Modulation of Cognitive Control Signals in Prefrontal Cortex by Rhythmic Transcranial Magnetic Stimulation

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT03828734
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 58
• Location: 1
• Arms: 2
• Actual Duration (Months): 9.3
• Patients Per Site Per Month: 6.3

Study Details

Study Description

Brief Summary

Purpose: In this study, the investigators will provide causal evidence for the role of alpha and theta oscillations in cognitive control.

Participants: Participants must be healthy, between the ages of 18 and 35, right handed, able to provide informed consent, willing to comply with all study procedures, and be available for the duration of the study, speak and understand English.

Procedures: Alpha and theta brain oscillations will be measured and then entrained using frequency specific rhythmic TMS during a retrospective cued cognitive control task.

Condition or Disease	Intervention/Treatment	Phase
Executive Function	Device: Theta TMS; Device: Alpha TMS; Device: Arrhythmic TMS	N/A

Detailed Description

Neural oscillations are proposed to be a mechanism of coordinating information processing across distributed regions of cortex. Different neural oscillations may correspond to different underlying neural computations. Noninvasive brain stimulation allows experimenters to modulate specific neural oscillations by targeting particular frequency bands. By collecting simultaneous electroencephalography (EEG), rhythmic transcranial magnetic stimulation (TMS) has been previously demonstrated to entrain neural oscillations at the frequency of stimulation. Furthermore, when the frequency of entrained neural oscillations is matched to the frequency of endogenous activity in a cognitive task, the brain stimulation improves behavioral performance. Therefore, noninvasive brain stimulation is a promising tool for improving cognition by inducing optimal neural activity via externally applied electromagnetic fields; e.g. cognitive control improvements.

Previous evidence has implicated neural activity in the alpha band (8-12 Hz) in information suppression and activity in the theta band (4-7 Hz) in information prioritization. Cognitive control task paradigms have been shown to elicit distinct activity in both of these bands. In this task, the stimuli are lateralized to the right and left visual field during encoding. After a short delay, a cue informs participants which stimuli (right or left) will be tested. Previous evidence found that alpha activity in parietal cortex is generated contralateral to irrelevant stimuli-supporting the role of alpha in information suppression-while theta activity in frontal cortex increases with the number of stimuli to be remembered-supporting the role of theta in information prioritization.

For the current study, the investigators propose to deliver rhythmic trains of TMS in either alpha frequency, theta frequency, or an arrhythmic control to modulate neural processing during a cognitive control task. By collecting simultaneous EEG with TMS, the investigators will be able to measure the entrained oscillations from rhythmic TMS. The goal of this experiment is to enhance the observed theta and alpha activity that is seen with the successful prioritization and suppression of information. To provide causal evidence that parietal cortex generates alpha activity and frontal cortex generates theta activity, the investigators will apply rhythmic TMS stimulation to two scalp locations: the anterior middle frontal gyrus and inferior intraparietal sulcus. By applying alpha frequency, theta frequency, and arrhythmic TMS at each location, the investigators will be able to examine the causal relationship of frontal theta oscillations in information prioritization and parietal alpha oscillations in information suppression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Modulation of Alpha and Theta Oscillations in a Cognitive Control Retrospective Cue Task With Frequency Specific Rhythmic Transcranial Magnetic Stimulation
• Actual Study Start Date: Feb 13, 2019
• Actual Primary Completion Date: Nov 22, 2019
• Actual Study Completion Date: Nov 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TMS to frontal cortex followed by TMS to parietal cortex Participants will receive TMS while performing a cognitive control task. In their first stimulation session, the TMS coil will be placed over the frontal cortex on the scalp. In their second session, the TMS coil will be placed over the parietal cortex on the scalp. During every session, subjects receive Theta TMS, Alpha TMS, and Arrhythmic TMS.	Device: Theta TMS; TMS will be administered at the frequency of each subject's endogenous theta oscillation (4-7Hz); Other Names: MagProX100 ; Device: Alpha TMS; TMS will be administered at the frequency of each subject's endogenous alpha oscillation (8-12 Hz); Other Names: MagProX100 ; Device: Arrhythmic TMS; TMS will be administered arrhythmically; i.e. a sequence of pulses with randomized timing; Other Names: MagProX100
Experimental: TMS to parietal cortex followed by TMS to frontal cortex Participants will receive TMS while performing a cognitive control task. In their first stimulation session, the TMS coil will be placed over the parietal cortex on the scalp. In their second session, the TMS coil will be placed over the frontal cortex on the scalp. During every session, subjects receive Theta TMS, Alpha TMS, and Arrhythmic TMS.	Device: Theta TMS; TMS will be administered at the frequency of each subject's endogenous theta oscillation (4-7Hz); Other Names: MagProX100 ; Device: Alpha TMS; TMS will be administered at the frequency of each subject's endogenous alpha oscillation (8-12 Hz); Other Names: MagProX100 ; Device: Arrhythmic TMS; TMS will be administered arrhythmically; i.e. a sequence of pulses with randomized timing; Other Names: MagProX100

Outcome Measures

Primary Outcome Measures

1. Number of Remembered Items [1 week]

   Participants make a button press on a keyboard to indicate if the probed items are matched or non-matched to the items held in memory after a retrospective cue is presented. The investigators calculate the percent correct for non-match conditions, defined as the hit rate, and the percent incorrect for match conditions, defined as the false alarm rate. 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. For TMS to frontal cortex, working memory capacity is reported when the participant was cued to the right. For TMS to parietal cortex, working memory capacity is reported when the participant was cued to the left.

2. Amplitude of Neural Oscillations [1 week]

   The electrical activity of the brain is recorded during performance of the task and brain stimulation. The investigators will perform Morlet wavelet convolution on the recorded electrical signal to calculate the amplitude of neural oscillations in the frequency bands: theta (4-7 hertz) and alpha (8-12 hertz). The amplitude of neural oscillations is reported during the second half of stimulation in the region that is being stimulated. The amplitude is normalized for each participant as the percent change from the amplitude during the baseline period (before the task begins). For TMS to frontal cortex the amplitude of theta oscillations are reported and for TMS to parietal cortex the amplitude of alpha oscillations are reported.

3. Response Time [1 week]

   Participants make a button press on a keyboard to indicate if the probe items are matched or non-matched to the items held in memory after a retrospective cue is presented. The investigators will calculate the response time of this choice as the difference between the time of the button press and presentation of the probe. For TMS to frontal cortex, response time is reported when the participant was cued to the right. For TMS to parietal cortex, response time is reported when the participant was cued to the left.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy

• Between the ages of 18 and 35

• Right handed

• Able to provide informed consent

• Willing to comply with all study procedures

• Available for the duration of the study

• Speak and understand English.

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 -Cardiac pacemaker -Any other implanted electronic device -History of current traumatic brain injury -(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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27516

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Flavio Frohlich, PhD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 10, 2019

More Information

Publications

• Albouy P, Weiss A, Baillet S, Zatorre RJ. Selective Entrainment of Theta Oscillations in the Dorsal Stream Causally Enhances Auditory Working Memory Performance. Neuron. 2017 Apr 5;94(1):193-206.e5. doi: 10.1016/j.neuron.2017.03.015. Epub 2017 Mar 23.
• Fries P. Rhythms for Cognition: Communication through Coherence. Neuron. 2015 Oct 7;88(1):220-35. doi: 10.1016/j.neuron.2015.09.034. Review.
• Hanslmayr S, Matuschek J, Fellner MC. Entrainment of prefrontal beta oscillations induces an endogenous echo and impairs memory formation. Curr Biol. 2014 Apr 14;24(8):904-9. doi: 10.1016/j.cub.2014.03.007. Epub 2014 Mar 27.
• Klimesch W, Sauseng P, Hanslmayr S. EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev. 2007 Jan;53(1):63-88. Epub 2006 Aug 1. Review.
• Popov T, Popova P, Harkotte M, Awiszus B, Rockstroh B, Miller GA. Cross-frequency interactions between frontal theta and posterior alpha control mechanisms foster working memory. Neuroimage. 2018 Nov 1;181:728-733. doi: 10.1016/j.neuroimage.2018.07.067. Epub 2018 Jul 31.
• Reinhart RMG. Disruption and rescue of interareal theta phase coupling and adaptive behavior. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11542-11547. doi: 10.1073/pnas.1710257114. Epub 2017 Oct 9.
• Romei V, Thut G, Silvanto J. Information-Based Approaches of Noninvasive Transcranial Brain Stimulation. Trends Neurosci. 2016 Nov;39(11):782-795. doi: 10.1016/j.tins.2016.09.001. Epub 2016 Sep 30. Review.
• Rouder JN, Morey RD, Morey CC, Cowan N. How to measure working memory capacity in the change detection paradigm. Psychon Bull Rev. 2011 Apr;18(2):324-30. doi: 10.3758/s13423-011-0055-3.
• Roux F, Uhlhaas PJ. Working memory and neural oscillations: α-γ versus θ-γ codes for distinct WM information? Trends Cogn Sci. 2014 Jan;18(1):16-25. doi: 10.1016/j.tics.2013.10.010. Epub 2013 Nov 19. Review.
• Thut G, Veniero D, Romei V, Miniussi C, Schyns P, Gross J. Rhythmic TMS causes local entrainment of natural oscillatory signatures. Curr Biol. 2011 Jul 26;21(14):1176-85. doi: 10.1016/j.cub.2011.05.049. Epub 2011 Jun 30.
• Wallis G, Stokes M, Cousijn H, Woolrich M, Nobre AC. Frontoparietal and Cingulo-opercular Networks Play Dissociable Roles in Control of Working Memory. J Cogn Neurosci. 2015 Oct;27(10):2019-34. doi: 10.1162/jocn_a_00838. Epub 2015 Jun 4.
• Wang XJ. Neurophysiological and computational principles of cortical rhythms in cognition. Physiol Rev. 2010 Jul;90(3):1195-268. doi: 10.1152/physrev.00035.2008. Review.
• Wolinski N, Cooper NR, Sauseng P, Romei V. The speed of parietal theta frequency drives visuospatial working memory capacity. PLoS Biol. 2018 Mar 14;16(3):e2005348. doi: 10.1371/journal.pbio.2005348. eCollection 2018 Mar.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT03828734
• Other Study ID Numbers: 18-1789; R01MH111889
• First Posted: Feb 4, 2019
• Last Update Posted: Nov 19, 2020
• Last Verified: Dec 1, 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Study Results

Participant Flow

Arm/Group Title	TMS to Frontal Cortex Followed by TMS to Parietal Cortex	TMS to Parietal Cortex Followed by TMS to Frontal Cortex
Arm/Group Description	Participants will receive transcranial magnetic stimulation (TMS) while performing a cognitive control task. In the first stimulation session, the TMS coil will be placed over the frontal cortex on the scalp. In the second session, the TMS coil will be placed over the parietal cortex on the scalp. During every session, participants receive Alpha TMS, Theta TMS, and Arrhythmic TMS.	Participants will receive TMS while performing a cognitive control task. In their first stimulation session, the TMS coil will be placed over the parietal cortex on the scalp. In their second session, the TMS coil will be placed over the frontal cortex on the scalp. During every session, participants receive Alpha TMS, Theta TMS, and Arrhythmic TMS.
Period Title: Baseline
STARTED	32	26
COMPLETED	32	26
NOT COMPLETED	0	0
Period Title: Baseline
STARTED	32	26
COMPLETED	29	25
NOT COMPLETED	3	1
Period Title: Baseline
STARTED	29	25
COMPLETED	25	25
NOT COMPLETED	4	0
Period Title: Baseline
STARTED	25	25
COMPLETED	25	24
NOT COMPLETED	0	1
Period Title: Baseline
STARTED	25	24
COMPLETED	25	24
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Participants will receive TMS while performing a cognitive control task. In one stimulation session, the TMS coil will be placed over the frontal cortex on the scalp. In another session, the TMS coil will be placed over the parietal cortex on the scalp. During every session, participants receive Alpha TMS, Theta TMS, and Arrhythmic TMS.
Overall Participants	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	22.2 (3.83)
Sex: Female, Male (Count of Participants)
Female	39 67.2%
Male	19 32.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 15.5%
Not Hispanic or Latino	48 82.8%
Unknown or Not Reported	1 1.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	16 27.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 5.2%
White	31 53.4%
More than one race	3 5.2%
Unknown or Not Reported	5 8.6%
Region of Enrollment (participants) [Number]
United States	58 100%
Number of Remembered Items (number of remembered items) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [number of remembered items]	1.8039 (0.4988)
Response Time (seconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seconds]	0.8225 (0.1605)

Outcome Measures

1. Primary Outcome

Title	Number of Remembered Items
Description	Participants make a button press on a keyboard to indicate if the probed items are matched or non-matched to the items held in memory after a retrospective cue is presented. The investigators calculate the percent correct for non-match conditions, defined as the hit rate, and the percent incorrect for match conditions, defined as the false alarm rate. 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. For TMS to frontal cortex, working memory capacity is reported when the participant was cued to the right. For TMS to parietal cortex, working memory capacity is reported when the participant was cued to the left.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

54 participants were randomized into the experiment arms. 5 participants did not complete both arms and are excluded from analysis. In addition, data from 2 participant was corrupted and 5 participants were excluded due to poor task performance. Analysis was run on 42 participants.

Arm/Group Title	TMS to Frontal Cortex	TMS to Parietal Cortex
Arm/Group Description	Participants receive TMS to frontal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.	Participants receive TMS to parietal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.
Measure Participants	42	42
Theta TMS	1.863 (0.613)	1.754 (0.524)
Alpha TMS	1.796 (0.495)	1.797 (0.572)
Arrhythmic TMS	1.803 (0.381)	1.864 (0.469)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMS to Frontal Cortex, TMS to Parietal Cortex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.263
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Amplitude of Neural Oscillations
Description	The electrical activity of the brain is recorded during performance of the task and brain stimulation. The investigators will perform Morlet wavelet convolution on the recorded electrical signal to calculate the amplitude of neural oscillations in the frequency bands: theta (4-7 hertz) and alpha (8-12 hertz). The amplitude of neural oscillations is reported during the second half of stimulation in the region that is being stimulated. The amplitude is normalized for each participant as the percent change from the amplitude during the baseline period (before the task begins). For TMS to frontal cortex the amplitude of theta oscillations are reported and for TMS to parietal cortex the amplitude of alpha oscillations are reported.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

54 participants were randomized into the experiment arms. 5 participants did not complete both arms and are excluded from analysis. In addition, data from 2 participant was corrupted and 5 participants were excluded due to poor task performance. Analysis was run on 42 participants.

Arm/Group Title	TMS to Frontal Cortex	TMS to Parietal Cortex
Arm/Group Description	Participants receive TMS to frontal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.	Participants receive TMS to parietal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.
Measure Participants	42	42
Theta TMS	1.443 (1.227)	-0.201 (0.505)
Alpha TMS	0.489 (0.412)	0.241 (1.045)
Arrhythmic TMS	0.944 (0.705)	-0.132 (0.600)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMS to Frontal Cortex, TMS to Parietal Cortex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.000001
	Comments
	Method	ANOVA
	Comments

3. Primary Outcome

Title	Response Time
Description	Participants make a button press on a keyboard to indicate if the probe items are matched or non-matched to the items held in memory after a retrospective cue is presented. The investigators will calculate the response time of this choice as the difference between the time of the button press and presentation of the probe. For TMS to frontal cortex, response time is reported when the participant was cued to the right. For TMS to parietal cortex, response time is reported when the participant was cued to the left.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

54 participants were randomized into the experiment arms. 5 participants did not complete both arms and are excluded from analysis. In addition, data from 2 participant was corrupted and 5 participants were excluded due to poor task performance. Analysis was run on 42 participants.

Arm/Group Title	TMS to Frontal Cortex	TMS to Parietal Cortex
Arm/Group Description	Participants receive TMS to frontal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.	Participants receive TMS to parietal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.
Measure Participants	42	42
Theta TMS	0.728 (0.157)	0.714 (0.154)
Alpha TMS	0.711 (0.162)	0.710 (0.162)
Arrhythmic TMS	0.720 (0.155)	0.717 (0.166)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TMS to Frontal Cortex, TMS to Parietal Cortex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.399
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	Adverse events were systematically assessed after the 3 hour session for both arms. Each session was 1 week apart. Thus, adverse events were monitored for approximately 1 week.
Arm/Group Title	TMS to Frontal Cortex		TMS to Parietal Cortex
Arm/Group Description	Participants receive TMS to frontal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.		Participants receive TMS to parietal cortex while performing a cognitive control task. During every session, participants receive Theta TMS, Alpha TMS, and Arrhythmic TMS.
All Cause Mortality
	TMS to Frontal Cortex		TMS to Parietal Cortex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/50 (0%)
Serious Adverse Events
	TMS to Frontal Cortex		TMS to Parietal Cortex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	TMS to Frontal Cortex		TMS to Parietal Cortex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/53 (47.2%)		25/50 (50%)
Ear and labyrinth disorders
Ringing or buzzing noise	0/53 (0%)	0	0/50 (0%)	0
General disorders
Sleepiness	10/53 (18.9%)	10	9/50 (18%)	9
Trouble concentrating	11/53 (20.8%)	11	6/50 (12%)	6
Dizziness	2/53 (3.8%)	2	0/50 (0%)	0
Flickering lights	0/53 (0%)	0	1/50 (2%)	1
Skin and subcutaneous tissue disorders
Headache	11/53 (20.8%)	11	11/50 (22%)	11
Neck pain	1/53 (1.9%)	1	1/50 (2%)	1
Scalp pain	9/53 (17%)	9	8/50 (16%)	8
Tingling	3/53 (5.7%)	3	2/50 (4%)	2
Burning sensation	3/53 (5.7%)	3	2/50 (4%)	2
Local redness	2/53 (3.8%)	2	2/50 (4%)	2
Itching	0/53 (0%)	0	2/50 (4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.