Ventral medial prefrontal cortex (vmPFC) as a target of the dorsolateral prefrontal modulation by transcranial direct current stimulation (tDCS) in drug addiction.

Here, we report some electrophysiologic and imaging effects of the transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (dlPFC) in drug addiction, notably in alcohol and crack-cocaine dependence. The low resolution electromagnetic tomography (LORETA) analysis obtained through event-related potentials (ERPs) under drug-related cues, more specifically in its P3 segment (300-500 ms) in both, alcoholics and crack-cocaine users, showed that the ventral medial prefrontal cortex (vmPFC) was the brain area with the largest change towards increasing activation under drug-related cues in those subjects that kept abstinence during and after the treatment with bilateral tDCS (2 mA, 35 cm(2), cathodal left and anodal right) over dlPFC, applied repetitively (five daily sessions). In an additional study in crack-cocaine, which showed craving decreases after repetitive bilateral tDCS, we examined data originating from diffusion tensor imaging (DTI), and we found increased DTI parameters in the left connection between vmPFC and nucleus accumbens (NAcc), such as the number of voxels, fractional anisotropy (FA) and apparent diffusion coefficient (ADC), in tDCS-treated crack-cocaine users when compared to the sham-tDCS group. This increasing of DTI parameters was significantly correlated with craving decreasing after the repetitive tDCS. The vmPFC relates to the control of drug seeking, possibly by extinguishing this behavior. In our studies, the bilateral dlPFC tDCS reduced relapses and craving to the drug use, and increased the vmPFC activation under drug cues, which may be of a great importance in the control of drug use in drug addiction.

A Randomized Placebo-Controlled Trial of Targeted Prefrontal Cortex Modulation with Bilateral tDCS in Patients with Crack-Cocaine Dependence.

BACKGROUND: Transcranial direct current stimulation over the dorsolateral prefrontal cortex has been shown to be clinically useful in the treatment of drug addiction. METHODS: We conducted a double-blind randomized clinical trial aiming to assess the effects of bilateral dorsolateral prefrontal cortex transcranial direct current stimulation (left cathodal/right anodal) on crack-cocaine addiction. We defined craving as the primary outcome, and other clinical measurements, including depressive and anxiety symptoms, and quality of life, as secondary outcomes. Seventeen male crack-cocaine users (mean age 30.4 ± 9.8 SD) were randomized to receive 5 sessions of active transcranial direct current stimulation (2 mA, 35 cm(2), for 20 minutes), every other day, and 19 males (mean age 30.3 ± 8.4 SD) to receive sham-transcranial direct current stimulation (placebo) as control group. RESULTS: Craving scores were significantly reduced in the transcranial direct current stimulation group after treatment when compared with sham-transcranial direct current stimulation (P = .028) and baseline values (P = .003), and decreased linearly over 4 weeks (before, during, and after treatment) in the transcranial direct current stimulation group only (P = .047). Changes of anxiety scores towards increase in the sham-transcranial direct current stimulation and decrease in the transcranial direct current stimulation group (P = .03), and of the overall perception of quality of life (P = .031) and of health (P = .048) towards decrease in the sham-transcranial direct current stimulation group and increase in the transcranial direct current stimulation group differed significantly between groups. CONCLUSIONS: Repetitive bilateral transcranial direct current stimulation over the dorsolateral prefrontal cortex reduced craving for crack-cocaine use, decreased anxiety, and improved quality of life. We hypothesize that transcranial direct current stimulation effects may be associated with increased prefrontal processing and regulation of craving behavior.

A randomized controlled trial of targeted prefrontal cortex modulation with tDCS in patients with alcohol dependence.

Preliminary small studies have shown that transcranial direct current stimulation (tDCS) reduces craving in alcoholic subjects. It is unclear whether tDCS also leads to changes in clinically meaningful outcomes for alcohol dependence in a properly powered phase II randomized clinical trial. We aimed to investigate whether repetitive tDCS changes the risk of alcohol use relapse in severe alcoholics from outpatient services. Thirty-five subjects were randomized to receive active bilateral [left cathodal/right anodal over the dorsolateral prefrontal cortex (dlPFC)] repetitive (five consecutive days) tDCS (2 mA, 35 cm2, two times daily stimulation for 13 min with a 20-min interval) or sham-tDCS. There were two dropouts before treatment. From 33 alcoholic subjects, 17 (mean age 45.5±8.9 s.d., 16 males) were randomized to sham and 16 (44±7.8 s.d., 16 males) to real tDCS treatment. By the end of the six months of follow-up, two subjects treated with sham (11.8%) and eight treated with real tDCS (50%) were still alcohol-abstinent [p=0.02, Long-rank (Mantel-Cox) Test, HR=0.35 (95% CI, 0.14-0.85)]. No differences with regard to changes on scores of craving, frontal function, global mental status, depressive or anxiety symptoms were observed between groups. However, subjects from the tDCS group improved with regard to their overall perception of quality of life (p=0.02), and increased their scores in the environment domain (p=0.04) after treatment. Bilateral tDCS over dlPFC reduces relapse probability in severe alcoholic subjects and results in improved perception of quality of life.

Multiple Sessions of Transcranial Direct Current Stimulation (tDCS) Reduced Craving and Relapses for Alcohol Use: A Randomized Placebo-Controlled Trial in Alcohol Use Disorder.

Background: Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has been studied as an adjunctive therapeutic agent for alcohol dependence. In a previous study, we showed that five consecutive sessions of tDCS applied bilaterally over the dorsolateral prefrontal cortex (dlPFC) reduced relapse to the use of alcohol in alcohol use disorder (AUD) outpatients. However, no changes on craving scores were observed. In the present study, we investigated if an extended number of sessions of the same intervention would reduce craving and relapses for alcohol use in AUD inpatients. Methods: Thus, a randomized, double-blind, sham-controlled, clinical trial with parallel arms was conducted (https://clinicaltrials.gov/ct2/show/NCT02091284). AUD patients from two private and one public clinics for treatment of drug dependence were randomly allocated to two groups: real tDCS (5 × 7 cm2, 2 mA, for 20 min, cathodal over the left dlPFC, and anodal over the right dlPFC) and sham-tDCS. Real or sham-tDCS was applied once a day, every other day, in a total of 10 sessions. Craving was monitored by a 5-item obsessive compulsive drinking scale once a week (one time before, three times during and once after brain stimulation) over about 5 weeks. Results: Craving scores progressively decreased over five measurements in both groups but were significantly reduced only in the real tDCS group after treatment. Corrected Hedges' within-group (initial and final) effect sizes of craving scores were of 0.3 for the sham-tDCS and of 1.1 for the real tDCS group. Effect size was 3-fold larger in the real tDCS group. In addition, the between-group analysis on craving score difference was nearly significant, and the effect size was 0.58, in favor for a larger effect in the real tDCS group when compared to sham-tDCS. Furthermore, in a 3-months follow-up after intervention, 72.2% of sham-tDCS group relapsed to the alcohol use whereas 72.7% of tDCS group were abstinent. Conclusions: Multiple sessions of bilateral prefrontal tDCS were well tolerated with no significant adverse events. Thus, extended repetitive bilateral tDCS over the dlPFC is a promising adjunctive clinical tool that could be used to reduce alcohol craving and relapses and facilitate alcoholism cessation.

FosB mRNA Expression in Peripheral Blood Lymphocytes in Drug Addicted Patients.

FosB gene heterodimerizes with Jun family proteins to form activator protein 1 (AP-1) complexes that bind to AP-1 sites in responsive genes to regulate transcription in all cells. The genic expression of FosB seems to be modified after long time exposure to drugs of abuse and these changes may be involved in craving and addicted behavior. This study investigated the FosB mRNA expression in peripheral blood lymphocytes of drug addicted patients using real-time PCR approach. Thus, patients with crack-cocaine use disorder (CUD, n = 10), alcohol use disorder (AUD, n = 12), and healthy non-addicted subjects (CONT, n = 12) were assessed. FosB mRNA expression was reduced by 1.15-fold in CUD and 2.17-fold in AUD when compared to CONT. Hedge's effect size gs over log FosB/Act was of 0.66 for CUD and of 0.30 for AUD when compared to controls. This study showed that FosB mRNA expression was detected in lymphocytes from peripheral blood for the first time, and it was less expressed in drug addicted patients. This molecular technique may constitute a potential peripheral marker for substance use disorder.

Lack of Effects of Extended Sessions of Transcranial Direct Current Stimulation (tDCS) Over Dorsolateral Prefrontal Cortex on Craving and Relapses in Crack-Cocaine Users.

Background: Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) has been investigated as additional therapeutic tool for drug use disorder. In a previous study, we showed that five sessions of tDCS applied bilaterally over the dorsolateral prefrontal cortex (dlPFC) reduced craving to the use of crack-cocaine in inpatients from a specialized clinic. In the present study, we examine if an extended number of sessions of the same intervention would reduce craving even further and affect also relapses to crack-cocaine use. Methods: A randomized, double-blind, sham-controlled, clinical trial with parallel arms was conducted (https://clinicaltrials.gov/ct2/show/NCT02091167). Crack-cocaine patients from two private and one public clinics for treatment of drug use disorder were randomly allocated to two groups: real tDCS (5 cm × 7 cm, 2 mA, for 20 min, cathodal over the left dlPFC and anodal over the right dlPFC, n = 19) and sham-tDCS (n = 16). Real or sham-tDCS was applied once a day, every other day, in a total of 10 sessions. Craving was monitored by a 5-item obsessive compulsive drinking scale once a week (one time before, three times during and once after brain stimulation) over about 5 weeks and relapse was monitored after their discharge from clinics for up to 60 days. Results: Craving scores progressively decreased over five measurements in both sham- and real tDCS groups. Corrected Hedges' within-group (initial and final) effect sizes of craving scores were of 0.77 for the sham-tDCS and of 0.97 for the real tDCS group. The between-groups effect size was of 0.34, in favor of the real tDCS group over sham-tDCS group. Relapse rates were high and quite similar between groups in the 30- and 60-days follow-up after discharge from the hospital. Conclusion: Extended repetitive bilateral tDCS over the dlPFC had no add-on effects over regular treatment when considering craving and relapses to the crack-cocaine use in a sample of crack-cocaine patients with severe use disorder. Different tDCS montages targeting other cortical regions and perhaps additional extension of sessions need to be investigated to reach more efficiency in managing craving and relapses to crack-cocaine use.

Behavioral effects of transcranial direct current stimulation (tDCS) induced dorsolateral prefrontal cortex plasticity in alcohol dependence.

Transcranial Direct Current Stimulation (tDCS) has been shown to reduce acute substance craving in drug addicts, and improve cognition in neuropsychiatric patients. Here we aimed to explore further tDCS induced behavioral and neurophysiological modulation including assessment of relapse rate over a prolonged time course in alcoholism. We examined the effects of repeated anodal tDCS (2mA, 35 cm(2), 20min) over the left dorsolateral prefrontal cortex (DLPFC) on relapse to the use of alcohol in alcoholics from outpatient services, who received additional routine clinical treatment. Furthermore, event related potentials (ERPs), cognitive and frontal executive processes, craving, depressive and anxiety symptoms were obtained before and after treatment. From thirteen alcoholic subjects, seven were randomized to sham-tDCS and six to real tDCS treatment (once a week for five consecutive weeks). Depressive symptoms and craving were reduced to a larger extent in the tDCS group compared to the sham group (p=0.005 and p=0.015, respectively). On the other hand, active tDCS was able to block the increase in neural activation triggered by alcohol related and neutral cues in prefrontal cortex (PFC) as indexed by ERP as seen in the sham-tDCS group. Finally, there was a trend for increased change in executive function in the tDCS group compared to the sham-tDCS group (p=0.082), and, similarly, a trend for more relapses in the tDCS group compared to sham tDCS (four alcoholic subjects (66.7%) vs. one (14.3%), p=0.053).These results confirm the previous findings of tDCS effects on craving in alcoholism and also extend these findings as we showed also tDCS-related mood improvement. However, potential increase in relapse is possible; thus the clinical value of an increase in craving and improvement in depression and executive function needs to be carefully assessed in further studies; including investigation of optimal parameters of stimulation.