Effect of Repetitive TMS on Executive Function in Alcohol Use Disorder

Alcohol Use Disorder (AUD) is a major public health problem that affects the physical, social, family, and mental integrity of the sufferer. Behavioral self-regulation is compromised in AUD, and a benefit has been reported with the application of repetitive transcranial magnetic stimulation and emotional self-regulation. The aim of this study is to investigate the efficacy of high-frequency rTMS to improve executive functions in patients in abstinence from AUD.

It is proposed that individuals predisposed to developing alcohol use disorder (AUD) exhibit alterations in executive functions, resulting from maladaptive cellular homeostatic processes and neuronal circuits activated by substance use. These alterations persist even after substance withdrawal (Nestler \& Aghajanian, 1997). As a multifactorial disorder, AUD has been linked to family history of alcohol use (Khemiri et al., 2020; Peterson et al., 1990; Tarter et al., 1989) and individual traits such as poor cognitive test performance relative to controls (Shnitko et al., 2018; Goudriaan et al., 2011), which may predict heavy alcohol consumption or AUD development.

These executive dysfunctions manifest as persistent negative behaviors that impede adaptive learning and reduced activation of the executive control network, both of which correlate with AUD severity (Mayhugh et al., 2014). Cognitive flexibility, a key executive function, enables adaptive adjustment of thoughts and behaviors in response to environmental demands (Uddin, 2021). Impaired cognitive flexibility is associated with AUD persistence and severity (Stalnaker et al., 2008), though recovery is observed after prolonged abstinence (Rourke \& Grant, 1999). Thus, cognitive flexibility may serve as a promising treatment biomarker.

McLellan et al. (2000) report that 40-60% of AUD patients relapse within the first year post-treatment, while at least 60% relapse within six months (Durazzo \& Meyerhoff, 2017; Kirshenbaum et al., 2009; Maisto et al., 2006a; Meyerhoff \& Durazzo, 2010). Given these challenges, non-invasive neuromodulation techniques like repetitive transcranial magnetic stimulation (rTMS) have emerged as adjunct therapies to standard treatments (Diana et al., 2017). For example, Addolorato et al. (2017) applied high-frequency (10 Hz) rTMS to the dorsolateral prefrontal cortex (DLPFC) in AUD patients and observed reduced alcohol consumption and increased abstinent days. Similarly, Del Felice et al. (2016) found that left DLPFC stimulation enhanced inhibitory control, selective attention, and mood in active alcohol users.

Stimulating the DLPFC, a hub of the executive control network, may enhance its functional connectivity and improve cognitive flexibility in AUD patients. These effects align with findings that rTMS bolsters inhibitory control and attention (Del Felice et al., 2016; Diana et al., 2017). To explore this further, we propose a longitudinal study assessing cognitive/behavioral traits in AUD patients that may contribute to disorder development. We will also evaluate rTMS effects using neuropsychological tools and MRI to measure structural/functional brain changes.

This study aims to investigate the short- and long-term clinical and cognitive effects of 10 Hz rTMS applied to the left DLPFC in abstinent AUD patients, alongside associated neurostructural and functional connectivity changes. Abstinent AUD patients will receive daily rTMS for four weeks. Clinical outcomes will be tracked for six months, with cognitive, structural, and functional connectivity measurements taken at baseline, post-intervention (4 weeks), and follow-up (6 months).

Eligibility Criteria:
Inclusion Criteria:

* Men and women of 25 to 59 years old
* The reading level of at least 6th grade of primary (equivalent to fifth grade of elementary school).
* Alcohol users with and AUDIT ≥ 20 puntos
* Abstinence from alcohol consumption from 8 weeks to 5 years, with CIWA-Ar scale scores ≤ 9 points.
* No disabling neuropsychiatric conditions (i.e. Schizophrenia)
* No substance use disorders except alcohol and nicotine.
* BrAC (Breath Alcohol) = 0.00 mg/dl in each of the assessments.
* No traces of alcohol consumption using urine test strips.
* No contraindications for TMS therapy.

Exclusion Criteria:

* Individuals with symptoms of severe agitation or who are unable to cooperate in the study
* History of epilepsy
* Sudden onset of stroke, focal neurological findings such as hemiparesis, sensory loss, visual field deficits and lack of coordination.
* Seizures or gait disturbances
* History of severe psychiatric disorders.
* Alterations in a conventional electroencephalogram.
* Pacemakers or intracranial metallic objects.

Elimination criteria

* At the subject's request
* The presence of adverse incidents that deteriorate the subject's health and would limit continuation of rTMS treatment.
* Exacerbation of cognitive or behavioral symptoms during treatment.