Investigating the neural mechanisms of transcranial direct current stimulation effects on human cognition: current issues and potential solutions.

Transcranial direct current stimulation (tDCS) has been studied extensively for its potential to enhance human cognitive functions in healthy individuals and to treat cognitive impairment in various clinical populations. However, little is known about how tDCS modulates the neural networks supporting cognition and the complex interplay with mediating factors that may explain the frequently observed variability of stimulation effects within and between studies. Moreover, research in this field has been characterized by substantial methodological variability, frequent lack of rigorous experimental control and small sample sizes, thereby limiting the generalizability of findings and translational potential of tDCS. The present manuscript aims to delineate how these important issues can be addressed within a neuroimaging context, to reveal the neural underpinnings, predictors and mediators of tDCS-induced behavioral modulation. We will focus on functional magnetic resonance imaging (fMRI), because it allows the investigation of tDCS effects with excellent spatial precision and sufficient temporal resolution across the entire brain. Moreover, high resolution structural imaging data can be acquired for precise localization of stimulation effects, verification of electrode positions on the scalp and realistic current modeling based on individual head and brain anatomy. However, the general principles outlined in this review will also be applicable to other imaging modalities. Following an introduction to the overall state-of-the-art in this field, we will discuss in more detail the underlying causes of variability in previous tDCS studies. Moreover, we will elaborate on design considerations for tDCS-fMRI studies, optimization of tDCS and imaging protocols and how to assure high-level experimental control. Two additional sections address the pressing need for more systematic investigation of tDCS effects across the healthy human lifespan and implications for tDCS studies in age-associated disease, and potential benefits of establishing large-scale, multidisciplinary consortia for more coordinated tDCS research in the future. We hope that this review will contribute to more coordinated, methodologically sound, transparent and reproducible research in this field. Ultimately, our aim is to facilitate a better understanding of the underlying mechanisms by which tDCS modulates human cognitive functions and more effective and individually tailored translational and clinical applications of this technique in the future.

Multi-session electrical neuromodulation effects on craving, relapse and cognitive functions in cocaine use disorder: A randomized, sham-controlled tDCS study.

BACKGROUND: The use of transcranial Direct Current Stimulation (tDCS) has previously shown promising results for reducing craving in cocaine use disorder. In this study we further explored the potential of tDCS as add-on intervention in the treatment of cocaine use disorder. METHODS: In a randomized, placebo-controlled, between subject study, we applied tDCS bilaterally with the anodal electrode targeting the right dorsolateral prefrontal cortex (DLPFC; https://clinicaltrials.gov/ct2/show/NCT03025321). Patients with cocaine use disorder were allocated to ten sessions of either active tDCS (n = 29) or sham (n = 30) on five consecutive days. Inhibitory control and risky decision-making were measured via a Go-NoGo task and a two-choice gambling task, respectively, each at baseline, one day after all tDCS sessions and after three months. Relapse at follow-up and craving were also assessed. RESULTS: There was no significant effect of active tDCS on the number of cocaine use days and craving. Relapse was frequent among patients who had received either active or sham tDCS (48.0 % and 69.2 %, respectively), despite an overall decrease in craving during the first two weeks of treatment. No effects were found on cognitive functions. An exploratory analysis for crack cocaine use only revealed that relapse rates were significantly reduced after active tDCS (n = 17) as compared to sham (n = 19). CONCLUSIONS: No beneficial effects of tDCS on number of cocaine use days, craving and cognitive functions were found in the present study, but somewhat promising results were obtained regarding relapse rates among crack-cocaine users specifically. Further research is required to determine the efficacy of tDCS as a complementary treatment in cocaine use disorder.

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.

Optimizing Electrode Montages of Transcranial Direct Current Stimulation for Attentional Bias Modification in Early Abstinent Methamphetamine Users.

Introduction: Chronic use of most psychoactive drugs may lead to substance dependence and drug addiction. Drug addiction is a chronically relapsing disorder, and current pharmacological and behavioral therapies are not fully efficient. Attentional bias (AB) is hypothesized to have a causal contribution to substance abuse, addiction development and, maintenance. Transcranial direct current stimulation (tDCS) has been of increasing interest in the past few years as a means for modulating neuroplasticity of the human brain. Although several studies have reported promising therapeutic effects for tDCS in drug abusers, there is no consensus about optimal electrode montages and target brain regions. This study was aimed to compare effectiveness of several electrode montages in modifying AB. Methods and Materials: Ninety early-abstinent methamphetamine users were recruited from several residential drug-rehabilitation centers in Tehran province. They were randomly assigned to six groups with different electrode montages, targeting the left or right dorsolateral prefrontal cortex (DLPFC) as follows: Two conditions with anodal tDCS over the right DLPFC (return electrode placed over the left shoulder or left supraorbital ridge), three conditions with the anode positioned over the left DLPFC (return electrode over the right shoulder, right supraorbital ridge, or contralateral DLPFC), and one sham condition. Active stimulation intensity was 2 mA DC, delivered for 13 min followed by a 20-min rest and another 13 min of stimulation. The probe detection task (PDT) was performed to assess AB. The positive and negative affect scale (PANAS), and the depression anxiety stress scales (DASS) were used to assess baseline affective status before the intervention. Results: Mixed model analysis showed that the left DLPFC/right shoulder and left DLPFC/right DLPFC montages reduced AB toward drug-cues in comparison with sham stimulation. Conclusion: Our findings indicate that anodal stimulation over the left DLPFC reduces AB in methamphetamine users. This study offers promising findings for further studies investigating tDCS as a clinical device to modify AB in drug users.

Transcranial DC stimulation modifies functional connectivity of large-scale brain networks in abstinent methamphetamine users.

Background: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation tool suited to alter cortical excitability and activity via the application of weak direct electrical currents. An increasing number of studies in the addiction literature suggests that tDCS modulates subjective self-reported craving through stimulation of dorsolateral prefrontal cortex (DLPFC). The major goal of this study was to explore effects of bilateral DLPFC stimulation on resting state networks (RSNs) in association with drug craving modulation. We targeted three large-scale RSNs; the default mode network (DMN), the executive control network (ECN), and the salience network (SN). Methods: Fifteen males were recruited after signing written informed consent. We conducted a double-blinded sham-controlled crossover study. Twenty-minute "real" and "sham" tDCS (2 mA) were applied over the DLPFC on two separate days in random order. Each subject received both stimulation conditions with a 1-week washout period. The anode and cathode electrodes were located over the right and left DLPFC, respectively. Resting state fMRI was acquired before and after real and sham stimulation. Subjective craving was assessed before and after each fMRI scan. The RSNs were identified using seed-based analysis and were compared using a generalized linear model. Results: Subjective craving decreased significantly after real tDCS compared to sham stimulation (p = .03). Moreover, the analysis shows significant modulation of DMN, ECN, and SN after real tDCS compared to sham stimulation. Additionally, alteration of subjective craving score was correlated with modified activation of the three networks. Discussion: Given the observed alteration of the targeted functional brain networks in methamphetamine users, new potentials are highlighted for tDCS as a network intervention strategy and rsfMRI as a suitable monitoring method for these interventions.

Analysis of Resting-State fMRI Topological Graph Theory Properties in Methamphetamine Drug Users Applying Box-Counting Fractal Dimension.

INTRODUCTION: Graph theoretical analysis of functional Magnetic Resonance Imaging (fMRI) data has provided new measures of mapping human brain in vivo. Of all methods to measure the functional connectivity between regions, Linear Correlation (LC) calculation of activity time series of the brain regions as a linear measure is considered the most ubiquitous one. The strength of the dependence obligatory for graph construction and analysis is consistently underestimated by LC, because not all the bivariate distributions, but only the marginals are Gaussian. In a number of studies, Mutual Information (MI) has been employed, as a similarity measure between each two time series of the brain regions, a pure nonlinear measure. Owing to the complex fractal organization of the brain indicating self-similarity, more information on the brain can be revealed by fMRI Fractal Dimension (FD) analysis. METHODS: In the present paper, Box-Counting Fractal Dimension (BCFD) is introduced for graph theoretical analysis of fMRI data in 17 methamphetamine drug users and 18 normal controls. Then, BCFD performance was evaluated compared to those of LC and MI methods. Moreover, the global topological graph properties of the brain networks inclusive of global efficiency, clustering coefficient and characteristic path length in addict subjects were investigated too. RESULTS: Compared to normal subjects by using statistical tests (P<0.05), topological graph properties were postulated to be disrupted significantly during the resting-state fMRI. CONCLUSION: Based on the results, analyzing the graph topological properties (representing the brain networks) based on BCFD is a more reliable method than LC and MI.

Noninvasive brain stimulation for addiction medicine: From monitoring to modulation.

Addiction is a chronic relapsing brain disease with significant economical and medical burden on the societies but with limited effectiveness in the available treatment options. Better understanding of the chemical, neuronal, regional, and network alterations of the brain due to drug abuse can ultimately lead to tailoring individualized and more effective interventions. To this end, employing new assessment and intervention procedures seems crucial. Noninvasive brain stimulation (NIBS) techniques including transcranial electrical and magnetic stimulations (tES and TMS) have provided promising opportunities for the addiction medicine in two main domains: (1) providing new insights into neurochemical and neural circuit changes in the human brain cortex and (2) understanding the role of different brain regions by using NIBS and modulating cognitive functions, such as drug craving, risky decision making, inhibitory control and executive functions to obtain specific treatment outcomes. In spite of preliminary positive results, there are several open questions, which need to be addressed before routine clinical utilization of NIBS techniques in addiction to medicine, such as how to account for interindividual differences, define optimal cognitive and neural targets, optimize stimulation protocols, and integrate NIBS with other therapeutic methods. Therefore, in this chapter we revise the available literature on the use of NIBS (TMS and tES) in the diagnostic, prognostic, and therapeutic aspects of the addiction medicine.

State dependent effect of transcranial direct current stimulation (tDCS) on methamphetamine craving.

Transcranial direct current stimulation (tDCS) has been shown to modulate subjective craving ratings in drug dependents by modification of cortical excitability in dorsolateral prefrontal cortex (DLPFC). Given the mechanism of craving in methamphetamine (meth) users, we aimed to test whether tDCS of DLPFC could also alter self-reported craving in abstinent meth users while being exposed to meth cues. In this double-blinded, crossover, sham-controlled study, thirty two right-handed abstinent male meth users were recruited. We applied 20 min 'anodal' tDCS (2 mA) or 'sham' tDCS over right DLPFC in a random sequence while subjects performed a computerized cue-induced craving task (CICT) starting after 10 min of stimulation. Immediate craving was assessed before the stimulation, after 10 min of tDCS, and after tDCS termination by visual analog scale (VAS) of 0 to 100. Anodal tDCS of rDLPFC altered craving ratings significantly. We found a significant reduction of craving at rest in real tDCS relative to the sham condition (p = 0.016) after 10 min of stimulation. On the other hand, cue-induced VAS craving was rated significantly higher in the real condition in comparison with sham stimulation (p = 0.012). Our findings showed a state dependent effect of tDCS: while active prefrontal tDCS acutely reduced craving at rest in the abstinent meth users, it increased craving during meth-related cue exposure. These findings reflect the important role of the prefrontal cortex in both cue saliency evaluation and urge to meth consumption.

Modulation of cold pain perception by transcranial direct current stimulation in healthy individuals.

OBJECTIVES: The aim of the current study was to evaluate the effect of transcranial direct current stimulation (tDCS) on cold pain perception in healthy individuals. METHODS: Anodal, cathodal (2 mA), or sham tDCSs were applied on the primary motor cortex of 22 healthy subjects in a random order. A cold pressor test was performed ten minutes after initiation of stimulation. Pain threshold and tolerance were defined as time latencies to the onset of pain perception and to the withdrawal from cold stimulus, respectively. Furthermore, pain intensity (on a scale from 0 to 10) was rated at tolerance. RESULTS: Time latencies to pain threshold and tolerance were altered by the type of stimulation (p < 0.05). Pairwise post hoc analysis revealed that anodal tDCS led to increment in pain threshold and tolerance compared with sham stimulation (13.3 ± 7.4 vs. 10.9 ± 6.0 sec for the comparison of pain threshold and 54.6 ± 26.0 vs. 45.3 ± 17.9 for the comparison of pain tolerance following anodal and sham stimulations, respectively, p < 0.05 for both comparisons). However, cathodal stimulation did not alter pain perception in comparison to anodal and sham stimulations (p > 0.05). Furthermore, pain intensity score at tolerance was not significantly affected by the type of stimulation (p > 0.05). CONCLUSION: Anodal stimulation of the primary motor area can be utilized to alleviate cold pain perception in healthy individuals.