Effects of tDCS during inhibitory control training on performance and PTSD, aggression and anxiety symptoms: a randomized-controlled trial in a military sample.

BACKGROUND: Post-traumatic stress disorder (PTSD), anxiety, and impulsive aggression are linked to transdiagnostic neurocognitive deficits. This includes impaired inhibitory control over inappropriate responses. Prior studies showed that inhibitory control can be improved by modulating the right inferior frontal gyrus (IFG) with transcranial direct current stimulation (tDCS) in combination with inhibitory control training. However, its clinical potential remains unclear. We therefore aimed to replicate a tDCS-enhanced inhibitory control training in a clinical sample and test whether this reduces stress-related mental health symptoms. METHODS: In a preregistered double-blind randomized-controlled trial, 100 active-duty military personnel and post-active veterans with PTSD, anxiety, or impulsive aggression symptoms underwent a 5-session intervention where a stop-signal response inhibition training was combined with anodal tDCS over the right IFG for 20 min at 1.25 mA. Inhibitory control was evaluated with the emotional go/no-go task and implicit association test. Stress-related symptoms were assessed by self-report at baseline, post-intervention, and after 3-months and 1-year follow-ups. RESULTS: Active relative to sham tDCS neither influenced performance during inhibitory control training nor on assessment tasks, and did also not significantly influence self-reported symptoms of PTSD, anxiety, impulsive aggression, or depression at post-assessment or follow-up. CONCLUSIONS: Our results do not support the idea that anodal tDCS over the right IFG at 1.25 mA enhances response inhibition training in a clinical sample, or that this tDCS-training combination can reduce stress-related symptoms. Applying different tDCS parameters or combining tDCS with more challenging tasks might provide better conditions to modulate cognitive functioning and stress-related symptoms.

Spatial anticipatory attentional bias for threat: Reliable individual differences with RT-based online measurement.

Cues that predict the future location of emotional stimuli may evoke an anticipatory form of automatic attentional bias. The reliability of this bias towards threat is uncertain: experimental design may need to be optimized or individual differences may simply be relatively noisy in the general population. The current study therefore aimed to determine the split-half reliability of the bias, in a design with fewer factors and more trials than in previous work. A sample of 63 participants was used for analysis, who performed the cued Visual Probe Task online, which aims to measure an anticipatory attentional bias. The overall bias towards threat was tested and split-half reliability was calculated over even and odd blocks. Results showed a significant bias towards threat and a reliability of around 0.7. The results support systematic individual differences in anticipatory attentional bias and demonstrate that RT-based bias scores, with online data collection, can be reliable.

Using subjective expectations to model the neural underpinnings of proactive inhibition.

Proactive inhibition - the anticipation of having to stop a response - relies on objective information contained in cue-related contingencies in the environment, as well as on the subjective interpretation derived from these cues. To date, most studies of brain areas underlying proactive inhibition have exclusively considered the objective predictive value of environmental cues, by varying the probability of stop-signals. However, by only taking into account the effect of different cues on brain activation, the subjective component of how cues affect behavior is ignored. We used a modified stop-signal response task that includes a measurement for subjective expectation, to investigate the effect of this subjective interpretation. After presenting a cue indicating the probability that a stop-signal will occur, subjects were asked whether they expected a stop-signal to occur. Furthermore, response time was used to retrospectively model brain activation related to stop-expectation. We found more activation during the cue period for 50% stop-signal probability, when contrasting with 0%, in the mid and inferior frontal gyrus, inferior parietal lobe and putamen. When contrasting expected vs. unexpected trials, we found modest effects in the mid frontal gyrus, parietal, and occipital areas. With our third contrast, we modeled brain activation during the cue with trial-by-trial variances in response times. This yielded activation in the putamen, inferior parietal lobe, and mid frontal gyrus. Our study is the first to use the behavioral effects of proactive inhibition to identify the underlying brain regions, by employing an unbiased task-design that temporally separates cue and response.

Threat-induced impulsivity in Go/Nogo tasks: Relationships to task-relevance of emotional stimuli and virtual proximity.

Threatening stimuli are thought to induce impulsive responses, but Emotional Go/Nogo task results are not in line with this. We extend previous research by testing effects of task-relevance of emotional stimuli and virtual proximity. Four studies were performed to test this in healthy college students. When emotional stimuli were task-relevant, threat both increased commission errors and decreased RT, but this was not found when emotional stimuli were task-irrelevant. This was found in both between-subject and within-subject designs. These effects were found using a task version with equal go and nogo rates, but not with 90-10% go-nogo rates. Proximity was found to increase threat-induced speeding, with task-relevant stimuli only, although effects on accuracy were less clear. Threat stimuli can thus induce impulsive responding, but effects depend on features of the task design. The results may be of use in understanding theoretically unexpected results involving threat and impulsivity and designing future studies.

A Clinical Trial with Combined Transcranial Direct Current Stimulation and Attentional Bias Modification in Alcohol-Dependent Patients.

BACKGROUND: Modifying attentional processes with attentional bias modification (ABM) might be a relevant add-on to treatment in addiction. This study investigated whether influencing cortical plasticity with transcranial direct current stimulation (tDCS) could increase training effects. tDCS could also help alcohol-dependent patients to overcome craving and reduce relapse, independent of training. These approaches were combined to investigate effects in the treatment of alcoholism. METHODS: Ninety-eight patients (analytical sample = 83) were randomly assigned to 4 groups in a 2-by-2 factorial design. Patients received 4 sessions of ABM (control or real training) combined with 2 mA tDCS (active: 20 minutes or sham: 30 seconds) over the left dorsolateral prefrontal cortex. Alcohol bias and craving were assessed, and treatment outcome was measured as relapse after 1 year. RESULTS: Attentional bias scores indicated that during the training only the group with active tDCS and real ABM displayed an overall avoidance bias (p < 0.05). From pre- to postassessment, there were no main or interaction effects of tDCS and ABM on the bias scores, craving, or relapse (p > 0.2). However, effects on relapse after active tDCS were in the expected direction. CONCLUSIONS: There was no evidence of a beneficial effect of tDCS or ABM or the combination. Whether the absence of effect was due to issues with the outcome measurements (e.g., lack of craving, high dropout, and unreliable measurements) or aspects of the intervention should be further investigated.

A clinical trial with combined transcranial direct current stimulation and alcohol approach bias retraining.

Two studies showed an improvement in clinical outcomes after alcohol approach bias retraining, a form of Cognitive Bias Modification (CBM). We investigated whether transcranial direct current stimulation (tDCS) could enhance effects of CBM. TDCS is a neuromodulation technique that can increase neuroplasticity and has previously been found to reduce craving. One hundred alcohol-dependent inpatients (91 used for analysis) were randomized into three experimental groups in a double-blind parallel design. The experimental group received four sessions of CBM while receiving 2 mA of anodal tDCS over the dorsolateral prefrontal cortex (DLPFC). There were two control groups: One received sham stimulation during training and one received active stimulation at a different moment. Treatment outcomes were abstinence duration (primary) and relapse after 3 and 12 months, craving and approach bias (secondary). Craving and approach bias scores decreased over time; there were no significant interactions with experimental condition. There was no effect on abstinence duration after three months (χ2(2) = 3.53, p = 0.77). However, a logistic regression on relapse rates after one year (standard outcome in the clinic, but not-preregistered) showed a trend when relevant predictors were included; relapse was lower in the condition receiving active stimulation during CBM only when comparing to sham stimulation (B = 1.52, S.E. = .836, p = .07, without predictors: p = .19). No strong evidence for a specific enhancement effect of tDCS on CBM was found. However, in a post-hoc analysis, tDCS combined with CBM showed a promising trend on treatment outcome. Important limitations are discussed, and replication is necessary to find more reliable effects.

Neural response to alcohol taste cues in youth: effects of the OPRM1 gene.

Genetic variations in the mu-opioid receptor (OPRM1) gene have been related to high sensitivity to rewarding effects of alcohol. The current study focuses on the neural circuitry underlying this phenomenon using an alcohol versus water taste-cue reactivity paradigm in a young sample at relatively early stages of alcohol use, thus limiting the confound of variations in duration of alcohol use. Drinkers (17-21 years old) were selected on genotype carrying the AA-(n = 20) or the AG-(n = 16) variant of the A118G single nucleotide polymorphism (SNP) of the OPRM1 gene (rs1799971), and underwent functional magnetic resonance imaging (fMRI). Magnitude of the neural activity and frontostriatal functional connectivity in response to alcohol versus water were investigated. The AG-group demonstrated reduced activation in prefrontal and parietal regions, including the inferior and middle frontal gyrus, superior and inferior parietal lobule, compared with the AA-group. No activation differences were observed in the mesolimbic pathway. Connectivity from the ventral-striatum to frontal regions for alcohol > water trials was higher in the AG than the AA group. For the dorsal-striatum seed region, the AG group showed increased connectivity to non-PFC regions. These results indicate that adolescents carrying the G-allele may be more vulnerable for the alcohol to hijack the reward system in the absence of frontal control to regulate craving. This implies that findings of hyperactivation in the mesolimbic structures of G-allele carriers in earlier studies might result from both genetic susceptibility and heavy drinking.

Electrophysiological and Behavioral Effects of Combined Transcranial Direct Current Stimulation and Alcohol Approach Bias Retraining in Hazardous Drinkers.

BACKGROUND: Cognitive bias modification (CBM) can be used to retrain automatic approach tendencies for alcohol. We investigated whether changing cortical excitability with transcranial direct current stimulation (tDCS) could enhance CBM effects in hazardous drinkers. We also studied the underlying mechanisms by including behavioral (craving, implicit associations, approach tendencies) and electrophysiological (event-related potentials) measurements. METHODS: The analytical sample consisted of 78 hazardous drinkers (Alcohol Use Disorders Identification Test >8) randomly assigned to 4 conditions in a 2-by-2 factorial design (control/active CBM and sham/active tDCS). The intervention consisted of 3 sessions of CBM, specifically alcohol approach bias retraining, combined with 15 minutes 1 mA tDCS over the left dorsolateral prefrontal cortex. There was a pre- and postassessment before and after the intervention that included experimental tasks (Approach Avoidance Task, Implicit Association Task) and an electroencephalogram with an oddball and cue-reactivity task. RESULTS: tDCS decreased cue-induced craving (but not overall craving) on postassessment. CBM did not induce an avoidance bias during assessment. During the training, active and control-CBM only differed in bias score during the first session. We found no enhancement effects of tDCS on CBM. Electrophysiological data showed no clear effects of active tDCS or CBM on the P300. CONCLUSIONS: There were no electrophysiological or behavioral effects of repeated CBM and/or tDCS, except for an effect of tDCS on craving. Applied in these specific ways these techniques appear to have limited effects in a hazardous drinking population.

Mediation of cognitive bias modification for alcohol addiction via stimulus-specific alcohol avoidance association.

BACKGROUND: Cognitive bias modification (CBM) studies have provided evidence that cognitive biases play a causal role in alcohol use disorders. In this study, data from a CBM experiment in alcoholic patients were re-analyzed. In the original study, no mediation by associations measured with an Implicit Association Test (IAT) was found. In this study, we explored the possibility that relevant alcohol-related automatic processes may be cue-specific. METHODS: Data from a previous clinical study in a sample of 214 alcohol-addicted patients were re-analyzed. Patients were assigned to a CBM intervention or control condition, performed an alcohol-approach IAT, and were followed up for relapse data a year after training. In this study, bias scores measured via the IAT were calculated and analyzed separately for different stimulus categories: Alcohol, Soft drink, Approach, and Avoid. RESULTS: Training reversed the alcohol-approach bias for all categories. This reversal of bias also predicted reduced relapse, but involved a complex stimulus category-dependent pattern in which an avoidance bias for Alcohol stimuli was most predictive of reduced relapse. CONCLUSIONS: The results contribute to evidence that CBM indeed affects relapse probability via changes in automatic processes, although future study is needed to determine the precise nature of mediating processes. Automatic processes underlying alcohol-related associations may be stimulus-specific, which may be important for the methods of future studies involving implicit measures.

Effects of cognitive bias modification training on neural signatures of alcohol approach tendencies in male alcohol-dependent patients.

Alcohol-dependent patients have been shown to faster approach than avoid alcohol stimuli on the Approach Avoidance Task (AAT). This so-called alcohol approach bias has been associated with increased brain activation in the medial prefrontal cortex and nucleus accumbens. Cognitive bias modification (CBM) has been used to retrain the approach bias with the clinically relevant effect of decreasing relapse rates one year later. The effects of CBM on neural signatures of approach/avoidance tendencies remain hitherto unknown. In a double-blind placebo-controlled design, 26 alcohol-dependent in-patients were assigned to a CBM or a placebo training group. Both groups performed the AAT for three weeks: in CBM training, patients pushed away 90 percent of alcohol cues; this rate was 50 percent in placebo training. Before and after training, patients performed the AAT offline, and in a 3 T magnetic resonance imaging scanner. The relevant neuroimaging contrast for the alcohol approach bias was the difference between approaching versus avoiding alcohol cues relative to soft drink cues: [(alcohol pull > alcohol push) > (soft drink pull > soft drink push)]. Before training, both groups showed significant alcohol approach bias-related activation in the medial prefrontal cortex. After training, patients in the CBM group showed stronger reductions in medial prefrontal cortex activation compared with the placebo group. Moreover, these reductions correlated with reductions in approach bias scores in the CBM group only. This suggests that CBM affects neural mechanisms involved in the automatic alcohol approach bias, which may be important for the clinical effectiveness of CBM.

Estimating the number of principal components via Split-Half Eigenvector Matching (SHEM).

Estimating the number of principal components to retain for dimension reduction is a critical step in many applications of principal component analysis. Common methods may not be optimal, however. The current paper presents an alternative procedure that aims to recover the true number of principal components, in the sense of the number of independent vectors involved in the generation of the data.•Data are split into random halves repeatedly.•For each split, the eigenvectors in one half are compared to those in the other.•The split between high and low similarities is used to estimate the number of principal components. The method is a proof of principle that similarity over split-halves of the data may provide a useful approach to estimating the number of components in dimension reduction, or of similar dimensions in other models.

An experimental test of integrating imagery with approach bias modification for alcohol: A cautionary tale.

OBJECTIVES: In terms of dual process models, behaviour can be conceived of as the outcome of an interplay between reflective, top-down and impulsive, bottom-up processes. Behaviour change interventions may benefit from targeting both types of processes in a coherent way. One approach to this, in the context of reducing hazardous drinking, is to combine imagery involving real-life situations involving alcohol with the simple actions involved in Approach Bias Modification (ApBM), a form of Cognitive Bias Modification. DESIGN: We developed and tested a version of this Imagery-enhanced Approach Bias Modification (IApBM) in an experimental design, with two independent factors: imagery versus control and ApBM versus control training components (N = 139). METHODS: An effect of integrating the training factors was hypothesized on the alcohol-approach bias of an alcohol Approach-Avoidance Task. Further exploratory analyses were performed for the bias on alcohol-related Single Attribute Implicit Association Tests and on alcohol-related questionnaires. Finally, the psychometric properties of an imagery interference effect during training were explored. RESULTS: Results showed no benefit of the training and in fact suggested a negative interaction in which combining the training components appeared to block reductions in craving effected by each in isolation. The reliability of the imagery-related interference effect was high and the effect was correlated with alcohol-related scales. CONCLUSIONS: In conclusion, it appears that interference between training components decreases their individual effects when combining imagery and ApBM in the current way. The imagery-related interference effects that could be measured during training conditions may be useful as an implicit measure of automatic processes underlying hazardous drinking.

Cognitive training and remediation interventions for substance use disorders: a Delphi consensus study.

AIMS: Substance use disorders (SUD) are associated with cognitive deficits that are not always addressed in current treatments, and this hampers recovery. Cognitive training and remediation interventions are well suited to fill the gap for managing cognitive deficits in SUD. We aimed to reach consensus on recommendations for developing and applying these interventions. DESIGN, SETTING AND PARTICIPANTS: We used a Delphi approach with two sequential phases: survey development and iterative surveying of experts. This was an on-line study. During survey development, we engaged a group of 15 experts from a working group of the International Society of Addiction Medicine (Steering Committee). During the surveying process, we engaged a larger pool of experts (n = 54) identified via recommendations from the Steering Committee and a systematic review. MEASUREMENTS: Survey with 67 items covering four key areas of intervention development: targets, intervention approaches, active ingredients and modes of delivery. FINDINGS: Across two iterative rounds (98% retention rate), the experts reached a consensus on 50 items including: (i) implicit biases, positive affect, arousal, executive functions and social processing as key targets of interventions; (ii) cognitive bias modification, contingency management, emotion regulation training and cognitive remediation as preferred approaches; (iii) practice, feedback, difficulty-titration, bias modification, goal-setting, strategy learning and meta-awareness as active ingredients; and (iv) both addiction treatment work-force and specialized neuropsychologists facilitating delivery, together with novel digital-based delivery modalities. CONCLUSIONS: Expert recommendations on cognitive training and remediation for substance use disorders highlight the relevance of targeting implicit biases, reward, emotion regulation and higher-order cognitive skills via well-validated intervention approaches qualified with mechanistic techniques and flexible delivery options.

Alcohol-related effects on automaticity due to experimentally manipulated conditioning.

BACKGROUND: The use of alcohol is associated with various forms of automatic processing, such as approach tendencies and attentional biases, which may play a role in addictive behavior. The development of such automaticity has generally occurred well before subjects perform tasks designed to detect them. Although it seems plausible that this development involves some form of alcohol-related conditioning, this process is not usually included in the experimental procedure. METHODS: The development of automaticity involving alcoholic or nonalcoholic stimuli was experimentally manipulated via a conditioning task. Subjects were presented with pairs of stimuli from a set of 4 stimuli: 2 pictures of alcoholic beverages, and 2 pictures of nonalcoholic beverages. One of the alcoholic and 1 of the nonalcoholic beverages was associated with reward, the other stimuli with punishment. Subjects had to learn to select the rewarded stimuli from pairs of 1 rewarded and 1 punished stimulus. The task, thus experimentally established reward versus punishment stimulus-response-outcome associations, for alcoholic and for nonalcoholic stimuli. Subsequently, a cued reversal task was used to test automaticity involving alcoholic versus nonalcoholic, and rewarded versus punished stimuli. RESULTS: An association was found between heavier drinking and an alcohol-related conditioning bias: heavier drinkers had more difficulty overcoming a conditioned response when it involved selecting a previously punished nonalcoholic stimulus over a previously rewarded alcoholic stimulus. CONCLUSIONS: The study provided novel information on secondary reinforcement involving alcoholic stimuli: heavier drinkers may more easily develop automaticity related to alcohol-reward contingencies. This may have implications for interventions and the interpretation of findings concerning alcohol-related automatic processing.

Anticipated Attack Slows Responses in a Cued Virtual Attack Emotional Sternberg Task.

Threatening stimuli have varying effects, including reaction time (RT) increase in working memory tasks. This could reflect disruption of working memory or, alternatively, a reversible state of freezing. In the current series of experiments, reversible slowing due to anticipated threat was studied using the cued Virtual Attack Emotional Sternberg Task (cVAEST). In this task visually neutral cues indicate whether a future virtual attack could or could not occur during the maintenance period of a Sternberg task. Three studies (N = 47, 40, and 40, respectively) were performed by healthy adult participants online. The primary hypothesis was that the cVAEST would evoke anticipatory slowing. Further, the studies aimed to explore details of this novel task, in particular the interval between the cue and probe stimuli and the memory set size. In all studies it was found that threat anticipation slowed RTs on the working memory task. Further, Study 1 (memory set size 3) showed a decrease in RT when the attack occurred over all Cue Stimulus Intervals (CSIs). In Study 2 a minimal memory set of one item was used, under which circumstances RTs following attacks were only faster shortly after cue presentation (CSI 200 and 500 ms), when RTs were high for both threat and safe cues. Study 3 replicated results of Study 2 with more fine-grained time intervals. The results confirm that anticipation of attack stimuli can reversibly slow responses on an independent working memory task. The cVAEST may provide a useful method to study such threat-induced response slowing.

Reduced functional coupling in the default-mode network during self-referential processing.

Activity within the default-mode network (DMN) is thought to be related to self-referential processing, such as thinking about one's preferences or personality traits. Although the DMN is generally considered to function as a network, evidence is starting to accumulate that suggests that areas of the DMN are each specialized for different subfunctions of self-referential processing. Here, we address the issue of functional specialization by investigating changes in coupling between areas of the DMN during self-referential processing. To this aim, brain activity was assessed during a task in which subjects had to indicate whether a trait adjective described their own personality (self-referential, Self condition), that of another person (other-referential, Other condition), or whether the trait was socially desirable (nonreferential, Control condition). To exclude confounding effects of cardiorespiratory processes on activity and functional coupling, we corrected the fMRI signal for these effects. Activity within areas of the DMN was found to be modulated by self-referential processing. More specifically, during the Self condition compared to the Other and Control condition, activity within the dorsal medial prefrontal cortex, ventral medial prefrontal cortex, and posterior cingulate cortex was increased. Moreover, coupling between areas of the DMN was reduced during the Self condition compared to the Other and Control condition, while coupling between regions of the DMN and regions outside the network was increased. As such, these results provide an indication for functional specialization within the DMN and support the notion that each area of the DMN is involved in different subfunctions of self-referential processing.

When the brain changes its mind: flexibility of action selection in instructed and free choices.

The neural mechanisms underlying the selection and initiation of voluntary actions in the absence of external instructions are poorly understood. These mechanisms are usually investigated using a paradigm where different movement choices are self-generated by a participant on each trial. These "free choices" are compared with "instructed choices," in which a stimulus informs subjects which action to make on each trial. Here, we introduce a novel paradigm to investigate these modes of action selection, by measuring brain processes evoked by an instruction to either reverse or maintain free and instructed choices in the period before a "go" signal. An unpredictable instruction to change a response plan had different effects on free and instructed choices. In instructed trials, change cues evoked a larger P300 than no-change cues, leading to a significant interaction of choice and change condition. Free-choice trials displayed a trend toward the opposite pattern. These results suggest a difference between updating of free and instructed action choices. We propose a theoretical framework for internally generated action in which representations of alternative actions remain available until a late stage in motor preparation. This framework emphasizes the high modifiability of voluntary action.

Predictive cues and spatial attentional bias for alcohol: Manipulations of cue-outcome mapping.

Previous studies suggest that cues predicting the outcome of attentional shifts provide a measure of anticipatory alcohol-related attentional bias that is correlated with risky drinking and has high reliability. However, this is complicated by potential contributions of visual features of cues to reliability, unrelated to their predictive value. Further, little is known of the sensitivity of the bias to variations in cue-outcome mapping manipulations, limiting our theoretical and methodological knowledge: Does the bias robustly follow varying cue-outcome mappings, or are there automatic cue-related associative processes involved? The current studies aimed to address these issues. Participants performed variations of the cued Visual Probe Task (cVPT) in which cues were non-predictive; in which there were multiple cue pairs, used simultaneously and serially; and in which the cue-outcome mapping was reversed. The major findings were, first, that previously found reliability cannot be attributed to aspects of the cues not related to outcome-prediction; second, that reliability of the bias does not survive deviations from a simple, consistent cue-outcome mapping; third, that all predictive versions of the task showed a bias towards alcohol; fourth, that the bias did not simply follow awareness of the cue-outcome mapping; and finally, that only in the case of simultaneous multiple cue pairs, an association with risky drinking was replicated. The results provide support for the reliability of the anticipatory attentional bias for alcohol, suggest that relatively persistent associative processes underlie the bias in the alcohol context, and provide a foundation for future work using the cVPT.

An exploration of prospective memory components and subtasks of the Memory for Intentions Test (MIST).

Introduction: Prospective Memory (PM), the ability to execute future intentions, decreases with age and memory-related disorders and may be an early predictor of dementia. The Memory for Intentions Test (MIST) allows the assessment of multiple aspects of PM using a range of subtasks. The current study evaluated and explored a Portuguese version of the MIST and its subtasks.Method: Forty-one patients with Mild Cognitive Impairment (MCI) and forty healthy participants performed the MIST, neuropsychological tests and questionnaires. Analyses were performed testing relationships between MCI and PM components of the MIST, and differences between subtasks of the test were explored.Results: Reliability of the PM component was acceptable within the patient group, but not within the control group. PM components were significantly lower in the MCI patients, but this effect was dependent on subtasks. Groups differed most strongly at shorter intervals. PM scores predicted MCI status. Correlations were found between PM components and cognitive functioning scales.Conclusions: The Portuguese version of the MIST seems suitable for use in clinical practice and research. MCI is differentially related to different PM components and subtasks of the MIST.