Theta Connectivity in Working Memory

NCT ID: NCT05204381

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 71 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-24
• Study Completion Date: 2024-12-20

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.

Conditions

Executive Function

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

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 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.

Group Type: EXPERIMENTAL

Arrhythmic near-zero phase lag stimulation

Intervention Type: 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.

Arrhythmic independent stimulation

Intervention Type: 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.

Alpha-frequency near-zero phase lag stimulation

Intervention Type: 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.

Alpha-frequency anti-synchrony stimulation

Intervention Type: 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.

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 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.

Group Type: EXPERIMENTAL

Theta-frequency near-zero phase lag stimulation

Intervention Type: 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.

Theta-frequency anti-synchrony stimulation

Intervention Type: 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.

Arrhythmic near-zero phase lag stimulation

Intervention Type: 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.

Arrhythmic independent stimulation

Intervention Type: 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.

Interventions

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.

Intervention Type: DEVICE

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.

Intervention Type: DEVICE

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.

Intervention Type: DEVICE

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.

Intervention Type: DEVICE

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.

Intervention Type: DEVICE

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.

Intervention Type: DEVICE

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Flavio Frohlich, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1R01MH124387

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21-0248

Identifier Type: -

Identifier Source: org_study_id