Vagus Nerve Stimulation Paired With Rehabilitation in the Home Environment for People With Chronic Post-Stroke Upper Limb Deficits: Preliminary Findings

Abstract

Background:

Implantable vagus nerve stimulation paired with upper limb (UL) rehabilitation (Paired VNS) is an effective therapy for chronic ischemic stroke currently being implemented in outpatient centers. However, issues such as constraints in transportation, mobility, or caregiver availability may decrease access to in-clinic therapy for some individuals. An alternative approach may be a mobile therapy model in which outpatient rehabilitation services are delivered in the individual’s home. The VNS-REHAB At-Home study is a single-arm trial aimed at assessing feasibility of therapist-activated Paired VNS in the home (or mobile Paired VNS) by examining protocol compliance, therapist/patient acceptance, and safety. The goal of this report was to present the preliminary findings from the first participant cohorts.

Methods:

Participants completed up to 36 hours of therapist-activated mobile Paired VNS within 18 weeks. Therapist-led sessions were supplemented with self-activated VNS during UL functional tasks. The primary feasibility endpoint was the proportion of participants who completed at least 24 hours of mobile Paired VNS. Outcomes included total session hours, therapist/participant acceptance, and safety. While this study was not designed to establish definitive treatment effects, UL impairment/activity, and patient-reported measures were assessed at multiple timepoints as secondary exploratory outcomes.

Results:

Participants (n = 11) completed a median of 37.8 (32.5-42.4) hours of mobile Paired VNS over 13 (8-18) weeks. All participants met the primary endpoint. Overall, participants and therapists were satisfied (n = 8) or very satisfied (n = 14). Fugl-Meyer Assessment-Upper Extremity scores improved by a median of 7 points. All participants reported improvements in measures of UL use, activities of daily living, and/or participation. Adverse events were reported amongst 3 participants, and there were no serious events related to procedure or device use.

Conclusions:

Preliminary data from the VNS-REHAB At-Home trial demonstrate that mobile Paired VNS was successfully implemented, well-accepted, and safe in the home setting, with observed meaningful UL improvements. These initial findings support the ongoing evaluation of mobile Paired VNS as an accessible alternative to clinic-based delivery.

Trial Registration:

NCT05691023; https://clinicaltrials.gov/study/NCT05691023

Keywords

stroke vagus nerve stimulation rehabilitation home care services upper extremity health equity

Introduction

Upper limb (UL) motor deficits impact approximately 50% of people after stroke.¹ While some early recovery may occur through a combination of spontaneous neurobiological processes and formal rehabilitation,^2,3 less than 50% of individuals with initial UL impairment recover functional arm and hand use in the chronic phase of stroke recovery.⁴ These persistent UL impairments often remain unaddressed or deteriorate by 3 to 5 years after stroke,⁵ making improved use of the paretic UL a top priority for many stroke survivors.⁶

The efficacy of current treatment options for improving UL recovery remains mixed.^7,8 The brain retains neuroplastic potential well beyond the chronic phase of stroke, and engaging these neuroplastic mechanisms often requires high-quality, intensive, and task-specific therapy to drive lasting meaningful UL motor improvements.^9
-12 One such therapeutic approach is implantable Paired Vagus Nerve Stimulation (Paired VNS).^13,14

Paired VNS involves pairing VNS with intensive, goal-oriented, functional tasks. Stimulation of the left vagus nerve has been shown to release neuromodulators, such as acetylcholine, norepinephrine, and serotonin, leading to specific plasticity when paired with a salient motor task and subsequent improvement in motor performance.^14,15 The pivotal, triple-blind, randomized controlled VNS-REHAB trial¹⁶ demonstrated the safety and efficacy of Paired VNS in individuals with chronic ischemic stroke and persistent UL deficits. A clinically meaningful response was achieved by 47% of participants who received Paired VNS. These positive results led to FDA approval of the Vivistim^® Paired VNS™ System (MicroTransponder Inc., Austin, TX) in 2021. Subsequent long-term follow-up analyses further demonstrated the durability of treatment effects, with clinically meaningful improvements in impairment or function observed in 66% of VNS-REHAB participants.¹⁷ Across published clinical studies, the benefits of Paired VNS were sustained years beyond the initial treatment.^17
-19

The Paired VNS therapy protocol employed in previous studies^16,20,21 and currently being implemented commercially^22,23 consists of pairing VNS during clinic-based outpatient rehabilitation sessions (ie, therapist-activated Paired VNS) supplemented by patient driven, out-of-clinic task practice (ie, self-activated Paired VNS). However, many individuals may be unable to access in-clinic rehabilitation services due to mobility, cognitive, transportation, and/or caregiver constraints. These obstacles highlight a need to expand what is traditionally considered “outpatient” rehabilitation beyond brick-and-mortar or hospital-based clinics to enhance accessibility and potentially improve patient engagement and recovery. To address this gap, outpatient therapy services delivered in the home, informally referred to as “mobile therapy,” have expanded substantially over the past 2 decades^24,25 and patients in the chronic phase of stroke have shown a growing interest for this therapy delivery model.

Mobile therapy may provide a feasible alternative to outpatient therapy for many chronic stroke survivors experiencing the barriers outlined above. Evidence suggests that mobile therapy may result in comparable outcomes to clinic-based interventions.^26,27 Furthermore, UL task-specific training is effective when delivered in the home.²⁷ Given its emphasis on task-specific training, Paired VNS may be well-suited for mobile therapy implementation where functional tasks can be practiced in a relevant environment to the patient, further facilitating independence both in and out of the home.²⁸ Therefore, there is a critical need to explore accessible and effective home-based delivery methods for Paired VNS.

The VNS-REHAB At-Home trial is an ongoing study aimed at evaluating the feasibility of a mobile therapy model of Paired VNS involving up to 36 hours of therapist-activated sessions for individuals with chronic post-stroke UL impairments.²⁹ The primary objective is to assess the feasibility by examining protocol compliance, therapist/patient acceptance, and safety. If feasible, mobile Paired VNS may offer a promising, practical and patient-centered approach to expand access to evidence-based therapy for individuals with chronic stroke. Other study objectives include characterizing changes in UL impairment and function, and patient-reported outcomes. The purpose of the current report was to evaluate preliminary findings from the first participant cohort of the VNS-REHAB At-Home trial.

Methods

Design

The VNS-REHAB At-Home study is a post market, ongoing single-arm trial for home-based delivery of therapist-activated Paired VNS by mobile therapists across the United States. The study was approved by the Western Institutional Review Board (WCG IRB), and the protocol, design, and detailed inclusion criteria were previously published elsewhere.²⁹ Briefly, the study includes 2 distinct stages (Figure 1A). In Stage 1, participants complete up to 36 hours of home-based, therapist-activated Paired VNS in 6 to 18 weeks, supplemented with self-activated VNS. Stage 2 is a 2-year follow-up period with self-activated Paired VNS. Both stages include outcome assessments at multiple timepoints.

Figure 1.

Study timeline (A) and therapist-activated and self-activated Paired VNS in the home (B and C). (A) Full timeline for the VNS-REHAB At-Home study. The current report includes data for Stage 1 which included assessments at Enrollment, Baseline, and after 12 hours (12-hour), 24 hours (24-hour), and 36 hours (36-hour) of therapist-activated VNS sessions delivered by mobile therapists over a 6 to 18 week period. Therapist-activated sessions were supplemented by self-activated Paired VNS. See Doherty et al (2025)²⁹ for further information. (B) Therapist-activated sessions involved up to 36 hours of pairing VNS with goal-oriented and high-repetition functional tasks in the home environment. The illustration shows an example functional task (toothbrushing) during therapist-activated Paired VNS. The therapist triggered VNS during key movements such as bringing the toothbrush to the mouth with the paretic arm. Additional key movements could also be triggered during this task. VNS was triggered using a wireless handheld remote. (C1) Self-activated sessions involved swiping a magnet over the implantable pulse generator (IPG) to trigger a 30-minute session of cyclical VNS. After a magnet swipe, participants performed therapist-prescribed activities, such as a structured home exercise program comprised of repetitive functional tasks (eg, socks grasp/release, C2) and/or daily activities related to the participant’s goals (eg, performing household tasks, C3).

Participant enrollment concluded in June 2025. In this report, we describe preliminary results from the first participant cohort who completed Stage 1 by February 2025.

Participants

All participants provided written informed consent to participate. Eligible participants were adults aged 18 years or older with chronic ischemic stroke and moderate-to-severe UL impairments. Participants had to be implanted or scheduled to be implanted with the Vivistim VNS device and deemed able to receive therapy in their home.²⁹

VNS Implantation

All participants were implanted with the VNS device prior to the start of mobile therapy sessions. Details of the procedure are similar to those performed during the VNS-REHAB trial and have been previously described.³⁰ In brief, the implantable pulse generator (IPG) is surgically placed beneath the chest wall, and a cuff electrode is wrapped around the left vagus nerve in the neck. The implantation is an outpatient procedure typically lasting 75 minutes³⁰ and patients usually start therapy within 7 to 14 days.

Study Procedures

Therapist Training

Mobile therapists were licensed occupational or physical therapists with experience in neurorehabilitation. All mobile therapists were trained in research ethics and regulations, study documentation procedures, proper administration of assessments and questionnaires, and delivery of Paired VNS as described elsewhere.²⁹

Therapist-Activated Paired VNS

Therapist-activated Paired VNS consists of supervised sessions where the therapist triggers VNS, via a handheld remote, during key active movement(s) for a given task (eg, while paretic arm brings toothbrush toward the mouth, Figure 1B). A laptop with a connected transmitter runs the Stroke Application Programming Software (SAPS). With each click, the system wirelessly transmits the signal to the IPG to trigger a 0.5-second VNS pulse train (0.8 mA, 100 µs pulse width, 30 Hz frequency).²⁹ Stimulation data for therapist-activated sessions are recorded in the IPG.

In this study, participants were expected to complete up to 36 hours of therapist-led in-home sessions consisting of goal-oriented, task-based, high-repetition UL therapy paired with VNS.^20,29 Therapists were encouraged to schedule 90-minute sessions 3 times per week with the goal of at least 300 repetitions/session, as implemented in previous studies^16,21,31 and commercially.^22,23 However, session duration could vary between 60 and 120 minutes and session frequency could go from 2 to 5 sessions per week, based on scheduling availability and the therapist’s clinical judgment for participant tolerance to high-repetitions sessions.²⁹ The flexibility in session scheduling was designed to reflect real-world considerations for mobile therapy and promote accessibility.

Therapists were instructed to provide at least 30 repetitions per functional task, with a minimum of 3 to 4 tasks/session, incorporating task gradations and variability for appropriate challenges (see Supplemental Material for the mobile Paired VNS protocol summary).²⁹ Unlike previous Paired VNS studies, spasticity management with botulinum toxin injections and/or medications was allowed in the current study to mirror real-world practices and stroke rehabilitation guidelines.³² Furthermore, depending on specific participant needs, therapists could use adjunct modalities (eg, functional electrical stimulation (FES), splinting, etc.) with VNS, for which guidance was provided during implementation.^23,29

Self-Activated Paired VNS

The Vivistim System allows individuals to engage in self-activated Paired VNS during which VNS is paired with UL functional tasks outside the therapist-activated sessions. Self-activated VNS is initiated with a single magnet swipe over the IPG which activates a 30-minute session of cyclical VNS consisting of a 0.5-second pulse triggered every 10 seconds (Figure 1C1); no further equipment is needed. Self-activated sessions are recorded in the IPG.

In this study, self-activated task practice included 2 therapist-prescribed components: (1) a structured program consisting of 2-3 repetitive functional tasks focused on patient-specific UL impairments (Figure 1C2); (2) daily functional activities that incorporated use of the hemiparetic UL (Figure 1C3). Unlike previous Paired VNS studies,^16,21 participants were instructed to begin self-activated VNS on the first therapist-activated session. Participants were encouraged to complete daily self-activated Paired VNS sessions as often as possible with a device usage limit set to 4 hours in a 24-hour period (ie, eight 30-minute sessions).

Therapists provided an individualized program to each participant and were encouraged to implement strategies to promote adherence, such as ongoing education, behavioral contracting, and reinforcement for the participant and caregiver. Therapists monitored and documented adherence to self-activated sessions by checking the total magnet swipes count (as recorded in SAPS) at every visit.

Assessment Schedule

Stage 1 assessment schedule has been previously reported and is shown in Supplemental Table 1.²⁹ Of note, the surgical implantation was not part of the protocol and could be performed prior to or following consent. Once enrolled and implanted, participants completed a pre-therapy baseline assessment visit, interim assessment visits after 12- and 24-hours of therapist-activated sessions, and a post-therapy 36-hour assessment. The pre- and post-therapy visits occurred within 3 days of the first and last mobile sessions, respectively. Assessments were conducted by the treating therapist in the home environment, although testing visits could be performed elsewhere if required. Video recording was completed at all assessments and at least 1 therapy session.²⁹

Outcomes and Study Endpoints

Primary: Feasibility

The primary study objective was to determine feasibility defined as protocol compliance, therapist/participant acceptance, and safety of mobile Paired VNS. The primary outcome measure to inform on feasibility was the total hours of therapist-activated sessions completed in the home setting (ie, Total Session Hours). Total session hours were calculated as the summed duration of all therapist-activated sessions documented by each therapist. Session hours completed were monitored and confirmed by the study sponsor as described in the Data Monitoring section.

The primary study endpoint was centered on protocol compliance and was defined as the proportion of participants who completed at least 24 total session hours within an 18-week period.²⁹ Completion of 24 total session hours was selected as the benchmark for feasibility based on data from the VNS-REHAB trial where participants were considered compliant if they completed at least two-thirds of their scheduled therapy sessions.¹⁶ Thus, in the current study, participants had to complete at least two-thirds of the total 36 hours (ie, 24 hours) to meet the primary endpoint. Based on experience from previous studies, we expected that at least 90% of participants would achieve this endpoint.²⁹

Mobile Paired VNS acceptance was measured with self-reported satisfaction surveys completed by therapists and participants separately at the 36-hour assessment. These surveys were developed by the study sponsor. Therapists with multiple participants completed a separate survey for each participant.

VNS has a well-established safety profile spanning multiple decades, with a low occurrence of serious adverse events. Although we expected similar safety outcomes to those seen in previous Paired VNS trials,^16,21,30,31 adverse events and device complications were monitored to confirm that there were no additional risks to delivering therapy in the participant’s home. Any adverse events from the first therapy visit through study end were documented by therapists and followed up accordingly.

Secondary: Changes From Baseline

Secondary study objectives included assessing UL impairment and function and patient-reported outcomes. Because this feasibility study was not designed to test treatment effects, these outcomes were evaluated descriptively to characterize observed changes. Secondary study endpoints consisted of changes from Baseline in motor and patient-reported outcomes (Supplemental Table 1). Motor outcomes included the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) motor scale,^33,34 Action Research Arm Test (ARAT),³⁵ Box & Block Test (BBT),³⁶ and 9-Hole Peg Test (9-HPT).³⁷ Patient-reported outcomes consisted of the Motor Activity Log (MAL),³⁸ Stroke Impact Scale (SIS),³⁹ a general health-related QOL measure,⁴⁰ and the Beck Depression Inventory (BDI).⁴¹ We also looked at non-motor outcomes to get an initial profile of participant baseline characteristics for cognitive status (Montreal Cognitive Assessment, MoCA),⁴² UL sensation (FMA-UE sensory scale),³³ and spasticity (Modified Ashworth Scale, MAS).⁴³

In addition to the analyses specified in the study protocol,²⁹ we explored 2 approaches to provide clinically meaningful context to the changes observed after mobile Paired VNS. The minimum clinically important difference (MCID)-level changes in the FMA-UE (⩾6-points) was calculated to examine clinically important changes through Stage 1.^16,34 We also examined functional goal achievements by each participant. At Baseline, participants identified 3 functional goals incorporating paretic UL use that they wished to achieve with the Paired VNS intervention. These participant-defined goals facilitated additional therapy goal development and the design of salient, goal-directed tasks for Paired VNS sessions. Functional goals were tracked, and therapists evaluated goal attainment through observation of task performance and/or participant self-report. New goals were introduced when existing goals were achieved or discontinued.

Additional Outcomes

To further characterize mobile Paired VNS feasibility, we evaluated practical implementation of Paired VNS therapy principles and system performance in the home. Total Task Hours was the cumulative amount of time spent on task practice during all sessions as recorded by the computer software (SAPS). Details of therapist-activated tasks, such as activity selection, movements targeted for VNS pairing, approximate repetitions, and application of mass and variable practice, were examined qualitatively to characterize implementation of mobile Paired VNS. Device and system performance were evaluated based on therapist feedback and reports of any technical issues. Collectively, these data were obtained through therapist documentation, SAPS, and/or video recordings.

Although the study did not introduce a new approach for self-activated Paired VNS, adherence to self-activated sessions was examined to provide insight into participant motivation, engagement, and potential impact on active use of the paretic UL in daily activities. Total Self-Activated Hours was defined as the total hours each participant’s device delivered self-activated Paired VNS during the period between the first mobile therapy session and the 36-hours assessment. We also examined the percentage of days with at least 1 self-activated session (ie, 30 minutes) to examine the overall adherence to self-activated VNS. This measure was defined as Self-Activated Adherence.

Data Monitoring and Study Oversight

Study investigators documented study data and monitored participant safety throughout the study. Adverse events and device-related complications were recorded from the start of therapy and reviewed for severity and potential relationship to the intervention by the study director. If an unexpected or serious adverse events were reported, these were reviewed promptly and a physician reviewer could be consulted when additional evaluation was warranted.

To support monitoring of study procedures and protocol compliance, all outcome assessments and select therapy sessions were video recorded. These recordings allowed the sponsor to review assessment administration, confirm adherence to study procedures, and observe the quality and integrity of therapy delivery. Because completion of therapist-activated therapy hours was the primary study endpoint, therapy dose was monitored throughout the study. Therapists documented the start and end time of each session and shared planned therapy schedules with the sponsor. Therapy hours were reviewed regularly to confirm cumulative therapy dose and ensure that interim and post-therapy assessments occurred according to the study protocol at the 12-, 24-, and 36-hour timepoints.

Data Analysis

Descriptive statistics were used to analyze all data, given the small sample size and preliminary nature of this report. Unless otherwise noted, all values are reported as median or median changes, and minimum-maximum values. Safety endpoints were analyzed descriptively.

Results

Participants

Eleven participants across 8 mobile therapy sites completed Stage 1 between June 2023 to February 2025. Nine participants did not have regular caregiver assistance at home or the ability to drive. At enrollment, none of the 11 participants had access to a clinic that provided Paired VNS.

Participant demographics and baseline clinical characteristics are shown in Table 1. Baseline FMA-UE motor scores ranged between 11 and 54 points, demonstrating a wide range of UL impairment. Most individuals had normal or near normal UL sensation, as shown by the Baseline FMA-UE sensory scores ⩾6.¹⁶ Three subjects exhibited considerable spasticity in at least 2 muscle groups (MAS ⩾ 3). For the remaining 8 participants, spasticity was less severe. Of these, 6 individuals presented with marked spasticity (MAS ⩾ 2) in elbow, wrist and/or digit flexors, which is a typical post-stroke pattern.⁴⁴ Spasticity was managed with oral medication (n = 1), botulinum toxin injections (n = 2), or both (n = 2). Dosage, administration schedule, and injection sites varied among participants, as determined by the prescribing physician. The MoCA scores indicated that none of the participants had severe cognitive impairment.⁴²

Table 1.

Participant Demographics and Baseline Clinical Characteristics (n = 11).

Variable	N or median (min-max)
Age	67.4 (27-74)
Sex
Male	9
Female	2
Race
White	8
Black	2
Asian	1
Ethnicity
Hispanic	2
Non-Hispanic	9
Time since stroke, years	3.1 (0.7-17.4)
Side of paresis (right:left)	6:5
Dominant hand affected	5
Modified Ashworth scale UL scores*
⩾3 in at least two muscle groups	3
⩾2 in elbow, wrist and/or digit flexors	6
<2 in all muscle groups	3
FMA-UE motor total score, baseline (out of 66)	30 (11-54)
FMA-UE sensory total score, baseline (out of 12)	12 (7-12)
MoCA, baseline (out of 30)	25 (15-30)

Abbreviations: FMA-UE, Fugl-Meyer Assessment-Upper Extremity; MoCA, Montreal cognitive assessment; UL = upper limb.

Participants may be represented in more than 1 muscle group in the Modified Ashworth Scale if demonstrating spasticity in multiple categories.

Stimulation Settings

For 9 participants, VNS settings were the same as in previous trials.^16,21,31 For the remaining 2 participants, the amplitude was set to 0.7 mA to adjust to their comfort level; 1 of these individuals was subsequently able to tolerate 0.8 mA and continued with this intensity after the 12-hour assessment. This variation in stimulation amplitude was also permitted in the VNS-REHAB trial and it did not affect efficacy. For self-activated sessions, all participants were set to default settings as described above. In 2 participants, self-activated session duration was adjusted to 15 minutes by the 12-hour (n = 1) and 24-hour (n = 1) assessments because these individuals wanted more flexibility in task practice duration.

Mobile Paired VNS

All participants (100%) completed at least 24 total session hours of Paired VNS and, therefore, met the primary study endpoint (Figure 2A). Participants completed a median of 37.8 (range: 32.5-42.4) total session hours over 24 (19-31) mobile therapy sessions in 13 weeks (8-18).

Figure 2.

Feasibility of mobile Paired VNS. (A) Total hours of therapist-activated sessions completed per participant. Dark blue bars denote total session hours in the home environment. The green horizontal line at 24 hours illustrates that 100% of participants met the primary study endpoint (total session hours ⩾ 24). Light blue bars represent the total task hours or cumulative time engaged in therapy tasks during the total session hours. (B) Paired VNS acceptance demonstrated by the satisfaction survey responses by participants (n = 11) and therapists (n = 11) at the 36-hour assessment. Therapists with multiple participants answered 1 survey per participant. Responses indicate that Paired VNS was well accepted in the home.

Median mobile session duration was 1.5 (1.2-2.1) hours. Participants engaged in approximately 32.1 (24.5-39.7) total task hours which represents 92% of the total session hours, indicating a high level of task engagement time during mobile sessions. Additional therapist-activated session data are provided in Figure 2A and Table 2.

Table 2.

Mobile Paired VNS Therapy Summary.

Therapist-activated sessions	Median (min-max)	Mean (±SD)
Total sessions	24 (19-31)	24.5 (±3.5)
Total session hours*	37.8 (32.5-42.4)	37.2 (±3.0)
Session duration (hours/session)	1.5 (1.2-2.1)	1.5 (±0.2)
Total task hours**	32.1 (24.5-39.7)	32.8 (±4.6)
Task hours/session	1.3 (1.1-1.9)	1.4 (±0.2)
Stimulations/session	575 (238-823)	558 (±152)
Number of tasks/session	5.3 (4.0-9.1)	5.7 (±1.4)
Self-activated sessions	Median (min-max)	Mean (±SD)
Total self-activated hours	119.3 (26.6-156.9)	105.6 (±41.7)
Hours/day	1.2 (0.4-1.8)	1.2 (±0.4)
Magnet swipes/day	2.5 (1-4.8)	2.6 (±1.0)
Adherence (% total days)	87 (54-95)	83 (±12)

Abbreviation: VNS, vagus nerve stimulation.

Based on therapist documentation, primary study endpoint (feasibility).

Total hours spent on task practice during therapist-activated sessions.

Participants engaged in a total of 119.3 (26.6-156.9) hours of self-activated VNS. Daily self-activated sessions totaled 1.2 hours (0.4-1.8) or approximately 2 to 3 magnet swipes per day (Table 2). Self-activated VNS adherence was 87% (54%-95%) indicating that participants completed at least 30-minutes of self-activated VNS on 87% of total days.

Mobile Paired VNS was well-accepted by participants and therapists (Figure 2B). Participants and therapists rated their overall satisfaction with Paired VNS as “satisfied” (n = 8) or “very satisfied” (n = 14). Two participants reported that therapist-activated sessions were “a little difficult,” whereas 9 reported that the sessions were “not difficult.” Therapists rated participants’ tolerance to Paired VNS sessions as “difficult” (n = 1), “just right” (n = 8) or “easy” (n = 2). Therapists were either “likely” (n = 1) or “very likely” (n = 10) to recommend Paired VNS to colleagues and patients, while participants were either “likely” (n = 2) or “very likely” (n = 9) to recommend Paired VNS to other stroke survivors.

No major barriers to implementation of at-home therapist-activated Paired VNS were reported by therapists or participants. Therapists successfully completed the sessions without significant technical issues, and no sessions were discontinued or significantly delayed due to device- or system-related problems.

As expected, Paired VNS did not result in safety events specific to the home setting. A total of 4 adverse events (AEs) were reported amongst 3 participants. All AEs were mild with 3 reported as possibly related to device use (headache, limited smell/taste for a few days, and increased bowel movements). A single participant experienced 2 serious adverse events (SAEs) associated with pre-existing sickle cell anemia (Supplemental Table 2). There were no SAEs related to surgery or device use. Despite these events, all participants were able to continue in the study.

Motor and Patient-Reported Outcomes

The median FMA-UE change from Baseline was 7 (−1 to 18) points at the 36-hour assessment (Figure 3A; Supplemental Table 3). A clinically meaningful improvement on the FMA-UE (⩾6-point change) was achieved by 1 participant (9%) at the 12-hour, 6 (55%) at the 24-hour, and 7 participants (64%) at the 36-hour timepoint.

Figure 3.

Changes from baseline in the FMA-UE (A) and patient-reported outcomes related to upper limb function (B and C) in Stage 1. (A-C) Box and whisker plots with individual datapoints overlayed. Bold horizontal blue lines in the center of each box denote the change in group median. Triangles represent outliers and X’s represent the mean change. (A) Box and whisker plots depicting changes in the FMA-UE at the 12-, 24-, and 36-hour assessments. The dashed black line at y = 6 represents a change from Baseline ⩾ 6 based on the minimal clinically important difference (MCID) for the FMA-UE.³⁰ Green points represent participants who achieved the MCID for the FMA-UE at each timepoint. Gray points represent individuals who did not achieve an MCID level change. The median and mean(±SD) changes in the FMA-UE were 4 points (3.5 ± 2.3) at 12-hour, 6 points (5.2 ± 4.0) at 24-hour, and 7 points (7.0 ± 4.8) at 36-hour. (B and C) Box and whisker plots depicting changes in patient-reported outcomes between Baseline and 36-hour for the MAL-AOU (B), SIS-Hand (C) and SIS-ADL (C). Individual change scores are reflected by black dots. The median and mean(±SD) change in the MAL-AOU was 0.56 points (0.6 ± 0.8) at 36-hour. The median and mean(±SD) changes in the SIS-Hand and SIS-ADL at 36-hour were 15 points (17.7 ± 11.4) and 2.5 points (8.5 ± 16.4). Additional data is included in Supplemental Tables 3 and 4.

The ARAT median change from Baseline was 4 points (0-13) at the 36-hour visit (Supplemental Table 3). There were no group level changes in the BBT, but 1 individual improved by 15 blocks and 2 others improved by 7 blocks by 36-hour. Only 2 participants were able to complete the 9-HPT at Baseline, and both made gains by 36-hours (−19 and −6 seconds; negative changes reflect improvement).

Patient-reported outcomes suggested improvements in several domains (Figure 3B and C, Supplemental Table 4). There was a median change of 0.56 points (−0.79 to 2.33) for amount of hand use (MAL-AOU) and 0.64 points (−0.64 to 2.44) for quality of hand use (MAL-QOM). All participants reported positive changes on the SIS-Hand, with an improvement of 15 points (5-35) at 36-hours. The change in the SIS-ADL was 2.5 points (−17.5 to 37.5). Additional SIS data indicated improvement trends for strength, memory, communication, mobility, participation, and general recovery. Participants also improved by 10 points (−10 to 40) on the EQ-5D general health status, and the BDI showed an improvement in mood of −7 points (−25 to 14; negative changes reflect improvement in the BDI).

Data on functional goal achievement further supported meaningful improvements by participants. Ten of 11 participants met at least 1 and up to 9 functional goals each by the end of Stage 1 (Figure 4). Gains were observed in tasks across different functional domains: activities of daily living (ADLs), instrumental ADLs, and participation activities.

Figure 4.

Functional goals met by each participant in Stage 1. At Baseline, participants and therapists identified at least 3 functional goals each involving paretic upper limb use. Goals included activities of daily living (ADLs), instrumental activities of daily living (IADLs), and participation (leisure, work or other). New goals were introduced by the therapist when existing goals were achieved or discontinued. Ten of 11 participants met at least 1 functional goal during Stage 1.

Discussion

Our initial findings indicate that therapist-activated Paired VNS was successfully implemented in the home setting. All participants met the primary study endpoint, demonstrating feasibility of Paired VNS in a mobile therapy delivery model. Mobile Paired VNS was safe and well-accepted by therapists and the first 11 participants.

In this sample, there were no major barriers to mobile Paired VNS implementation. Participants and therapists were 100% compliant with the therapy protocol schedule and, as a result, missed sessions or scheduling conflicts were not barriers in this study. Therapists adapted to administering Paired VNS therapy in the participants’ home environment, effectively managing variations in space and environmental conditions. Notably, no sessions were discontinued or significantly delayed because of technical issues with Paired VNS delivery. This suggests practical readiness and indicates that the training adequately prepared therapists for independent software/hardware use. Furthermore, mobile Paired VNS demonstrated a high acceptability among therapists and participants, with all individuals reporting being at least “satisfied” with the treatment, and most therapists (10 of 11) indicating they were “very likely” to recommend Paired VNS to other stroke survivors. Thus, the initial findings suggest that Paired VNS can be feasibly implemented in the home environment.

Paired VNS therapy emphasizes evidence-based neurorehabilitation practices such as high-repetition, task-specificity, and salience as fundamental components of the approach. Overall, total session hours confirmed the high treatment dose, and total task hours indicated a high level of dedicated active task engagement during therapist-activated sessions (Figure 2, Table 2). Even though sessions could last from 1 to 2 hours per study protocol, mobile sessions had a median duration of 1.5 hours which is in line with the typical outpatient session duration of 90 minutes implemented in previous studies and commercially.^16,21
-23 Additionally, videos and therapist documentation for each task practiced during mobile sessions indicated that task-specific and salient practice were implemented. Therefore, our findings suggest that mobile therapists and patients can deliver and receive high quality therapy in the home setting, supporting broader adoption and access to evidence-based post-stroke care.

Spasticity can be a common challenge when considering neurorehabilitation interventions.⁴⁴ In our sample, baseline UL spasticity ranged from mild to moderate and, consistent with real world practice, participants continued with their prescribed medical treatment plan. Importantly, spasticity did not appear to significantly limit participation or tolerance during therapist-led activities, as evidenced by session documentation and therapist survey responses (Figure 2). Beyond pharmacological intervention, participant tolerance may also be attributed to therapists’ use of tone management strategies during Paired VNS sessions. Therapists mitigated fluctuations in spasticity levels while maintaining therapeutic intensity by employing stretch breaks, variation of task types and demands, and utilization of adjunct modalities (FES, functional splints) as needed.²³ As the heterogeneous chronic stroke population seeking home-based services exhibits diverse characteristics and variable spasticity levels, this study further demonstrates the feasibility of delivering mobile Paired VNS across a real-world population.

The incorporation of self-activated sessions is essential to maintaining and even improving UL function, as has been seen in long-term outcomes from Paired VNS clinical trials.^17
-19 Mobile Paired VNS may have facilitated adherence to self-activated sessions by allowing functional tasks to be taught and practiced in the participant’s natural environment during the therapist-activated sessions. For example, a participant could practice loading/unloading the dishwasher in their own kitchen or perform grooming tasks using personal items in their bathroom while working with the therapist and then continue practicing these same tasks independently during self-activated sessions and daily routine. This context-specific training may be motivating for longer-term adherence and likely contributes to successful task transference and greater participant confidence in engaging the paretic UL in daily activities. Furthermore, the high adherence to self-activated sessions in this study (87%) suggests that participants showed motivation to continue UL task practice beyond the therapist-led sessions. Therapist support for self-activated sessions based on ongoing magnet swipe checks and adjustments of the individualized program may have further contributed to this high adherence. Notably, unlike previous studies,^16,21 participants were allowed and encouraged to engage in self-activated therapy as early as the first therapist-activated session, whereas the previous trials permitted self-activated VNS only after the in-clinic (ie, therapist-activated) intervention was completed. The combined approach used in our study follows real world practice of establishing a home program at therapy onset, which likely encouraged adherence to self-activated Paired VNS.²³

Our secondary outcomes suggest meaningful gains with mobile Paired VNS. Over half of the participants (64%, n = 7) achieved clinically meaningful improvement in arm impairment as measured by the FMA-UE (MCID ⩾ 6 points)³⁴ and a median overall gain of 7 points from Baseline. Additionally, interim data collected at the 12- and 24-hour assessments provided insight into meaningful improvements over time. There was a progressive number of participants who met the FMA-UE MCID (Figure 3), and individuals who achieved clinical improvement at an earlier assessment retained their gains at the following timepoint. Although exploratory, these findings align with existing evidence indicating that greater therapy dosage is associated with better outcomes.^45
-47 Further, all participants reported improvements on measures of arm/hand use, ADLs, and/or participation. Notably, 10 of 11 participants met at least 1 and up to 9 personalized functional goals (Figure 4). Functional goals spanned ADLs (eg, grooming, bathing, toileting, eating), instrumental ADLs (eg, light household chores, preparing a meal, carrying and holding dishes, doing groceries) and participation (eg, typing, golfing, using a professional camera, playing a musical instrument). Achievement of these functional goals represents a more participant-centered measure of progress by capturing meaningful gains from the individual’s perspective. Collectively, these outcomes suggest mobile Paired VNS facilitates meaningful motor recovery and functional gains.

The mobile therapy delivery model tested in this study showed that translating the Paired VNS rehabilitation paradigm into the home environment was feasible, which suggests that the key principles of Paired VNS can be implemented effectively in a home-based setting when best practice protocols are followed. While the study showed that the magnitude and direction of outcomes were broadly in line with those observed in previous Paired VNS studies,^16,21 the present study was not designed or powered to test for equivalence to in-clinic therapy. Because the efficacy of Paired VNS has previously been established in randomized controlled trials,^16,17,21 the present study focused on feasibility of implementing therapy with a mobile, home-based model rather than testing treatment effects. The smaller sample size, absence of a control arm, differences in the number of therapist-activated sessions, and earlier onset of self-activated sessions preclude a direct comparison with previously reported studies. Therefore, our findings should be interpreted as preliminary evidence that mobile Paired VNS delivery is feasible and may support meaningful motor gains.

Limitations

It is important to note that assessments were not blinded as assessors also served as the treating therapists. To mitigate potential observer bias, all assessments were reviewed via video by secondary study staff to confirm standardized assessment administration and scoring as part of the data validation process. We acknowledge that adherence to self-activated VNS was measured via magnet swipe counts which indicate device use but do not confirm actual task performance by participants. Future studies incorporating wearable monitors and/or self-reported activity logs could address this by more directly capturing UL task engagement during self-activated sessions. We also acknowledge that definitive conclusions are limited by the study design and preliminary nature of this report. The results from the complete VNS-REHAB At-Home trial are expected to provide additional insight into the mobile therapy delivery model, functional improvements, and goal attainments achieved in a larger cohort and over a longer period of time. Additional studies may further explore alternative Paired VNS therapy delivery and implementation models.

Conclusions

Results from the first participant cohort demonstrated that therapist-activated Paired VNS can be successfully implemented in the home setting and is well-accepted by both therapists and participants. Importantly, none of the participants had access to Paired VNS outpatient clinics at the time of enrollment, highlighting a critical gap and underscoring the need for alternative models of therapy delivery. Mobile Paired VNS followed the same neuroplasticity-based principles of high-dose, high-repetition, salient, and task-specific practice implemented in outpatient settings, which may have contributed to the benefits observed across outcomes in this study. At the 36-hour assessment, there were clinically meaningful changes in UL motor impairment and improved paretic hand use in daily activities, similar to previous studies using in-clinic therapist-activated Paired VNS.^16,21,31

This report highlights the feasibility and acceptability of mobile Paired VNS, serving as an important first step toward expanding access to evidence-based chronic stroke care for individuals limited by geography, transportation, mobility, and caregiver constraints. These preliminary findings provide a foundation for the broader implementation of a mobile Paired VNS delivery model, which may enable more stroke survivors to receive evidence-based interventions while allowing for continued recovery directly in their homes.

Supplemental Material

sj-docx-1-rpo-10.1177_27536351261447473 – Supplemental material for Vagus Nerve Stimulation Paired With Rehabilitation in the Home Environment for People With Chronic Post-Stroke Upper Limb Deficits: Preliminary Findings

Supplemental material, sj-docx-1-rpo-10.1177_27536351261447473 for Vagus Nerve Stimulation Paired With Rehabilitation in the Home Environment for People With Chronic Post-Stroke Upper Limb Deficits: Preliminary Findings by Ruchi Patel, Lisa Spinelli-Guglielmo, Kathleen A. Antares, Annie Diedrich and Sarah M. Zera in Advances in Rehabilitation Science and Practice

Footnotes

Acknowledgements

The authors thank all participants for their contribution to this research. We thank Ashleigh Parkman (OTR/L), Leann Vitale (MS, OTR/L, CSRS), and Jack Dumsa (OTR/L) for their contribution as investigators in the study. The authors acknowledge Dr Isha Vora for medical writing support in preparing the publication, funded by MicroTransponder, Inc. We thank Dr Cecília Prudente for managing the study, assisting with data analysis/validation, and for editorial support. We also thank Dr Reema Adham-Hinds and Diana Hansen for assistance with data entry and review; Brooks Fowler and David Pierce for assistance with data analysis; Lionel Dacpano, Andrew Schmid, and Shelley Coppola for technical support with SAPs programming and device management; and Brent Tarver, Dr Shannon Doherty, and Dr Navzer Engineer for editorial assistance.

ORCID iDs

Ruchi Patel

Sarah M. Zera

Ethical Considerations

This study was approved by the Western Copernicus Group Institutional Review Board (approval #: 0226640) on December 20, 2022.

Consent to Participate

All participants provided written informed consent prior to participating in this study.

Consent for Publication

Not applicable.

Author Contributions

RP: Conceptualization, Investigation, Project Administration, Data Analysis, Writing – Original Draft, Writing – Review & Editing. LSG: Investigation, Project Administration, Writing – Review & Editing. KAA: Investigation, Project Administration, Writing – Review & Editing. AD: Investigation, Project Administration, Writing – Review & Editing. SMZ: Investigation, Project Administration, Writing – Review & Editing.

Funding

The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article: MicroTransponder, Inc. (study sponsor).

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ruchi Patel and Sarah Zera are consultants for MicroTransponder however have not received any consultation fees for the authorship of this manuscript.

Data Availability Statement

Data sharing requires a signed data access agreement with specific outside funding explicitly stated to access the database without any support from investigators or MicroTransponder. Data will be shared after all enrolled participants have completed the study (final visit) and an initial data analysis has been completed. Requests should be sent to VNSdatarequest@gmail.com.

Supplemental material

Supplemental material for this article is available online.

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