Transcranial Direct Current Stimulation on Inhibitory Control in Addictions.

Transcranial Direct Current Stimulation on Inhibitory Control in Addictions: a Triple-blinded, Sham-controlled Clinical Trial.

The research in neuroscience of the last 20 years is defined, in addition to continuing to advance in the field of behavioral and pharmacological therapy, by the birth and development of a new therapeutic category, called neuromodulation. Neuromodulation offers the possibility of producing changes in the Nervous System (SN) and therefore, in behavior, in addition to lasting over time. One of the most used non-invasive neuromodulation techniques is transcranial direct current stimulation (tDCS). The benefits of tDCS are promising and varied, so it is a potential neurorehabilitation tool, which has also shown its greatest effectiveness when accompanied by complementary rehabilitation treatment. The present study focuses on the effect of tDCS on addiction. Specifically, there is a great problem with the high rates of relapse presented by those individuals who try to abandon addictive behavior. Therefore, the maintenance of the abstinence period is the central theme of addiction research and the main challenge of rehabilitation at present. For that aim, the intervention will be carried out in a sample in the intermediate phase (internal) in the NOESSO (No EstáS Sólo) therapeutic community (Almería, Spain), between day 15 after arrival and the first day to leave on leave (day 45-60). The research will be made up of a previous period of selection and collection of data related to addiction, together with two phases or moments of correlative intervention and evaluation. Users will receive a bilateral (F3/F4) and repeated stimulation of 2 mA intensity for 20 min each, that is, every 24h for 5 consecutive days in each phase. Through this procedure, the aim is to seek to increase adherence to treatment in the early intervention phase and decrease the dropout rate due to the enhancement of inhibitory control. On the other hand, in the second phase, advanced intervention is sought to reduce craving, through an improvement in inhibitory and emotional control at the time of returning to the context of real consumption. In order to increase the knowledge about intra-individual differences in the effect of tDCS, researchers will compare the early intervention (Phase 1, at the begging of the rehabilitation process) with the advanced intervention (Phase 2, right before the first leave).

The research in behavioral neuroscience of the last 20 years is defined, in addition to continuing to advance in the field of behavioral and pharmacological therapy, by the birth and development of a new therapeutic category, called neuromodulation. Neuromodulation, especially non-invasive neuromodulation, has had a great impact on the current scientific landscape, encompassing the participation and interest of different disciplines such as medicine, bioengineering, psychology, and neuroscience. Scientific publications, as well as the media impact of this type of technique, have been increasing and continue to grow today. Neuromodulation offers the possibility of producing changes in the Nervous System (SN), and these also last over time. These techniques were born with the idea of avoiding the side effects of pharmacological therapy while offering a direct impact on the improvement of pathological symptoms. The changes produced by neuromodulation are promoted, among others, by ultrasound, microscale magnetic fields, and electricity. This last resource, electrical energy, is used by electrical neuromodulation techniques, one of the most studied branches of neuromodulation currently. Electrical neuromodulation starts from the basis that the neurons of our SN communicate with each other through chemical and electrical processes. By applying low-intensity electricity directly to the SN, it is possible to modulate the neuronal communication of the stimulated area by increasing or decreasing the excitability of the membrane of the target neuron field. Electrical neurostimulation encompasses different techniques, among which is Transcranial Direct Current Stimulation (tDCS). The present project focuses on tDCS since it is the technique that has demonstrated higher success rates as well as fewer, or no, side effects. The tDCS consists of a device that contains a ≈9-volt battery. Two electrodes generally emanate from this device: the anode (positive pole), and the cathode (negative pole). Once placed non-invasively on the scalp, electricity flows between both electrodes at very low intensity (maximum 2 mA) for an approximate time of 20 minutes. This flow is barely noticeable to the user, who usually feels only a slight itch in the area of the electrodes that disappear after 60 seconds. However, under the skull, in the brain, electrical changes occur in the neurons in the area. Usually, under the anode there is a depolarization of the neuronal membrane, generating excitability, that is, the first step to greater activity. Under the cathode, most of the time, the opposite process occurs, a polarization that precedes a neuronal inhibition. This change in activity has been recorded by different studies and methods, directly measuring the change in cortical excitability, oxyhemoglobin level, white matter or the change in the levels of neurotransmitters such as gamma-aminobutyric acid (GABA) and Glutamate. So far, tDCS has proven to be an effective yet safe technique, including relatively simple use causing the least discomfort to the user. The most common side effect that has been recorded is the slight itching in the area of the electrodes that also decreases after 60 seconds. This sensation can be controlled and reduced by using an adequate amount of conductive fluid, as well as by greater separation between both electrodes. In fact, tDCS has been shown to be a safe technique for use in children, adolescents, and older people. Administration of tDCS has been shown not to change indirect biomarkers of brain damage (N-acetyl-asperate), as well as levels of other related metabolites. In addition, no adverse effects on cardiac function have been found from stimulation and no convulsive effects have been associated with tDCS. However, to ensure effective and safe stimulation, possible skin sensitivity, medication, substance use, psychiatric disorders or a history of epilepsy should be recorded for each participant, thus controlling their possible interaction. A recent study conducted an updated tDCS safety exploration with more than 1,000 subjects, including participants from vulnerable populations, with an application of more than 33,200 sessions of tDCS, with stimulation of up to 4 mA and up to 40 minutes per session. The results showed no evidence of any serious adverse effects or irreversible damage. The interesting thing about tDCS is not only the direct changes it produces on brain activity but those it produces directly on behavior and are perceptible. In a recent review on tDCS conducted by our research team, it was found that tDCS produces beneficial effects on human motor function when the motor cortex and cerebellum are stimulated. In addition, it has been found that the application of tDCS can reduce neuropathic pain, improve psychopathologies such as depression, schizophrenia and anxiety, as well as improving cognitive processes such as learning, perception and memory. The benefits of tDCS are promising and varied, so it is a potential neurorehabilitation tool, which has also shown its greatest effectiveness when accompanied by complementary rehabilitation treatment. The excitatory or inhibitory effect of a single session of tDCS has been shown to last up to 90 minutes after stimulation. However, what makes this neurorehabilitation technique really interesting is its long-term effect. It has been proven that when stimulation is performed continuously, in repeated sessions, there is a therapeutic benefit that has been maintained up to 3 months after the last stimulation session. In fact, the alteration produced by tDCS in the glutamatergic system has been shown to be related to an increase in brain-derived neurotrophic factor (BDNF), a key molecule for synaptic plasticity. That is, there are changes in the brain that last over time. tDCS and addiction The present study focuses on the effect of tDCS on addiction. Substance addiction is one of the most important mental health problems today. Specifically, there is a great problem with the high rates of relapse presented by those individuals who try to abandon addictive behavior. Therefore, the maintenance of the abstinence period is the central theme of addiction research and the main challenge of rehabilitation in the present. In this line, it has been found that stimulating through tDCS areas related to the circuits of addiction and decision making, preferably the dorsolateral prefrontal cortex (DLPFC) has been possible to modulate the processes of addiction. Anodal stimulation with tDCS over DLPFC has been shown to improve cognitive processes, such as working memory and decision making. This is because this brain area is involved in key processes of addiction, such as impulse control and stimulus salience. Neuroimaging studies have shown that DLPFC dysfunction is related, in addition to these processes, directly to compulsive drug use. To date, stimulation of this brain region has been found to decrease craving for the substance of addiction, relapse rate, and level of substance use such as alcohol, tobacco, cocaine and methamphetamine. Therefore, tDCS is presented as a potential rehabilitation tool that can produce great benefits for addiction, especially in the withdrawal phase, preventing relapse. In addition to addiction-related behaviors, such as craving, relapse, and the emotions that accompany addiction, such as depressive or anxiety symptoms, the present study aims to deeply analyze the psychological process underlying addiction: inhibitory control. Inhibitory control is the ability to contain or stop an inappropriate behavior or response, and its alteration leads to maladaptive behaviors such as impulsivity and compulsivity. Previous studies have found a direct relationship between addiction and high impulsivity, high compulsivity, and a preference for risky decision-making. With tDCS, it has been possible to improve impulsivity and compulsivity, not only in addiction, but also in behaviors related, such as pathological gambling and binge eating disorders. Although there are increasingly consolidated literature on the therapeutic benefits of tDCS applied to DLPFC (F3/F4) on addiction, the latest review on tDCS and addiction points out the need to study its effect on polyaddiction to different substances, which constitutes a population much closer to reality, addiction to a single substance being uncommon. In addition, it is postulated that the samples used in tDCS studies are too small. Finally, a determining limitation is that the opportune moment to apply tDCS is not yet known, if in a more initial phase of addiction rehabilitation, or in a later phase when the rehabilitation process is in a more advanced state. Therefore, this study aims to cover in a longitudinal study an important sample of people with polyaddiction treated in their therapeutic context, to verify the effects of tDCS on the direct components of addiction, such as craving and relapse, as well as on the basic psychological process that underlies addiction: inhibitory control. The intervention will be applied in the initial phase of rehabilitation, as well as in an advanced phase of it. Through the sham condition of tDCS, a control group will be created. All patients will participate in an intervention program while receiving tDCS treatment. This procedure aims to study the efficacy of tDCS for the improvement of inhibitory control and addiction in a process of addiction rehabilitation. It is expected, therefore, that through the neuromodulation of inhibitory control through the application of tDCS in DLPFC there will be a benefit in the rehabilitation of a population with polyaddiction, which is reflected in greater control of the levels of impulsivity and compulsiveness, better decision making, and therefore, lower rates of anxiety, craving for the substance, relapse rate and an increase in quality of life. This project is proposed in collaboration and close coordination with the NOESSO (No EstáS Sólo) Association. NOESSO is dedicated, as a non-profit association, to the reception and treatment of people with addictions. It is integrated into the healthcare network for the treatment of addiction of the Junta de Andalucía, in Spain. It is composed of various rehabilitation and integration centers in the province of Almeria. In Laujar de Andarax there is located the center of primary rehabilitation reception (Cortijo La Quita Therapeutic Community), where patients referred from various centers are admitted. The rehabilitation process follows a strict protocol, in accordance with national and regional guidelines, which combines a multidisciplinary strategy. After the first period of detoxification of a minimum of 15 days, the patient enters a therapeutic program where doctors, psychologists, educators, and social workers work according to an individualized program. The rehabilitation process is completed with a progressive program of departures from the center so that patients gradually face their previous environment. The first departure occurs between 45 and 60 days after admission, at the discretion of the clinical team. NOESSO receives between 90-100 admissions annually. Of these, between 15-20% reach therapeutic discharge, and 25-30% achieve partially achieve objectives. They voluntarily abandon between 20-25% and the rest enter other casuistries without therapeutic success. Therefore, the percentage of dropouts and relapses is high. In fact, in the first scheduled departure from the center, about 20% of relapses are recorded, objectified by control of substances by urinalysis. Hypothesis: Through the neuromodulation of inhibitory control through the application of tDCS in DLPFC there will be a benefit in the rehabilitation of a population with polyaddiction, which is reflected in greater control of the levels of impulsivity and compulsiveness, better decision making, and therefore, lower rates of anxiety, craving for the substance, relapse rate and an increase in quality of life. General objective: to reduce the relapse rate, thus increasing the success rate, and increasing the quality of life of patients undergoing a rehabilitation process for substance addiction. The objectives of this project are aimed at improving the inhibitory control of patients with polyaddiction through the repeated application of stimulation with tDCS. It is expected that the consequence of this improvement will be reflected in greater adherence to treatment, that is, in a significant reduction in the rate of relapse and abandonment. The objectives, therefore, can be divided into three different categories, although all of them are interrelated. Throughout the four evaluations that will be carried out (pre and post of each phase), the objective is to induce a progressive improvement of all the components of inhibitory control that will be measured by neurobehavioral tasks. That is, the goal is for participants who receive tDCS to show a lower rate of risky decisions, i.e. a higher Net Score in the Iowa Gambling Task and a lower number of false alarms in the Go/No Go task. It is expected for participants who have received tDCS to show lower scores on the compulsivity (MOCI) and impulsivity (BIS-11) questionnaires, as well as a better emotional state reflected in more favorable scores on symptoms of depression (BDI-BECK), anxiety (STAI-E/R), fatigue (VAS) and consequently, a higher score on the perceived quality of life (WHOQOL-BREF). The change that treatment with tDCS can suppose on these variables is expected to be reflected in the primary objective of this work, which is the reduction of substance craving (VAS), and therefore, greater adherence to treatment, reflected in a lower relapse rate and a greater number of patients who do not abandon therapy. These changes produced in a population with polyaddiction will be a novelty in the panorama of the scientific literature regarding neuromodulation, since to date there is still a demand for studies on tDCS in the rehabilitation of several substances, a situation closer to the reality of this health problem.

substance abuse, transcraneal electrical stimulation, tDCS, inhibitory control, drug craving, treatment adherence

Group 1: Active-stimulation in Phase 1 and Phase 2 Group 2: Active-stimulation in Phase 1 and Sham-stimulation in Phase 2 Group 3: Sham-stimulation in Phase 1 and Active-stimulation in Phase 2 Group 4: Sham-stimulation in Phase 1 and Phase 2

Care providers communicate to the PI for participants' availability each week. PI assigns an anonymization code that serves to activate the stimulation device in active or sham-mode, blinded to investigators or participants.

Participants will receive active-tDCS stimulation (anode F4 / cathode F3) at 2 mA during 20 min in Phase 1 (5 sessions, intersession time-24h) and in Phase 2 (5 sessions, intersession time-24h).

Participants will receive active-tDCS stimulation (anode F4 / cathode F3) at 2 mA during 20 min in Phase 1 (5 sessions, intersession time-24h), and sham-tDCS at 2 mA (active-stimulation lasting for 1 min) in Phase 2 (5 sessions, intersession time-24h).

Participants will receive sham-tDCS stimulation (anode F4 / cathode F3) at 2 mA (active-stimulation lasting for 1 min) in Phase 1 (5 sessions, intersession time-24h), and active-tDCS at 2 mA during 20 min in Phase 2 (5 sessions, intersession time-24h).

Participants will receive sham-tDCS stimulation (anode F4 / cathode F3) at 2 mA (active-stimulation lasting for 1 min) in Phase 1 (5 sessions, intersession time-24h), and sham-tDCS at 2 mA (active-stimulation lasting for 1 min) in Phase 2 (5 sessions, intersession time-24h).

Number of participants that abandon the treatment phase before the first free weekend outside the center

Dropouts phase 2: participants that abandon the treatment after the first free weekend outside the center

Quantification fo drug craving by Visual Analogue Scale (VAS): This is a visual analog scale, which means that it does not present lexical items. On the contrary, the user only has to mark on the scale from 0 to 10 the degree of a perceived sensation or state of health, in this case the desire for drug (craving)

Quantification fo drug craving by Visual Analogue Scale (VAS): This is a visual analog scale, which means that it does not present lexical items. On the contrary, the user only has to mark on the scale from 0 to 10 the degree of a perceived sensation or state of health, in this case fatigue.

Questionnaire of anxiety state / trait STAI-E / R, is one of the most used tests to measure anxiety, since it allows to differentiate between the stable anxiety in the own time of people with threatening attribution to a wide range of situations, and the anxiety that occurs at that specific moment or transitory emotional state, that the subject is conscious.

WHOQOL-BREF is the Spanish version of the most used test in the field of health to evaluate quality of life in a generic and self-reported way. It consists of 26 items, classified into 4 dimensions (physical, psychological, social relations and environment). It is fast and effective, however it does not allow specific clinical areas to be evaluated in a concrete way.

Beck BDI-BECK-II inventory is widely used to assess the degree of depression. It consists of 21 items indicative of symptoms such as sadness, crying, loss of pleasure, guilt, and desire for suicide according to the Diagnostic and Statistical Manual of Mental Disorders (DSM). Its administration is self-report and provides a measure of presence and severity in adults and adolescents. It is indicated for clinical psychology, neuropsychology, and forensics.

Barratt impulsivity scale (BIS-11). It evaluates impulsivity and its subtypes: cognitive impulsivity, motor impulsivity and impulsivity related to non-planning. The scale consists of 30 Likert-type items and its administration is self-reported. This scale is widely applied in research related to clinical population and substance abuse.

Maudsley Obsessional-Compulsive Inventory (MOCI) (Spanish version). It evaluates compulsivity and its subtypes: (a) checking, (b) cleanliness, (c) slowness and repetition, and (d) doubt and awareness. It has been developed in order to investigate the traits of compulsivity. The questionnaire comprises 30 items with true/false answers. The results are interpreted as a measure of the intensity of compulsive behaviors since the high false alarms in the Go/no-go task are related to a high score in the MOCI questionnaire.

Iowa Gambling Task (IGT): is a neurobehavioral task that measures risky decision-making. Four decks of cards will appear on the computer screen. Each participant will have to choose a card from any deck by clicking on it. The task will consist of 100 essays. In each choice, decks A and B will generate a profit of 100 points and decks C and D of 50 points. However, every 10 trials the choice of the first deck will result in a net loss of 250 points, while the choice of the second will result in a net gain of the same amount. All participants will start with 2000 points and will be instructed to maximize their profits. The main variable Net Score: is the total score obtained by the participant. People with a low Net Score have shown a deficit in performing this task, such as people with substance addiction.

Go/no-go task has been widely used to assess cognitive control, compulsion, and inhibitory control of behavior. A recently published version by our research group will be used. It consist of the presentation of circles of two different colors separated by a fixing point, during 200 tests. What participants should do is respond by pressing the computer's keyboard space bar as quickly as possible if the circle that appears is green (Go test), and avoid responding to the appearance of blue circles (No-Go test). 80% of the trials will be Go trials. Both stimuli will appear on the screen for 350ms. The presentation time will be adjusted to the participant's reaction time (+50ms or -50ms). The interval between stimuli will be variable, between 800ms and 1500ms. The main variable is "false alarms", pressing the key in No-Go trials.

Inclusion Criteria: Substance abuse Under clinical treatment at the Noesso Addiction Rehabilitation Center La Quinta, Laujar de Andarax, Spain Participation approved by the clinical team Participation approved by the experimental team by means of the Göttingen screening questionnaire Signed informed consent At least 26 points in the Montreal Cognitive Assessment (MOCA) evaluation Exclusion Criteria: Epilepsy or history of epilepsy (convulsions due compsumtion not included) Cardiopathy or cardiac electronic devices Skin reaction or high sensitivity to tDCS Head metallic implant Serious mental disease Exclusion because of clinical criteria (physician, psychologist)

All collected Individual Participants Data (IPD) will be shared in .csv files together with readme.txt files describing data processing

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