Welcome to the e-INS 2023 Interactive Program

Introduction

Since the first report of transcutaneous spinal direct current stimulation (tsDCS) on humans in 2008¹, more than 50 experimental studies have been published. However, systematic reports of adverse effects (AEs) and unspecific effects (UEs) of tsDCS are scarce. In this study, we aimed to systematically record tsDCS AEs via a structured questionnaire and also record UEs via tsDCS – concurrent monitoring of skin conductance, electrocardiographic and respiratory activity.

Materials / Methods

Twenty healthy participants (10 females, 20-40 years old) were recruited for this study. All of them underwent three consecutive sessions (at least 1 week apart) with active (anodal/cathodal) or sham stimulation in double-blinded way. A pair of rubber-electrodes was placed over the twelfth thoracic vertebra (anode) and the suprascapular region (cathode). The active stimulation was applied at 2.5 mA for 20 min with 15 sec for fade-in/fade-out, the sham stimulation only lasted for 45 sec with same intensity and fade-in/fade-out setting. Spontaneous skin conductance responses (SCR) were recorded from the right hand and electrocardiographic (ECG: heart-rate and its variability) and respiratory activity (breathing-rate and its variability) was measured from the chest. A tsDCS adverse effects questionnaire (Figure 1, adapted from Brunoni and colleagues2) was filled in by participants directly after tsDCS termination.

Results

Several potential AEs and whether they were deemed to be associated with tsDCS were recorded (Figure 2). Skin redness (60.66%), burning (40%), tinging (26.67%), and itching (20%) were the most reported AEs (with skin redness being reported by the experimenter). Most reported AEs occurred within the first minute of tsDCS onset, lasted for 1-2 minutes and solely occurred at the skin area beneath the electrodes. In some sessions, sleepiness (6.67%) and trouble concentrating (1.67%) were reported, but instead of being strongly associated with tsDSC, they were likely due to no task during tsDCS according to the participants' feedback. For all the AEs separately reported by participants, as well as their aggregation into one overall score, Bayesian Wilcoxon Signed-rank tests were employed to compare active (anodal or cathodal) and sham tsDCS. These were more indicative for an absence of differences between active and sham conditions (Figure 3, not a single Bayes Factor [BF] above 3, with several below 1/3 [thus providing moderate evidence against differences]). Similar results were obtained for UEs (Figure 4), which were analysed with a Bayesian repeated-measures ANOVA: no BF was above 3, with nearly all BFs being below 1 and often close to 1/3.

Discussion

Skin-related changes at the site of electrode contact were the main reported AEs. Bayesian testing provided moderate evidence for an absence of differences in several AEs and in no case was there evidence for a difference. Such a pattern of results is reassuring from a safety and blinding perspective, as it indicates that both active and sham interventions have a similar profile in terms of AEs. Somewhat weaker, but qualitatively similar results for autonomic responses between active and sham tsDCS suggests it possibly has minimal impact on the autonomic nervous system. However, further research is needed to validate these results in larger samples as well as for other locations (e.g. cervical tsDCS) and explore potential individual variations that may influence tsDCS related AEs.

Conclusions

In this pioneering study, we present a systematic recording of AEs and UEs associated with tsDCS in healthy participants. As research in this area expands, there is an increasing demand for safety-focused investigations, and our study offers the first comprehensive assessment, contributing valuable insights to the field.

References

1. Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A. Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol. 2008;119(11):2636-2640.

2. Brunoni AR, Amadera J, Berbel B, Volz MS, Rizzerio BG, Fregni F. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol. 2011;14(8):1133-1145.

Learning Objectives

1. Discuss with colleagues and experts in non-invasive neuromodulation field and look forward to geeting constructive advice.

2. Practice my presenting skills to clearly convey the idea of my research.

3. Establish a professional network and look forward to future collaborations that can be initiated.

Introduction

Materials / Methods

Results

Sub-analysis by non-surgical spine pathologies demonstrates that improvements in pain (VAS), disability (ODI) and quality of life (EQ-5D) are equally substantial and durable compared to the overall study population. Participants with an MRI-based diagnosis of stable grade-1 listhetic segments at baseline (n=36/204) showed more rapid and substantial improvements than those without this diagnosis. At 1 year, these differences were statistically significant and clinically relevant for pain (VAS; p=0.004), disability (ODI; p=0.03) and quality of life (EQ-5D; p=0.01).

Discussion

Conclusions

References

Learning Objectives

Objective 1: Degenerative spine pathologies and associated nociception may be the consequence of persistent functional instability of the lumbar spine.

Desired result 1: Physicians should consider resolution of the underlying root-cause of pain symptoms a primary treatment objective before resorting to palliation.

Objective 2: Non-surgical degenerative spine pathologies should not be considered exclusion criteria for restorative neurostimulation.

Desired result 2: Awareness of the clinical evidence supporting use of restorative neurostimulation in qualifying patients with degenerative spine pathologies.

Objective 3: Restorative or disease modifying therapies have a different time-course than palliative analgesic therapies, and long-term outcomes should be considered.

Desired result 3: Physicians should expect and rely on long-term clinical evidence when selecting a treatment of chronic low back pain.

Introduction

Low back pain is among the leading causes of years lived with disability.1 The pathophysiology of chronic low back pain (CLBP) is complex with overlapping mechanisms including modifications to motor control, reflex inhibition and inflammatory mechanisms.

Clinical evidence for the role of restorative neurostimulation in treating CLBP has emerged from both prospective follow-up and randomised clinical trials, demonstrating substantial improvements in clinical outcomes such as pain, disability, and health related quality of life (HRQoL).2–4 Here we demonstrate the generalizability, durability and safety by reporting the three-year outcomes from the United Kingdom PMCF cohort.

Materials / Methods

Patients consented to participate in an open label five-year prospective follow-up for the treatment of chronic mechanical low back pain of nociceptive origin with restorative neurostimulation using the ReActiv8 (Mainstay Medical, Dublin, Ireland) device between September 2017 and September 2018. Data was collected at five sites across the UK (ClinicalTrials.gov Identifier: NCT01985230).

Pain, disability and HRQoL outcomes were collected at baseline, 45, 90, and 180 days, and 1, 2 and 3 years after the activation visit. Patients were eligible if they met the instructions for use associated with the CE mark with the intention of reflecting real world clinical practice.

Results

42 patients were implanted with the device, and 33 (79%) were available at the 3-year appointment. Patients ipresented with severe chronic low back pain (NRS = 7.0 ± 0.2) and severe disability (ODI 46.6 ± 12.0). The health-related quality of life was severely impacted (EQ-5D 0.426 ± 0.061).

Changes in pain, disability, and quality of life at three-year follow-up demonstrated a statistically significant improvement between baseline and 1, 2 and 3 years. After 3 years of therapy, average NRS scores had reduced to 2.7± 0.3 and mean ODI score to 26.0 ± 3.1, EQ-5D-5L index improved to 0.707 ± 0.036. Imputation for missing data increased these values marginally but improvements remained substantial and statistically significant. Longitudinal analysis showed the improvements between 1 and 3 years were statistically significant, consistent with the restorative mechanism of action.

Discussion

This study gathered data on the performance and residual risks of ReActiv8 in the standard clinical practice post-approval/ CE Mark. There were no specific inclusion or exclusion criteria beyond the regulated instructions for use. This study demonstrates results generalisable to clinical practice.

Conclusions

This cohort demonstrates that restorative neurostimulation provides a statistically significant, clinically meaningful, and durable response across multiple outcome measures for patients suffering chronic low back pain refractory to conventional management.

References

1. Hoy, D., Brooks, P., Blyth, F. & Buchbinder, R. The Epidemiology of low back pain. Best Practice and Research: Clinical Rheumatology 24, 769–781 (2010).

2. Gilligan, C. et al. An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: a randomized sham-controlled clinical trial. Pain 162, 2486–2498 (2021).

3. Gilligan, C. et al. Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial. Neuromodulation 26, 87–97 (2023).

4. Gilligan, C. et al. Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction. Neuromodulation 26, 98–108 (2023).

Learning Objectives

1 Learn about the relatively new treatment available for chronic low back pain

2 Learn that outcomes are durable, safe and effective at 3 years in a "Real World" UK cohort

3 Understand how this evidence complements the randomised clinical trial, known as Reactiv8 B study

Introduction

In patients with mechanical chronic low back pain (mCLBP) and impaired neuromuscular control of the multifidus muscle, the prognosis is poor and palliative management is the only remaining option. An implantable Restorative Neurostimulation system stimulates the L2 medial branches to (re)activate the multifidus and facilitate motor control restoration. A randomized sham-controlled trial provided evidence of effectiveness, durability, and safety (NCT02577354).[1–3] We report 4-year results.

Materials / Methods

Participants enrolled at 26 multidisciplinary centers in the pivotal trial had activity limiting mCLBP (VAS ≥6cm; Oswestry Disability Index (ODI) ≥21 points) on at least half the days in the year before enrolment. They were refractory to medical management, including at least pain medications and physical therapy, had no indications for spine surgery and a positive prone instability test consistent with impaired neuromuscular control of the multifidus muscle. All participants were implanted with a restorative neurostimulation system (ReActiv8® by Mainstay Medical) and during the open-label phase of the trial self-administered up to two 30-minute therapeutic stimulation sessions per day. Outcome measures were assessed and compared to baseline at six months and annually thereafter. Ongoing safety reporting included serious device- or procedure-related adverse events, which were actively solicited and documented at each visit.

Results

At baseline (N=204), participants were 47±9 years of age, had back pain for 14±11 years, an average low back pain VAS of 7.3±0.7 cm, ODI of 39±10, EQ-5D of 0.585±0.174 points and reported pain on 97±8% of days in the year prior to enrollment.

At 4 years (N=115), mean VAS had improved by 5.0±2.4 cm, ODI by 23.6±15.3 points, and EQ-5D by 0.236±0.211 (all P<0.0001); 73% of participants had ≥50% VAS improvement; 64% reported LBP-Resolution (VAS≤2.5 cm); 63% had ≥20-point ODI improvement; and 79% had ≥50% improvement in VAS and/or ≥20 points in ODI. Of participants using opioids at baseline, 70% voluntarily discontinued or decreased consumption. Device removal was requested by 12/204 (6%) participants after the resolution of pain and 26/204 (13%) for inadequate pain relief.

Discussion

The relatively small attenuation of effectiveness measures across all outcome measures between the completed case and imputed analyses and the statistical significance and clinical relevance of results in both instills confidence in the robustness of our data and the validity of the conclusions drawn.

Conclusions

Restorative neurostimulation has proved effective, durable, and safe. It provides specialists with a reversible treatment option targeting impaired neuromuscular control of lumbar spine stability in patients with refractory CLBP and no indications for surgery.

References

1.Gilligan C, Volschenk W, Russo M, et al. An implantable restorative-neurostimulator for refractory mechanical chronic low back pain: a randomized sham-controlled clinical trial. Pain. 2021;162(00):2486-2498.

2.Gilligan C, Volschenk W, Russo M, et al. Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial. Neuromodulation Technol Neural Interface. Published online 2022:1-11. doi:10.1016/j.neurom.2021.10.011

3.Gilligan C, Volschenk W, Russo M, et al. Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction. Neuromodulation Technol Neural Interface. Published online 2022. doi:10.1016/j.neurom.2022.08.457

Learning Objectives

Mechanism of action of multifidus muscle stimulation

Patient Selection for multifidus muscle stimulation

The durability of restorative Neurostimulation

Introduction

Chronic Lumbar back pain (CLBP) is one of the most common chronic pain conditions resulting in both individual suffering and a burden to societies. For these patients there are several interventional treatment options such as surgery, blocks, radiofrequency, and spinal cord stimulation. Lately also Dorsal Root Ganglion Stimulation (DRG-S) has been mentioned as an option, by targeting bilateral T12 dorsal ganglia. In this study we will present the outcome of 11 patients with CLBP treated with bilateral T12 DRG-S.

Materials / Methods

13 patients with CLBP with and without leg pain were treated with bilateral T12 DRG-S. Three of the patients also received a third lumbar lead due to leg pain. 11 of the patients had a more than 50% pain relief during the per- or/and postoperative testing and received a fully implantable neurostimulator. Pain intensity, general health status, quality of life, pain catastrophizing, mental status, sleeping disorder, physical activity and patient satisfaction were followed using NRS, PROMIS-29, PCS, GAD-7, PHQ-9, ISI and patient satisfaction questionnaire at baseline before implantation, 3 months and 6 months. The results were analyzed based on 6 domains: pain relief, sleeping disorder, social ability, mental status, physical activity, and satisfaction. To be identified as a responder the patients should show a significant improvement in the pain relief domain together with at least two other domains. All responders were given the opportunity to test 4 Hz DRG-S and compare it with traditional 20 Hz stimulation.

Results

All 11 patients were identified as responders at six months. 5 of the patients had a more than 80% pain relief with an average NRS score reduction of 71 % for the whole group. Significant improvement could be observed in 3 domains for one patient, 4 domains for three patients, 5 domains for six patients and 6 domains for one patient. Seven patients chose to try 4 Hz stimulation. All seven identified 4 Hz stimulation at least as good or better than 20 Hz stimulation and chose to continue with 4 Hz stimulation.

Discussion

Bilateral T12 DRG-S seems to be an effective treatment for chronic low back pain with significant beneficial effect not only on pain but also on quality of life, pain catastrophizing, mental status, sleeping disorder and physical activity. 4 Hz DRG-S gave comparable or better result than 20 Hz stimulation.

Conclusions

T12 level could be a good target for DRG-S for CLBP. 4Hz DRG-S seems to be at least as good as 20Hz.

References

None

Learning Objectives

1. DRG-S could be a valuable treatment option for patients suffering from CLBP.

2. DRG-S have beneficial effects not only on pain but also other health metrics.

3. 4 Hz DRG-S seems to have comparable or at least as godd effect as 20 Hz stimulation.

Introduction

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) was shown to be a potential complementary rehabilitation intervention for recovery after a spinal cord injury (SCI)¹. The safety and neuromodulatory outcomes of some promising HF-rTMS protocols tested in rodent models of SCI² needs to be further investigated in humans.

Materials / Methods

For this study, we investigated the effects of a HF-rTMS paradigm combined with 30 minutes of targeted hand motor training in individuals with chronic cervical SCI. The therapeutic stimulation protocol were previously published¹. We will present the data obtained from 3 participants with complete and incomplete SCI. The intensity of the HF-rTMS stimuli was adjusted to the session-specific individual resting motor threshold (RMT) measure and was set to induce visible hand twitches. We assessed changes in RMT and motor performance, as the percentage difference in the number of repetitions to perform a given motor task for 10 min, between 1^st (baseline) to the 8^th (mid) and mid to 15^th (last) training session. TMS / rTMS side-effects’ questionnaires were also administered at the end of each session. Brief EMG Burst (BEB)³ monitoring was constant.

Results

The proposed protocol repeated over 15 sessions was safely tested and well-tolerated in 3 SCI individuals. BEB was not detected. Mainly mild and transient headaches and tingling were reported by the participants after the HF-rTMS. Preliminary results reveal the neuromodulatory potential and the benefits on motor function of the therapeutic protocol; with increases in CSE (ΔRMT_KS1 = -5%MSO, ΔRMT_KS2 = -2%MSO) and motor performances (Δrepetition_KS2 = +31%, Δrepetition_KS3 = +5%) comparing between the baseline-to-mid and mid-to-last training sessions.

Discussion

Results suggest the potential of HF-rTMS as an intervention to combine with training for inducing neuroplasticity and boosting recovery after chronic complete and incomplete SCI. These few participants seem to respond differently to the treatment most likely because of the difference in the level and severity of the injury among them, suggesting injury severity-dependent neuroplasticity and function recovery as a result of the combined HF-rTMS and motor training protocol, without adverse effects.

Conclusions

The HF-rTMS combined with motor task training seems to be beneficial in improving corticospinal excitability and upper extremity motor function in individuals with SCI. However, they seem to respond differently to the treatment perhaps due to the level and severity of the injury, suggesting individualized underlying mechanisms.

Acknowledgments: This project has received a precious support from the New York State Department of Health (C34462GG, PI: J. Zhong), the Kessler Foundation and the Tim Reynolds Foundation.

References

1. Brihmat N, Bayram MB, Allexandre D, Saleh S, Yue GH, Guan X, Zhong J, Forrest GF. High-Frequency rTMS Combined with Task-Specific Hand Motor Training Modulates Corticospinal Plasticity in Motor Complete Spinal Cord Injury: A case report. In: 2022 44th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC). IEEE, p. 2385–2389.

2. Boato F, Guan X, Zhu Y, et al. Activation of MAP2K signaling by genetic engineering or HF-rTMS promotes corticospinal axon sprouting and functional regeneration. Sci Transl Med. 2023;15(677):eabq6885. doi:10.1126/scitranslmed.abq6885

3. E. M. Wassermann, “Risk and safety of repetitive transcranial magnetic stimulation : report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation , June 5 – 7 , 1996,” Electroencephalogr. Clin. Neurophysiol., vol. 108, pp. 1–16, 1998

Learning Objectives

1. Demonstrate the HF-rTMS could be used as an adjunct intervention for SCI rehabilitation.

2. Confirm patient-specific underlying mechanisms based on injury level and severity.

3. Demonstrate a translational neuromodulatory protocol for SCI.