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 Table of Contents  
PERSPECTIVE
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 106-111

New perspective on neuromodulation techniques: Breathing-controlled electrical stimulation as an innovative neuromodulation technique for management of neuropathic pain after spinal cord injury


Department of Physical Medicine and Rehabilitation, McGovern Medical School, University of Texas Health Science Center; Neurorecovery Research Center, TIRR Memorial Herman Hospital, Houston, TX, USA

Date of Submission23-Apr-2020
Date of Decision15-Jul-2020
Date of Acceptance27-Jul-2020
Date of Web Publication12-Nov-2020

Correspondence Address:
Dr. Sheng Li
Department of Physical Medicine and Rehabilitation, McGovern Medical School, University of Texas Health Science Center, Houston, TX; TIRR Memorial Herman Hospital, Houston, TX
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisprm.jisprm_23_20

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  Abstract 


Neuropathic pain after spinal cord injury is common and debilitating. Several nonpharmacological neuromodulation techniques have been tried with controversial outcomes. A novel intervention called breathing-controlled electrical stimulation (BreEStim) is developed based on discoveries about the systemic effects of voluntary breathing and the physiological interactions with body systems. Recent laboratory research studies are reviewed. The results demonstrated that BreEStim produced effective analgesic effects with the restoration of autonomic dysfunction via central neuromodulatory mechanisms. A case of long-term application of BreEStim highlights its clinical therapeutic potential.

Keywords: Electrical stimulation, neuromodulation, neuropathic pain, spinal cord injury


How to cite this article:
Li S, Stampas A, Frontera JE, Davis ME, Li S. New perspective on neuromodulation techniques: Breathing-controlled electrical stimulation as an innovative neuromodulation technique for management of neuropathic pain after spinal cord injury. J Int Soc Phys Rehabil Med 2020;3:106-11

How to cite this URL:
Li S, Stampas A, Frontera JE, Davis ME, Li S. New perspective on neuromodulation techniques: Breathing-controlled electrical stimulation as an innovative neuromodulation technique for management of neuropathic pain after spinal cord injury. J Int Soc Phys Rehabil Med [serial online] 2020 [cited 2020 Nov 28];3:106-11. Available from: https://www.jisprm.org/text.asp?2020/3/4/106/300596




  Introduction Top


Neuropathic pain (NP) after spinal cord injury (SCI) is common and debilitating.[1],[2],[3] It is characterized by spontaneous and ongoing pain, described as burning, shooting, prickling or electrical, and/or pain in response to innocuous stimuli (allodynia) and exaggerated pain in response to noxious stimuli (hyperalgesia).[4] About 65–85 percent of people with SCI experience NP, and in about a third of them, the pain is severe.[5] It does not resolve over time, and in some cases, it worsens.[6] NP has increasingly been recognized as an important contributor to suffering, poor rehabilitation outcomes, and reduced quality of life (QoL).[7],[8],[9],[10] Medication fails to provide sufficient relief and has side effects, which makes the search for nonpharmacological interventions important. Several noninvasive neuromodulation techniques via peripheral (e.g., transcutaneous electric nerve stimulation)[11] or central (e.g., transcranial direct current stimulation)[12],[13],[14] electrical stimulation (EStim) have been used. However, their effectiveness is still limited and controversial.[15] A novel neuromodulation technique, breathing-controlled EStim (BreEStim), has been developed. BreEStim has shown promising analgesic effects for NP after SCI. From a neuromodulation point of view, BreEStim is a novel neuromodulatory technique to provide effective analgesic effects for NP after SCI. In this perspective article, we summarize the technique, possible underlying mechanisms, and research findings. A case of long-term application of BreEStim is presented to showcase its clinical application potential.


  The Novel Neuromodulation Technique – Breathing-Controlled Electrical Stimulation Top


EStim therapy, which uses small electrodes to send electrical currents through the skin to target certain muscle groups or nerves, has a broad range of applications in rehabilitation to achieve functional and therapeutic goals, from spasm relaxation to pain management. However, traditional EStim functions more locally and the effect is short lasting. Based on discoveries of the systemic effects of voluntary breathing and the physiological interactions among body systems during voluntary breathing, we have invented a protocol called breathing-controlled EStim (BreEStim) to augment the effects of EStim in people with NP.[16] Briefly, in the BreEStim treatment [Figure 1] Adopted from Hu et al.[17], a painful single pulse of electrical stimulation is triggered and delivered to the target area (usually median nerve at the wrist) when the airflow rate of each individual breath reaches a certain threshold during forceful voluntary inhalation (usually set at 40% of maximal airflow to ensure forceful voluntary inhalation).[16] The users themselves control the intensity of EStim to increase the intensity gradually to a painful but tolerable level. As compared to conventional EStim, the novelty of BreEStim is that EStim is delivered only during deep inhalation.
Figure 1: Breathing-controlled electrical stimulation and experimental setting. This figure depicts the experimental setting with the breathing-controlled electrical stimulation treatment. A subject breathes through a facemask (left panel) to collect breathing signals. When the airflow rate (right upper panel) reaches a predetermined threshold, the central controller sends a command to the electrical stimulator, which provides electric stimulation through the surface electrode to the median nerve transcutaneously (right lower panel)

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  Analgesic Effects of Breathing-Controlled Electrical Stimulation Top


We have tested BreEStim in a series of studies, comparing EStim only or breathing only. We compared the electrical pain thresholds between BreEStim and EStim after one session of treatment in pain-free healthy controls in a crossover design.[18] All subjects received both BreEStim and EStim to the median nerve at the wrist of the dominant side in a random order with at least 1 week apart. The intensity and dose of EStim were comparable between BreEStim and EStim. After BreEstim treatment, we observed an increase in the electrical pain threshold in the bilateral hands but no change in either hand after the EStim treatment. A similar pattern of results was observed when the ulnar nerve was stimulated during the BreEStim treatment.[19] We also tested pain-free healthy controls with BreEStim versus breathing only using the same experimental design.[17] The results consistently showed electrical pain threshold increased only with BreEStim treatment. Subsequently, we further compared the analgesic effects between EStim and BreEStim in a cohort of SCI subjects (paraplegia or tetraplegia) with chronic NP.[20] The results confirmed that BreEStim had a better and longer-lasting analgesic effect as compared to EStim. Collectively, these results suggest that BreEStim has systemic de-sensitization effects for analgesia.


  Possible Mechanisms of Breathing-Controlled Electrical Stimulation Top


The analgesic effect of BreEStim is attributed to intrinsic physiological interactions between the respiratory and sensory/pain systems that are activated and integrated by the coupling of EStim during this particular window of voluntary inhalation. Distinctly different from autonomic breathing, during voluntary breathing, such as talking and singing, humans voluntarily suppress autonomic breathing by activating the respiratory centers of the brain.[21],[22] These cortical and subcortical areas that are activated during voluntary breathing are also involved with muscle tone, posture, mood, pain, speech, heartbeats, and other functions. For example, the insula and anterior cingulate cortex (ACC) are activated during voluntary breathing, among other brain areas, according to brain imaging studies.[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34] The ACC and the insula are also known to selectively process the aversive quality of noxious stimulation[35],[36] but do not influence the sensation of the stimulation.[37] When aversive stimulation is delivered during activation of the insular cortex, item-specific anterograde amnesia to the stimulation occurs.[38] In other words, the memory of the noxious stimulation is impaired or “forgotten” after BreEStim, i.e., noxious stimulation is felt less “noxious” or normal, resulting in analgesic effects of BreEStim. Findings of concomitant changes of autonomic function with induced analgesia further support the response of the insula and ACC during BreEStim (details are described below). Taken together, BreEStim likely integrates several internal coping mechanisms,[39] including (1) activation of internal pain modulation mechanisms; (2) EStim effect; (3) anterograde amnesia of pain stimulation; (4) habilitation of aversive stimuli; and (5) central neuromodulatory mechanisms. As a result, BreEStim increases the pain threshold and pain tolerance, resulting in analgesic effects.


  Central Neuromodulatory Effects of Breathing-Controlled Electrical Stimulation Top


Voluntary breathing-activated brain areas, such as the insula and ACC, are involved in other networks. The insula and ACC are part of the pain neuromatrix and the central autonomic network as well. Due to shared areas in both pain and central autonomic networks, people demonstrate autonomic responses when anticipating or experiencing pain, for example, skin blood flow changes.[40] It is therefore expected that analgesic effects could be accompanied by modulation of autonomic functions. Heart rate variability (HRV), the physiology variance in the interbeat intervals, is a tool for quantitative assessment of autonomic function.[41] Furthermore, an increasing number of studies have supported HRV as a potential biomarker for pain.[42],[43],[44],[45],[46],[47] Our recent study has shown that people with SCI and NP demonstrated an overall decreased parasympathetic activity as compared to SCI without NP, regardless of the level and severity of the injury.[47]

Recent studies provide the support that BreEStim-induced analgesic effects are accompanied by modulation of the above-mentioned shared pain and autonomic networks. We compared changes in the pain scale (visual analog scale [VAS]) and HRV parameters between BreEStim- and breathing-only treatments in SCI subjects with chronic NP (SCI + NP) in a crossover design.[48] In this study, SCI + NP subjects wore the same facemask during both breathing-only (null) and BreEStim (active) treatments, with surface electrodes placed over the same peripheral nerve. The only difference was that subjects received an EStim in the active treatment, while no electrical stimulus was delivered in the null treatment. The active treatment produced analgesic effects, while no such effects were seen after the null treatment. As shown in [Figure 2], Adopted from Karri et al.[48] pain reduction was accompanied by concomitant increases in NN50 and pNN50. These are HRV parameters that reflect increased parasympathetic function. The results support the association between pain and autonomic networks and BreEStim-induced modulation in these networks. In other words, pain reduction is accompanied by the restoration of autonomic balance in SCI + NP subjects. An interesting set of results were observed when we compared the analgesic effects and associated HRV changes between SCI + NP subjects and pain-free healthy controls after the active BreEStim treatment.[49] As expected, BreEStim produced pain reduction in SCI + NP subjects and increased pain threshold in pain-free healthy controls. Pain reduction in SCI + NP subjects was associated with increased parasympathetic function; however, there were no HRV changes in healthy controls. This study further suggests that the shared areas of pain and autonomic networks had maladaptive plasticity in SCI subjects with chronic NP.[47] Their dysfunction could be modulated by BreEStim.
Figure 2: The changes in various parameters across pre- and posttest time points for null and active experiments in the spinal cord injury + neuropathic pain study group (n = 10). Parameters displayed include (a) VAS: Visual analog scale, (b) SDNN: Standard deviation in N–N intervals, (c) NN50: Pairs of successive R–R beat lengths varying by >50 m s, and (d) pNN50: Proportion of NN50 for total number of pNN50. Standard error bars are shown; asterisks denote statistically significant differences

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  Long-Term Effects of Breathing-Controlled Electrical Stimulation Top


The long-term analgesic and neuromodulatory effects of BreEStim have been tested in an SCI subject with chronic NP. The SCI subject (MC) was a 59-year-old male with tetraplegia for 40 years (C5 ASIA C). MC had constant below-the-level NP, primarily in the left lower back area. Despite the fact that MC took scheduled pain medications as prescribed by his treating physician, his pain level remained at 5–6 throughout the day. Using the same BreEStim protocol,[20],[48],[49],[50] MC received daily weekday BreEStim treatment for 10 sessions and was then followed for 3 weeks. Throughout the treatment and follow-up period, the subject was explicitly instructed to maintain the pain regime (same medications, dose, and frequency). VAS scores were recorded daily during the BreEStim treatment and the 3-week follow-up period. Electrocardiogram (ECG) recordings for HRV analysis were obtained before and 30 min after the BreEStim treatments on session 1 (day 1) and session 10 (day 12). ECG recordings were also obtained during the follow-up visits on postintervention day 5 and day 14. The experimental protocol for ECG recordings and HRV analyses was used from our recent studies.[48],[49]

[Figure 3] displays the daily pain log during the treatment and the follow-up period. During the 1st week, BreEStim had analgesic effects after each session of the treatment. On average, pain scores decreased from 6 to 2. The duration of analgesic effects lasted from 4 h to 23 h with an average of 16 h/day. The patient reported that on day 7, his pain score was 0, which had not happened in his recent memories over the years. His pain level remained low during the second five sessions of treatment except day 10 when MC had a urinary tract infection. It was noted that the global pain intensity remained low (1.5–2) during this period. There was no further change in VAS scores after BreEStim treatment. However, it is noteworthy to point out that his pain level remained at very low levels throughout the whole day during the 2nd week, and the analgesic effects continued for another 7 days. The baseline pain level gradually returned to the pre-BreEStim level.
Figure 3: Daily pain log during the breathing-controlled electrical stimulation treatment period and during the follow-up period. *Denotes urinary tract infection. It was successfully treated with antibiotics. Detailed description is shown in the text.

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[Figure 4] summarizes the neuromodulatory and analgesic effects of 10 sessions of active BreEStim treatments. After the first session of BreEStim, the global pain level decreased from 5 to 1.5. This analgesic effect was paralleled, with an increase in NN50 counts from 1 to 20. At the end of 10 sessions, the pretreatment pain level was low (0.5). Although there was no further decrease in pain level, NN50 counts continue to increase from 17 to 27. During the follow-up period, an increase in VAS scores (from F/U day 5 to F/U day 14) was accompanied by a parallel decrease in NN50 counts. The pain level returned to the pre-EStim baseline at F/U day 14, as did NN50 counts. As previously shown [Figure 2], BreEStim-induced analgesic effects are accompanied with the restoration of parasympathetic activity (increased NN50). Furthermore, this case demonstrates a dynamic pattern of centrally mediated neuromoduatory effect.
Figure 4: Neuromodulatory and analgesic effects of 10 sessions of active breathing-controlled electrical stimulation treatment. F/U: Follow-up; VAS: Visual analog scale; NN50: An HRV parameter that reflects the parasympathetic activity. Details are described in the text.

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In this case of long-term use of BreEStim, MC tolerated the BreEStim treatment well. MC stated that “before the BreEStim treatment, my back pain severely affected my daily life. Once starting the treatment, the pain is very much manageable.” After five sessions, he had significant pain relief which continued 7 days after completing treatment, resulting in peaceful and relaxing days which otherwise had not been attained. Limitation in this case study is the lack of a control group and measures of analgesic medication use. Further investigations would need to include these elements as well as a disease-specific SCI-QoL survey to quantify improvements.


  Summary Top


BreEStim is a novel neuromodulation technique. A recent series of studies demonstrate that BreEStim produces effective analgesic effects with the restoration of autonomic dysfunction via central neuromodulatory mechanisms. BreEStim has the potential to be an effective neuromodulation technique for the management of NP after SCI. Further translational research, such as double-blinded clinical trials with additional measures, including QOL surveys, are needed to investigate whether BreEStim can be utilized as a clinical tool for NP management.

Acknowledgment

Research studies were supported in part by grants from Mission Connect, a program of TIRR Foundation, and NIH/NICHD/NCMRR R21HD087128.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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