Executive Function
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DEVICETheta-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.
DEVICETheta-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.
DEVICEArrhythmic 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.
DEVICEArrhythmic 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.
DEVICEAlpha-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.
DEVICEAlpha-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.
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
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Between the ages of 18 and 35 * Right-handed * Able to provide informed consent * Have normal to corrected vision without color blindness * Willing to comply with all study procedures and be available for the duration of the study Speak and understand English * Participants will be invited back to the second session only if they are able to perform the task. The criteria for demonstrating the cognitive process of interest is that participants must show a benefit to their working memory percent correct during trials with an informative retro-cue relative to trials with an uninformative neutral cue
Exclusion criteria
* Attention Deficit Hyperactivity Disorder (ADHD) (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 * Failure to pass a colorblindness test * (For females) Pregnancy 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Remembered Items | Measured concurrent with stimulation throughout a 3-hour session | 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. |
| Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Measured concurrent with stimulation throughout a 3-hour session | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | Measured concurrent with stimulation throughout a 3-hour session | 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| 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. | 23 |
| Total | 39 |
Baseline characteristics
| Characteristic | Theta Stimulation | Alpha Stimulation | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 23 Participants | 39 Participants |
| Age, Continuous | 21.4 years STANDARD_DEVIATION 4 | 22.0 years STANDARD_DEVIATION 3.7 | 21.7 years STANDARD_DEVIATION 3.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 4 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 19 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 8 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 15 Participants | 26 Participants |
| Region of Enrollment United States | 16 Participants | 23 Participants | 39 Participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 23 |
| other Total, other adverse events | 2 / 16 | 3 / 23 |
| serious Total, serious adverse events | 0 / 16 | 0 / 23 |
Outcome results
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.
Time frame: Measured concurrent with stimulation throughout a 3-hour session
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theta-frequency Near-zero Phase Lag Stimulation | Number of Remembered Items | 1.72 remembered items | Standard Deviation 0.48 |
| Theta-frequency Anti-synchrony Stimulation | Number of Remembered Items | 1.68 remembered items | Standard Deviation 0.42 |
| Arrhythmic Near-zero Phase Lag Stimulation | Number of Remembered Items | 1.68 remembered items | Standard Deviation 0.38 |
| Arrhythmic Independent Stimulation | Number of Remembered Items | 1.65 remembered items | Standard Deviation 0.37 |
| Alpha-frequency Near-zero Phase Lag Stimulation | Number of Remembered Items | 1.71 remembered items | Standard Deviation 0.38 |
| Alpha-frequency Anti-synchrony Stimulation | Number of Remembered Items | 1.72 remembered items | Standard Deviation 0.4 |
Comparison: Mixed-factors ANOVA for the interaction between stimulation frequency (theta or alpha) and synchrony (in-phase or anti-phase).p-value: 0.783ANOVA
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.
Time frame: Measured concurrent with stimulation throughout a 3-hour session
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theta-frequency Near-zero Phase Lag Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.143 weighted phase lag index | Standard Deviation 0.118 |
| Theta-frequency Anti-synchrony Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.167 weighted phase lag index | Standard Deviation 0.158 |
| Arrhythmic Near-zero Phase Lag Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.116 weighted phase lag index | Standard Deviation 0.074 |
| Arrhythmic Independent Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.086 weighted phase lag index | Standard Deviation 0.057 |
| Alpha-frequency Near-zero Phase Lag Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.149 weighted phase lag index | Standard Deviation 0.104 |
| Alpha-frequency Anti-synchrony Stimulation | Strength of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 0.156 weighted phase lag index | Standard Deviation 0.126 |
Comparison: Mixed-factors ANOVA for the interaction between stimulation frequency (theta or alpha) and synchrony (in-phase or anti-phase).p-value: 0.965ANOVA
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.
Time frame: Measured concurrent with stimulation throughout a 3-hour session
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Theta-frequency Near-zero Phase Lag Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 182.2 degrees | Standard Deviation 5.73 |
| Theta-frequency Anti-synchrony Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 177.4 degrees | Standard Deviation 14.43 |
| Arrhythmic Near-zero Phase Lag Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 182.2 degrees | Standard Deviation 4.16 |
| Arrhythmic Independent Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 181.2 degrees | Standard Deviation 4.32 |
| Alpha-frequency Near-zero Phase Lag Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 183.1 degrees | Standard Deviation 6.03 |
| Alpha-frequency Anti-synchrony Stimulation | Average Phase Lag of Functional Connectivity Between Frontal and Parietal Cortex in Theta-frequency | 183.1 degrees | Standard Deviation 6.69 |
Comparison: Mixed-factors ANOVA for the interaction between stimulation frequency (theta or alpha) and synchrony (in-phase or anti-phase).p-value: 0.089ANOVA