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
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
scTS mapping: Each intervention session will be approximately 2 hours each which includes time to place the scTS stimulating pads and other sensors as needed. Participants will be asked to train 3 days per week during the intervention periods so that they achieve at least 12 sessions. In instances in which availability is limited or they must cancel a session, the intervention period will need to be extended slightly (up to a maximum of four weeks) so that they can achieve at least 12 sessions (1-month intervention period) or 24 sessions (2-month intervention periods) of training. The main study interventions are described below. Step-scTS: Step-scTS is spinal cord transcutaneous stimulation (scTS) targeted for stepping function. The scTS mapping assessment(s) will assist the study team in determining optimized stimulation parameters for each body and f
Frazier Rehab Institute
Louisville, Kentucky, United States
RECRUITINGA. Assessment of Multisegmental Motor Responses (MMR)
Multisegmental motor responses in different leg muscles evoked by non-invasive stimulation of the dorsal lumbosacral spinal cord will be recorded. Such responses are the basic components of the lower-limb muscle responses that are elicited by transcutaneous stimulation of posterior lumbar cord structures. Multi-Segmental Motor Responses will be evoked transcutaneously by using a constant current stimulator (Cosyma, Inc. or Digitimer-Constant Current Stimulator, e.g., DS8R) between the C2 spinous process and the Coccyx. Small cathodes (pre-gelled, soft surface electrodes) will be placed over the skin between the C2 spinous process and Coccyx (midline with a single cathode or left and right of midline with a split cathode) while larger anode(s) will be placed over the anterior spine at different levels, at segments just below the cathode, on the abdomen, or along the pelvis.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Spinal Cord Transcutaneous Stimulation (scTS) Mapping electromyography (EMG)
Mapping will be carried out through assessment of electrophysiological and functional changes. EMG will be used to assess muscle activity. The mapping assessment may take place with the participant in supine, side-lying in a gravity-neutral device, upright while standing, or upright while stepping. Assistance will be provided as needed. A safety limit of 250 mA will be implemented. Other stimulation parameters include: 5-10 kHz carrier frequency for modulation of discomfort from stimulation, 0.25-3.0 ms pulse width duration, and 10-100 Hz.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Spinal Cord Transcutaneous Stimulation (scTS) Mapping electroencephalography (EEG)
Mapping will be carried out through assessment of electrophysiological and functional changes. EEG will be used to assess brain activity. The mapping assessment may take place with the participant in supine, side-lying in a gravity-neutral device, upright while standing, or upright while stepping. Assistance will be provided as needed. A safety limit of 250 mA will be implemented. Other stimulation parameters include: 5-10 kHz carrier frequency for modulation of discomfort from stimulation, 0.25-3.0 ms pulse width duration, and 10-100 Hz.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Stepping Performance in a Gravity-Neutral Device (GND) with electromyography (EMG).
Limb coordination and muscle activation during visual imaginary stepping and gravity-neutral ambulation will be assessed with surface EMG of multiple trunk and lower extremity muscles including pelvic stabilizers (quadratus lumborum), hip extensors (gluteus), hip flexors (iliopsoas), knee extensor (rectus femoris), knee flexor (biceps femoris), ankle dorsiflexor (tibialis anterior), and ankle plantar flexor (medial gastrocnemius and soleus) without and with scTS.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Stepping Performance in a Gravity-Neutral Device (GND) with kinematics.
Limb coordination during visual imaginary stepping and gravity-neutral ambulation will be assessed with gait kinematics determined with goniometers at the top arm, hip, knee, and/or ankle and/or with 3D motion capture.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Stepping Performance in a Gravity-Neutral Device (GND) with plantar stimulation.
Limb coordination during visual imaginary stepping and gravity-neutral ambulation will be assessed with plantar pressure stimulation (Korvit) to be used based on participant presentation. When used, pressure sensing insoles (Noraxon Ultium) will be placed in orthotics to track inflation under the heel and forefoot and synchronize with other data types.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Stepping Performance in a Gravity-Neutral Device (GND) with electroencephalography (EEG).
EEG will be recorded before, during, and after scTS. Cortical activity will be correlated with gait performance/limb kinematics.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
D. Assessment of Balance and Gait: Tinetti Balance & Gait Test, Rating Instrument to Assess Festination and Freezing Gait, and Push & Release Test
The Tinetti Balance and Gait Test, also known as the performance-oriented mobility assessment, uses a standardized scoring system to assess participants' balance and gait. The examiner will be near the participant during each part of the assessment in case the participant exhibits any risk of falling. Scoring is ordinal with a range from 0 to 2; 0 indicates severe impairment and 2 indicates independence. For the balance assessment, the participant starts in a seated position on a hard, armless, stable chair and is instructed to rise from seated without using their arms or hands. Once standing, the participant is instructed to move their feet as close together as possible. The examiner then presses on the participant's sternum with their palm three times while the participant's eyes are open and three times while the participant's eyes are closed. During the last component of the balance assessment, the participant is asked to make a 360-degree turn and sit back in the chair.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
New Freezing of Gait Questionnaire (NFOG-Q)
The Freezing of Gait Questionnaire is a six-item scale (range 0-24); four items assess FOG severity, and two items assess general gait difficulties. The New Freezing of Gait Questionnaire was developed to address limitations of the original questionnaire. The NFOG-Q adds an initial item to the original questionnaire; based on the answer to this initial item, part II includes questions about FOG severity, and part III includes questions about impact. The NFOG-Q was found to be test-retest reliability and high agreement between patients with Parkinson's disease and their carers.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)
The Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Task Force revised and expanded the UPDRS. It has four parts: I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the participant. The Non-motor Experiences of Daily Living (part I) include questions on cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, dopamine dysregulation syndrome, sleep, pain and other sensations, urinary problems, constipation problems, orthostatic hypotension, and fatigue. Motor Experiences of Daily Living (part II) include questions related to speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, participating in hobbies and other activities, turning in bed, tremor, getting out of bed, walking and balance, and freezing.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Time to Navigate (TTN) Test
The Time to Navigate (TTN) test was developed as a practical and objective clinical measure of FOG severity. The TTN test involves similar situations as those in the Rating Instrument to Assess Festination and Freezing of Gait with single-tasking and dual-tasking. The TTN does not include navigating through a door but instead includes a longer walking pass and navigating around an object and a narrow corridor. Completing both assessments with participants who opt into participating will allow comparison between the two clinical measures and additional information about participants' functional presentation and what kinds of activities elicit FOG.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
Modified Ashworth Scale (MAS) and Range of Motion (ROM) Testing
The modified Ashworth Scale scores muscle spasticity by assessing the resistance observed during passive muscle stretching. A six-category ordinal scale (0 = no increase in muscle tone; 1 = Slight increase in muscle tone with catch and release; 1+ = Slight increase in tone with catch; 2 = Marked increase in muscle tone but affected parts move easily; 3 = considerable increase in muscle tone and passive movement is difficult; 4 = affected part(s) rigid in flexion or extension) is used to score the participant's spasticity in the muscles of interest. During the MAS, range of motion (ROM) testing will also be completed to track any musculoskeletal abnormalities and/or improvements in ROM. sEMG, fine wire EMG, joint kinematics, and body weight force will be measured.
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Time frame: From date of screening until the date of data is analyzed, up to 48 months.
10-Meter Walk Test
The 10-meter walk test (10MWT) assesses walking speed in meters per second over a short duration. Assistive devices can be used during this test. Participants will be given space to accelerate to their preferred walking speed before the start of the 10-meter distance. sEMG, fine wire EMG, joint kinematics, and body weight force will be measured. Following an initial 10MWT without stimulation and adequate rest, participants who are able will repeat the test with multi-site scTS.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.
6-Minute Walk Test
The 6-minute walk test (6MWT) assesses walking endurance over a specific time window. Assistive devices can be used during this test. Participants will be permitted to take standing breaks during the 6-minute period, but if participants require a seated rest break, the 6MWT will be completed at that point. sEMG, fine wire EMG, joint kinematics, and body weight force will be measured. Following an initial 6MWT without stimulation and adequate rest, participants who are able will repeat the test with multi-site scTS.
Time frame: From date of screening until the date of data is analyzed, up to 48 months.