Open label pilot of personalized, neuroimaging-guided theta burst stimulation in early-stage Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD) is characterized by cerebral amyloid plaques and neurofibrillary tangles and disruption of large-scale brain networks (LSBNs). Transcranial magnetic stimulation (TMS) has emerged as a potential non-invasive AD treatment that may serve as an adjunct therapy with FDA approved medications.

Methods: We conducted a 10-subject open label, single site study evaluating the effect of functional connectivity-resting state functional MRI guided-approach to TMS targeting with dysfunctional LSBNs in subjects with biomarker-confirmed early-stage AD (https://clinicaltrials.gov/study/NCT05292222). Subjects underwent pre-post imaging and testing to assess connectivity dysfunction and cognition. All participants received intermittent theta burst stimulation [(iTBS), (80% motor threshold; 5 sessions per day; 5 days; 3 targets; 18,000 pulses/day)] over 2 weeks. Three Human Connectome Project (HCP) defined parcellations were targeted, with one common right temporal area G dorsal (RTGd) target across all subjects and two personalized.

Results: We identified the following parcellations to be dysfunctional: RTGd, left area 8A ventral (L8Av), left area 8B lateral (L8BL), and left area 55b (L55b). There were no changes in these parcellations after treatment, but subjects showed improvement on the Repeatable Battery for the Assessment of Neuropsychological Status attention index (9.7; p = 0.01). No subject dropped out of the treatment, though 3 participants were unable to tolerate the RTGd target due to facial twitching (n = 2) and anxiety (n = 1).

Conclusion: Accelerated iTBS protocol was well-tolerated and personalized target-based treatment is feasible in early-stage AD. Further sham-controlled clinical trials are necessary to determine if this is an effective adjunctive treatment in early-stage AD.

Keywords: clinical trial; functional connectivity; human connectome project; large-scale brain networks; transcranial magnetic stimulation.

Figure 1

Study design and visits. Figure provides details regarding participants measures and workflow for the study. MMSE, mini mental status examination; CDR, clinical dementia rating; RBANS, repeatable battery for the assessment of neuropsychological status, GDS, Geriatric Depression Scale; T1, structural imaging; rs-fMRI, resting state functional magnetic resonance imaging; DTI, diffusion tensor imaging; TBS, theta burst stimulation; MT, motor threshold.