Cortical Network Modulation by Subthalamic Nucleus DBS

Overview

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, we 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. We 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. We 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.

Full Title of Study: “Cortical Network Modulation by Subthalamic Nucleus Deep Brain Stimulation”

Study Type

  • Study Type: Observational [Patient Registry]
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: April 2026

Arms, Groups and Cohorts

  • Pilot Group
    • Participants (ages 20-75 years) who enroll as part of the Pilot Group of up to10, will follow the same inclusion criteria as the Control group with the exception of matching the age and sex distribution of the DBS group. The purpose of this group is to test the fluidity of the testing day as well as all of the measures, assessments, and scans (DOT and MRI).
  • Control Group
    • Controls will match the age and sex distributions of the pre and post-surgical DBS groups. Participants will be males or females between 50 and 75 years of age who do not meet criteria for clinically definite PD. This group must be able to complete the testing day as well as all of the measures, assessments, and scans (DOT and MRI).
  • Pre-Surgical Group
    • Subjects with PD who have been clinically consented for bilateral STN DBS surgery will be recruited from the DBS program within the Movement Disorders Clinic at WUSM. Pre-surgical STN DBS patients will be males or females between 50 and 75 years of age who meet criteria for clinically definite PD. This group must be able to complete the testing day as well as all of the measures, assessments, and scans (DOT and MRI).
  • Post-Surgical Group
    • STN DBS: Subjects with PD who have been clinically consented for bilateral STN DBS surgery will be recruited from the DBS program within the Movement Disorders Clinic at WUSM (directed by Dr. Ushe, co-I). STN DBS patients will be males or females between 50 and 75 years of age who meet criteria for clinically definite PD. This group must be able to complete the testing day as well as all of the measures, assessments, and scan (DOT).

Clinical Trial Outcome Measures

Primary Measures

  • Functional Connectivity measures
    • Time Frame: measures will be fully available at the end of this 5 yr study
    • Average correlation values for specific functional networks (Somatomotor, visual, auditory and frontoparietal) obtained from HD-DOT.

Participating in This Clinical Trial

Inclusion Criteria

  • Pilot Group: Participants who enroll as part of the Pilot Group of up to10, will follow the same inclusion criteria as the Control group with the exception of matching the age and sex distribution of the DBS group. Pilot participants will be males or females between 20 and 75 years of age who do not meet criteria for clinically definite PD. – Control Group: Participants who enroll as part of the Control Group will match the age and sex distributions of the DBS groups. Control participants will be males or females between 50 and 75 years of age who do not meet criteria for clinically definite PD. – Pre-Surgical DBS Group: Participants with PD who have been clinically consented for bilateral STN DBS surgery will be recruited from the DBS program within the Movement Disorders Clinic at WUSM. Pre-surgical STN DBS patients will be males or females between 50 and 75 years of age who meet criteria for clinically definite PD. – Post-Surgical DBS Group: Participants with PD who have had bilateral STN DBS surgery will be males or females between 50 and 75 years of age who meet criteria for clinically definite PD. Exclusion Criteria:

  • Pilot Group: Exclusions include any significant past or current neurologic or psychiatric diagnosis or any other condition which could interfere with testing (e.g. severe visual loss, non-English speaking, and illiteracy) and contraindications for MRI. – Control Group: Exclusions include any significant past or current neurologic or psychiatric diagnosis or any other condition which could interfere with testing (e.g. severe visual loss, non-English speaking, and illiteracy) and contraindications for MRI. – Pre-Surgical DBS Group: Patients will have already passed clinical screening for neurological and psychiatric comorbidities, including dementia. From this group of potential subjects, we will also exclude those with contraindications for MRI pre-surgically, inability to tolerate off medication or off DBS states, or any other condition which could interfere with testing (e.g. severe visual loss, non-English speaking, illiteracy). – Post-Surgical DBS Group: Patients will have already passed clinical screening for neurological and psychiatric comorbidities, including dementia. From this group of potential subjects, we will also exclude those with contraindications for MRI pre-surgically, clinically determined dementia manifesting after surgery, significant complications of surgery (e.g. stroke), inability to tolerate off medication or off DBS states, or any other condition which could interfere with testing (e.g. severe visual loss, non-English speaking, illiteracy).

Gender Eligibility: All

Minimum Age: 25 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Washington University School of Medicine
  • Collaborator
    • National Institute of Neurological Disorders and Stroke (NINDS)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Tamara G Hershey, Principal Investigator, Washington University Medical School
  • Overall Contact(s)
    • Samantha Ranck, MSW, MA, 314-362-6514, blankens@wustl.edu

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