PROJECT SUMMARY Mild Cognitive Impairment (MCI) is a heterogenous syndrome of cognitive and neuropsychiatric symptoms. As much as 40% of MCI patients have comorbid depression, which can significantly increase risk for dementia. We propose that repetitive transcranial magnetic stimulation (rTMS), an FDA-approved treatment for depression, may be a promising treatment to prevent dementia in MCI. By stimulating shared neurocircuitry implicated in both affective and cognitive control, prior work has shown that conventional rTMS to left dorsolateral prefrontal cortex (l-dlPFC) improves both affective and cognitive symptoms in various neuropsychiatric syndromes. Thus, our main hypothesis is that excitatory rTMS to the l-dlPFC, which is hypoactive in MCI, may simultaneously ameliorate depression and bolster cognitive abilities, potentially preventing dementia incidence. To test this hypothesis, we first need to address a critical gap which is to resolve the functional form of the dose-response curve to identify the optimal dose for symptom remediation. This has yet to be established for accelerated, high- dose intermittent theta burst (iTBS)-rTMS, which reduces the conventional rTMS treatment course by >50%. We present Preliminary Data from two open-label phase I trials that support the safety, feasibility, and acceptability of iTBS-rTMS to l-dlPFC in patients with amnestic MCI due to AD or Vascular Cognitive Impairment due to stroke. While these trials were not explicitly dosed for efficacy, we found large effect size improvements in fluid cognition in both groups. We therefore propose to conduct a double-blind, randomized sham-controlled, parallel group, dose-ranging phase II trial, where 60 participants will be recruited to undergo 6 treatment days within a span of 2 weeks. Participants will be randomized to 1 of 6 dose-step combinations of active/sham iTBS-rTMS, ranging from 0 active pulses (all sham; dose step 1) to 36,000 total active pulses (all active; dose step 6). Site targeting will be highly individualized using innovative fMRI methods. Participants who have MCI due to AD and/or cerebro- vascular disease with at least moderate depression will be recruited using rigorous diagnostic and psychometric criteria. All will undergo clinical assessments and brain MRI at pre-treatment and at 1-week post-treatment, and clinical assessments at 8-weeks and 6-months post-treatment. We will use established primary outcomes and supplement these with psychometrically robust secondary outcomes. As a team with collective expertise in rTMS, MCI, neuropsychology, affective neuroscience, and clinical trials biostatistics, we seek to establish the dose-response curves for reduced depression (Aim 1) and improved cognition (Aim 2) following iTBS-rTMS. We also seek to examine alterations in functional connectivity following treatment as an Exploratory Aim. This trial will pave the way for subsequent randomized controlled trials to optimize therapeutic delivery, including variations in sites beyond dlPFC, indications such as other prodromal states or symptom presentations, and combinatorial designs where behavioral interventions provide potent adjuncts to rTMS-induced neuroplasticity.

PROJECT NARRATIVE Mild Cognitive Impairment (MCI) is a heterogenous syndrome of cognitive and neuropsychiatric symptoms, with as much as 40% of patients being diagnosed with comorbid depression. The goal of this project is to establish the dose-response curves of a safe and clinically feasible non-invasive brain stimulation technique (intermittent theta-burst repetitive transcranial magnetic stimulation [iTBS-rTMS]) to improve both depression and cognitive function in MCI patients with comorbid depression. These results will inform future clinical trials of iTBS-rTMS for MCI such that the optimal dose can be used when targeting dysfunction in shared brain circuitry underlying both cognitive and neuropsychiatric symptoms, with the long-term goal of developing an efficacious treatment to prevent dementia.