Mechanism of Action of tACS for the Treatment of MDD

The device used for non-invasive brain stimulation is investigational and has not been approved by the FDA, though it has been designated as a nonsignificant risk (NSR) device study by the FDA. Half of the participants will receive tACS and half will receive sham stimulation, an inactive control procedure for comparison use only. Participation in this study includes up to eight appointments, each one lasting from 30 minutes to four hours over the course of 3 weeks. The first two appointments will be remote interviews to determine eligibility. If the subjects qualify, the next five appointments will be scheduled as consecutive stimulation sessions in the Carolina Center for Neurostimulation at the Vilcom office. The follow-up appointment will be in our center two weeks after the completion of the stimulation sessions. We estimate the total time needed to complete study participation to be about 17 hours.

• tACS (Device): XCSITE100
• Sham tACS (Device): XCSITE100

Primary outcomes

• Change in the Amplitude of Left Frontal Alpha Oscillations Measured Durin Resting-state EEG Recordings From Baseline to Day 5 of Stimulation. [Baseline, Day 5]: Fourier transform is applied to 2 second epochs of resting-state EEG data and averaged across epochs. The amplitude of alpha oscillations is calculated and averaged across left frontal electrodes. The difference between the baseline recording on the first day of stimulation is compared to the recording on the fifth day of the intervention prior to stimulation.
• Change in the Amplitude of Left Frontal Alpha Oscillations Measured During Resting-state EEG Recordings From Baseline to Two-week Follow-up of Stimulation. [Baseline, two-week follow-up visit]: Fourier transform is applied to 2 second epochs of resting-state EEG data and averaged across epochs. The amplitude of alpha oscillations is calculated and averaged across left frontal electrodes. The difference between the baseline recording on the first day of stimulation is compared to the recording on the two-week follow-up after intervention.

Secondary outcomes

• Correlation Between Changes in the Amplitude of Left Frontal Alpha Oscillations From Baseline to Day 5 of Intervention and Changes in Symptoms of Depression. [Baseline, Day 5]: Correlation Coefficient (r) will be used to determine if there is a relationship between the change in Hamilton Depression Rating Scale (HDRS) scores from baseline to Day 5 and the two-week follow up and change in the amplitude of left frontal alpha oscillations before stimulation at baseline and Day 5 of stimulation. The HDRS is a clinician-rated measure of depression severity where higher scores indicate greater depression severity. To calculate the amplitude of left frontal alpha oscillations, Fourier transform is applied to 2 second epochs of resting-state EEG data and averaged across epochs. The amplitude of alpha oscillations is calculated and averaged across left frontal electrodes.
• Correlation Between Changes in the Amplitude of Left Frontal Alpha Oscillations From Baseline to Two-week Follow-up and Depression Symptoms. [Baseline, two-week follow-up visit]: Correlation Coefficient (r) will be used to determine if there is a relationship between the change in Hamilton Depression Rating Scale (HDRS) scores from baseline, Day 5 and to two-week follow up and change in the amplitude of left frontal alpha oscillations before stimulation at baseline and Day 5 of stimulation. The HDRS is a clinician-rated measure of depression severity where higher scores indicate greater depression severity. To calculate the amplitude of left frontal alpha oscillations, Fourier transform is applied to 2 second epochs of resting-state EEG data and averaged across epochs. The amplitude of alpha oscillations is calculated and averaged across left frontal electrodes.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Ages 18-70 years
* DSM-IV diagnosis of MDD; unipolar, non-psychotic
* Hamilton Rating Depression Rating Scale (HRDS-17) score >8
* Low suicide risk as determined by a score of <3 on the Suicide Item on the HDRS-17 and based on additional information from the C-SSRS (no intent)
* Capacity to understand all relevant risks and potential benefits of the study (informed consent)

Exclusion Criteria:

* DSM-V diagnosis of moderate or severe alcohol use disorder (AUD) within the last 12 months.
* DSM-V diagnosis of moderate to severe substance use disorder (excluding tobacco) within the last 12 months.
* Current axis I mood, or psychotic disorder other than major depressive disorder
* Lifetime comorbid psychiatric bipolar or psychotic disorder
* Eating disorder (current or within the past 6 months)
* Obsessive-compulsive disorder (lifetime)
* Post-traumatic stress disorder (PTSD, current or within the last 6 months)
* Change of ADHD medication within the last 4 weeks.
* Change of benzodiazepines or anti-epileptic medication within the last 4 weeks
* Antidepressant drugs taken for less than 4 weeks (i.e., recently initiated)
* Neurological disorders, including but not limited to history of seizures (except childhood febrile seizures and ECT-induced seizures), dementia, history of stroke, Parkinson's disease, multiple sclerosis, cerebral aneurysm.
* Medical or neurological illness (unstable cardiac disease, AIDS, malignancy, liver or renal impairment) or treatment for a medical disorder that could interfere with study participation; comorbid neurological condition (i.e. seizure disorder, brain tumor)
* History of traumatic brain injury that required subsequent cognitive rehabilitation, or cause cognitive sequelae.
* Prior brain surgery and/or any brain devices/implants, including cochlear implants and aneurysm clips
* Current pregnancy or lactation. If the ability to become pregnant exists, unwillingness to use appropriate birth control measures during study participation
* 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
* Non-English speakers

Participant flow

Outcome results

• Change in the Amplitude of Left Frontal Alpha Oscillations Measured Durin Resting-state EEG Recordings From Baseline to Day 5 of Stimulation. (Primary), Mean, microvolts^2/Hz: Alpha Transcranial Alternating Current Stimulation (tACS) 0.042 +/- 0.221; Sham Stimulation 0.169 +/- 0.338 (p 0.332)
• Change in the Amplitude of Left Frontal Alpha Oscillations Measured During Resting-state EEG Recordings From Baseline to Two-week Follow-up of Stimulation. (Primary), Mean, microvolts^2/Hz: Alpha Transcranial Alternating Current Stimulation (tACS) -0.016 +/- 0.199; Sham Stimulation 0.012 +/- 0.243 (p 0.790)
• Correlation Between Changes in the Amplitude of Left Frontal Alpha Oscillations From Baseline to Day 5 of Intervention and Changes in Symptoms of Depression. (Secondary), Number, Pearson Correlation Coefficient: Alpha Transcranial Alternating Current Stimulation (tACS) -0.263; Sham Stimulation -0.109 (p 0.464)
• Correlation Between Changes in the Amplitude of Left Frontal Alpha Oscillations From Baseline to Two-week Follow-up and Depression Symptoms. (Secondary), Number, Pearson Correlation Coefficient: Alpha Transcranial Alternating Current Stimulation (tACS) 0.624; Sham Stimulation 0.087 (p 0.072)

Adverse events

Time frame: Adverse Events were assessed at Day 1, Day 2, Day 3, Day 4, Day 5 and 2-week follow-up

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2022-05-02)

• David Rubinow, MD, Principal investigator, University of North Carolina at Chapel Hill - Department of Psychiatry