Spinal Cord Stimulation for Parkinson's Disease Rehabilitation

This study explores the use of multifunctional, non-invasive spinal cord transcutaneous stimulation (scTS) to address axial motor symptoms, particularly gait dysfunction, in Parkinson's disease (PD). These symptoms, resistant to levodopa and inadequately managed by deep brain stimulation (DBS), arise from maladaptive spinal network changes. A non-invasive approach like scTS could overcome limitations associated with invasive spinal cord stimulation (SCS), which requires surgical implantation and lacks adaptability in stimulation site adjustments.

Gait dysfunction in PD stems from disrupted interactions between spinal and supraspinal networks. scTS provides a non-invasive alternative, shown to enhance locomotor functions in conditions such as spinal cord injury, stroke, and cerebral palsy. This study hypothesizes that scTS applied at multiple spinal levels-cervical (C3-C4), thoracic (T11-T12), and lumbar (L1, L2-L3)-can synergistically activate locomotor central pattern generators (CPGs) and improve gait and postural control in PD. Additionally, it is hypothesized that proprioceptive input, combined with scTS, can counteract disruptions in spinal networks and restore voluntary movement.

The primary goal is to evaluate the effects of scTS on stepping performance, postural control, and locomotor recovery in PD. Specific objectives include:

1. Enhancing Locomotor Networks

   * Determine optimal scTS parameters for inducing rhythmic stepping in PD patients.
   * Assess interactions between spinal and supraspinal networks during imagined stepping under scTS in a gravity-neutral setting.
2. Improving Postural Networks

   o Evaluate the effectiveness of scTS in restoring postural control and integrating postural-locomotor functions.
3. Facilitating Neuroplasticity for Movement Recovery o Combine scTS with activity-based recovery training to promote adaptive plasticity in spinal and cortical networks, reducing freezing of gait (FOG).

The research will measure scTS's capacity to generate coordinated stepping and postural movements, integrate proprioceptive feedback, and induce long-term improvements in gait parameters. By targeting spinal locomotor and postural systems, scTS offers a novel, non-invasive approach to addressing gaps in the management of PD gait dysfunction. This work has the potential to significantly enhance the quality of life for individuals with PD, providing a safe, adaptable, and patient-centered therapeutic solution.

Background:

Particular motor symptoms of Parkinson's disease (PD) are currently managed using electrical stimulation of deep structures in the brain. While deep brain stimulation effectively improves tremor, rigidity, bradykinesia, and medication-induced dyskinesias, it does not address axial gait symptoms. Gait symptoms are a late-developing phenomenon in the progression of PD and represent a therapeutic challenge given their poor response to levodopa therapy and deep brain stimulation. This problem, related to spinal maladaptive disorganization as part of pathophysiological changes associated with PD (Tisch et al., 2007), can be approached by electrical spinal cord stimulation (SCS) for alleviation of levodopa-resistant motor symptoms of PD (de Andrade et al., 2016). Thus far, only invasive SCS has been investigated for Parkinsonian gait, with paddle electrodes proving to be the most successful method of stimulation (Milekovic et al., 2023).

While few studies have probed spinal cord stimulation for axial PD symptoms, the optimal location(s) to stimulate the spinal cord are currently unknown (Sarica et al., 2023). Invasive SCS with paddle placement is suboptimal in addressing this gap due to three considerable drawbacks: (i) only one location of the spinal cord can be stimulated with each paddle, (ii) the stimulated location cannot be changed after the SCS paddle is placed, and (iii) paddle SCS placement requires surgery with a laminectomy, which harbors significant risks. To address this gap, a non-invasive stimulation paradigm is needed that permits concomitant stimulation of multiple spinal cord sites to map out the effects on gait during daily life activities and allows altering the stimulation location without the need for surgical intervention.

Previous research suggests that non-invasive multifunctional spinal cord transcutaneous stimulation (scTS) is an effective tool for initiating locomotion in healthy individuals (Gerasimenko et al., 2018) as well as for initiation and rehabilitation of locomotor functions in individuals with motor deficits, including spinal cord injury (SCI) (Gerasimenko et al., 2018; Gerasimenko et al., 2015), stroke (Moon et al., 2024), and cerebral palsy (CP) (Singh et al., 2023).

It is hypothesized that scTS applied to cervical (e.g., C3-C4), thoracic (e.g., T11-T12), and lumbar (e.g., L1, L2-L3) levels, activating locomotor CPGs of upper and lower limbs, as well as postural CPGs, will synergistically facilitate locomotor performance in individuals with PD. Additionally, proprioceptive input is required for gait initiation and locomotion (Zemmar et al., 2024, In Review). Based on these observations, it is hypothesized that concomitant stimulation of (i) multiple motor sites and (ii) proprioceptive feedback tracts activating brain stem nuclei, thalamic nuclei, and the cerebral cortex is required to effectively address gait in individuals with PD.

Therefore, activation of spinal locomotor-related systems in combination with activation of lemniscal and brainstem systems is proposed to promote disruption of anti-kinetic oscillatory synchronization in cortico-basal ganglia circuits, resulting in improved voluntary control of movements in individuals with PD.

Objectives:

The main goal of this project is to determine how multifunctional non-invasive spinal cord stimulation affects stepping performance in individuals with Parkinson's disease (PD). The basic premise is that if the spinal locomotor network is maladaptively affected in PD, then spinal neuromodulation of this network using scTS will be sufficient to correct Parkinsonian gait. One of the most classical features of individuals with PD is the very short and rapid stride length during stepping and the inability to initiate and terminate stepping in a timely manner. The hypothesis is that it will be possible to take advantage of the spinal locomotor-related network to overcome disruptive signals generated in Parkinsonian individuals that disrupt the spinal locomotor network. It is currently unknown whether the spinal locomotor network of individuals with PD has sufficient automaticity potential to generate postural control and rhythmic, coordinated weight-bearing stepping with the aid of multi-site scTS stimulation. It is further hypothesized that the sensory input derived from postural and stepping movements, combined with neuromodulation provided by scTS, can overcome disruptive supraspinal descending signals in individuals with Parkinsonian gait.

The first objective is to determine whether a novel multimodal scTS strategy can transform the spinal locomotor networks of individuals with PD to a functional state enabling rhythmic voluntary movement. Specifically, the goal is to define the specificity of site, frequency, and intensity of scTS required to induce stepping movements and volitionally oscillate leg movements in individuals with PD in a gravity-neutral condition. Interactions between spinal and supraspinal networks in facilitating locomotor movements will be examined when individuals with PD imagine rhythmic stepping movements in the presence of scTS in a gravity-neutral condition.

The second objective is to determine whether a novel multimodal scTS strategy can transform the spinal postural networks of individuals with PD to a functional state enabling postural ability. Specifically, the effectiveness of multimodal scTS to control postural stability will be defined, and the effectiveness of multimodal scTS for the regulation of postural-locomotor integration in individuals with PD will be evaluated.

Lastly, the third objective is to determine whether a novel multimodal scTS strategy, combined with activity-based recovery training, can promote adaptive plasticity of the spinal and cortical locomotor-related networks of individuals with PD to recover voluntary control of movement, particularly by reducing freezing of gait (FOG).

Study Design and Research Procedures:

The overall strategy outlined in this proposal is based on previous data reporting gait improvement in individuals with spinal cord injury (SCI) through activation of spinal locomotor networks located in the lumbosacral region, which are capable of generating full weight-bearing stepping when epidural stimulation is combined with transcutaneous stimulation of the cervical spinal cord (Angeli \& Gerasimenko, 2023). Building on knowledge from SCI studies, the approach in this study will be to modulate ascending proprioceptive fibers, important for feedback and posture control, and to overcome disruptive signals from descending systems, which presumably occur in individuals with PD (Sarica et al., 2023). This will be achieved by leveraging the intrinsic abilities of the lumbosacral spinal network to generate stepping. This is a prospective non-blinded, non-randomized study. All data will be stored for offline analysis.

Participants will be identified as individuals with Parkinson's disease and Parkinsonian gait symptoms who consent to participate in the study. Participants will take part in multiple assessment and intervention sessions over a 9-12 month period to track gait and postural improvements over time. Each participant will undergo a detailed medical evaluation prior to baseline assessment. Assessments will last up to 4 hours. Following the completion of baseline assessments, participants will begin the first study intervention period. Post-intervention assessments will be performed approximately 1 week between intervention periods. Each intervention training session will last approximately 2 hours. Participants will train 3 days per week during the intervention periods to achieve at least 12 sessions (1-month intervention period) or 24 sessions (2-month intervention periods). The study timeline, descriptions of assessments, and interventions are outlined below:

Initial Visit:

* Medical Evaluation: Includes a review of medical history, discussion of current medical status, and current medications. A study physician may also complete a physical examination.
* Baseline Assessments: Performed prior to interventions.

Months 1-2:

* Intervention 1: Step-scTS in a gravity-neutral device (GND), 3 sessions per week for 1 month.
* Post-Intervention 1 Assessments: Conducted following the intervention.

Months 2-4:

* Intervention 2: Combination of Step-scTS and locomotor training. Includes 2 sessions per week of Step-scTS with body-weight support treadmill training (BWS) and 1 session per week of Step-scTS with overground locomotor training using an assistive device, for a total of 3 sessions per week over 2 months.
* Post-Intervention 2 Assessments: Conducted following the intervention.

Months 4-6:

* Intervention 3: Step-scTS combined with overground locomotor training using an assistive device, 3 sessions per week for 2 months.
* Post-Intervention 3 Assessments: Conducted following the intervention

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of Parkinson's disease;
* Adults aged 18 to 80 years;
* Competent to give informed consent for the research protocol;
* Able to understand instructions;
* Able to ambulate 10-meters.

Exclusion Criteria:

* Co-morbidities affecting gait;
* Clinically significant cognitive dysfunction;
* Clinically significant depression or major active psychiatric illness such as schizophrenia, bipolar disorder, or major depressive disorder;
* Terminal illness associated with \<12-month survival;
* Have a current diagnosis or condition such as major cardiac insufficiency, determined clinically by the study doctors;
* Current alcohol or substance abuse that is uncontrolled or unmanageable;
* Individuals unable to communicate with the investigator and study staff; and/or
* Individuals with any illness that, in the study doctors' opinion, may preclude them from spinal cord transcutaneous stimulation, activity-based recovery training, or participation in study assessments.