Neurostimulation of the Nucleus Basalis of Meynert for the cognitive-motor syndrome in Parkinson's disease

Cognitive decline begins in early stages of Parkinson’s disease (PD) and progresses to dementia in 75% of
people with PD after ten years. Dopaminergic medication and deep brain stimulation (DBS) provide long-term
improvement of cardinal motor symptoms in PD, but cognitive decline remains largely unaddressed and
untreated, despite a long window for potential intervention before dementia occurs. Pre-clinical evidence
indicates that intermittent DBS of the Nucleus Basalis of Meynert (NBM) offers the potential to stabilize
deterioration of the cholinergic system and its negative impact on cognitive and cognitive-motor function in
individuals with mild cognitive impairment and PD. We propose to apply the three predictors of a successful
outcome for motor (dopaminergic) DBS to cognitive-motor (cholinergic) DBS: 1) select well-characterized
candidates before the stage of dementia 2) optimize target selection, lead location, and volume of tissue
activated (VTA), and 3) use intermittent neurostimulation patterns. We will utilize the UG3 phase to establish the
feasibility of a novel approach to target the NBM for DBS via tractography modeling and translate novel patterned
stimulation technology, in partnership with Boston Scientific and their research based Chronos software, for a
first in human study. We will obtain an Investigational Device Exemption to use Chronos for the first time in
human subjects and in a novel DBS target (i.e., NBM fiber bundles). Only after successful completion of the UG3
milestones related to these aspects of the project will we then transition to the UH3 phase of the study which will
consist of a small pilot clinical trial investigating the safety, tolerability, and effect of combined STN and
intermittent NBM DBS. Ten individuals with PD with cognitive impairment in at least one domain, but who do not
have dementia, will undergo implantation of STN + NBM DBS. A vertical approach targeting the central anterior
NBM region will be used in 5 participants, and a novel lateral approach targeting the lateral efferent fiber bundle
outflow of the NBM will be used in the other 5 participants. Participants will receive standard high-frequency
continuous STN stimulation and 1 hour/day of intermittent (60 Hz, 20 sec on, 40 sec off/minute) NBM stimulation.
Behavioral and cognitive measures will be measured every 6 for up to two years with the primary outcomes at
12 months. An independent scientific outcome will use fluorodeoxyglucose (FDG)-positron emission tomography
(PET) to assess the effect of continuous or intermittent NBM stimulation on cortical blood flow and glucose
metabolism.

Grant Number: 5UH3NS128150-04
NIH Institute/Center: NIH
Principal Investigator: Helen Bronte-Stewart