Effect of Repetitive TMS on Executive Function in Alcohol Use Disorder

Effect of Repetitive Transcranial Magnetic Stimulation on the 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 people with a greater predisposition to develop AUD have alterations in executive functions, due to maladaptive cellular homeostatic processes and neuronal circuits stimulated by substances, and that these alterations persist even after the withdrawal of the substance (Nestler and Aghajanian, 1997). Also as a multifactorial disorder, it has been considered the implication of family history of consumption (Khemiri et al., 2020; Peterson et al., 1990 & Tarter et al., 1989) and individual traits, like poor performance on a cognitive test compared to controls, (Shnitko et al., 2018 & Goudriaan et al., 2011) as a predictor to develop heavy alcohol consumption or AUD. The alteration in executive functions seems to manifest with the perseverance of negative behaviors that prevent new forms of learning and adaptation to situations, and the decrease in the activation of the executive control network, which is correlated with the severity of the AUD (Mayhugh et al., 2014). One executive function that may be related to AUD and treatment success is cognitive flexibility, whose role is to allow thoughts and behaviors to be appropriately adjusted in response to environmental cognitive demands (Uddin., 2021). Studies have shown that the persistence and severity of AUD have been related to impaired cognitive flexibility (Stalnaker et al., 2008), and it is recovered after prolonged alcohol abstinence (Rourke & Grant, 1999). Therefore, cognitive flexibility may be a treatment biomarker worth exploring. According to a review by McLellan et al. (2000), 40 to 60 % of the patients who are treated for AUD relapse before the first year of follow-up after discharge. At least 60% of those treated for an AUD will relapse within 6 months of treatment (Durazzo and Meyerhoff, 2017; Kirshenbaum et al., 2009; Maisto et al., 2006a; Meyerhoff and Durazzo, 2010). It is for this reason that new treatments are still being sought in addition to standard pharmacological and psychotherapeutic treatments, where non-invasive neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) have shown promising results (Diana et al., 2017). The Food and Drug Administration (FDA) in 2020 approved the use of rTMS as a therapeutic option for nicotine use disorder, but not for AUD in which positive changes have been found. For example, Addolorato et al., (2017) used high frequency (10 Hz) rTMS in areas of the dorsolateral prefrontal cortex (DLPFC) in humans with AUD and found a reduction in alcohol consumption and an increase in the number of days of drinking abstinence. It has been found that rTMS on the left DLPC increased inhibitory control and selective attention, and reduced depressive and somatization features, in subjects with active alcohol consumption (Del Felice et al., 2016). Since DLPFC is an important region of the executive control network, rTMS in this region in patients with AUD could induce an increase in functional connectivity of this network and consequently increase cognitive flexibility. About the effects of rTMS on cognitive functions, it was found to increase inhibitory control and selective attention (Del Felice et al., 2016, Diana et al., 2017). For all the above, we proposed to conduct a longitudinal study that will assess the cognitive and behavioral characteristics of people with a history of AUD that could play in the first place a crucial part to have developed the disorder. And the effects of TMS on this population, using the non-invasive technique of MRI and the neuropsychological tool to assess the cognitive and behavioral effects. The aim of this study is to investigate the short- and long-term clinical and cognitive effects of repetitive transcranial magnetic stimulation (rTMS) at a frequency of 10 Hz on the left dorsolateral prefrontal cortex in patients with alcohol use disorder in abstinence and to examine possible changes in brain structure and functional connectivity associated with this intervention. To do this, the investigators will recruit alcohol-dependent patients and stimulate them by rTMS twice daily for 4 weeks. The investigators will follow the patients to determine clinical outcomes at 6 months. The investigators will also measure clinical, cognitive, structural, and functional brain connectivity to assess short- and long-term intervention-related changes (measurements at baseline, 4 weeks, and 6 months).

mri, rtms, tms, repetitive transcranial magnetic stimulation, mexico, magnetic resonance imaging, executive function

Single blind. The participants will be the only ones blinded. The rTMS coil will be put backwards in the Sham group.

The intervention will be Repetitive Transcranial Magnetic Stimulation. Each patient will receive treatment stimulation in the left dorsolateral prefrontal cortex (lDLPFC) with a frequency of 10 Hz, that includes 2 sessions per day for 20 consecutive business days for 4 weeks. Each session will consist of the application of rTMS at a frequency of 10 Hz, to 100% of the motor threshold. The lDLPFC target will be determined using their resting state functional connectivity between anterior cingulate cortex and lDLPFC. Our algorithm performs a calculation of the individual localization of the participant's lDLPFC, which will be used for the whole study in that particular participant.

The intervention will be Repetitive Transcranial Magnetic Stimulation (Sham). For this patients the coil will be located backwards to the skull. Each patient will receive sham stimulation in the left dorsolateral prefrontal cortex (lDLPFC) with a frequency of 10 Hz, that includes 2 sessions per day for 20 consecutive business days for 4 weeks. Each session will consist of the application of rTMS at a frequency of 10 Hz, to 100% of the motor threshold. The lDLPFC target will be determined using their resting state functional connectivity between anterior cingulate cortex and lDLPFC. Our algorithm performs a calculation of the individual localization of the participant's lDLPFC, which will be used for the whole study in that particular participant.

The investigators will use a Magstim Rapid 2 stimulator, Airfilled coil (AFC), 8 shape (magnetic field of 0.8 Teslas, 3Kg, pulse 0.5 ms) Each patient will receive high frequency 10 Hz stimulation at 100% of motor threshold over the dorsolateral prefrontal cortex (DLPFC) at 1500 pulses per session with 30 trains of 5 seconds and 0.5 ms stimuli and an inter-train distance of 15 seconds. In 2 daily sessions 4 days a week for 4 weeks.

The investigators will use a Magstim Rapid 2 stimulator, Airfilled coil (AFC), 8 shape (magnetic field of 0.8 Teslas, 3Kg, pulse 0.5 ms) Each patient will receive consistent treatment in 2 sessions a day for 20 consecutive business days for 4 weeks. The coil will be placed facing away from the skull to avoid an effect.

Functional connectivity of the dorsolateral prefrontal with the anterior cingulate cortex, measured with fMRI defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.

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 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.

All clinical and MRI data will be shared with each patient's written consent. Identification information will not be shared, only the RID, and all MRI structural data will be defaced prior to sharing. MRI data will be uploaded to Open Neuro while the clinical data will be uploaded to Zenodo.