Network-targeted Theta-burst Stimulation for Episodic Memory Improvement in Mild Cognitive Impairment

Study Overview
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Brief Summary
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The purpose of this study is to see if stimulation of the brain can improve memory. The investigators will use a device called transcranial magnetic stimulation that can stimulate and activate a specific part of the brain that is important for memory. The study will enroll MCI subjects and subjects with subjective memory complaints who will be randomly assigned to receive active or sham brain stimulation. 'Blinded' or 'sham-controlled' means that the subject will not know whether the treatment they receive is the active treatment or the non-active stimulation. In the 'sham' condition, the stimulator will turn on but will not actually be stimulating the target brain region.

Official Title
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Network-targeted Theta-burst Stimulation for Episodic Memory Improvement in Mild Cognitive Impairment

Conditions
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Cognitive Dysfunction, Memory Disorders in Old Age

Intervention / Treatment
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* Device: Active Theta Burst Stimulation
* Device: Sham Theta Burst Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Agreement to participate in the study 55-100 years of age Right-handedness In good general health Living independently Subjective memory complaints (self-report and positive score on MFQ) Katz ADL scale and Lawton iADL scale: We will review scores on a case-by-case basis if they did not score 100%. We will exclude if the scores show impairment in ADLs that suggests problems with independent functioning due to cognitive impairment. MMSE score > 24 PHQ Depression score =< 7 Ability to read, write, and speak English fluently Diagnosis of mild neurocognitive disorder according to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) criteria. Participants with subjective memory complaints without an aMCI diagnosis will be reviewed on a case-by-case basis based on neuropsychological scores. No change in use of psychotropic medication for treatment of depression, anxiety, ADHS or psychosis 1 month prior and during the study. Screening diagnostic criteria for aMCI will be subjective memory complaints, intact instrumental and basic activities of daily living (Smith et al., 1996), PHQ, MMSE, BVMT-R (25-minute delay), CVLT-II (20-minute delay), Rey-Osterrieth Complex Figure Task (30-minute delay). Baseline assessments will include neuropsychological testing of all study subjects. Exclusion Criteria: Unwilling or unable to provide informed consent Diagnosis of dementia Active major medical, psychiatric, or neurologic disorder associated with neurocognitive impairment History of alcohol or substance abuse Recent (< 6 months) alcohol or substance abuse (excluding nicotine or caffeine) History of stroke (if the stroke in our judgment is related to the memory problem), traumatic brain injury with loss of consciousness, or other neurologic disorder (e.g., epilepsy, Huntington's disease, Parkinson's disease) Non-English speaking participants Not right handed based on self-report or evaluation based on a standard report Has received TMS before (not TMS naïve) Poorly controlled hypertension or cardiovascular disease Current enrollment in a memory-enhancement study or course Contraindication to TMS or MRI including claustrophobia, metal in body, surgery within 60 days, certain implants, or previous abnormal MRI results. scanning facial tattoos is okay if safe with MRI is taking: anticholinergic medication (e.g., Detrol, Cogentin); sedating antihistamine (e.g., Benadryl); any drug that has significant anticholinergic or antihistaminic side effects (e.g., tricyclic antidepressant medications, Remeron). benzodiazepines. While not a strict rule out, this will be decided on a case-by-case basis depending on the dose.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active TBS<br>Theta burst stimulation (TBS) will be delivered at 100% of motor threshold (MT). | Device: Active Theta Burst Stimulation<br>* Theta burst transcranial magnetic stimulation (TBS) will be delivered at 80% of motor threshold (MT).<br>|
| Sham Comparator: Sham TBS<br>Sham stimulation will be delivered at 0% of motor threshold (MT), with all other parameters matching the active TBS condition. | Device: Sham Theta Burst Stimulation<br>* Sham stimulation will be delivered at 10% of motor threshold (MT), with all other parameters matching the active TBS condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verbal recall performance change | Verbal memory will be measured using a free recall task where participants learn a list of everyday words and are asked to recall as many words as they can remember after a period of distraction. Proportion of recollected words will be used to quantify memory performance changes. | Baseline: Day 2; During stimulation: Day 3, Day 7, Day 12, Day 17; Follow-up appointments: Day 18, Day 19, Day 20. | 
| Object recognition memory performance change | Object memory will be measured using an recognition task where participants view photos of everyday objects and are asked to identify them as OLD or NEW during a memory test wherein unseen novel objects and very similar but new photos of identical objects are shown. Recollection and discrimination index will be used to quantify memory performance changes. | Baseline: Day 2; During stimulation: Day 3, Day 7, Day 12, Day 17; Follow-up appointments: Day 18, Day 19, Day 20. | 
| Associative memory performance change | Associative memory will be tested using the Face Name Memory Test wherein participants are shown faces and associated names. Participants are then shown faces only and asked to recall the associated name. | Baseline: Day 2; During stimulation: Day 3, Day 7, Day 12, Day 17; Follow-up appointments: Day 18, Day 19, Day 20. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting state fMRI functional connectivity | Resting state fMRI activity will be measured before the first and after the last TBS treatment | Baseline (Day 2) before the first treatment and after the last treatment (Day 17) | 
| EEG activity | EEG functional connectivity with stimulated region and medial temporal source localized power in the theta band will be recorded during a resting period as well as during the treatment itself both before and after treatments | During treatment (Days 3, 7 and 12), and after the last treatment (Day 17) |