Cortical Network Modulation by Subthalamic Nucleus Deep Brain Stimulation

Deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson's disease (PD) can provide substantial motor benefit yet can also produce unwanted mood and cognitive side effects. Although the neural mechanisms underlying benefits and side effects are not well understood, current hypotheses center on the potentially measurable yet currently undefined effects within downstream cortical networks. Limitations of current tools have impeded attempts to assess network connectivity directly and dynamically in humans with implanted DBS; PET lacks the necessary temporal resolution while fMRI is neither optimal nor safe for patients with implanted DBS. In this proposal, to overcome these significant limitations, the investigators apply high-density diffuse optical tomography (HD-DOT) methods to investigate how STN DBS modulates cortical functional networks and behavior in PD patients. HD-DOT uses a collection of functional near-infrared spectroscopy (fNIRS) measurements, free of radiation exposure concerns, and without electrical/metal artifacts or contraindications or safety concerns for DBS. However, common fNIRS systems are critically hampered by typically sparse measurement distributions that lead to poor anatomical specificity, unreliable image quality due to crosstalk with scalp signals, poor spatial resolution, limited field of view, unstable point spread functions, and uneven spatial coverage. HD-DOT solves these problems by using high-density interlaced source and detector imaging arrays that support densely overlapping measurements and anatomical head models that together result in higher spatial resolution, stable point spread functions, and greatly improved isolation of brain signals from scalp signals. The investigators have demonstrated that HD-DOT accurately maps functional connectivity (FC) within and between cortical resting state networks (RSNs) in the outer ~1cm of cortex with comparable temporal and spatial resolution to fMRI. Preliminary data in older controls and STN DBS patients that directly establish validity and feasibility for the proposed studies are provided.

A recent comprehensive evaluation of FC in PD (without DBS) using fMRI found reduced within-network FC in visual, somatomotor, auditory, thalamic and cerebellar networks and reduced between-network FC involving predominantly cortical RSNs (somatomotor, sensory and association), some of which correlated with cognitive and motor dysfunction in PD. Notably, striatal RSNs were not abnormal. These data suggest that PD affects the interrelationships of cortical networks in a behaviorally meaningful way, far downstream of focal subcortical neuropathology. STN DBS is known to alter activity in downstream cortical regions that function as nodes within these dynamic cortical networks supporting movement and cognition. Thus, cortical network FC may play a critical role in mediating the impact of STN DBS on motor and non-motor behavior. Location of the stimulating contact may further modulate these downstream effects, due to the complex functional organization of the STN region.

Study procedures include motor and cognitive tests, questionnaires, HD-DOT scanning, and MRI scans.

The investigators propose to investigate how STN DBS influences downstream cortical network FC using HD-DOT.

This information could lead to more efficient clinical optimization of DBS, identify potential cortical targets for less invasive neuromodulation, and lay the groundwork for future more complex experimental manipulations to determine the full range of STN DBS-induced cortical network responses to up-stream focal electrical perturbations, revealing fundamental properties of functional network plasticity.