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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01MH124387 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
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| National Institute of Mental Health (NIMH) | NIH |
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The participants will perform a cognitive control task. During the task, rhythmic trains of transcranial magnetic stimulation will be delivered to the prefrontal cortex and parietal cortex. Participants will be screened for their ability to perform the task. Magnetic resonance imaging will be used to localize regions of interest to be targeted. Electroencephalography will be collected concurrent with stimulation.
This study is a pilot, five-session study with transcranial magnetic stimulation (TMS), electroencephalography (EEG), and magnetic resonance imaging (MRI) to understand the neural oscillatory basis of output-gating. The first session of the experiment will be screening session, in which participants provide written consent to participate, screened for colorblindness, complete questionnaires, and perform a working memory task with retrospective cues. Participants will be invited back to the second session if they show a benefit to their working memory percent correct by use of the informative retro-cue relative to the uninformative neutral cue. This session will also be used to select the number of items that will be used in the working memory task for subsequent sessions. The criteria for difficulty titration is task performance between 60% and 85% correct for retro-cue trials and a benefit of at least 5% greater than neutral cue trials. Thus, different participants will perform the task with different numbers of items to be encoded into working memory. Titration of task difficulty as described here is critical for experiments that use causal manipulation (e.g. transcranial magnetic stimulation) to modulate performance. If participants are performing at ceiling (close to 100%) or at floor (close to random change), then any experimental manipulation of behavior is less likely to impact performance as the task is too "easy" or too "hard." For the second session of the experiment, participants perform the working memory retro-cue task while EEG is recorded. In addition, participants will complete a simple perception color task in which participants see a color and choose the matching color from the color circle. This task tests for the precision of perception throughout the color circle. The EEG data from the second session will be preprocessed and a Morlet wavelet convolution analysis will be conducted. The resulting spectrogram will be contrasted between the informative retro-cue and uninformative neutral cue to derive the theta frequency with peak amplitude in prefrontal cortex, and contrasted between a leftward and rightward retro-cue to derive the alpha frequency with peak amplitude in parietal cortex. These peak frequencies will be used for stimulation in the fourth and fifth session. In the third session, the investigators will acquire structural and functional MRI for each participant. The functional MRI data will be analyzed to identify regions in the anterior middle frontal gyrus and posterior intraparietal sulcus that are functionally connected within the frontal-parietal, "executive control," network. A previous meta-analysis of functional MRI studies found that the regions with peak retro-cue activity was at Montreal Neurological Institute coordinates (-40, 36, 28) for anterior middle frontal gyrus and (-38, -48, 44) for inferior intraparietal sulcus. Therefore, the investigators will constrain the search light to the anatomical landmarks and these coordinates. The center of mass in these regions will be used for targeting with TMS in the subsequent fourth and fifth sessions. In the fourth and fifth sessions, stimulation will be delivered at the timing relative to retro-cue, frequency, and spatial location based on previous localizers. During stimulation, the location of the TMS coil needs to be aligned to the targeted brain region with neuro-navigation software that records the accuracy of each TMS pulse relative to the target. On each trial, the stimulation type will be randomly selected, counter-balanced, and inter-mixed. The effects of rhythmic TMS are not expected to last for more than a few cycles beyond stimulation itself. Therefore, the experimental design randomly intermixes the stimulation type within every task block.
The study 'Theta Connectivity in Working Memory (STAR)', NCT05204381, investigated alpha and theta frequency neural oscillations in the context of cognitive control. Following study completion and during data analysis, a previously unrecognized error in the code of the randomization software used in the conduct of the trial was identified. As a function of the software error, group allocation did not occur as intended and the study design became, de facto and post hoc, a parallel arm design with participants receiving either alpha stimulation or theta stimulation in both stimulation sessions, as opposed to alpha stimulation then theta stimulation in a counterbalanced fashion. The outcomes reported herein of the resulting parallel arm design remain a scientifically valid and appropriate design to investigate the roles of alpha and theta oscillations in the context of cognitive control and additionally resulted in greater statistical power to detect a potential difference between groups.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Theta Stimulation | Experimental | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the fourth and fifth sessions, stimulation is delivered in near-zero phase lag theta-frequency, anti-synchrony theta-frequency, near-zero phase lag arrhythmic-in-synchrony stimulation, and arrhythmic-independent stimulation. The near-zero phase lag arrhythmic-in-synchrony stimulation and arrhythmic-independent stimulation is delivered in both the fourth and fifth session to serve as an active control. Each session is separated by at least one day as a washout period. |
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| Alpha Stimulation | Experimental | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the fourth and fifth sessions, stimulation is delivered in near-zero phase lag alpha-frequency, anti-synchrony alpha-frequency, near-zero phase lag arrhythmic-in-synchrony stimulation, and arrhythmic-independent stimulation. The near-zero phase lag arrhythmic-in-synchrony stimulation and arrhythmic-independent stimulation is delivered in both the fourth and fifth session to serve as an active control. Each session is separated by at least one day as a washout period. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Theta-frequency near-zero phase lag stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in theta-frequency (approximately 6 Hz) with a near-zero phase lag. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Remembered Items | The number of remembered items, often referred to as working memory capacity, is calculated as the number of items to be remembered (2, 3, or 4) times the hit rate minus the false alarm rate, divided by one minus the false alarm rate. The range of values is 0 to 4 where larger values mean better performance. | Measured concurrent with stimulation throughout a 3-hour session |
| Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Functional connectivity will be measured using weighted phase lag index (wPLI) which is the mean of the imaginary component of the difference in theta-frequency phase between frontal and parietal electrical activity during the second half of the stimulation train for every trial. The values range from 0 to 1 where a greater value represents greater functional connectivity. | Measured concurrent with stimulation throughout a 3-hour session |
| Measure | Description | Time Frame |
|---|---|---|
| Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Phase lag is calculated as the resulting phase angle after averaging the phase difference between frontal and parietal cortex electrical signals during the second half of the stimulation train for every trial. The values range from 0 to 360 degrees. A value closer to 0 degrees or closer to 360 degrees represent a near-zero phase lag, where as a value closer to 180 degree represent a larger phase lag. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Flavio Frohlich, PhD | University of North Carolina, Chapel Hill | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | 27599 | United States |
Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with the University of North Carolina at Chapel Hill.
From 9 to 36 months following publication
Investigator who proposes to use the data has IRB, IEC, or REB approval and an executed data use/sharing agreement with the University of North Carolina at Chapel Hill.
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Sessions prior to randomization: Session 1 (S1;baseline behavioral task), Session 2 (S2;baseline EEG), Session 3 (S3;MRI). 71 participants enrolled in S1 (n=1 did not complete, n=13 excluded for performance). n=7 lost to follow-up prior to S2. 50 started S2 (n=1 excluded for performance). n=3 lost to follow-up prior to S3. 46 participants started S3 (n=1 excluded, MRI contraindication). n=6 lost to follow-up prior to S4. 39 participants were randomized to intervention groups.
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| ID | Title | Description |
|---|---|---|
| FG000 | Theta Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag theta-frequency, anti-synchrony theta-frequency, near-zero phase lag arrhythmic-in-synchrony, and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. Theta-frequency near-zero phase lag stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in theta-frequency (approximately 6 Hz) with a near-zero phase lag. Theta-frequency anti-synchrony stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in theta-frequency (approximately 6 Hz) with a 180 degree phase offset, anti-synchrony. Arrhythmic near-zero phase lag stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in an arrhythmic pattern with a near-zero phase lag matched in duration to the rhythmic stimulation for that session. Arrhythmic independent stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in different independent arrhythmic patterns matched in duration to the rhythmic stimulation for that session. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Session 4 |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 21, 2025 |
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| Theta-frequency anti-synchrony stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in theta-frequency (approximately 6 Hz) with a 180 degree phase offset, anti-synchrony. |
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| Arrhythmic near-zero phase lag stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in an arrhythmic pattern with a near-zero phase lag matched in duration to the rhythmic stimulation for that session. |
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| Arrhythmic independent stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in different independent arrhythmic patterns matched in duration to the rhythmic stimulation for that session. |
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| Alpha-frequency near-zero phase lag stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a near-zero phase lag. |
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| Alpha-frequency anti-synchrony stimulation | Device | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a 180 degree phase offset, anti-synchrony. |
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| Measured concurrent with stimulation throughout a 3-hour session |
| FG001 | Alpha Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag alpha-frequency, anti-synchrony alpha-frequency, near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. Arrhythmic near-zero phase lag stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in an arrhythmic pattern with a near-zero phase lag matched in duration to the rhythmic stimulation for that session. Arrhythmic independent stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in different independent arrhythmic patterns matched in duration to the rhythmic stimulation for that session. Alpha-frequency near-zero phase lag stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a near-zero phase lag. Alpha-frequency anti-synchrony stimulation: Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a 180 degree phase offset, anti-synchrony. |
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| NOT COMPLETED |
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| Washout (At Least 1 Day) |
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| Session 5 |
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| ID | Title | Description |
|---|---|---|
| BG000 | Theta Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag theta-frequency, anti-synchrony theta-frequency, near-zero phase lag arrhythmic-in-synchrony, and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. |
| BG001 | Alpha Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag alpha-frequency, anti-synchrony alpha-frequency, near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Number of Remembered Items | The number of remembered items, often referred to as working memory capacity, is calculated as the number of items to be remembered (2, 3, or 4) times the hit rate minus the false alarm rate, divided by one minus the false alarm rate. The range of values is 0 to 4 where larger values mean better performance. | Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation were delivered in both intervention arms (Theta stimulation arm AND Alpha stimulation arm); therefore, the number analyzed for Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation includes all randomized participants from both arms. | Posted | Mean | Standard Deviation | remembered items | Measured concurrent with stimulation throughout a 3-hour session |
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| Primary | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Functional connectivity will be measured using weighted phase lag index (wPLI) which is the mean of the imaginary component of the difference in theta-frequency phase between frontal and parietal electrical activity during the second half of the stimulation train for every trial. The values range from 0 to 1 where a greater value represents greater functional connectivity. | Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation were delivered in both intervention arms (Theta stimulation arm AND Alpha stimulation arm); therefore, the number analyzed for Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation includes all randomized participants from both arms. | Posted | Mean | Standard Deviation | weighted phase lag index | Measured concurrent with stimulation throughout a 3-hour session |
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| Secondary | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Phase lag is calculated as the resulting phase angle after averaging the phase difference between frontal and parietal cortex electrical signals during the second half of the stimulation train for every trial. The values range from 0 to 360 degrees. A value closer to 0 degrees or closer to 360 degrees represent a near-zero phase lag, where as a value closer to 180 degree represent a larger phase lag. | Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation were delivered in both intervention arms (Theta stimulation arm AND Alpha stimulation arm); therefore, the number analyzed for Arrhythmic near-zero phase lag stimulation and Arrhythmic independent stimulation includes all randomized participants from both arms. | Posted | Mean | Standard Deviation | degrees | Measured concurrent with stimulation throughout a 3-hour session |
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Adverse Events were not assessed prior to randomization and group assignment at the start of Session 4. Adverse Events were monitored at Session 4 (up to 3 hours) and Session 5 (up to 3 hours). A systematic assessment was conducted at the end of Session 4 and at the end of Session 5.
A stimulation adverse effects questionnaire was used based on common side effects experience with TMS. This questionnaire was administered at the end of each session in which the participant receives TMS (sessions 4 and 5). This questionnaire was used as a safety measure and to collect data on participant experience. Following the questionnaire, a structured interview was conducted as needed based upon responses on the stimulation adverse effects questionnaire.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Theta Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag theta-frequency, anti-synchrony theta-frequency, near-zero phase lag arrhythmic-in-synchrony, and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. | 0 | 16 | 0 | 16 | 2 | 16 |
| EG001 | Alpha Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to frontal and parietal cortex during performance of a cognitive control task while electroencephalography (EEG) is recorded. In the 4th and 5th sessions, TMS is delivered in near-zero phase lag alpha-frequency, anti-synchrony alpha-frequency, near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS. The near-zero phase lag arrhythmic-in-synchrony and arrhythmic-independent TMS is delivered in both the 4th and 5th session to serve as an active control. | 0 | 23 | 0 | 23 | 3 | 23 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Trouble concentrating | General disorders | Systematic Assessment |
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| Scalp pain | General disorders | Systematic Assessment |
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| Change in Mood | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Zachary Stewart | University of North Carollina at Chapel Hill | 919-966-9929 | zachary_stewart@med.unc.edu |
| Oct 14, 2025 |
| Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 16, 2022 | Jan 22, 2025 | ICF_000.pdf |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| OG002 | Arrhythmic Near-zero Phase Lag Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in an arrhythmic pattern with a near-zero phase lag matched in duration to the rhythmic stimulation for that session. This active control stimulation was delivered in both arms of the study (Theta stimulation intervention arm AND Alpha stimulation intervention arm). |
| OG003 | Arrhythmic Independent Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in different independent arrhythmic patterns matched in duration to the rhythmic stimulation for that session. This active control stimulation was delivered in both arms of the study (Theta stimulation intervention arm AND Alpha stimulation intervention arm). |
| OG004 | Alpha-frequency Near-zero Phase Lag Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a near-zero phase lag. This intervention was only delivered in the Alpha stimulation arm. |
| OG005 | Alpha-frequency Anti-synchrony Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a 180 degree phase offset, anti-synchrony. This intervention was only delivered in the Alpha stimulation arm. |
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| OG002 | Arrhythmic Near-zero Phase Lag Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in an arrhythmic pattern with a near-zero phase lag matched in duration to the rhythmic stimulation for that session. This active control stimulation was delivered in both arms of the study (Theta stimulation intervention arm AND Alpha stimulation intervention arm). |
| OG003 | Arrhythmic Independent Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in different independent arrhythmic patterns matched in duration to the rhythmic stimulation for that session. This active control stimulation was delivered in both arms of the study (Theta stimulation intervention arm AND Alpha stimulation intervention arm). |
| OG004 | Alpha-frequency Near-zero Phase Lag Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a near-zero phase lag. This intervention was only delivered in the Alpha stimulation arm. |
| OG005 | Alpha-frequency Anti-synchrony Stimulation | Rhythmic transcranial magnetic stimulation (TMS) is delivered to both frontal and parietal cortex in alpha-frequency (approximately 10 Hz) with a 180 degree phase offset, anti-synchrony. This intervention was only delivered in the Alpha stimulation arm. |
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