Neurobiological Effects of Transcranial Direct Current Stimulation Treatment in Alcohol Use Disorder

Transcranial Direct Current Stimulation (tDCS) consists in the application on the scalp of electrodes (anode and cathode) delivering a direct current of low intensity that cannot be perceived by the stimulated subject. In recent years, tDCS stimulation has been increasingly used in psychiatric clinical research and in the addiction field. Although there are some studies showing the anti-craving action of tDCS in alcohol use disorder (AUD), there are some differences between the stimulation parameters used in these works. Furthermore, there is a lack in the international scientific literature of studies that have investigated the neurobiological basis of tDCS activity. This double-blind randomized sham-controlled trial consist in an intensive daily tDCS stimulation for the first week, then 3 months of follow up with tDCS stimulation (one tDCS stimulation/week) and then 3 months of follow up without tDCS stimulation. Psychometric evaluations will be performed at: baseline, end of the first week of stimulation, 2 weeks, 3 months, 6 months. A venous blood sample will be collected before the first stimulation and after the last stimulation of the intensive first week treatment. The primary outcome of the study is the evaluation of the short-term clinical efficacy of the application of tDCS in subjects with AUD, applying a anodal stimulation (1 mA) on the right Dorso-Lateral Prefrontal Cortex (DLPFC) for 20 minutes for 5 consecutive days. The results on some psychiatric psychometric scales (examine possible changes in mood, cognition and other psychiatric domains) will represent additional criteria. Another outcome is to assess the neuromodulation at the level of DLPFC evaluating the changes in serum levels of the brain-derived neurotrophic factor (BDNF) and its precursor (pro-BDNF). After screening and informed consent, participants will undergo active or sham tDCS for one week during the intensive treatment phase, and a maintenance intervention (twice a week for 3 months), during the tDCS follow-up phase. Following this phase, participants will be followed for further 3 months, during which no rTMS will be delivered but clinical and imaging data will be collected.

Procedure: The project consists of: Screening Visit (baseline), phase 1 (intensive treatment phase), phase 2 (3 months- tDCS follow-up), phase 3 (3 months follow-up without rTMS). In the screening visit, a clinical interview to assess the eligibility of participant (following the inclusion and exclusion criteria) will be performed. The signature of the informed consent and the baseline clinical and cognitive data will be acquired. In Phase 1, all participants will be randomized in the active or sham arm. Participants will receive 20 minutes of anodal right DLPFC stimulation for 5 consecutive days. The assessor will evaluate the acute effect of treatment on craving , consumption and on the psychometric variable considered at the end of this phase. A venous blood sample will be collected before the first stimulation and after the last stimulation of the intensive-stimulation period to asses the BDNF and pro-BDNF level. In Phase 2, each participant will undergo the same treatment (active or sham) of the Phase 1 for three months receiving stimulation once per week. The same psychometric and behavioral data of the phase 1 will be collected monthly. During Phase 3 participants will not receive any tDCS stimulation. Also in this phase, the same psychometric and behavioral data of the phase 1 will be collected monthly.

• Changes in Montgomery-Asberg Depression Scale (MADRS) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Change in substances consumption as assessed by Urine Drug Screen (UDS) [Time frame: Baseline, after tDCS treatment: one week and randomly at follow-up meetings]
• Changes in the Frontal Assessment Battery (FAB) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Hamilton Rating Scale for Anxiety (HAM-A) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Hamilton Rating Scale for Depression (HAM-D) 21 items Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Barratt Impulsiveness Scale - 11 (BIS-11) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Toronto Alexithymia Scale (TAS-20) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Beck Depression Inventory-II scale (BDI-II) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Evaluation of South Oaks Gambling Screen (SOGS) Total Score [Time frame: Baseline]
• Changes in Leuven Affect and Pleasure Scale (LAPS) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Gambling Symptom Assessment Scale (G-SAS) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]
• Changes in Young Mania Rating Scale (YMRS) Total Score [Time frame: Baseline, after tDCS treatment: one week, two weeks, 6 weeks, 3 months, 6 months]