Overview
The goal of this phase II study is to establish the dose-response curves of a safe and clinically feasible non-invasive brain stimulation technique (accelerated Transcranial Magnetic Stimulation (TMS)) to improve both depression and cognitive function in Mild Cognitive Impairment (MCI) patients with comorbid depression. It is known that TMS can effectively treat depression. Identifying the right dose of accelerated TMS in MCI patients is necessary prior to designing subsequent trials to determine efficacy. These results will inform future clinical trials of accelerated TMS for MCI, with the long-term goal of developing an efficacious treatment to prevent dementia.
Description
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 phase II trial is to establish the functional form of the dose-response curves for accelerated intermittent theta burst stimulation (iTBS) to ameliorate depression and cognitive function in MCI. Identifying the right dose is necessary prior to designing subsequent trials to ascertain the efficacy of accelerated iTBS for MCI. In our two phase I trials, we chose treatment parameters based on robust prior literature on accelerated, high-dose rTMS delivery (i.e. accelerated iTBS, 600 pulses at 50 Hz per session), intensity (at 120% resting motor threshold [rMT]), stimulation site left dorsolateral prefrontal cortex (l-dlPFC), and site targeting (Beam F3). The course of treatment was guided by our clinical experience with mild cognitive impairment and vascular cognitive impairment patients as to what we hypothesized they would comfortably tolerate, which was confirmed by the acceptability ratings. In this phase II trial, we focus on manipulating one dosing parameter
- total number of active pulses - to rigorously model the dose-response curves such that future phase II/III trials can be more efficient, decrease treatment burden, and accelerate response time.
Aim 1: Establish the dose-response curves for reduced depression following accelerated iTBS in MCI.
Aim 2: Establish the dose-response curves for improved cognition following accelerated iTBS in MCI.
Exploratory Aim 1: Examine alterations in functional connectivity following accelerated iTBS-rTMS in MCI.
Exploratory Aim 2: Examine blood-based biomarkers of neurodegeneration as effect modifiers.
Eligibility
Inclusion Criteria:
i. Age 60-85 (inclusive). ii. English as a first/primary language. iii. Adequate
sensorimotor function and verbal expressive abilities to complete all assessments.
iv. Must have a Co-Participant (e.g. spouse, adult child or relative, sibling, cohabitator,
friend, caregiver) who has at least weekly in-person contact with the participant and is
willing to participate in the study as a collateral informant.
v. Is on fixed pharmacotherapy (i.e. a stable dose of medication/s) for at least 4 weeks
prior to enrollment.
vi. A documented diagnosis of MCI per NIA-AA criteria or Mild Neurocognitive Disorder per
DSM-5 criteria by a healthcare provider within the past 2 years, with a presumed etiology
of either (or both): vi.a Possible or probable AD vi.b Chronic cerebrovascular disease
(CVD), specifically small vessel disease as defined in STRIVE-2 which includes small
subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, cerebral
micro bleeds, cortical superficial siderosis, or cortical cerebral microinfarcts. .
vii. Met actuarial neuropsychological criteria for MCI within the past 2 years (i.e. ≥2
impaired scores within one cognitive domain, or ≥1 impaired scores in ≥3 domains, where an
impaired score is defined as ≤16th percentile using appropriate demographically-corrected
norms).
viii. Major Depressive Disorder of at least mild severity per DSM-5 and a HAM-D Total ≥ 8.
Exclusion Criteria:
i. A TICS score of ≤ 19 suggestive of dementia and a PHQ-9 score of 0-4, indicating the
absence of major depressive disorder.
ii. Prior diagnosis of Dementia (NIA-AA) or Major Neurocognitive Disorder (DSM-5).
iii. Daily/weekly anticholinergic or sedative use. Stimulants may be allowed pending
investigator review. Cholinesterase inhibitors, NMDA receptor antagonists, and
antidepressants are allowed if on a stable regimen for at least 4 weeks prior to
enrollment.
iv. History of significant or unstable condition/s or treatments for these condition/s that
may impact cognition (as determined by the study investigators) such as significant cardiac
(e.g. heart failure), infectious (e.g. HIV, urinary tract infection), or metabolic disease
(e.g. labile diabetes), cancer (e.g. brain cancer, chemotherapy-induced cognitive
impairment), developmental disorder (e.g. autism spectrum disorder, intellectual
disability), or other neurologic disease (e.g. movement disorder, multiple sclerosis,
moderate to severe brain injury, seizures).
v. Past or current treatment for AD/MCI with monoclonal antibody therapy. vi. Enrolled in a
clinical trial or has received an investigational medication or device in the last 30 days.
vii. MRI and TMS contraindications (e.g. ferromagnetic implants, claustrophobia, conditions
or treatments that lower seizure threshold, taking medications that have short half-lives,
no identifiable motor threshold).
viii. Current alcohol or substance use disorder, bipolar disorder, schizophrenia spectrum
or other psychotic disorder, suicidal/homicidal intent within the past month, or any
suicide attempts within the past year.