Breathing-controlled Electrical Stimulation (BreEStim) for Management of Neuropathic Pain and Spasticity

Electrical stimulation (EStim) refers to the application of electrical current to muscles or nerves in order to achieve functional and therapeutic goals. It has been extensively used in various clinical settings, e.g., transcutaneous electrical nerve stimulation (TENS) for pain management¹, peroneal nerve stimulation for foot drop², neuromuscular electrical stimulation (NMES) for activation and strengthening of paralyzed or weakened muscles³. When NMES is used to achieve a functional task, it is termed functional electrical stimulation (FES)⁴. Electromyogram (EMG)-triggered neuromuscular stimulation has been used to augment effectiveness of electrical stimulation in motor recovery ^5-14 and spasticity reduction after stroke ^{7, 15}. In this paper, a new EStim protocol – Breathing-controlled electrical stimulation (BreEStim), is introduced, according to recent research findings on the systemic effect of voluntary breathing^{16, 17}.

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological modality for pain management¹. TENS is noninvasive, inexpensive, safe and easy to use¹⁸. TENS is usually applied at varying frequencies, intensities, and pulse durations of stimuli for a prescribed treatment time. TENS has been applied to a variety of pain conditions, including neuropathic pain. The clinical effectiveness of TENS is controversial, particularly in spinal cord injury (SCI) and amputation (see Reviews ^{1, 19, 20}). The possible mechanisms are the gate control theory ²¹ and the release of endogenous opioids ^{22, 23}. Acupuncture from Traditional Chinese Medicine is another non-pharmacological modality for pain management. It has been well accepted in Western Medicine²⁴. In modern acupuncture, the traditional acupuncture needle has been replaced by a surface electrode (or equivalent). A specialized electrode is place over traditional acupoints and an electrical stimulation is delivered. This modification has been termed electroacupuncture^{25, 26}. Needle acupuncture and electroacupuncture are both effective in analgesia via the release of endogenous opioids ^{27, 28}. The effect of electroacupuncture is usually reliable, however the effect is dependent on intensity and frequency of delivered electrical stimulation. Different frequencies of electrical stimulation generate different endogenous opioids, and the analgesic effect is naloxone-reversible ^{26, 27}. Recently, it has been found that repetitive painful stimulation (aversiveness) leads to significant pain attenuation. The induced pain attenuation is not naloxone-reversible ²⁹. Integrating of these pain coping mechanisms (acupuncture, electrical stimulation, aversiveness) into a possible new intervention could improve its clinical efficacy.

EMG-triggered neuromuscular stimulation has been used for many years to facilitate post-stroke motor recovery of finger extension impairments ^{5-10, 12-14, 34}. Recovery of hand function is important for stroke patients, and yet is very challenging. Roughly one third of all people who experience a stroke will have some residual impairment of the upper extremity ^30-32, with major impairments in hand function ³³. The EMG-triggered NMES intervention protocol involves initiation of a voluntary contraction of extensor muscles for a specific movement until the muscle activity reaches a threshold level. As soon as the EMG activity reaches a target threshold, an assisting electrical stimulus begins to facilitate the movements. This intervention protocol is superior to regular NMES in motor recovery^{6, 7}. Chae and Yu ³⁵ stated that all randomized controlled studies reported improvement in motor function using this intervention protocol, with mild to moderately impaired patients improving the most. It is most likely that this intervention takes advantage of active engagement of patients (by setting a target EMG threshold) and this results in measureable changes in recovery as well as documented changes in the cortex^{6, 7}. This is supported by a recent functional MRI study that showed a significant increase in cortical intensity in the ipsilateral somatosensory cortex after treatment in the NMES group, as compared with the control group³⁶. Furthermore, electrical stimulation may also help to reduce spasticity after stroke^{7, 15}, but the effect is short-lasting, about ³⁰ min after EStim³⁷. In contrast, our recent invention of breathing-controlled electrical stimulation (BreEStim) has a long-lasting effect on spasticity reduction, even after a single session of treatment ¹⁶.

Human breathing is a very unique motor act. It can be controlled reflexively (automatic breathing), e.g., during sleep, and also voluntarily when needed (voluntary breathing), e.g., singing, speech, etc. During voluntary breathing, humans need to voluntarily suppress autonomic control of breathing through voluntary cortical activation (the “cortical respiratory center”) ^{38, 39}. Brain imaging studies ^40-51 have demonstrated extensive respiratory-related involvement of cortical areas bilaterally, including the primary motor cortex (M1), the premotor cortex, the supplementary motor area, the primary and secondary somatosensory cortices, the insula, the anterior cingulate cortex and amygdala, and the dorsolateral prefrontal cortex. The insula is known to have strong connections to brainstem centers and is involved in pain processing ⁵². During autonomic breathing, inspiration is active while expiration is passive, mainly relying on recoil force of the chest wall. Similarly, volitional inspiration activates more respiratory-related cortical and subcortical areas when compared to volitional expiration ⁴⁶. These cortical and subcortical areas activated during voluntary breathing are also involved in different functions ⁵³, such as muscle tone, pain, posture, mood, speech, etc. Therefore, it is not unreasonable to associate interactions in breathing with modulation of other functions.

Recently, we have discovered that there exist interactions between respiratory and motor systems during voluntary breathing. Specifically, there is a finger extension-inspiration coupling ^{16, 54-56}. When electrical stimulation is delivered to the finger extensors during the inspiratory phase of voluntary breathing, a long-lasting effect of reduction in finger flexor spasticity (muscle tone) in chronic stroke patient is observed ¹⁶. In another study ¹⁷, shooting phantom pain in a patient with an above-the-knee amputation disappeared after the BreEStim treatment, but re-appeared ²⁸ days later after receiving a sustained electrical stimulation accidentally. This case study provides a unique opportunity to understand that the affective component of noxious stimuli of neuropathic pain (shooting phantom pain) has been modified by the BreEStim treatment, but then re-triggered by an accidental stimulation. These observations of tone and pain reduction have demonstrated that voluntary breathing, inspiration in particular, could be integrated into an electrical stimulation paradigm to improve its efficacy in neuropathic pain management and post-stroke spasticity management.

Case Presentations

Case 1: Post-stroke Spasticity Management

The patient was a 69 years-old male who had right hemiplegia secondary to a stroke 22 months ago. He was medically stable and had been discharged from outpatient physical and occupational therapy programs. No brain imaging results were available at the time of experiments. He had weakness on his right side but was able to walk independently without an assistive device. He had residual voluntary finger flexion and extension, but with limited active range of motion at his right metacarpophalangeal (MCP) joints, from 90 ° to 70 ° of MCP flexion, i.e., not able to sufficiently open his hand and fingers for functional use. Muscle tone of his right finger flexors was moderately increased. Modified Ashworth Scale (MAS) was 1+. Sensation of his right hand and fingers, however, was intact to light touch. He received approximately a 30-min BreEStim to the finger extensors. His finger flexor spasticity decreased to minimum (MAS=0) and voluntary finger extension became nearly normal immediately after the treatment. This patient regained his hand function as well. He reported that he could cut meat with a knife and button shirts using his impaired hand. More strikingly, the recovery retained at least 8 weeks during follow-up visits (Figure 1).

Case 2: Neuropathic Pain Management

The patient was a 40 years-old male who suffered a spinal cord injury 4.5 years ago in a motor vehicle accident, resulting in T8 ASIA A spinal cord injury. The patient complained of neuropathic pain at the injury level, while he had no other active medical issues. He had been stable on a pain regime for 2 weeks prior to the treatment. He received EStim (one session per day for five consecutive days) first, waited 1 week as a washout, and then received BreEStim with the same dose (one session per day for 5 consecutive days). Each treatment session consisted of 120 stimuli (EStim or BreEStim). Surface electrodes were placed on acupoints (Neiguan and Weiguan) of the right forearm. Modified Visual Analogue Scale (mVAS) was used to compare the effect of each intervention (EStim and BreEStim). As shown in Figure 2, BreEStim had a greater pain reduction effect than EStim, except for Day 2 during BreEStim when the patient had a urinary tract infection (UTI) which was successfully treated with antibiotics. The intensity of electrical stimulation was similar between EStim and BreEStim (Figure 2). He tolerated both interventions well (maximum output intensity from the stimulator was used), even during the UTI. During the entire experimental period (4 weeks), the subject maintained the same dose and schedule of pain medications. Both BreEStim and EStim treatment sessions were performed at the same time of the day (between 11 AM to Noon), such that changes in the pain rating could possibly be attributed to stimulation effects and not diurnal variation.