Mediating effects of impulsivity and alexithymia in the association between traumatic brain injury and aggression in incarcerated males.

Studies suggest both alexithymia and impulsivity (partially) explain aggressive behavior in traumatic brain injury (TBI) patients, but none of these studies use both questionnaire and performance-based measures as recommended, nor simultaneously investigate both impulsivity and alexithymia. The available studies therefore likely miss part of the constructs of alexithymia and impulsivity, and do not comprehensively assess the mediating effects of both constructs in the relationship between TBI and aggression. A sample of N = 281 incarcerated individuals were recruited from Dutch penitentiary institutions, and completed the Buss Perry Aggression Questionnaire (aggression), BIS-11 (impulsivity) and Toronto Alexithymia Scale-20 (alexithymia) questionnaires, as well as a stop-signal task and an emotion recognition paradigm. Several multiple mediation analyses were conducted using structural equation modelling, to assess the viability of a causal theoretical model of aggression. The final planned models were the original models with a good fit with the data (comparative fit index > 0.95, root mean square error of approximation and Standardized root mean square residual < 0.05), and results indicate that only questionnaire-based impulsivity mediated the relationship between TBI and aggression. TBI was unrelated to alexithymia, stop-signal or emotion recognition performance. Aggression was predicted by both alexithymia and impulsivity, but not by the performance measures. Post hoc analyses shows that alexithymia moderates the relationship between impulsivity and aggression. These results imply that aggressive incarcerated individuals showing impulsive behavior should be screened for TBI, since TBI is often overlooked or misdiagnosed, and indicate that both impulsivity and alexithymia are potential focus points for aggression reduction treatment in TBI patients.

White matter integrity between left basal ganglia and left prefrontal cortex is compromised in gambling disorder.

Pathological gambling (PG) is a behavioral addiction characterized by an inability to stop gambling despite the negative consequences, which may be mediated by cognitive flexibility deficits. Indeed, impaired cognitive flexibility has previously been linked to PG and also to reduced integrity of white matter connections between the basal ganglia and the prefrontal cortex. It remains unclear, however, how white matter integrity problems relate to cognitive inflexibility seen in PG. We used a cognitive switch paradigm during functional magnetic resonance imaging in pathological gamblers (PGs; n = 26) and healthy controls (HCs; n = 26). Cognitive flexibility performance was measured behaviorally by accuracy and reaction time on the switch task, while brain activity was measured in terms of blood oxygen level-dependent responses. We also used diffusion tensor imaging on a subset of data (PGs = 21; HCs = 21) in combination with tract-based spatial statistics and probabilistic fiber tracking to assess white matter integrity between the basal ganglia and the dorsolateral prefrontal cortex. Although there were no significant group differences in either task performance, related neural activity or tract-based spatial statistics, PGs did show decreased white matter integrity between the left basal ganglia and prefrontal cortex. Our results complement and expand similar findings from a previous study in alcohol-dependent patients. Although we found no association between white matter integrity and task performance here, decreased white matter connections may contribute to a diminished ability to recruit prefrontal networks needed for regulating behavior in PG. Hence, our findings could resonate an underlying risk factor for PG, and we speculate that these findings may extend to addiction in general.

Brain function during cognitive flexibility and white matter integrity in alcohol-dependent patients, problematic drinkers and healthy controls.

Cognitive flexibility has been associated with prefrontal white matter (WM) integrity in healthy controls (HCs), showing that lower WM integrity is associated with worse performance. Although both cognitive flexibility and WM integrity have been found to be aberrant in alcohol-dependent (AD) patients, the relationship between the two has never been tested. In this study, we investigated the association between WM tract density and cognitive flexibility in patients with AD (n = 26) and HCs (n = 22). In order to assess the influence of AD severity, we also included a group of problematic drinkers (PrDs; n = 23) who did not meet the AD criteria. Behavioral responses and brain activity during a cognitive flexibility task were measured during functional magnetic resonance imaging. Probabilistic fiber tracking was performed between the dorsolateral prefrontal cortex and the basal ganglia; two crucial regions for task switching. Finally, the task-related functional connectivity between these areas was assessed. There were no significant group differences in the task performance. However, compared with HCs, AD patients and PrDs showed decreased WM integrity and increased prefrontal brain activation during task switching. Evidence is presented for a compensatory mechanism, involving recruitment of additional prefrontal resources in order to compensate for WM and neural function impairments in AD patients and PrDs. Although present in both alcohol groups, the PrDs were more successful in invoking this compensatory mechanism when compared to the AD patients. We propose that this may therefore serve as a protective factor, precluding transition from problematic drinking into alcohol dependence.

Contingency learning in alcohol dependence and pathological gambling: learning and unlearning reward contingencies.

BACKGROUND: Patients with alcohol dependence (AD) and pathological gambling (PG) are characterized by dysfunctional reward processing and their ability to adapt to alterations of reward contingencies is impaired. However, most neurocognitive tasks investigating reward processing involve a complex mix of elements, such as working memory, immediate and delayed rewards, and risk-taking. As a consequence, it is not clear whether contingency learning is altered in AD or PG. Therefore, the current study aimed to examine performance in a deterministic contingency learning task, investigating discrimination, reversal, and extinction learning. METHODS: Thirty-three alcohol-dependent patients (ADs), 28 pathological gamblers (PGs), and 18 healthy controls (HCs) performed a contingency learning task in which they learned stimulus-reward associations that were first reversed and later extinguished while receiving deterministic feedback throughout. Accumulated points, number of perseverative errors and trials required to reach a criterion in each learning phase were compared between groups using nonparametric Kruskal-Wallis rank-sum tests. Regression analyses were performed to compare learning curves. RESULTS: PGs and ADs did not differ from HCs in discrimination learning, reversal learning, or extinction learning, on the nonparametric tests. Regression analyses, however, showed differences in the initial speed of learning: PGs were significantly faster in discrimination learning compared to ADs, and both PGs and ADs learned slower than HCs in the reversal learning and extinction phases of the task. CONCLUSIONS: Learning rates for reversal and extinction were slower for the alcohol-dependent group and PG group compared to HCs, suggesting that reversing and extinguishing learned contingencies require more effort in ADs and PGs. This implicates a diminished flexibility to overcome previously learned contingencies.

White matter integrity in delinquent emerging adults and non-delinquent controls, and its relationship with aggression, psychopathic traits, and cannabis use.

Background: Atypical white matter integrity may be one of the biological factors related to delinquency. In adults, decreased white matter integrity has been related to antisocial behavior, but findings from research in adolescent and young adult populations are either mixed or lacking. Here we investigated this association within a naturalistic sample of delinquent young adults (age 18-27). Methods: In a sample of 95 young adult, delinquent men and 22 age and gender matched controls, we assessed white matter integrity through fractional anisotropy and mean diffusivity measures. We compared white matter integrity between the groups, and within the delinquent group assessed the association between white matter integrity and aggression, psychopathic traits, and cannabis use. Results: We found no differences in fractional anisotropy or mean diffusivity between delinquent young adults and non-delinquent controls. Additionally, within the group of delinquent young adults, we found no associations between white matter integrity and aggression, psychopathic traits, or cannabis use. Conclusion: Our null findings suggest that white matter integrity differences may be unrelated to antisocial behavior in emerging adults, and/or that white matter differences between delinquent populations and controls may only arise later in life.

The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Emotion Processing, Reappraisal, and Craving in Alcohol Use Disorder Patients and Healthy Controls: A Functional Magnetic Resonance Imaging Study.

Impaired cognitive-motivational functioning is present in many psychiatric disorders, including alcohol use disorder (AUD). Emotion regulation is a key intermediate factor, relating to the (cognitive) regulation of emotional and motivational states, such as in regulation of craving or negative emotions that may lead to relapse in alcohol use. These cognitive-motivational functions, including emotion regulation, are a target in cognitive behavioral therapy and may possibly be improved by neurostimulation techniques. The present between-subjects, single-blind study assesses the effects of sham-controlled high-frequency neuronavigated repetitive transcranial magnetic stimulation (10 Hz) of the right dorsolateral prefrontal cortex (dlPFC) on several aspects relevant for emotion regulation (emotion processing and reappraisal abilities) and related brain activity, as well as self-reported craving in a sample of alcohol use disorder patients (AUD; n = 39) and healthy controls (HC; n = 36). During the emotion reappraisal task, participants were instructed to either attend or reappraise their emotions related to the negative, positive, neutral, and alcohol-related images, after which they rated their experienced emotions. We found that repetitive transcranial magnetic stimulation (rTMS) reduces self-reported experienced emotions in response to positive and negative images in AUD patients, whereas experienced emotions were increased in response to neutral and positive images in HCs. In the functional magnetic resonance imaging (fMRI) analyses, we found that rTMS reduces right dlPFC activity during appraisal of affective images relative to sham stimulation only in AUD patients. We could not confirm our hypotheses regarding the effect of rTMS craving levels, or on reappraisal related brain function, since no significant effects of rTMS on craving or reappraisal related brain function were found. These findings imply that rTMS can reduce the emotional impact of images as reflected in blood oxygenation level-dependent (BOLD) response, especially in AUD patients. Future studies should replicate and expand the current study, for instance, by assessing the effect of multiple stimulation sessions on both explicit and implicit emotion regulation paradigms and craving, and assess the effect of rTMS within subgroups with specific addiction-relevant image preferences. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Emotion Processing, Reappraisal, and Craving in Alcohol Dependence: A Functional Magnetic Resonance Imaging Study.

Alcohol dependence has long been related to impaired emotion regulation-including reappraisal-but little is known about the performance and associated neural activity of alcohol-dependent patients (ADPs) on an emotion reappraisal task. This study, therefore, compares reappraisal of negative, positive, neutral, and alcohol-related images at a behavioral and neural level between ADPs and healthy controls (HCs). Thirty-nine ADPs and 39 age-, gender-, and education-matched HCs performed an emotion reappraisal task during functional magnetic resonance imaging (fMRI), and craving was measured before and after the reappraisal task. During the emotion reappraisal task, participants were instructed to either attend or reappraise positive, negative, neutral, or alcohol-related images, and to indicate their experienced emotion on a visual analogue scale (VAS). Both ADPs and HCs completed the emotion reappraisal task successfully, showing significant differences in self-reported experienced emotion after attending versus reappraising visual stimuli and in brain activity in emotion processing/reappraisal relevant areas. ADPs were not impaired in cognitive reappraisal at a behavioral or neural level relative to HCs, nor did ADPs indicate any difference in self-reported emotion while attending emotional images. However, ADPs were different from HC in emotion processing: ADPs revealed a blunted response in the (posterior) insula, precuneus, operculum, and superior temporal gyrus while attending emotional images compared neutral images compared to HCs, and in ADPs, higher baseline craving levels were associated with a less blunted response to alcohol-related images than in HCs. These results reveal that ADPs do not show impaired reappraisal abilities when instructed, although future studies should assess voluntary reappraisal abilities in alcohol-dependent patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02557815.

Differential Effects of Left and Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation on Resting-State Functional Magnetic Resonance Imaging in Healthy Individuals.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained great interest in multiple clinical and research fields and is believed to accomplish its effect by influencing neuronal networks. The dorsolateral prefrontal cortex (dlPFC) is frequently chosen as the cortical target for HF-rTMS. However, very little is known about the differential effect of HF-rTMS over the left and right dlPFC on intrinsic functional connectivity networks in patients or in healthy individuals. The current study assessed the differential effects of left or right HF-rTMS (corrected for sham) on intrinsic independent component analysis (ICA)-defined functional connectivity networks in a sample of 45 healthy individuals. All subjects had a first scanning session in which baseline functional connectivity was assessed. During the second session, individuals received one session of left, right, or sham dlPFC HF-rTMS (60 5-sec trains of 10 Hz at 110% motor threshold). The sham condition was used to correct for time and placebo effects. ICAs were performed to assess baseline differences and stimulation effects on within- and between-network functional connectivity. Stimulation of the left dlPFC resulted in decreased functional connectivity in the salience network, whereas right dlPFC stimulation resulted in increased functional connectivity within this network. No differences between left or right dlPFC stimulation were found in between-network connectivity. These results suggest that left and right HF-rTMS may have differential effects, and more research is needed on the clinical consequences.

Resting state connectivity in alcohol dependent patients and the effect of repetitive transcranial magnetic stimulation.

Alcohol dependence is thought to result from an overactive neural motivation system and a deficient cognitive control system, and rebalancing these systems may mitigate excessive alcohol use. This study examines the differences in functional connectivity of the fronto-parietal cognitive control network (FPn) and the motivational network (striatum and orbitofrontal cortex) between alcohol dependent patients (ADPs) and healthy controls (HCs), and the effect of repetitive transcranial magnetic stimulation (rTMS) on these networks. This randomized controlled trial included 38 ADPs and 37 HCs, matched on age, gender and education. Participants were randomly assigned to sham or right dorsolateral prefrontal cortex (dlPFC) stimulation with rTMS. A 3T resting state functional Magnetic Resonance Imaging (fMRI) scan was acquired before and after active or sham 10Hz rTMS. Group differences of within and between network connectivity and the effect of rTMS on network connectivity was assessed using independent component analysis. Results showed higher connectivity within the left FPn (p=0.012) and the left fronto-striatal motivational network (p=0.03) in ADPs versus HCs, and a further increase in connectivity within the left FPn after active stimulation in ADPs. ADPs also showed higher connectivity between the left and the right FPns (p=0.025), and this higher connectivity was related to fewer alcohol related problems (r=0.30, p=0.06). The results show higher within and between network connectivity in ADPs and a further increase in fronto-parietal connectivity after right dlPFC rTMS in ADPs, suggesting that frontal rTMS may have a beneficial influence on cognitive control and may result in lower relapse rates.

Effects of non-invasive neurostimulation on craving: a meta-analysis.

This meta-analysis was conducted to evaluate the available evidence regarding the effects of non-invasive neurostimulation of the dorsolateral prefrontal cortex (DLPFC), on craving in substance dependence and craving for high palatable food. Non-invasive neurostimulation techniques were restricted to repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS). A total of 17 eligible studies were identified. Random effects analysis revealed a pooled standardized effect size (Hedge's g) of 0.476 (CI: 0.316-0.636), indicating a medium effect size favouring active non-invasive neurostimulation over sham stimulation in the reduction of craving (z=5.832, p<0.001). No significant differences were found between rTMS and tDCS, between the various substances of abuse and between substances of abuse and food, or between left and right DLPFC stimulation. In conclusion, this meta-analysis provides the first clear evidence that non-invasive neurostimulation of the DLPFC decreases craving levels in substance dependence.