Project Summary/Abstract
Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) is an established therapy for PD
patients with motor fluctuations and dyskinesias. While STN DBS is an effective treatment for motor symptoms,
it can produce unintended side effects cognition including executive function, language and attention deficits
which affect quality of life and independence. Developing an individualized STN DBS approach which optimizes
patient selection prior to surgery and enhances specificity when targeting neural networks is significant because
it has the potential to reduce DBS induced cognitive decline. The research proposed in this K99/R00 Pathway
to Independence Award will lay the groundwork needed to establish this approach by determining 1) how limited
cognitive reserve prior to surgery and 2) how direct DBS interference with cognitive networks contribute to
cognitive decline. Cholinergic and dopaminergic network hubs (i.e., the Nucleus Basalis of Meynert; NBM, and
striatum) support cognition, however, these regions degenerate in PD and may be indirectly modulated by STN
stimulation. Thus, the central objective of this proposal is to determine how vulnerability (K99) and the direct
modulation (R00) of the NBM, and striatal networks contribute to cognitive decline in individuals with STN DBS.
NBM/striatal vulnerability will be measured using diffusion kurtosis imaging (DKI) which reflects microstructural
changes associated with the progressive degeneration of neuronal tissue. Network interference will be measured
by assessing the change in NBM/striatal connectivity using combined DBS-fMRI which allows functional MRI
data to be collected while simultaneously cycling stimulation. The central hypothesis of this proposal is that
pre-surgical microstructural integrity (K99) and DBS induced interference (R00) of the NBM, and striatal networks
will be associated with greater cognitive decline. Preliminarily data demonstrates that reduced mean kurtosis of
diffusion within the NBM and striatum are associated with reduced executive function and language deficits in
those with PD. In the 2-year mentored K99 phase of this proposal, I will establish the relationship between
NBM/striatal microstructure and cognition (Aim 1) and cognitive decline 1-year following STN-DBS surgery (Aim
2). To accomplish these aims I will collect DKI and longitudinal neurocognitive data from 50 participants with PD
planning to undergo clinical STN-DBS treatment. Additionally, I will receive training in DBS as a research tool,
neurocognitive testing, combined DBS-fMRI and DKI analysis/interpretation. This will be facilitated by my
mentoring team which includes DKI co-developer Dr. Jens Jensen (Primary Mentor) and DBS neurologist Dr.
Gonzalo Revuelta (Co-mentor). After securing a tenure track faculty position, I will transition into the R00 phase
of the award to investigate the relationship between STN-DBS modulation of the NBM/striatal networks and
cognitive decline (Aim 3). This independent R00 phase will build upon my technical training and mentoring skills
established during the K99 phase. Ultimately, this award will generate the pilot data necessary to apply for a R01
and establish a research program in individualized neuromodulation therapies for movement disorders.