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Principal Investigator: Daniel Lench
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $127,386
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Abnormal Movements><Acceleration><Acetylcholine><Affect><Anatomic Sites><Anatomic structures><Anatomy><Anterior><Attention><Attentional deficit><Award><Basal Nucleus of Meynert><Behavioral><Body Tissues><Brain><Brain Nervous System><Brain region><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cerebral cortex><Clinical><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive Manifestations><Cognitive Symptoms><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Corpus Striatum><Corpus striatum structure><DWI (diffusion weighted imaging)><DWI-MRI><Data><Deep Brain Stimulation><Diffusion><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disabling><Disturbance in cognition><Dopamine><Dorsal><Dose><Dysfunction><Dyskinesia Syndromes><Dyskinesias><Dyskinetic syndrome><Encephalon><Evaluation><Faculty><Frequencies><Functional MRI><Functional Magnetic Resonance Imaging><Functional disorder><Hydroxytyramine><Image><Impaired cognition><Individual><Interruption><K-Awards><K-Series Research Career Programs><Knowledge><Language><Language Disorders><Lead><Lesion><Measures><Medial><Memory><Mentors><Mission><Motor><Movement Disorder Syndromes><Movement Disorders><NIH><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><National Institutes of Health><Nerve Degeneration><Nerve Transmitter Substances><Nervous System Diseases><Nervous System Disorder><Neurobehavioral Manifestations><Neurobehavioral Signs and Symptoms><Neurocognitive><Neurologic Disorders><Neurological Disorders><Neurologist><Neuron Degeneration><Neuropsychologies><Neuropsychology><Neurotransmitters><Nucleus Basalis of Meynert><Nucleus Subthalamicus><Operative Procedures><Operative Surgical Procedures><Paralysis Agitans><Parkinson><Parkinson Disease><Participant><Pathway interactions><Patient Selection><Patients><Pb element><Phase><Physiopathology><Position><Positioning Attribute><Post-Operative><Postoperative><Postoperative Period><Prefrontal Cortex><Primary Parkinsonism><QOL><Quality of life><Research><Research Career Program><STN stimulation><Scanning><Schedule><Secure><Source><Specificity><Striate Body><Striatum><Structure><Structure of subthalamic nucleus><Subthalamic Nucleus><Surgical><Surgical Interventions><Surgical Procedure><System><Tissues><Training><United States National Institutes of Health><Visuospatial><attentive deficit><career><cholinergic><cingulate cortex><cognitive defects><cognitive dysfunction><cognitive loss><cognitive performance><cognitive reserve><dMRI><diffused><diffuses><diffusing><diffusion tensor imaging><diffusions><disability><disease duration><disease length><effective therapy><effective treatment><executive control><executive function><experience><fMRI><heavy metal Pb><heavy metal lead><illness length><imaging><imaging study><improved><innervation><language deficit><motor symptom><nerve supply><neural><neural control><neural degeneration><neural network><neural regulation><neurobehavioral symptom><neurocognitive test><neurodegeneration><neurodegenerative><neuroimaging biomarker><neuroimaging marker><neurological degeneration><neurological disease><neuromodulation><neuromodulatory><neuronal degeneration><neuropsychologic><neuroregulation><nucleus basalis><pathophysiology><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><programs><recruit><side effect><skills><striatal><subthalamic nucleus stimulation><surgery><tenure process><tenure track><tool><visual spatial>