFC) and anterior cingulate gyrus and in long-presentation trials in lingual gyrus. In an exploratory post hoc functional connectivity analyses, for long-presentation trials, connectivity strength was higher between right inferior frontal gyrus, which was associated with inhibition processing in previous studies, and cue reactivity-related regions (left orbitofrontal cortex and ventral striatum) in PCGPs. We observed behavioral and neural effects in PCGPs, which are comparable with those found in substance-related addiction. However, cue-related brain responses were depending on duration of cue presentation. Together with the connectivity result, these findings suggest that top-down inhibitory processes might suppress the cue reactivity-related neural activity in long-presentation trials.

Effects of baclofen on insular gain anticipation in alcohol-dependent patients - a randomized, placebo-controlled, pharmaco-fMRI pilot trial.

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.