Clinical trial NCT05460468: Neuromodulation of Memory in Aging
Official title: Adaptive Neuromodulation of Working Memory Networks in Aging and Dementia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Mild Cognitive Impairment
MCI
Keywords: TMS
Transcranial Magnetic Stimulation
Memory
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2022-07-15
Enrollment: 150
Sex: ALL
Minimum age (years): 60
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: The study has three Aims and thus three models.

For Aim 1, the primary outcome measure is fMRI BOLD. Researchers will estimate the dose-response relationship between TMS intensity and BOLD response in two cortical sites for response to TMS.

For Aim 2 the primary outcome measure is impact of closed-loop TMS treatment on working memory task performance.

For Aim 3, the primary outcome measure is the strength of mediation of brain health (e.g., vascular density) predictors of cognition.
Primary purpose: BASIC_SCIENCE

Brief summary: The proposed research will use closed-loop transcranial magnetic stimulation (TMS) based on individualized brain networks to establish parameters that can reliably control brain states. This will be tested in healthy aging and mild cognitive impairment (MCI) cohorts. The investigators will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory and then target this network using closed-loop TMS to the Prefrontal Cortex. Investigators will measure the impact of TMS on working memory performance and task-based neural activity. The project will use brain stimulation and network modeling techniques to enhance working memory in healthy older adults and MCI and will demonstrate the value of closed-loop, network-guided TMS for future clinical applications.

Detailed description: Dementia due to Alzheimer's disease (AD) is a leading public health concern in the US with enormous care costs and no effective pharmacotherapy despite multiple clinical trials. Multiple studies have shown mild cognitive impairment (MCI) to be a precursor risk for AD and to be more amenable to intervention. While preclinical studies have shown that directly modulating activity in the prefrontal cortex (PFC) using non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), can modulate cognitive function in healthy older adults, there is little evidence of reliable efficacy in MCI.

The investigators posit three reasons for this lack of efficacy. First, there is no established means of estimating a reliable biomarker and unique dose-response relationship between TMS intensity and brain activity. Second, standard TMS protocols fail to capture the dynamic nature of cognitive states and the reaction of endogenous brain states to exogenous neuromodulation. Third, no studies using TMS in AD-related populations have accounted for the influence of cerebrovascular disease in the response to TMS. The investigators propose to address these shortcomings by using closed-loop TMS, based on individualized brain networks to establish parameters that can reliably control brain states during normal memory functioning in healthy aging and MCI.

To achieve this goal, the investigators will study network activation and neural oscillatory mechanisms underlying the network that regulates working memory (WM), a cognition function with a reliable prefrontal cortex (PFC) network characterization. The investigators will then target this network using closed-loop TMS to the PFC and measure the impact on WM performance and task-based neural activity. This approach uses concurrent TMS-fMRI to identify dose-response relationships in the working memory network. Next, the investigators apply novel closed-loop TMS to perturb this network using temporally-precise TMS-EEG. Lastly, the investigators will integrate information collected via fMRI and EEG into a single computational framework to model spatiotemporal dynamics of the global brain network and predict the success of the TMS-related response in our MCI cohort. The project will use cutting-edge brain stimulation and network modeling techniques to enhance WM in healthy older adults and MCI and will provide a demonstration of the value of closed-loop, network-guided TMS for future clinical applications.

Eligibility criteria: Inclusion Criteria:

* English Speaking
* Willing to provide consent

Exclusion Criteria:

* History of any Axis I DSM-V disorder, excluding major depressive disorder or generalized anxiety disorders
* Current history of substance abuse or dependence (excluding nicotine)
* Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants, or electrodes), cardiac pacemakers, or vagus Nerve stimulation device
* Increased risk of seizure for any reason, including prior diagnosis of epilepsy, seizure disorder, increased intracranial pressure, or history of significant head trauma with loss of consciousness for ≥ 5 minutes.
* Neurological disorder including, but not limited to: space occupying brain lesion; any history of seizures, history of cerebrovascular accident; fainting, cerebral aneurysm, Dementia, Hungtington chorea; Multiple Sclerosis.
* Current use of medications known to lower the seizure threshold and/or affect working memory

Primary outcomes:
measure: Working Memory Task
timeFrame: Collected during TMS-EEG (Day 4)
measure: Functional network connectivity
timeFrame: Collected during the initial neuroimaging session (Day 2)
measure: Vascular density (VAD)
timeFrame: Collected during the second neuroimaging session (Day 3)
measure: EEG-based connectivity
timeFrame: Collected during TMS-EEG (Day 4)
Secondary outcomes:
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: Collected during the initial screening visit (Day 1)
measure: National Institutes of Health (NIH) Toolbox Cognitive Battery
timeFrame: Collected during the initial screening visit (Day 1)
measure: Hopkins Verbal Learning Test (HVLT-2)
timeFrame: Collected during the initial screening visit (Day 1)
measure: Brief Visuospatial Memory Test (BVMT-R)
timeFrame: Collected during the initial screening visit (Day 1)
measure: Number Span Forwards/ Backwards
timeFrame: Collected during the initial screening visit (Day 1)
measure: Category & Phonemic Verbal Fluency
timeFrame: Collected during the initial screening visit (Day 1)
measure: Trail Making Test
timeFrame: Collected during the initial screening visit (Day 1)
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Hospital
state: North Carolina
Study officials:
affiliation: Duke University
name: Simon W Davis, PhD
role: PRINCIPAL_INVESTIGATOR
References: