Behavioral Flexibility, Healthy Volunteers, High Risk Alcohol Use
Conditions
Keywords
alcohol, brain stimulation, MRI, EEG
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.
Interventions
OTHER10 Hz transcranial alternating current stimulation (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.
Sham tACS: The procedure for sham stimulation will be identical, but it will last for 2 minutes instead of 30 minutes.
Sponsors
University of North Carolina, Chapel Hill
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
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.
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.
Eligibility
Sex/Gender
ALL
Age
22 Years to 50 Years
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Proportion of Errors | Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after | 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. |
| Change in Prefrontal GABA:Glutamate/Glutamine Ratio | Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in C-reactive Protein | Baseline, study completion (an average of 2 weeks) | The researchers will measure the effect of transcranial alternating current stimulation (tACS) of bilateral dorsolateral prefrontal cortex on C-reactive protein. |
| Change in Interleukin-6 (IL-6) | Baseline, study completion (an average of 2 weeks) | The researchers will measure the effect of transcranial alternating current stimulation (tACS) of bilateral dorsolateral prefrontal cortex on interleukin-6 (IL-6). |
| Change in Tumor Necrosis Factor-alpha (TNF-alpha) | Baseline, study completion (an average of 2 weeks) | The researchers will measure the effect of transcranial alternating current stimulation (tACS) of bilateral dorsolateral prefrontal cortex on tumor necrosis factor-alpha (TNF-alpha). |
| 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 | The effect of 10Hz-tACS on resting-state functional connectivity between the bilateral dorsolateral prefrontal cortex (dlPFC) and anterior insular cortex (aIC) was quantified as the Fisher Z-transformed Pearson correlation coefficient. The BOLD timeseries for regions of interest were first extracted and then transformed into Z-scores using the Fisher r-to-z transformation. The Z-score represents the number of standard deviations away from the mean of the functional connectivity distribution. A Z-score of 0 represents the mean connectivity in the sample, with positive values indicating greater connectivity after stimulation, and a negative Z-score indicating less connectivity after stimulation. |
| 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 | The effect of 10Hz-tACS on resting-state functional connectivity between the bilateral dorsolateral prefrontal cortex (dlPFC) and limbic striatum was quantified as the Fisher Z-transformed Pearson correlation coefficient. The BOLD timeseries for regions of interest were first extracted and then transformed into Z-scores using the Fisher r-to-z transformation. The Z-score represents the number of standard deviations away from the mean of the functional connectivity distribution. A Z-score of 0 represents the mean connectivity in the sample, with positive values indicating greater connectivity after stimulation, and a negative Z-score indicating less connectivity after stimulation. |
| Change in Functional Connectivity Between aIC and Limbic Striatum | Pre-stimulation (Session 2) up to 2 weeks before, post-stimulation (Session 3), immediately after | The effect of 10Hz-tACS on resting-state functional connectivity between the aIC and limbic striatum was quantified as the Fisher Z-transformed Pearson correlation coefficient. The BOLD timeseries for regions of interest were first extracted and then transformed into Z-scores using the Fisher r-to-z transformation. The Z-score represents the number of standard deviations away from the mean of the functional connectivity distribution. A Z-score of 0 represents the mean connectivity in the sample, with positive values indicating greater connectivity after stimulation, and a negative Z-score indicating less connectivity after stimulation. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORCharlotte A Boettiger, PhD
University of North Carolina, Chapel Hill
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 34.0 years STANDARD_DEVIATION 10.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 0 | 0 / 1 | 0 / 0 | 0 / 0 |
Outcome results
None listed