Flexibility, Alcohol Misuse, and Excitation

NCT06634771 | Terminated Results

• 2 other identifiers: 23-1702P60AA011605
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to learn whether a single non-invasive brain stimulation alpha-transcranial alternating current stimulation (alpha-tACS) session changes measures of excitability in the prefrontal cortex. It will also learn whether these changes predict differences in habitual action selection in a laboratory task and whether the effects depend on alcohol use history. The main questions it aims to answer are: Does alpha-tACS reduce habitual action selection by reducing excitability in the prefrontal cortex? Is alpha-tACS most effective in reducing habitual action selection in hazardous drinkers who engaged in binge-drinking during adolescence? Researchers will compare alpha-tACS to sham stimulation to see if alpha-tACS changes habitual action selection by changing prefrontal excitability. Participants will: Visit the lab for behavioral training Visit the imaging center for an MRI session Visit the lab to receive alpha-tACS or sham stimulation during behavioral testing and undergo EEG recordings before and after stimulation Visit the imaging center for a repeat MRI session Provide a small sample of blood from a finger-prick in the first and last visits.

Conditions

Healthy Volunteers; High Risk Alcohol Use; Behavioral Flexibility

Keywords

alcohol; brain stimulation; MRI; EEG

Outcome Measures

Primary Outcomes (2)

• Change in Proportion of Errors

  In the HABIT task participants are trained to associate abstract images on the computer screen with specific responses (button presses). They initially learn two stimulus-response pairings and then practice these two pairings at the beginning of each session; these are referred to as the familiar (FAM) sets. At sessions 2 and 3 they also learn two new stimulus-response pairings, which are referred to as the novel (NOV) sets and which they do not encounter at later sessions. During sessions 2 and 3 they undergo a reversal test, during which the correct responses for one familiar set and one novel set are changed, and they must learn the new correct responses by trial and error. The outcome measure here is the proportion of total errors made in response to the devalued familiar set during the reversal test that are perseverative errors, or errors in which they respond with a button press that was previously correct but is no longer correct.

  Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after

• Change in Prefrontal GABA:Glutamate/Glutamine Ratio

  The researchers will evaluate the difference in the gamma-aminobutyric acid (GABA):glutamate/glutamine ratios in the left dorsolateral prefrontal cortex, measured via single voxel magnetic resonance spectroscopy (MRS) at rest.

  Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after

Secondary Outcomes (6)

• Change in C-reactive Protein

  Baseline, study completion (an average of 2 weeks)

• Change in Interleukin-6 (IL-6)

  Baseline, study completion (an average of 2 weeks)

• Change in Tumor Necrosis Factor-alpha (TNF-alpha)

  Baseline, study completion (an average of 2 weeks)

• Change in Functional Connectivity Between the Bilateral dlPFC and the aIC

  Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after

• Change in Functional Connectivity Between the dlPFC and Limbic Striatum

  Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after

Study Arms (2)

10Hz bi-frontal tACS

EXPERIMENTAL

For Session 3, participants will complete a Habitual Association between Images Task (HABIT) Test Session in the Howell Hall Neurostimulation Core Lab or electroencephalogram (EEG) Core Lab, which is located one floor below the Boettiger Lab. Participants will receive either 10Hz bi-frontal transcranial alternating current stimulation (tACS) or sham tACS. 10 Hz bi-frontal tACS: Alternating current stimulation is delivered by an XCSITE 100 device (Pulvinar Neuro, Chapel Hill, NC), through three conductive carbon-rubber electrodes. Electrodes are placed over the apex of the head (Cz) and the prefrontal cortex bilaterally (F3 and F4). Stimulation is delivered during the second half of the HABIT Test session. Stimulation parameters: 2mA peak-to-peak 10Hz sine-wave flanked by 10 second linear envelope ramps in and out for a total duration of 30 min and 20 seconds.

Other: 10 Hz transcranial alternating current stimulation (tACS)

sham tACS

SHAM COMPARATOR

Sham transcranial alternating current stimulation (tACS): The procedure for sham stimulation will be identical, but the actual stimulation will last for 2 minutes instead of 30 minutes. Participants generally report that stimulation is felt most strongly at the beginning of active stimulation, before they adjust to the sensation. Sham stimulation is meant to mimic this progression in terms of tactile salience. Stimulation is delivered for 2 minutes at the beginning of the HABIT reversal task, flanked by 10 second linear envelope ramps. The stimulating electrodes are left on the head until completion of the HABIT task, as is the case in active stimulation. There is no visual or auditory indication to the participant or researcher when the 2-minute sham stimulation period has ended, allowing the sham stimulation condition to feel similar to active stimulation.

Other: sham transcranial alternating current stimulation (tACS)

Interventions

sham transcranial alternating current stimulation (tACS) OTHER

Sham tACS: The procedure for sham stimulation will be identical, but it will last for 2 minutes instead of 30 minutes.

sham tACS

10 Hz transcranial alternating current stimulation (tACS) OTHER

10 Hz bi-frontal tACS: Alternating current stimulation is delivered by an XCSITE 100 device (Pulvinar Neuro, Chapel Hill, NC), through three conductive carbon-rubber electrodes. Electrodes are placed over the apex of the head (Cz) and the prefrontal cortex bilaterally (F3 and F4). Stimulation is delivered during the second half of the HABIT Test session. Stimulation parameters: 2mA peak-to-peak 10Hz sine-wave flanked by 10 second linear envelope ramps in and out for a total duration of 30 min and 20 seconds.

10Hz bi-frontal tACS

Eligibility Criteria

• Age: 22 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 22-50 years old
• Have a high school diploma or equivalent
• Medically healthy
• Fluent in English
• For RISK group only:
• High risk alcohol use in the past month \[World Health Organization (WHO ) risk level 2-4\]
• No history of adolescent binge drinking
• For RISK+ Adolescent binge alcohol (AIE) group only:
• High risk alcohol use in the past month (WHO risk level 2-4)
• High levels of adolescent alcohol use (4 or more binge drinking episodes before age 18)
• For Control (CON) group only:
• Low risk alcohol use throughout the lifetime (WHO risk level 0-1)
• No history of adolescent binge drinking
• No lifetime history of Alcohol Use Disorder (AUD)

You may not qualify if:

• Any individual who meets one or more of the following criteria will be excluded from participation \[excluding positive breath alcohol concentration (BAC), urine drug screen, psychiatric diagnoses, and color blindness, all will be self-reported\]:
• Lifetime history of a substance use disorder (SUD; including nicotine) but participants will not be excluded for an AUD.
• Neurological disease such as dementia, seizures or head trauma
• History of psychosis or psychotic episodes
• Diagnosis of attention deficit hyperactivity disorder (ADHD)
• Any systemic or inflammatory disease that could affect cognitive functioning (e.g., cancer, cardiovascular disease)
• Any motor or visual disturbances that could hinder task performance (e.g., color blindness)
• Use of psychoactive recreational drugs in the past month (excluding caffeine and alcohol)
• Use of psychotropic medications in the past month including antidepressants, mood stabilizers, antipsychotics, anxiolytics, stimulants, or hypnotics (excluding antidepressant use when dosage has been stable for 1 month or longer)
• Use of therapeutic brain stimulation \[e.g. transcranial magnetic stimulation (TMS) or electroconvulsive therapy (ECT)\] in the past month
• Any history of brain surgery
• History of migraine headaches
• Pregnancy
• Any brain implants or devices
• First degree relative with primary epilepsy

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute on Alcohol Abuse and Alcoholism (NIAAA): collaborator

Study Sites (1)

University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (32)

• Zaehle T, Rach S, Herrmann CS. Transcranial alternating current stimulation enhances individual alpha activity in human EEG. PLoS One. 2010 Nov 1;5(11):e13766. doi: 10.1371/journal.pone.0013766.

  PMID: 21072168 BACKGROUND

• Wood W, Runger D. Psychology of Habit. Annu Rev Psychol. 2016;67:289-314. doi: 10.1146/annurev-psych-122414-033417. Epub 2015 Sep 10.

  PMID: 26361052 BACKGROUND

• Viner RM, Taylor B. Adult outcomes of binge drinking in adolescence: findings from a UK national birth cohort. J Epidemiol Community Health. 2007 Oct;61(10):902-7. doi: 10.1136/jech.2005.038117.

  PMID: 17873228 BACKGROUND

• Vanderhasselt MA, De Raedt R, Brunoni AR, Campanha C, Baeken C, Remue J, Boggio PS. tDCS over the left prefrontal cortex enhances cognitive control for positive affective stimuli. PLoS One. 2013 May 21;8(5):e62219. doi: 10.1371/journal.pone.0062219. Print 2013.

  PMID: 23704874 BACKGROUND

• Smittenaar P, FitzGerald TH, Romei V, Wright ND, Dolan RJ. Disruption of dorsolateral prefrontal cortex decreases model-based in favor of model-free control in humans. Neuron. 2013 Nov 20;80(4):914-9. doi: 10.1016/j.neuron.2013.08.009. Epub 2013 Oct 24.

  PMID: 24206669 BACKGROUND

• Siqueira L, Smith VC; COMMITTEE ON SUBSTANCE ABUSE. Binge Drinking. Pediatrics. 2015 Sep;136(3):e718-26. doi: 10.1542/peds.2015-2337.

  PMID: 26324872 BACKGROUND

• Sellers KK, Mellin JM, Lustenberger CM, Boyle MR, Lee WH, Peterchev AV, Frohlich F. Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test. Behav Brain Res. 2015 Sep 1;290:32-44. doi: 10.1016/j.bbr.2015.04.031. Epub 2015 Apr 28.

  PMID: 25934490 BACKGROUND

• Rehm J, Shield KD, Roerecke M, Gmel G. Modelling the impact of alcohol consumption on cardiovascular disease mortality for comparative risk assessments: an overview. BMC Public Health. 2016 Apr 28;16:363. doi: 10.1186/s12889-016-3026-9.

  PMID: 27121289 BACKGROUND

• Ostlund SB, Balleine BW. Lesions of medial prefrontal cortex disrupt the acquisition but not the expression of goal-directed learning. J Neurosci. 2005 Aug 24;25(34):7763-70. doi: 10.1523/JNEUROSCI.1921-05.2005.

  PMID: 16120777 BACKGROUND

• Olsen RW, Liang J. Role of GABAA receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model. Mol Brain. 2017 Sep 20;10(1):45. doi: 10.1186/s13041-017-0325-8.

  PMID: 28931433 BACKGROUND

• Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24:167-202. doi: 10.1146/annurev.neuro.24.1.167.

  PMID: 11283309 BACKGROUND

• McKim TH, Dove SJ, Robinson DL, Frohlich F, Boettiger CA. Addiction history moderates the effect of prefrontal 10-Hz transcranial alternating current stimulation on habitual action selection. J Neurophysiol. 2021 Mar 1;125(3):768-780. doi: 10.1152/jn.00180.2020. Epub 2020 Dec 23.

  PMID: 33356905 BACKGROUND

• McKim TH, Bauer DJ, Boettiger CA. Addiction History Associates with the Propensity to Form Habits. J Cogn Neurosci. 2016 Jul;28(7):1024-38. doi: 10.1162/jocn_a_00953. Epub 2016 Mar 11.

  PMID: 26967944 BACKGROUND

• Matsumoto H, Ugawa Y. Adverse events of tDCS and tACS: A review. Clin Neurophysiol Pract. 2016 Dec 21;2:19-25. doi: 10.1016/j.cnp.2016.12.003. eCollection 2017.

  PMID: 30214966 BACKGROUND

• Lam NH, Borduqui T, Hallak J, Roque A, Anticevic A, Krystal JH, Wang XJ, Murray JD. Effects of Altered Excitation-Inhibition Balance on Decision Making in a Cortical Circuit Model. J Neurosci. 2022 Feb 9;42(6):1035-1053. doi: 10.1523/JNEUROSCI.1371-20.2021. Epub 2021 Dec 9.

  PMID: 34887320 BACKGROUND

• Kearney-Ramos TE, Dowdle LT, Lench DH, Mithoefer OJ, Devries WH, George MS, Anton RF, Hanlon CA. Transdiagnostic Effects of Ventromedial Prefrontal Cortex Transcranial Magnetic Stimulation on Cue Reactivity. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Jul;3(7):599-609. doi: 10.1016/j.bpsc.2018.03.016. Epub 2018 Apr 10.

  PMID: 29776789 BACKGROUND

• Herrmann CS, Rach S, Neuling T, Struber D. Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes. Front Hum Neurosci. 2013 Jun 14;7:279. doi: 10.3389/fnhum.2013.00279. eCollection 2013.

  PMID: 23785325 BACKGROUND

• Hasin DS, Stinson FS, Ogburn E, Grant BF. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2007 Jul;64(7):830-42. doi: 10.1001/archpsyc.64.7.830.

  PMID: 17606817 BACKGROUND

• Guerri C, Pascual M. Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence. Alcohol. 2010 Feb;44(1):15-26. doi: 10.1016/j.alcohol.2009.10.003.

  PMID: 20113871 BACKGROUND

• Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, Pickering RP, Ruan WJ, Smith SM, Huang B, Hasin DS. Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015 Aug;72(8):757-66. doi: 10.1001/jamapsychiatry.2015.0584.

  PMID: 26039070 BACKGROUND

• Grant BF, Chou SP, Saha TD, Pickering RP, Kerridge BT, Ruan WJ, Huang B, Jung J, Zhang H, Fan A, Hasin DS. Prevalence of 12-Month Alcohol Use, High-Risk Drinking, and DSM-IV Alcohol Use Disorder in the United States, 2001-2002 to 2012-2013: Results From the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017 Sep 1;74(9):911-923. doi: 10.1001/jamapsychiatry.2017.2161.

  PMID: 28793133 BACKGROUND

• Gbadeyan O, McMahon K, Steinhauser M, Meinzer M. Stimulation of Dorsolateral Prefrontal Cortex Enhances Adaptive Cognitive Control: A High-Definition Transcranial Direct Current Stimulation Study. J Neurosci. 2016 Dec 14;36(50):12530-12536. doi: 10.1523/JNEUROSCI.2450-16.2016.

  PMID: 27974612 BACKGROUND

• Friedman NP, Robbins TW. The role of prefrontal cortex in cognitive control and executive function. Neuropsychopharmacology. 2022 Jan;47(1):72-89. doi: 10.1038/s41386-021-01132-0. Epub 2021 Aug 18.

  PMID: 34408280 BACKGROUND

• Ersche KD, Gillan CM, Jones PS, Williams GB, Ward LH, Luijten M, de Wit S, Sahakian BJ, Bullmore ET, Robbins TW. Carrots and sticks fail to change behavior in cocaine addiction. Science. 2016 Jun 17;352(6292):1468-71. doi: 10.1126/science.aaf3700.

  PMID: 27313048 BACKGROUND

• Ewing SW, Sakhardande A, Blakemore SJ. The effect of alcohol consumption on the adolescent brain: A systematic review of MRI and fMRI studies of alcohol-using youth. Neuroimage Clin. 2014 Jul 5;5:420-37. doi: 10.1016/j.nicl.2014.06.011. eCollection 2014.

  PMID: 26958467 BACKGROUND

• Degenhardt L, O'Loughlin C, Swift W, Romaniuk H, Carlin J, Coffey C, Hall W, Patton G. The persistence of adolescent binge drinking into adulthood: findings from a 15-year prospective cohort study. BMJ Open. 2013 Aug 19;3(8):e003015. doi: 10.1136/bmjopen-2013-003015.

  PMID: 23959750 BACKGROUND

• Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci. 2003 Jul;28(4):263-74.

  PMID: 12921221 BACKGROUND

• Crews FT, Vetreno RP, Broadwater MA, Robinson DL. Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev. 2016 Oct;68(4):1074-1109. doi: 10.1124/pr.115.012138.

  PMID: 27677720 BACKGROUND

• Cohen E, Feinn R, Arias A, Kranzler HR. Alcohol treatment utilization: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. Drug Alcohol Depend. 2007 Jan 12;86(2-3):214-21. doi: 10.1016/j.drugalcdep.2006.06.008. Epub 2006 Aug 17.

  PMID: 16919401 BACKGROUND

• Brunye TT, Elliott G, Loverro K. Examining state-dependent effects of transcranial direct current stimulation on visual search and executive function tasks. Neuroreport. 2021 Jan 6;32(1):1-7. doi: 10.1097/WNR.0000000000001549.

  PMID: 33165194 BACKGROUND

• Brosnan MB, Wiegand I. The Dorsolateral Prefrontal Cortex, a Dynamic Cortical Area to Enhance Top-Down Attentional Control. J Neurosci. 2017 Mar 29;37(13):3445-3446. doi: 10.1523/JNEUROSCI.0136-17.2017. No abstract available.

  PMID: 28356395 BACKGROUND

• Boettiger CA, D'Esposito M. Frontal networks for learning and executing arbitrary stimulus-response associations. J Neurosci. 2005 Mar 9;25(10):2723-32. doi: 10.1523/JNEUROSCI.3697-04.2005.

  PMID: 15758182 BACKGROUND

Results Point of Contact

• Title: Grace Elliott, MA
• Organization: University of North Carolina at Chapel Hill

gelliott@unc.edu

919-843-9193

Study Officials

• Charlotte A Boettiger, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study team will be provided a numeric code to enter into the XCSITE 100 tACS system, which will conceal the stimulation parameters from the study team, ensuring double blinding. The XSCITE 100 device allows for the programming of stimulation codes corresponding to sham or active stimulation, both of which are set to a total duration of 30 minutes, allowing for reliable double-blinding.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Study design consists of 3 groups of participants: 1. Control (CON): no adolescent binge drinking (AIE) and current (past month) World Health Organization (WHO) risk drinking levels of either 0 or 1 (abstinent or low-risk) 2. (RISK): no AIE and current WHO level 2, 3, or 4 (medium risk, high risk, or very high risk) 3. (RISK+AIE): history of adolescent binge drinking and current WHO risk level 2, 3, or 4. Within each group (n=22), participants will be randomly assigned to either the 10Hz tACS (stim) group or the sham tACS (sham) group. Study design requires randomly assigning individuals to a stimulation group after completing Session 1. Prior to study onset, Dr. Boettiger will create a randomization table in which stimulation type (true or sham) is pseudo randomly ordered within groups, stratified by sex. Dr. Boettiger will provide assignment to the study team based on this predefined randomization table in order to ensure balanced sex and group for each stimulation type.

Study Record Dates

• First Submitted: October 3, 2024
• First Posted: October 10, 2024
• Study Start: July 18, 2024
• Primary Completion: January 24, 2025
• Study Completion: January 24, 2025
• Last Updated: March 27, 2026
• Results First Posted: March 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: SAP
• Time Frame: Upon approval of the study data structure by the NIMH Data Archive (NDA), data will be uploaded every six months. For each manuscript based on findings from this project, investigators will submit to the NDA: data, list of variables, analytic plan, and results.
• Access Criteria: The researchers will determine who will have access to which aspects of the project data based on NIH's data access principles. The researchers will provide access to person-level data for research purposes only, based on Data Use Certifications. Data on UNC servers will be made available to investigators with appropriate IRB approval and Data Use Agreements.

Locations

US (1)