Interventional clinical trial findings from targeted multiday repetitive transcranial magnetic stimulation to treat memory loss in amnestic mild cognitive impairment

Background Memory loss is the hallmark cognitive symptom of Alzheimer’s disease (AD), and it affects independence, autonomy, and identity. AD‐related memory deficits are associated with pathological changes in brain structure and function, and current treatments offer limited relief. Targeted repetitive transcranial magnetic stimulation (rTMS) of AD‐vulnerable intrinsic brain networks can enhance memory abilities in healthy adults (Wang et al., 2014). To test rTMS approaches as a potential treatment for clinical memory loss, we administered a local clinical trial (ClinicalTrials.gov #alz081816) that enrolled patients with amnestic mild cognitive impairment (aMCI), a frequent precursor to AD (target enrollment of 16). Here, we report cognitive and brain findings from our trial. Method Patients with aMCI completed two weeklong interventions consisting of pre‐stimulation brain and cognitive measurement, rTMS for five consecutive days, and post‐stimulation brain and cognitive measurement. Brain measures included structural and resting‐state functional MRI data; cognitive assessments included measures of memory function. Interventions were identically formatted except for rTMS intensity (treatment/sham). Stimulation used ß‐frequency pulse sequences which alternated 2‐sec. 20 Hz stimulation with 28‐sec. rest for 20 min (1600 pulses); stimulation location was a left lateral parietal cortex location coactive with a hippocampus‐centered functional network. Stimulation intensity varied with each participant’s resting motor threshold (treatment, 100%; sham, 10%). Condition order was counterbalanced. Result We identified hippocampus‐centered networks in each participant, then localized parietal rTMS targets. Critically, we observed changes in brain and cognitive (memory) measures in the treatment‐intensity condition that were not observed in the sham‐intensity condition. Furthermore, we observed changes in intrinsic network connectivity within the stimulated hippocampus‐centered network. Conclusion Our trial of patients with aMCI measured changes in brain and cognitive variables after rTMS of a brain network supporting memory processes. We found evidence consistent with neural plasticity, and we frequently observed memory improvement in patients with aMCI after treatment‐intensity rTMS. Our findings suggest that rTMS can improve memory in clinical populations. This is important because, counterintuitively, new disease modifying therapies for AD may increase need for s