Aging
Conditions
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.
Interventions
DEVICErTMS
excitatory 5Hz rTMS will be used
DEVICESham rTMS
an electrical sham coil reproducing the same clicking sound and tactile sensation than the active rTMS will be used
Sponsors
National Institute on Aging (NIA)
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active or Sham rTMS Over the DLPFC (Aim1a) excitatory rTMS applied over the DLPFC (fMRI-guided)
rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design | 83 |
| Active or Sham rTMS Over the Parietal Cortex (Aim1b) excitatory rTMS applied over the parietal cortex (fMRI-guided)
rTMS: excitatory 5Hz. Active and Sham rTMS will be tested in a within subject design | 42 |
| Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c) 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 | 58 |
| Active or Sham rTMS Over the DLPFC (Aim1a), Then Active or Sham rTMS Over the DLPFC (Aim1c) 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 | 1 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Contraindication, moving during the scan, low behavior, or Covid-19 | 17 | 20 | 17 | 0 |
| Overall Study | Withdrawal by Subject | 17 | 5 | 13 | 0 |
Baseline characteristics
| Characteristic | 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) | Active or Sham rTMS Over the DLPFC (Aim1a) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 0 Participants | 0 Participants | 26 Participants | 50 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 58 Participants | 1 Participants | 57 Participants | 134 Participants |
| Age, Continuous | 67.26 years STANDARD_DEVIATION 6.23 | 23.65 years STANDARD_DEVIATION 4.14 | 28 years STANDARD_DEVIATION 1.4 | 40.85 years STANDARD_DEVIATION 23.09 | 41.31 years STANDARD_DEVIATION 22.47 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 13 Participants | 0 Participants | 14 Participants | 27 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 11 Participants | 1 Participants | 6 Participants | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 37 Participants | 33 Participants | 0 Participants | 62 Participants | 132 Participants |
| Region of Enrollment United States | 42 Participants | 58 Participants | 1 Participants | 83 Participants | 184 Participants |
| Sex: Female, Male Female | 16 Participants | 34 Participants | 0 Participants | 52 Participants | 102 Participants |
| Sex: Female, Male Male | 26 Participants | 24 Participants | 1 Participants | 31 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 83 | 0 / 83 | 0 / 42 | 0 / 42 | 0 / 58 | 0 / 58 | 0 / 1 | 0 / 1 |
| other Total, other adverse events | 0 / 83 | 0 / 83 | 0 / 42 | 0 / 42 | 0 / 58 | 0 / 58 | 0 / 1 | 0 / 1 |
| serious Total, serious adverse events | 0 / 83 | 0 / 83 | 0 / 42 | 0 / 42 | 0 / 58 | 0 / 58 | 0 / 1 | 0 / 1 |
Outcome results
Primary
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.
Time frame: During the rTMS session, on average 2 hours per visit.
Population: Subjects who completed the study. Data not collected on five subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active or Sham rTMS Over the DLPFC (Aim1a) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Sham rTMS | 46.49 percentage of accuracy | Standard Deviation 7.35 |
| Active or Sham rTMS Over the DLPFC (Aim1a) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Active rTMS | 50.43 percentage of accuracy | Standard Deviation 7.37 |
| Active or Sham rTMS Over the Parietal Cortex (Aim1b) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Active rTMS | 55.42 percentage of accuracy | Standard Deviation 5.5 |
| Active or Sham rTMS Over the Parietal Cortex (Aim1b) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Sham rTMS | 57.76 percentage of accuracy | Standard Deviation 5.7 |
| Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Active rTMS | 83.93 percentage of accuracy | Standard Deviation 8.09 |
| Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Accuracy (in Percentage) | Sham rTMS | 83.27 percentage of accuracy | Standard Deviation 10.88 |
Primary
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.
Time frame: During the rTMS session, on average 2 hours per visit
Population: Subjects who completed the study. Data not collected on five subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active or Sham rTMS Over the DLPFC (Aim1a) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Active rTMS | 2368 ms | Standard Deviation 335 |
| Active or Sham rTMS Over the DLPFC (Aim1a) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Sham rTMS | 2388 ms | Standard Deviation 345 |
| Active or Sham rTMS Over the Parietal Cortex (Aim1b) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Active rTMS | 2214 ms | Standard Deviation 231 |
| Active or Sham rTMS Over the Parietal Cortex (Aim1b) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Sham rTMS | 2224 ms | Standard Deviation 180 |
| Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Active rTMS | 1911 ms | Standard Deviation 356 |
| Active or Sham rTMS Over the DLPFC and the Parietal Cortex (Aim 1c) | Acute Effect of a rTMS Session on the Performance for a Working Memory Task, as Measured by Reaction Time of Correct Response (in ms) | Sham rTMS | 1924 ms | Standard Deviation 332 |