Effects of 10 add-on HF-rTMS treatment sessions on alcohol use and craving among detoxified inpatients with alcohol use disorder: a randomized sham-controlled clinical trial.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is a chronic disorder with high relapse rates. There are currently few clinical trials of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) to reduce alcohol use among AUD patients, and results are mixed. The current study tested the effect of 10 add-on sessions of HF-rTMS over the right dorsolateral pre-frontal cortex (DLPFC) on alcohol use and craving. DESIGN: Single-center, single blind sham-controlled parallel-group RCT (n = 80), with 3 and 6 months follow-up. SETTING: Clinical treatment center in Amsterdam, the Netherlands. PARTICIPANTS: Eighty detoxified and abstinent AUD inpatients in clinical treatment (20 females, average age = 44.35 years). INTERVENTION: Ten sessions of active or sham HF-rTMS (60 10 Hz trains of 5 sec at 110% motor threshold) over the right DLPFC on 10 consecutive work-days. MEASUREMENTS: The primary outcome measure is the number of abstinent days over 6-month follow-up (FU). Secondary outcome measures are craving over 6-month FU (alcohol urge questionnaire and obsessive-compulsive drinking scale), time to first relapse over 6-month FU and grams of alcohol consumed over 6-month FU. Additional outcome measures: full abstinence over 6-month FU and treatment success over 12-month FU. FINDINGS: HF-rTMS did not affect the number of abstinent days over 6 months FU [sham = 124 ± 65.9 days, active = 115 ± 69.8 days, difference: 9 days, 95% confidence interval (CI) = Poisson model: 0.578-3.547]. Moreover, HF-rTMS did not affect craving (AUQ/OCDS) (sham = 15.38/5.28, active = 17.48/4.75, differences = 2.1/-0.53, 95% CI mixed-effects model = -9.14 to 2.07/-1.44 to 2.40). CONCLUSIONS: There was no clear evidence that high-frequency repetitive transcranial magnetic stimulation over the right dorsolateral pre-frontal cortex treatment has a long-term positive effect on alcohol use or craving as add-on treatment for alcohol use disorder. High treatment response at 6-month follow-up could have limited the possibility to find an effect.

The effect of non-invasive brain stimulation on executive functioning in healthy controls: A systematic review and meta-analysis.

In recent years, there has been a heightened interest in the effect of non-invasive brain stimulation on executive functioning. However, there is no comprehensive overview of its effects on different executive functioning domains in healthy individuals. Here, we assessed the state of the field by conducting a systematic review and meta-analysis on the effectiveness of non-invasive brain stimulation (i.e. repetitive transcranial magnetic stimulation and transcranial direct current stimulation) over prefrontal regions on tasks assessing working memory, inhibition, flexibility, planning and initiation performance. Our search yielded 63 studies (n = 1537), and the effectiveness of excitatory and inhibitory non-invasive brain stimulation were assessed per executive functioning task. Our analyses showed that excitatory non-invasive brain stimulation had a small but positive effect on Stop Signal Task and Go/No-Go Task performance, and that inhibitory stimulation had a small negative effect on Flanker Task performance. Non-invasive brain stimulation did not affect performance on working memory and flexibility tasks, and effects on planning tasks were inconclusive.

Effects of Ten Sessions of High Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) Add-on Treatment on Impulsivity in Alcohol Use Disorder.

INTRODUCTION: Alcohol use disorder (AUD) is characterized by increased impulsivity, which is multifactorial and can be assessed by tests like the delay discounting, Go-Nogo, and stop signal task (SST). Impulsivity has been related to poor treatment outcomes in substance use disorders, including AUD. In order to decrease impulsivity or improve inhibitory control, high frequency transcranial magnetic stimulation (HF-rTMS) has gained interest. Studies applying HF-rTMS over the DLPFC of individuals suffering from AUD assessing its effects on impulsivity measures are scarce, and results are inconclusive. METHODS: The current study (registered in Netherlands Trial Register with trial number 5291: https://www.trialregister.nl/trial/5151) applied 10 sessions of HF-rTMS [sixty 10 Hz trains of 5 s at 110% motor threshold (MT)] over the right DLPFC of 80 alcohol dependent patients in clinical treatment on 10 consecutive workdays. At baseline, halfway and after the HF-rTMS treatment, the delay discounting, Go-NoGo, and SST were assessed. RESULTS: Ten sessions of HF-rTMS over the right DLPFC versus sham HF-rTMS did not affect performance on the delay discounting, Go-NoGo, and SSTs. A significant effect of age was found for the Go-NoGo task, with higher age associated with better performance. Furthermore, no significant correlations were found between difference scores of task performance and baseline impulsivity or severity of AUD. DISCUSSION: Results of this study, in combination with other studies using HF-rTMS studies in alcohol and substance use disorder, indicate mixed and inconclusive findings of HF-rTMS on impulsivity. Future studies within patient groups hospitalized at the same department are recommended to consider using a sham coil that mimics the sensations on the scalp of active HF-rTMS and to measure motivation across test sessions.

Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine: A consensus paper on the present state of the science and the road ahead.

There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

Mega-Analysis of Gray Matter Volume in Substance Dependence: General and Substance-Specific Regional Effects.

OBJECTIVE: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. METHOD: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. RESULTS: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. CONCLUSIONS: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Effects of Non-invasive Neuromodulation on Executive and Other Cognitive Functions in Addictive Disorders: A Systematic Review.

Background: In order to improve the current treatment of addictive disorders non-invasive neuromodulation over the dorsolateral prefrontal cortex (DLPFC) has gained attention. The DLPFC is crucially involved in executive functioning, functions which are related to the course of addictive disorders. Non-invasive stimulation of the DLPFC may lead to changes in executive functioning. Currently an overview of effects of neuromodulation on these functions is lacking. Therefore, this systematic review addresses the effects of non-invasive neuromodulation on executive functioning in addictive disorders. Methods: The current review is conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015 (PRISMA-P 2015) guidelines and has been registered in PROSPERO International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/prospero/, registration number: CRD42018084157). Original articles were searched using the Ovid MEDLINE, Embase and PsycINFO database. Results: The systematic search resulted in 1,228 unique studies, of which sixteen were included in the current review. Some of these studies do not address the classic definition of executive functions, but another cognitive function. However, they were included in this review since the field is small and still under development and we aim to give an inclusive overview in its broadest sense. The following executive and other cognitive functioning domains were assessed: attention, cognitive flexibility, response inhibition, memory and learning, problem solving, social cognition, risk taking, cognitive bias modification and overall executive functioning. The executive function domain most positively affected was social cognition followed by memory & learning, response inhibition, cognitive flexibility and attention. Conclusions: The studies addressed in the current review used a large variability of stimulation protocols and study designs which complicates comparability of the results. Nevertheless, the results of these studies are promising in light of improvement of current treatment. Therefore, we recommend future studies that compare the effect of different types of stimulation, stimulation sides and number of stimulation sessions in larger clinical trials. This will significantly increase the comparability of the studies and thereby accelerate and clarify the conclusion on whether non-invasive neuromodulation is an effective add-on treatment for substance dependence.

Repetitive transcranial magnetic stimulation (rTMS) in alcohol dependence: study protocol of a randomized controlled clinical trial of efficacy and working mechanisms.

BACKGROUND: High frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained interest as a neuromodulation treatment technique for alcohol dependence. Single sessions of HF-rTMS have consistently shown to decrease craving for substances. However, the results of randomized controlled clinical trials investigating the effect of multiple HF-rTMS sessions in alcohol dependence on abstinence rates and craving are inconsistent. Furthermore, they lack information on the effect of HF-rTMS on cognition and brain functioning. METHODS: A single center, single blind, randomized controlled trial with 80 abstinent alcohol dependent subjects in treatment randomized (1:1) to either treatment as usual (TAU) plus ten sessions of active HF-rTMS or TAU plus 10 sessions of placebo/ sham HF-rTMS will be performed. The effects of ten HF-rTMS sessions on craving and neurocognitive functions are obtained. In addition a subset of participants will undergo an MR scanning session before the first and after the last HF-rTMS session in order to investigate the effect of ten HF-rTMS sessions on brain functioning. The primary outcome is the continued abstinence rate after the add-on HF-rTMS treatment. DISCUSSION: This study uses a randomized controlled trial to examine the clinical, neurocognitive and brain functioning effects of ten add-on HF-rTMS sessions in alcohol dependent individuals in treatment. If the add-on treatment is effective, this may add to the evidence needed for approval of this additional treatment method for alcohol dependence by regulatory authorities. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR), NTR5291 , 6-July-2015.

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.

Aversive Counterconditioning Attenuates Reward Signaling in the Ventral Striatum.

Appetitive conditioning refers to the process of learning cue-reward associations and is mediated by the mesocorticolimbic system. Appetitive conditioned responses are difficult to extinguish, especially for highly salient reward such as food and drugs. We investigate whether aversive counterconditioning can alter reward reinstatement in the ventral striatum in healthy volunteers using functional magnetic resonance imaging (fMRI). In the initial conditioning phase, two different stimuli were reinforced with a monetary reward. In the subsequent counterconditioning phase, one of these stimuli was paired with an aversive shock to the wrist. In the following extinction phase, none of the stimuli were reinforced. In the final reinstatement phase, reward was reinstated by informing the participants that the monetary gain could be doubled. Our fMRI data revealed that reward signaling in the ventral striatum and ventral tegmental area following reinstatement was smaller for the stimulus that was counterconditioned with an electrical shock, compared to the non-counterconditioned stimulus. A functional connectivity analysis showed that aversive counterconditioning strengthened striatal connectivity with the hippocampus and insula. These results suggest that reward signaling in the ventral striatum can be attenuated through aversive counterconditioning, possibly by concurrent retrieval of the aversive association through enhanced connectivity with hippocampus and insula.

Genetic imaging consortium for addiction medicine: From neuroimaging to genes.

Since the sample size of a typical neuroimaging study lacks sufficient statistical power to explore unknown genomic associations with brain phenotypes, several international genetic imaging consortia have been organized in recent years to pool data across sites. The challenges and achievements of these consortia are considered here with the goal of leveraging these resources to study addiction. The authors of this review have joined together to form an Addiction working group within the framework of the ENIGMA project, a meta-analytic approach to multisite genetic imaging data. Collectively, the Addiction working group possesses neuroimaging and genomic data obtained from over 10,000 subjects. The deadline for contributing data to the first round of analyses occurred at the beginning of May 2015. The studies performed on this data should significantly impact our understanding of the genetic and neurobiological basis of addiction.