WMTMS: Using TMS to Increase Executive Function in Older Adults

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02767323
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 184
• Location: 1
• Arms: 3
• Actual Duration (Months): 43
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

Cognitive decline and dementia have become important public health issues in our time as medical science has increased lifespan and our society becomes progressively older. A great deal of the cognitive decline due to aging can be explained by decline in working memory (WM), a mental function central to cognition in which aging deficits appear almost universally. Attempts to use WM training to increase WM ability in older adults has had some success, but the transfer of performance enhancements caused by this training to other cognitive skills is controversial. Another intervention that shows much promise is noninvasive stimulation of cerebral cortex using transcranial magnetic stimulation (TMS), which has been shown to increase performance in many cognitive tasks.

Here, the investigator proposes to use fMRI-guided rTMS to enhance working memory performance. This will be achieved through three Aims. In the first, registered on this record, the investigator will stimulate both old and young healthy adults while they perform the WM task that will engage the frontoparietal network. To define the optimal rTMS target, rTMS will be applied over the dorsolateral prefrontal cortex (DLPFC: Aim 1a); or over the parietal cortex (PC: Aim 1b). These regions are involved not only in the maintenance of items in WM, but also in their manipulation, therefore applying rTMS over these areas should create WM performance enhancements that will be long-lasting. In Aim 1c, a direct within-subject comparison of these 2 targeted sites is performed.

In the second and third Aims, older adults will receive active or sham rTMS over the optimal target (defined in Arm 1) during two weeks of daily sessions while they perform the WM tasks. In the second Aim, the investigator hopes to demonstrate that the cumulative effect of multiple TMS sessions, in tandem with the synergistic effects of simultaneous TMS + WM training, create WM performance enhancements greater than those found with WM training alone, whose effects are long-lasting, continuing a month following the course of TMS sessions. In the third, the investigator will investigate whether the WM enhancements generated by the two weeks of TMS sessions will generalize to other cognitive tasks. The success of these 3 Aims will provide proof in principle for long-lasting, transferable effects of TMS in remediating WM and more general cognitive deficits due to aging, and point to a possible non-invasive brain stimulation therapy for cognitive decline in healthy aging and in dementia. This record is a reflection of Aim1, Aim 2 and 3 will be registered separately.

Condition or Disease	Intervention/Treatment	Phase
Aging	Device: rTMS; Device: Sham rTMS	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 184 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Using fMRI-guided TMS to Increase Central Executive Function in Older Adults
• Actual Study Start Date: Aug 15, 2016
• Actual Primary Completion Date: Mar 16, 2020
• Actual Study Completion Date: Mar 16, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active or Sham rTMS over the DLPFC (Aim1a) excitatory rTMS applied over the DLPFC (fMRI-guided). Active and Sham rTMS will be tested in a within subject design	Device: rTMS; excitatory 5Hz rTMS will be used; Device: Sham rTMS; an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used
Experimental: Active or Sham rTMS over the Parietal cortex (Aim1b) excitatory rTMS applied over the parietal cortex (fMRI-guided). Active and Sham rTMS will be tested in a within subject design	Device: rTMS; excitatory 5Hz rTMS will be used; Device: Sham rTMS; an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used
Experimental: Active or Sham rTMS over the DLPFC and the Parietal cortex (Aim1c) excitatory rTMS applied over the DLPFC and the parietal cortex (fMRI-guided). Active and Sham rTMS will be tested in a within subject design	Device: rTMS; excitatory 5Hz rTMS will be used; Device: Sham rTMS; an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used

Outcome Measures

Primary Outcome Measures

1. Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) [During the rTMS session, on average 2 hours per visit.]

   Accuracy (in percentage) will be assessed to evaluate the acute effect of rTMS. The accuracy provided below are the ones obtained in the hardest condition of the working memory task.

2. Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) [During the rTMS session, on average 2 hours per visit]

   Reaction Time of correct response (in ms) will be assessed to evaluate the acute effect of rTMS. The reaction times provided below are the ones obtained in the hardest condition of the working memory task.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age Restrictions: Young Group (from 18 to 35 years old), Elderly Group (from 60 to 80 years old).

• Use of effective method of birth control for women of childbearing capacity.

• Willing to provide informed consent.

Exclusion Criteria:

• Current or recent (within the past 6 months) history of substance abuse or dependence.

• Current serious medical illness.

• History of seizure, epilepsy, stroke, brain surgery, head injury, cranial metal implants, known structural brain lesion, devices that may be affected by rTMS or MRI (pacemaker, medication pump, cochlear implant, implanted brain stimulator)

• Inability or unwilling to give informed consent.

• Diagnosed any Axis I DSM-IV disorder (MINI, DSM-IV).

• For subjects age > 59 years, a total scaled score < 8 on the Dementia Rating Scale-2.

• Clinically defined neurological disorder.

• Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure, or currently taking medication that lowers the seizure threshold.

• Claustrophobia (MRI scanner).

• Pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27705

Sponsors and Collaborators

• Duke University
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Lawrence Appelbaum, Duke University

Study Documents (Full-Text)

• Study Protocol - Jan 19, 2021
• Statistical Analysis Plan - Jan 19, 2021

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT02767323
• Other Study ID Numbers: Pro00065334; 1R01AG050618-01
• First Posted: May 10, 2016
• Last Update Posted: Apr 5, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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	Active or Sham rTMS Over the DLPFC (Aim1a)	Active or Sham rTMS Over the Parietal Cortex (Aim1b)	Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)	Active/Sham rTMS Over DLPFC (Aim1a), Then Active/Sham rTMS Over DLPFC and Parietal Cortex (Aim1c)
Arm/Group Description	excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the DLPFC (fMRI-guided) and the Parietal cortex rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design
Period Title: Overall Study
STARTED	83	42	58	1
COMPLETED	49	17	28	1
NOT COMPLETED	34	25	30	0

Baseline Characteristics

Arm/Group Title	Active or Sham rTMS Over the DLPFC (Aim1a)	Active or Sham rTMS Over the Parietal Cortex (Aim1b)	Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)	Active or Sham rTMS Over the DLPFC (Aim1a), Then Active or Sham rTMS Over the DLPFC (Aim1c)	Total
Arm/Group Description	excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design	Total of all reporting groups
Overall Participants	83	42	58	1	184
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	57 68.7%	18 42.9%	58 100%	1 100%	134 72.8%
>=65 years	26 31.3%	24 57.1%	0 0%	0 0%	50 27.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.85 (23.09)	67.26 (6.23)	23.65 (4.14)	28 (1.4)	41.31 (22.47)
Sex: Female, Male (Count of Participants)
Female	52 62.7%	16 38.1%	34 58.6%	0 0%	102 55.4%
Male	31 37.3%	26 61.9%	24 41.4%	1 100%	82 44.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	14 16.9%	0 0%	13 22.4%	0 0%	27 14.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	6 7.2%	5 11.9%	11 19%	1 100%	23 12.5%
White	62 74.7%	37 88.1%	33 56.9%	0 0%	132 71.7%
More than one race	1 1.2%	0 0%	1 1.7%	0 0%	2 1.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	83 100%	42 100%	58 100%	1 100%	184 100%

Outcome Measures

1. Primary Outcome

Title	Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage)
Description	Accuracy (in percentage) will be assessed to evaluate the acute effect of rTMS. The accuracy provided below are the ones obtained in the hardest condition of the working memory task.
Time Frame	During the rTMS session, on average 2 hours per visit.

Outcome Measure Data

Analysis Population Description

Subjects who completed the study. Data not collected on five subjects.

Arm/Group Title	Active or Sham rTMS Over the DLPFC (Aim1a)	Active or Sham rTMS Over the Parietal Cortex (Aim1b)	Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)
Arm/Group Description	excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used. Active and Sham rTMS will be tested in a within subject design
Measure Participants	46	15	29
Active rTMS	50.43 (7.37)	55.42 (5.50)	83.93 (8.09)
Sham rTMS	46.49 (7.35)	57.76 (5.70)	83.27 (10.88)

2. Primary Outcome

Title	Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms)
Description	Reaction Time of correct response (in ms) will be assessed to evaluate the acute effect of rTMS. The reaction times provided below are the ones obtained in the hardest condition of the working memory task.
Time Frame	During the rTMS session, on average 2 hours per visit

Outcome Measure Data

Analysis Population Description

Subjects who completed the study. Data not collected on five subjects.

Arm/Group Title	Active or Sham rTMS Over the DLPFC (Aim1a)	Active or Sham rTMS Over the Parietal Cortex (Aim1b)	Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)
Arm/Group Description	excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used. Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design	excitatory rTMS applied over the the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used. Active and Sham rTMS will be tested in a within subject design
Measure Participants	46	15	29
Active rTMS	2368 (335)	2214 (231)	1911 (356)
Sham rTMS	2388 (345)	2224 (180)	1924 (332)

Adverse Events

Time Frame	During the rTMS session and a few minutes after, up to 10 minutes
Arm/Group Title	Active rTMS Over the DLPFC (Aim1a)		Sham rTMS Over the DLPFC (Aim1a)		Active rTMS Over the Parietal Cortex (Aim 1b)		Sham rTMS Over the Parietal Cortex (Aim 1b)		Active rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Active rTMS Over the DLPFC (Aim1a) Then Active rTMS Over the DLPFC and Parietal Cortex(Aim1c)		Sham rTMS Over the DLPFC (Aim1a) Then Sham rTMS Over the DLPFC and Parietal Cortex(Aim1c)
Arm/Group Description	excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the DLPFC (fMRI-guided) rTMS: excitatory 5Hz Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design		excitatory rTMS applied over the DLPFC and the parietal cortex (fMRI-guided) rTMS: excitatory 5Hz rTMS will be used Active and Sham rTMS will be tested in a within subject design
All Cause Mortality
	Active rTMS Over the DLPFC (Aim1a)		Sham rTMS Over the DLPFC (Aim1a)		Active rTMS Over the Parietal Cortex (Aim 1b)		Sham rTMS Over the Parietal Cortex (Aim 1b)		Active rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Active rTMS Over the DLPFC (Aim1a) Then Active rTMS Over the DLPFC and Parietal Cortex(Aim1c)		Sham rTMS Over the DLPFC (Aim1a) Then Sham rTMS Over the DLPFC and Parietal Cortex(Aim1c)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/83 (0%)		0/83 (0%)		0/42 (0%)		0/42 (0%)		0/58 (0%)		0/58 (0%)		0/1 (0%)		0/1 (0%)
Serious Adverse Events
	Active rTMS Over the DLPFC (Aim1a)		Sham rTMS Over the DLPFC (Aim1a)		Active rTMS Over the Parietal Cortex (Aim 1b)		Sham rTMS Over the Parietal Cortex (Aim 1b)		Active rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Active rTMS Over the DLPFC (Aim1a) Then Active rTMS Over the DLPFC and Parietal Cortex(Aim1c)		Sham rTMS Over the DLPFC (Aim1a) Then Sham rTMS Over the DLPFC and Parietal Cortex(Aim1c)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/83 (0%)		0/83 (0%)		0/42 (0%)		0/42 (0%)		0/58 (0%)		0/58 (0%)		0/1 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Active rTMS Over the DLPFC (Aim1a)		Sham rTMS Over the DLPFC (Aim1a)		Active rTMS Over the Parietal Cortex (Aim 1b)		Sham rTMS Over the Parietal Cortex (Aim 1b)		Active rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c)		Active rTMS Over the DLPFC (Aim1a) Then Active rTMS Over the DLPFC and Parietal Cortex(Aim1c)		Sham rTMS Over the DLPFC (Aim1a) Then Sham rTMS Over the DLPFC and Parietal Cortex(Aim1c)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/83 (0%)		0/83 (0%)		0/42 (0%)		0/42 (0%)		0/58 (0%)		0/58 (0%)		0/1 (0%)		0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.