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.

Study Overview

• Status: Not yet recruiting
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Device: Repetitive Transcranial Magnetic Stimulation; Device: Repetitive Transcranial Magnetic Stimulation (Sham)

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alejandra Lopez Castro, MD, MSc; Phone Number: 4422381038; Email: alejandraloc@comunidad.unam.mx

Study Locations

• Mexico
  • Queretaro
    • Querétaro City, Queretaro, Mexico, 76230
      • Unidad de Resonancia Magnética
      • Contact: Alejandra Lopez Castro, MD, MSc; Phone Number: 4422381038; Email: alejandraloc@comunidad.unam.mx
      • Principal Investigator: Eduardo A Garza Villarreal, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active rTMS frequency at 10 Hz; 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.	Device: Repetitive Transcranial Magnetic Stimulation; 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.
Sham Comparator: Sham rTMS frequency at 10 Hz; 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.	Device: Repetitive Transcranial Magnetic Stimulation (Sham); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Wisconsin Card Sorting Task	Measured by Wisconsin Card Sorting Task (WCST) to evaluate cognitive flexibility	Baseline, 4 weeks, 6 months
Change STROOP effect	Measured by STROOP test to evaluate control inhibition	Baseline, 4 weeks, 6 months
Change Visoespatial Memory	Measured by Visoespatial Memory test to evaluate visoespatial memory	Baseline, 4 weeks, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Taskswitching Task Switch cost	Measured by Taskswitching task to evaluate cognitive flexibility	Baseline, 4 weeks
Change in Flanker Task Flanker Efect	Measured by Flanker task to evaluate control inhibition	Baseline, 4 weeks
Change in Nback Task accuracy	Measured by Nback task to evaluate working memory	Baseline, 4 weeks
Change in Alcohol Craving (VAS)	The craving will be measured using a 100 mm visual analogue scales	Baseline, 4 weeks, 6 months
Changes in psychopathological symptoms	Measured by the Symptoms Questionnaire 90 (SCL-90)	Baseline, 4 weeks, 6 months
Changes in WHODAS score	Measured by Disability Assessment Schedule (WHODAS)	Baseline, 4 weeks, 6 months
Changes in Anxiety	Measured by Hamilton Anxiety Rating Scale (HARS)	Baseline, 4 weeks, 6 months
Changes in Depression	Measured by Hamilton Depression Rating Scale (HDRS)	Baseline, 4 weeks, 6 months
Changes in functional connectivity	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.	Baseline, 4 weeks

Collaborators and Investigators

• Sponsor: Universidad Nacional Autonoma de Mexico
• Collaborators: National Council of Science and Technology, Mexico
• Investigators: Principal Investigator: Eduardo A Garza-Villarreal, MD, PhD, Universidad Nacional Autonoma de Mexico

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2023
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: August 10, 2023
• First Submitted That Met QC Criteria: August 10, 2023
• First Posted (Actual): August 18, 2023

Study Record Updates

• Last Update Posted (Actual): August 18, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: magnetic resonance imaging; repetitive transcranial magnetic stimulation; executive function; mri; tms; rtms; mexico
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism
• Other Study ID Numbers: 101.H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: Data will be shared once the study is finished and published, aproximately in 2027
• IPD Sharing Access Criteria: open access
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No