Anhedonia, Major Depressive Disorder
Conditions
Keywords
transcranial Alternating Current Stimulation, Goal-directed behavior, Cross-frequency coupling, Reward-based decision-making
Brief summary
Investigating whether delta-beta cross-frequency transcranial alternating current stimulation can increase goal-directed behavior in participants with major depressive disorder and elevated symptoms of anhedonia.
Detailed description
The purpose of this clinical trial is to investigate the causal role that delta-beta coupling plays in goal-directed behavior in participants with major depressive disorder (MDD) and symptoms of anhedonia. The participants will perform a reward-based decision-making task. During the task, cross-frequency transcranial alternating current stimulation (tACS) will be delivered at delta-beta frequency, a control-frequency, or an active sham. Electroencephalography will be collected in intermittent resting-state periods. Structural and functional magnetic resonance imaging (MRI) will be collected during the resting-state and during performance of the task.
Interventions
DEVICECross-frequency transcranial alternating current stimulation via the NeuroConn Direct Current Stimulator Plus
Stimulation will be delivered via the NeuroConn Direct Current Stimulator Plus, an investigational electrical non-invasive brain stimulation device that is being used for foundational neuroscience and translational research.
Sponsors
National Institute of Mental Health (NIMH)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Masking description
This study is designed to be double-blind. Participants and the researchers are unaware of each participant's assignment until the completion of all data collection. This is accomplished using randomization codes. Furthermore, this study utilizes an active sham stimulation. This means that the active sham condition includes some stimulation, mimicking the skin sensations associated with tACS. In a previously concluded trial, participants in the delta-beta tACS, theta-gamma tACS, and active sham groups responded similarly to the blinding questionnaire, indicating that the active sham stimulation successfully blinded the participants.
Intervention model description
Participants are randomized into one of three arms of the study: delta-beta tACS, control tACS in theta-gamma, or active sham. Randomization is stratified by SHAPS level such that there are an equal number of participants that are high anhedonia (SHAPS \> 33) and low anhedonia (SHAPS \<=33).
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Able to provide informed consent * Have normal to corrected vision * Willing to comply with all study procedures and be available for the duration of the study * Speak and understand English * Low suicide risk as determined by the Columbia Suicide Severity Rating Scale (C-SSRS), and by the Hamilton Depression Rating Scale (HAM-D; less than 3 for the suicidality item). * Negative pregnancy test for female participants * Patient Health Questionnaire (PHQ) with 9 items greater than or equal to 10 and a diagnosis of major depressive disorder on the Mini International Neuropsychiatric Interview (MINI)
Exclusion criteria
* Attention deficit (hyperactivity) disorder (currently under treatment) * Neurological disorders and conditions, including, but not limited to: History of epilepsy, seizures (except childhood febrile seizures), dementia, history of stroke, Parkinson's disease, multiple sclerosis, cerebral aneurysm, brain tumors * Medical or neurological illness or treatment for a medical disorder that could interfere with study participation (e.g., unstable cardiac disease, HIV/AIDS, malignancy, liver or renal impairment) * Prior brain surgery * Any brain devices/implants, including cochlear implants and aneurysm clips * History of current traumatic brain injury * (For females) Pregnant or breast feeding * Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude the participant's full compliance with or completion of the study * Diagnostic and Statistical Manual of Mental Disorders version 5 diagnosis of present moderate or severe substance use disorder or alcohol use disorder, and past severe substance use disorder or alcohol use disorder, or psychotic disorder within the last 12 months * Not taking medications for attention deficit (hyperactivity) disorder or benzodiazepines as these medications often produce specific EEG activity that may disrupt our interpretation of the findings * If major depressive disorder is experienced in episode, the participant must currently be within a depressive episode. * Contraindications for magnetic resonance imaging (MRI): ferrous metal inside the body, jewelry must be removable, pacemaker or cochlear implant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Percentage of Trials That the Participant Chooses to Perform the Hard Task | Baseline (Hour 1), Stimulation (Hours 2 through 3) | In the Expenditure of Effort for Reward Task, participants are faced with a decision on every trial: to choose an easy task with a low effort exertion for a chance at winning a low amount of money or a hard task with a high effort exertion for a chance at winning a greater amount of money. The incentive for the high effort exertion is changed on each trial and the participant gets physically tired from repeated effort exertion. Goal-directed behavior was calculated as the percentage of trials in which the participant decides to perform the high effort exertion. The average of the 4 blocks prior to stimulation served as a baseline (1st hour). The effect of the intervention was the average of the next 8 blocks during stimulation (hours 2 through 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Coupling Strength Between Low-frequency Prefrontal Signals and High-frequency Posterior Signals | Baseline (Hour 1), Stimulation (Hours 2 through 3) | Coupling strength was estimated using the Mean Vector Length calculation between the phase of low-frequency electrical activity in prefrontal electrodes and amplitude of high-frequency activity in posterior cortex. A hybrid signal was created using high-frequency amplitude and low-frequency phase. The magnitude of the average of this signal over time is the coupling strength. Coupling strength was normalized using a z-transformation relative to a null distribution generated by randomly time-shifting the high-frequency data relative to the low-frequency data (z-score). A value of zero represents no coupling. A higher value represents greater coupling strength, which is generally associated with better cognition. Values range from -3 to 3 and a score greater than 1.6 means the coupling is present. The average of the 4 blocks prior to stimulation served as a baseline (1st hour). The effect of the intervention was the average of the next 8 blocks during stimulation (hours 2 through 3). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Delta-beta tACS The study is investigating the use of transcranial alternating current stimulation (tACS). The stimulation is delivered at 1 milliampere (mA) zero-to-peak amplitude at the target electrodes and 2 mA zero to-peak amplitude at the return electrode. For the experimental arm, the tACS will be delivered using the cross-frequency stimulation waveform delta-beta (3-20Hz).
Cross-frequency transcranial alternating current stimulation via the NeuroConn Direct Current Stimulator Plus: Stimulation will be delivered via the NeuroConn Direct Current Stimulator Plus, an investigational electrical non-invasive brain stimulation device that is being used for foundational neuroscience and translational research. | 11 |
| Theta-gamma tACS This arm serves as an active control where tACS will be delivered using the cross-frequency stimulation waveform theta-gamma (5-50Hz).
Cross-frequency transcranial alternating current stimulation via the NeuroConn Direct Current Stimulator Plus: Stimulation will be delivered via the NeuroConn Direct Current Stimulator Plus, an investigational electrical non-invasive brain stimulation device that is being used for foundational neuroscience and translational research. | 12 |
| Active-sham tACS For active sham stimulation, either delta-beta or theta-gamma stimulation is delivered for 10 seconds and then returns to baseline. This is intended to mimic the skin sensations (e.g., itching, burning, tingling) that are experienced at the onset of stimulation, assisting with blinding the participant's assignment.
Cross-frequency transcranial alternating current stimulation via the NeuroConn Direct Current Stimulator Plus: Stimulation will be delivered via the NeuroConn Direct Current Stimulator Plus, an investigational electrical non-invasive brain stimulation device that is being used for foundational neuroscience and translational research. | 12 |
| Total | 35 |
Baseline characteristics
| Characteristic | Delta-beta tACS | Theta-gamma tACS | Active-sham tACS | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 12 Participants | 12 Participants | 35 Participants |
| Age, Continuous | 27.8 years STANDARD_DEVIATION 12.9 | 27.0 years STANDARD_DEVIATION 10.3 | 31.8 years STANDARD_DEVIATION 15.6 | 28.9 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 12 Participants | 11 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 10 Participants | 10 Participants | 29 Participants |
| Region of Enrollment United States | 11 Participants | 12 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 8 Participants | 26 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 3 / 11 | 3 / 12 | 1 / 12 |
| serious Total, serious adverse events | 0 / 11 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change in the Percentage of Trials That the Participant Chooses to Perform the Hard Task
In the Expenditure of Effort for Reward Task, participants are faced with a decision on every trial: to choose an easy task with a low effort exertion for a chance at winning a low amount of money or a hard task with a high effort exertion for a chance at winning a greater amount of money. The incentive for the high effort exertion is changed on each trial and the participant gets physically tired from repeated effort exertion. Goal-directed behavior was calculated as the percentage of trials in which the participant decides to perform the high effort exertion. The average of the 4 blocks prior to stimulation served as a baseline (1st hour). The effect of the intervention was the average of the next 8 blocks during stimulation (hours 2 through 3).
Time frame: Baseline (Hour 1), Stimulation (Hours 2 through 3)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Delta-beta tACS | Change in the Percentage of Trials That the Participant Chooses to Perform the Hard Task | -0.30 percentage of trials | Standard Deviation 0.15 |
| Theta-gamma tACS | Change in the Percentage of Trials That the Participant Chooses to Perform the Hard Task | -0.22 percentage of trials | Standard Deviation 0.12 |
| Active-sham tACS | Change in the Percentage of Trials That the Participant Chooses to Perform the Hard Task | -0.09 percentage of trials | Standard Deviation 0.29 |
p-value: 0.049ANOVA
Secondary
Change in Coupling Strength Between Low-frequency Prefrontal Signals and High-frequency Posterior Signals
Coupling strength was estimated using the Mean Vector Length calculation between the phase of low-frequency electrical activity in prefrontal electrodes and amplitude of high-frequency activity in posterior cortex. A hybrid signal was created using high-frequency amplitude and low-frequency phase. The magnitude of the average of this signal over time is the coupling strength. Coupling strength was normalized using a z-transformation relative to a null distribution generated by randomly time-shifting the high-frequency data relative to the low-frequency data (z-score). A value of zero represents no coupling. A higher value represents greater coupling strength, which is generally associated with better cognition. Values range from -3 to 3 and a score greater than 1.6 means the coupling is present. The average of the 4 blocks prior to stimulation served as a baseline (1st hour). The effect of the intervention was the average of the next 8 blocks during stimulation (hours 2 through 3).
Time frame: Baseline (Hour 1), Stimulation (Hours 2 through 3)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Delta-beta tACS | Change in Coupling Strength Between Low-frequency Prefrontal Signals and High-frequency Posterior Signals | 0.95 Z-score | Standard Deviation 0.68 |
| Theta-gamma tACS | Change in Coupling Strength Between Low-frequency Prefrontal Signals and High-frequency Posterior Signals | -0.97 Z-score | Standard Deviation 1.04 |
| Active-sham tACS | Change in Coupling Strength Between Low-frequency Prefrontal Signals and High-frequency Posterior Signals | 0.13 Z-score | Standard Deviation 1.78 |
p-value: 0.004ANOVA