Using TMS to Increase Executive Function in Older Adults

Study Overview
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Brief Summary
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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.

Official Title
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Using fMRI-guided TMS to Increase Central Executive Function in Older Adults

Conditions
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Aging

Intervention / Treatment
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* Device: rTMS
* Device: Sham rTMS


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | 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. | During the rTMS session, on average 2 hours per visit. | 
| Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | 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. | During the rTMS session, on average 2 hours per visit |