Clinical trial NCT06634771: Flexibility, Alcohol Misuse, and Excitation
Official title: Frontal E/I Balance Mediation of TACS Effects on Behavioral Flexibility
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Behavioral Flexibility
Healthy Volunteers
High Risk Alcohol Use
Keywords: alcohol
brain stimulation
MRI
EEG
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2024-10-10
Enrollment: 66
Sex: ALL
Minimum age (years): 22
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: BASIC_SCIENCE

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.

Detailed description: This study is designed to probe the role of the balance between excitatory (E) and inhibitory (I) signaling (E/I) in key nodes of control circuitry in mediating the relationship between alcohol misuse and inflexible behavior. In addition, the investigators aim to determine whether adolescent binge alcohol exposure amplifies the effects of binge exposure in adulthood. The investigators will accomplish this goal via a single multi-session study. Participants (n=66) will comprise three groups: adults self-reporting high risk drinking \[World Health Organization (WHO) risk levels 2, 3, or 4\], with (n=22) or without (n=22) a history of adolescent alcohol misuse (AIE), and lifetime low risk drinking adults (WHO risk levels 0 or 1; n=22).

Design: a 3-session study that includes an initial screening session and behavioral training (Session 1), behavioral testing and a magnetic resonance imaging (MRI) scan session (Session 2), bifrontal 10Hz-transcranial alternating current stimulation (tACS; true or sham) during behavioral testing with pre- and post-electroencephalogram (EEG) recording in a resting-state, followed by a second MRI scan session (Session 3). The investigators predict that adolescent and adult binge history will have interacting effects on E/I balance indices derived from EEG and magnetic resonance spectroscopy (MRS) and on behavioral flexibility measured in the Hidden Association between Images Task (HABIT) Test and that E/I balance indices will mediate the relationship between alcohol misuse and behavioral flexibility. The investigators also propose to test a causal relationship between E/I balance and behavioral flexibility by testing whether 10Hz-tACS to bilateral dorsolateral prefrontal cortex (dlPFC) alters habitual action selection in the HABIT Test in proportion to its effects on the dlPFC 1/f EEG slope and/or the MRS-derived gamma-amino-butyric acid (GABA)/glutamate+glutamine (Glx) ratio. The investigators predict that changes in indices of E/I balance induced by tACS will inversely associate with changes in habitual response selection. The investigators will collect a small amount of blood from a finger prick in Sessions 1 and 3 will use the collected dried blood spots to measure inflammatory markers.

Eligibility criteria: Inclusion Criteria:

* • 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)

Exclusion Criteria:

* 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
  * Claustrophobia
  * Any magnetic resonance imaging (MRI) contraindication based on the University of North Carolina Biomedical Research Imaging Center's MRI safety checklist
  * Breath alcohol above 0.0% at time of session
  * Positive urine drug screen at time of session

If a participant should have an exclusion criterion arise in the course of their participation (e.g. pregnancy or psychotic episode), their participation in the study will end unless the circumstances are transitory in nature (e.g. positive breath alcohol or urine drug screen).

Primary outcomes:
measure: Change in habitual action selection
timeFrame: at study completion, an average of 2 weeks
measure: Prefrontal GABA:glutamate/glutamine ratio
timeFrame: at study completion, an average of 2 weeks
Secondary outcomes:
measure: Inflammatory markers
timeFrame: at study completion, an average of 2 weeks
measure: Control circuit functional connectivity
timeFrame: at study completion, an average of 2 weeks
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina, Chapel Hill
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Charlotte A Boettiger, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Siqueira L, Smith VC; COMMITTEE ON SUBSTANCE ABUSE. Binge Drinking. Pediatrics. 2015 Sep;136(3):e718-26. doi: 10.1542/peds.2015-2337.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.