This study was supported in part by NIH grants (NIH/NINDS R01NS060774; NIH/NICHD/NCMRR R24 HD050821-08 under subcontract with Rehabilitation Institute of Chicago). The author thanks Craig Ditommaso, MD for his editing and helpful suggestions.

The following BreEStim protocol could be applied for both finger flexor spasticity and neuropathic pain management. The main difference lies in surface electrode placement and adjustment of stimulation intensity. These differences are explained in detail for each application.
1. Subject Preparation and Setup
<ol>
	<li>Seat the subject comfortably. Place the arms and hands comfortably on the treatment table.</li>
	<li>Identify and localize the area of interest for surface electrode placement.
	<ol>
		<li>For spasticity management, palpate the muscle belly of finger extensors and confirm with electrical stimulation.</li>
		<li>For pain management, locate acupuncture points of Neiguan and Weiguan on the forearm24 ipsilateral to the side of interest, e.g., amputation17, or on the side with more symptoms, e.g., SCI. Neiguan is located about 3-finger width above the wrist crease on the volar side and in the middle between medial and lateral boards of the forearm (i.e., distal 1/6 of the forearm)24 (Figure 3). Weiguan is the counterpart of Neiguan, located in the dorsal aspect of the forearm24.</li>
	</ol>
	</li>
	<li>Trim each self-adhesive electrode to about a 2cm x 2cm square to provide focal and isolated electrical stimulation.
	<ol>
		<li>For spasticity management, place the cathode over the finger extensor muscle belly (Figure 4). Attach the anode to a site 1~2 cm distal to the cathode. Optimize the sites for the anode and cathode when eliciting the largest and isolated finger extension response with a minimal wrist response.</li>
		<li>For pain management, place the cathode electrode on Neiguan, and the anode electrode on Weiguan.</li>
	</ol>
	</li>
	<li>Connect surface electrodes to the electrical stimulator (Digitimer DS7A, UK, <a href="http://www.digitimer.com" target="_blank">www.digitimer.com</a>).</li>
	<li>Place and secure facemask. Select the size of facemask carefully to fit individual's face to prevent air leakage and to provide comfort of wearing the mask (Figure 5).</li>
	<li>Connect facemask to a pneumotach system (Series 1110A, Hans Rodolph Inc; Kansas City, Missouri; <a href="http://www.rudolphkc.com" target="_blank">http://www.rudolphkc.com</a>).</li>
</ol>
2. Instruction on Voluntary Breathing
Voluntary breathing, particularly voluntary inhalation, plays a critical role in this intervention. Voluntary inhalation is defined as effortful deep and fast inhalation. Instruct the subject to take a single isolated deep breath, similar to routine deep breaths, but faster and stronger. There is no need to perform voluntary exhalation preceding forced inhalation in a breathing cycle. Allow the subject to have 8~10 practice trials to understand the instructions.
3. Electrical Stimulation Settings
<ol>
	<li>Set a single electrical stimulus as a single square-wave pulse with 0.1ms duration. The intensity of electrical stimulation is different for different applications. Since a single electrical stimulus is delivered each time, there is no need to set frequency parameter.</li>
	<li>For spasticity management, determine the intensity of electrical stimulation when 1) isolated finger extension responses are elicited with minimal involvement of wrist joint responses; 2) the highest level that the subject could tolerate. The absolute magnitude of stimulation intensity could be different for different subjects. Encourage the highest intensity that the subject could tolerate to achieve the best outcome.</li>
	<li>For pain management, allow the subject to determine incremental changes of the stimulation intensity. The starting intensity is zero. The highest level is the maximal output of the stimulator or the level the subject could tolerate. However, explicitly instruct the subject that discomfort or painfulness, even "aversiveness" of electrical stimulation is part of treatment; therefore, encourage the subject to select the highest level that the subject could tolerate.</li>
</ol>
4. Control of Electrical Stimulation
<ol>
	<li>Write a customized LabView (National Instrument, Austin, TX) program to control delivery of electrical stimulation in two ways: BreEStim and EStim.</li>
	<li>Breathing-controlled electrical stimulation (BreEStim) (Figure 6):
	<ol>
		<li>Determine the peak airflow rate during voluntary inhalation, i.e., during the deepest and fast inhalation.</li>
		<li>Determine the threshold which is 40% peak airflow rate. Of note, set the threshold higher than the airflow rate during normal breathing to encourage deeper and faster voluntary breathing.</li>
		<li>Then set the trigger function. When the instantaneous airflow rate of an isolated voluntary inhalation reaches or beyond the threshold, the LabView program triggers and delivers a single electrical stimulus with preset duration and intensity16. Allow the subject to rest upon request.</li>
	</ol>
	</li>
	<li>Randomly-triggered electrical stimulation (EStim):
	<ol>
		<li>Allow the subject breathe normally without specific instructions on breathing.</li>
		<li>The LabView program randomly delivers a single electrical stimulus with preset duration and intensity every 4 to 7 sec. Similarly, allow the subject to rest upon request.</li>
	</ol>
	</li>
</ol>
5. Dose of BreEStim
It is recommended that each session of treatment has 100 to 120 BreEStim stimuli. It lasts approximately 30-40 min.
6. Recording and Monitoring
<ol>
	<li>Make sure there is no air leakage from the facemask, since voluntary inhalation plays an important role in this protocol.</li>
	<li>Monitor signs of hypoxemia and hyperventilation when the subject wears facemask. Allow rest at the subject's request for this purpose.</li>
	<li>Record any side effect, tolerance of voluntary breathing via a face mask, and any psycho-social effects.</li>
	<li>For pain management, record any reduction of pain, i.e., visual analogue scores (VAS) 57 and duration of the effect. Use the modified VAS (mVAS) to further quantify the effect of pain reduction, i.e., how much pain is reduced and how long it lasts (reduction &times; hours). Also record the average intensity for each session, since the intensity of electrical stimulation varies during each session of treatment.</li>
	<li>For spasticity management, record the Modified Ashworth Scale (MAS) value of the target muscle and other clinical measurements, including strength, sensation, and range of motion.</li>
</ol>

Method and apparatus of breathing-controlled electrical simulation for skeletal muscles (inventor: S.L., pending patent, application number 12146176).

Breathing-controlled electrical stimulation (BreEStim), as shown in the above two cases, has demonstrated clinical efficacy in spasticity management and subsequent hand function recovery in chronic stroke patients16, as well as management of neuropathic pain of central origin in the above patient with a spinal cord injury or of peripheral origin in a patient with above-the-knee amputation17. This enhanced clinical outcome and broader clinical applications of BreEStim are attributed to its unique approach. Intervention with electrical stimulation targeted at the short window of voluntary breathing-associated cortical and subcortical activation 40-51 could augment its clinical efficacy via intrinsic physiological coupling, e.g., respiratory-motor coupling for spasticity management16. In this intervention, voluntary breathing becomes critical, particularly voluntary inspiration. Education for patients on proper breathing techniques and accurate measurement of breathing parameters (e.g., no air leakage) are measures to prevent failure of the BreEStim intervention.
The new intervention protocol - BreEStim, has a few advantages, in addition to better efficacy and broader applications.
BreEStim is patient-centered. BreEStim encourages active engagement of patients since voluntary breathing is required 17. Patients feel they actively participate in managing their pain, rather than "a passive participant in their own care". For example, the patient controls the intensity of electrical stimulation, starting from zero to the highest level that the patient could tolerate17. This may enhance their treatment compliance. EMG-triggered EStim also involves active participation36, but the patient can not control the intensity of electrical stimulation.
BreEStim takes an integrative, system-based approach. As demonstrated in an earlier study17, different pain coping mechanisms are integrated into one protocol, including electrical stimulation, acupuncture, aversive stimulation, and the systemic effects of voluntary breathing. As such, patients are able to tolerate high levels of electrical stimulation, leading to enhanced analgesic effects. Such a positive feedback loop (activation of the reward system) results in greater clinical efficacy. Using this integrative, system-based approach, certain signals of voluntary breathing could also be used to identify the time window of interactions between systems. As such, BreEStim could be applied to patients with severe spasticity. These patients are usually not able to perform voluntary contraction, thus "clean" EMG signals from the target muscle are not available. In EMG-triggered electrical stimulation, EMG signals from the targeted muscles (e.g., finger extensors) are required to trigger electrical stimulation. Therefore, application of EMG-triggered EStim is limited to patients with mild to moderate spasticity.
BreEStim is a non-invasive, non-pharmacological treatment. This is critical because patients often require a long-term use of medications, and most medications for chronic pain and spasticity have side effects that can sometimes be very severe. The possible side effects include addiction, overdose, withdrawal symptoms, and constipation, etc. These potential side effects could be avoided in the BreEStim treatment.
BreEStim is an alternative choice. The alternative non-pharmacological treatment with better analgesic effects is important, particularly when neuropathic pain is difficult to manage. For example, only 7% of responders reported pharmacological treatment is effective for neuropathic pain following SCI in a postal survey 58.
In summary, this breathing-driven stimulation, BreEStim, is based on the newly discovered phenomenon of intrinsic physiological coupling activated during voluntary breathing. The BreEStim protocol has demonstrated clinical efficacy for neuropathic pain and post-stroke spasticity management. Further research is warranted to examine underlying mechanisms that mediate the intervention effect. Importantly, there may be other applications that have not yet discerned.

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 breathing16, 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 electroacupuncture25, 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 recovery6, 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 cortex6, 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 stroke7, 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 &deg; to 70 &deg; 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.

<table border="1">
 <tbody>
 <tr>
 <td>Name of Reagent/Material</td>
 <td>Company</td>
 <td>Catalogue Number</td>
 <td>Comments</td>
 </tr>
 <tr>
 <td>Electrical stimulator</td>
 <td>Digitimer</td>
 <td>DS7A</td>
 <td><a href="http://www.digitimer.com/" target="_blank">http://www.digitimer.com</a></td>
 </tr>
 <tr>
 <td>Pneumotach system</td>
 <td>Hans Rodolph Inc</td>
 <td>Series 1110A</td>
 <td><a href="http://www.rudolphkc.com/" target="_blank">http://www.rudolphkc.com</a></td>
 </tr>
 </tbody>
</table>

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. Based upon recent discoveries related to the systemic effects of voluntary breathing and intrinsic physiological interactions among systems during voluntary breathing, a new EStim protocol, Breathing-controlled Electrical Stimulation (BreEStim), has been developed to augment the effects of electrical stimulation. In BreEStim, a single-pulse electrical stimulus is triggered and delivered to the target area when the airflow rate of an isolated voluntary inspiration reaches the threshold. BreEStim integrates intrinsic physiological interactions that are activated during voluntary breathing and has demonstrated excellent clinical efficacy. Two representative applications of BreEStim are reported with detailed protocols: management of post-stroke finger flexor spasticity and neuropathic pain in spinal cord injury.

Breathing-controlled electrical stimulation (BreEStim) has demonstrated excellent clinical efficacy in management of neuropathic pain in spinal cord injury and post-stroke finger flexor spasticity. Spasticity reduction after BreEStim treatment depends on the severity of pretreatment conditions. As shown in Figure 1, the finger flexor spasticity was greatly reduced after BreEStim treatment. Finger flexor spasticity has been reduced from MAS 1+ to minimum (MAS=0). The patient is able to open his hand and fingers for functional use. It is important to note that other patients may not have the same degree of spasticity reduction and functional improvement. In a patient with severe finger flexor spasticity (MAS=3) and without residual voluntary finger extension (as shown in Figure 4), finger flexor spasticity was reduced to MAS=1. This makes it easier for the patient to range her fingers, but does not restore functional use of her hand.
BreEStim also demonstrates better and longer pain reduction effects. Figure 2 shows that with similar intensity of electrical stimulation, BreEStim has better outcome than regular electrical stimulation. However, BreEStim did not affect pain scores on Day 2 when the patient had a urinary tract infection. This suggests that BreEStim has no effect on pain reduction when pain is confounded by infection.
Voluntary breathing plays a key role in BreEStim. It is important to choose a facemask that fits the patient (Figure 5) to prevent air leakage. The airflow rate is relatively low during normal breathing (1.6 liter/sec, Figure 6). Forceful voluntary inhalation could greatly increase the airflow rate (about 8 liter/sec). Placement of surface electrodes is also important. As described in detail and shown in Figure 3 and Figure 4, placement for pain and spasticity management is different. It is necessary to note that location of muscle belly of finger extensors may change as a result of atrophy, deformity after stroke.
<img alt="Figure 1" src="/files/ftp_upload/50077/50077fig1.jpg" /> 
 Figure 1. Comparison of hand posture pre- and post-BreEStim. The stroke patient could open his hand after BreEStim.
<img alt="Figure 2" fo:content-width="4.5in" fo:src="/files/ftp_upload/50077/50077fig2highres.jpg" src="/files/ftp_upload/50077/50077fig2.jpg" /> 
 Figure 2. Comparison of BreEStim and EStim effects on pain reduction.
<img alt="Figure 3" src="/files/ftp_upload/50077/50077fig3.jpg" /> 
 Figure 3. Location of Neiguan. Note, Waiguan is the counterpart of Neiguan on the dorsal aspect of the forearm.
<img alt="Figure 4" src="/files/ftp_upload/50077/50077fig4.jpg" /> 
 Figure 4. Placement of surface electrodes on finger extensors.
<img alt="Figure 5" src="/files/ftp_upload/50077/50077fig5.jpg" /> 
 Figure 5. A patient during BreEStim. Surface electrodes are placed on Neiguan and Waiguan.
<img alt="Figure 6" fo:content-width="4.5in" fo:src="/files/ftp_upload/50077/50077fig6highres.jpg" src="/files/ftp_upload/50077/50077fig6.jpg" /> 
 Figure 6. real-time measurement of airflow rate during voluntary inspiration and resting inspiration. Note that the airflow rate is much higher during voluntary inspiration than resting inspiration. It is noticeable that patient's breathing was interrupted by electrical stimulation.

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

The purpose is to present a new method, breathing-control electrical stimulation (BreEStim) for management of neuropathic pain and spasticity.

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. ...

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22.8K Views.  University of Texas Health Science Center at Houston. The purpose is to present a new method, breathing-control electrical stimulation (BreEStim) for management of neuropathic pain and spasticity.

Video: Breathing-controlled Electrical Stimulation BreEStim for Management of Neuropathic Pain and Spasticity

Programmed Electrical Stimulation in Mice

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ventricular arrhythmias, and sudden cardiac death.1 Intracardiac pacing studies can be performed in mice using a 1.1F octapolar catheter inserted into the jugular vein, and advanced into the right atrium and ventricle. Here, we illustrate the steps involved in performing programmed electrical stimulation in mice. Surface ECG and intracardiac electrograms are recorded simultaneously in the atria, atrioventricular junction, and ventricular myocardium, whereas intracardiac pacing of the atrium is performed using an external stimulator. Thus, programmed electrical stimulation in mice provides unique opportunities to explore molecular mechanisms underlying conduction defects and cardiac arrhythmias.

Programmed electrical stimulation provides the ability to determine conduction properties of the heart, and the possibility to induce and terminate cardiac arrhythmias using various pacing protocols. Using a transvenous catheter, intracardiac electrogram recordings can be obtained in mice following programmed electrical stimulation protocols to identify arrhythmogenic substrates.

Genetically-modified mice have emerged as a preferable animal model to study the molecular mechanisms underlying conduction abnormalities, atrial and ...

A Murine Model of Muscle Training by Neuromuscular Electrical Stimulation

Neuromuscular electrical stimulation (NMES) is a common clinical modality that is widely used to restore1, maintain2 or enhance3-5 muscle functional capacity. Transcutaneous surface stimulation of skeletal muscle involves a current flow between a cathode and an anode, thereby inducing excitement of the motor unit and the surrounding muscle fibers. 
NMES is an attractive modality to evaluate skeletal muscle adaptive responses for several reasons. First, it provides a reproducible experimental model in which physiological adaptations, such as myofiber hypertophy and muscle strengthening6, angiogenesis7-9, growth factor secretion9-11, and muscle precursor cell activation12 are well documented. Such physiological responses may be carefully titrated using different parameters of stimulation (for Cochrane review, see 13). In addition, NMES recruits motor units non-selectively, and in a spatially fixed and temporally synchronous manner14, offering the advantage of exerting a treatment effect on all fibers, regardless of fiber type. Although there are specified contraindications to NMES in clinical populations, including peripheral venous disorders or malignancy, for example, NMES is safe and feasible, even for those who are ill and/or bedridden and for populations in which rigorous exercise may be challenging. 
Here, we demonstrate the protocol for adapting commercially available electrodes and performing a NMES protocol using a murine model. This animal model has the advantage of utilizing a clinically available device and providing instant feedback regarding positioning of the electrode to elicit the desired muscle contractile effect. For the purpose of this manuscript, we will describe the protocol for muscle stimulation of the anterior compartment muscles of a mouse hindlimb.

A murine model of neuromuscular electrical stimulation (NMES), a safe and inexpensive clinical modality, to the anterior compartment muscles is described. This model has the advantage of modifying a readily available clinical device for the purpose of eliciting targeted and specific muscle contractions in mice.

Neuromuscular electrical stimulation (NMES) is a common clinical modality that is widely used to restore1, maintain2 or enhance3-5 muscle functional ...

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the &#34;cuff model&#34; of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

Neuropathic pain is a consequence of a lesion or disease affecting the somatosensory system. The &#8220;cuff model&#8221; of neuropathic pain in mice consists of the implantation of a polyethylene cuff around the main branch of the sciatic nerve. Mechanical allodynia is tested using von Frey filaments.

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in ...

Chronic Constriction Injury of the Rat's Infraorbital Nerve (IoN-CCI) to Study Trigeminal Neuropathic Pain

Animal models are important tools to study the pathophysiology and pharmacology of neuropathic pain. This manuscript describes the surgical and behavioral procedures to study trigeminal neuropathic pain in rats. To meet the specificity of trigeminal neuropathic pain syndromes, the infraorbital nerve (IoN) is subjected to a chronic constriction injury (CCI) by loosely ligating the nerve. An intra-orbital approach is presented here to expose and ligate the IoN in the orbital cavity. After IoN ligation, rats exhibit changes in spontaneous behavior and in response to von Frey hair stimulation that are indicative of persistent pain and mechanical allodynia. Two phases can be defined in the development of the behavioral changes. During the first week following IoN-CCI (phase 1), rats show an increased and asymmetric face grooming activity, i.e., with face wash strokes primarily directed to the nerve-injured IoN territory. A distinction is made between face grooming behavior that is part of a more general body grooming behavior, which remains largely unaffected by IoN-CCI, and face grooming that is neither preceded nor followed by body grooming, which is significantly increased after IoN-CCI. During this period, responsiveness to mechanical stimulation of the IoN territory is reduced. This hyporesponsiveness is abruptly replaced by an extreme hyperresponsiveness whereby even very weak stimulus intensities provoke nocifensive behavior (phase 2). The phenomenological similarities between these behavioral alterations and reported signs of facial pain (i.e., responses to noxious stimulation of the face) suggest the presence of dysesthesia/paresthesia and mechanical allodynia in the ligated IoN territory.

Chronic Constriction Injury of the Rat&#039;s Infraorbital Nerve IoN-CCI to Study Trigeminal Neuropathic Pain

This manuscript describes a rodent model to study trigeminal neuropathic pain. The methods described include surgical procedures to perform a chronic constriction injury of the rat&#8217;s infraorbital nerve and the post-surgical behavioral tests to measure the changes in spontaneous and evoked behavior that are indicative of persistent pain and allodynia.

Animal models are important tools to study the pathophysiology and pharmacology of neuropathic pain. This manuscript describes the surgical and behavioral ...

Subcutaneous Trigeminal Nerve Field Stimulation for Refractory Facial Pain

Chronic or neuropathic trigeminal facial pain can be challenging to treat. Neurosurgical procedures should be applied when conservative treatment fails. Neuromodulation techniques for chronic facial pain include deep brain stimulation and motor cortex stimulation, which are complex to perform. Subcutaneous nerve field stimulation is certified for chronic back pain and is the least invasive form of neuromodulation. We applied this technique to treat chronic and neuropathic trigeminal pain as an individual therapy concept. First, trial stimulation is performed. Subcutaneous leads are placed in the painful trigeminal dermatome under local anesthesia. The leads are connected to an external neurostimulator that applies constant stimulation. Patients undergo a 12 day outpatient trial to assess the effect of the stimulation. Electrodes are removed after the trial. If the patient reports pain reduction of at least 50% in intensity and/or attack frequency, a reduction in medication or increase in quality of life, permanent implantation is scheduled. New electrodes are implanted under general anesthesia and are subcutaneously tunneled to an infraclavicular internal pulse generator. Patients are able to turn stimulation on and off and to increase or decrease the stimulation amplitude as needed.
This technique represents a minimal invasive alternative to other more invasive means of neuromodulation for trigeminal pain such as motor cortex stimulation or deep brain stimulation.

Treating chronic or neuropathic facial pain can be challenging when medical or standard treatment fails. Subcutaneous nerve field stimulation is the least invasive form of neuromodulation and is used for chronic back pain. We applied this technology to treat chronic and neuropathic trigeminal facial pain.

Chronic or neuropathic trigeminal facial pain can be challenging to treat. Neurosurgical procedures should be applied when conservative treatment fails. ...

Updated Technique for Reliable, Easy, and Tolerated Transcranial Electrical Stimulation Including Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of brain stimulation presents several potential advantages compared to other techniques, as it is noninvasive, cost-effective, broadly deployable, and well-tolerated provided proper equipment and protocols are administered. Even though tDCS is apparently simple to perform, correct administration of the tDCS session, especially the electrode positioning and preparation, is vital for ensuring reproducibility and tolerability. The electrode positioning and preparation steps are traditionally also the most time consuming and error-prone. To address these challenges, modern tDCS techniques, using fixed-position headgear and pre-assembled sponge electrodes, reduce complexity and setup time while also ensuring that the electrodes are consistently placed as intended. These modern tDCS methods present advantages for research, clinic, and remote-supervised (at home) settings. This article provides a comprehensive step-by-step guide for administering a tDCS session using fixed-position headgear and pre-assembled sponge electrodes. This guide demonstrates tDCS using commonly applied montages intended for motor cortex and dorsolateral prefrontal cortex (DLPFC) stimulation. As described, selection of the head size and montage-specific headgear automates electrode positioning. Fully assembled pre-saturated snap-electrodes are simply affixed to the set position snap-connectors on the headgear. The modern tDCS method is shown to reduce setup time and reduce errors for both novice and expert operators. The methods outlined in this article can be adapted to different applications of tDCS as well as other forms of transcranial electrical stimulation (tES) such as transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). However, since tES is application specific, as appropriate, any methods recipe is customized to accommodate subject, indication, environment, and outcome specific features.

When administering transcranial direct current stimulation (tDCS), reproducible electrode preparation and placement are vital for a tolerated and effective session. The purpose of this article is to demonstrate updated modern setup procedures for the administration of tDCS and related transcranial electrical stimulation techniques, such as transcranial alternating current stimulation (tACS).

Transcranial direct current stimulation (tDCS) is a noninvasive method of neuromodulation using low-intensity direct electrical currents. This method of ...

Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies

Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. Chronic neuropathic pain results from lesions or diseases in the somatosensory system. To investigate potential therapies with reduced side effects, animal pain models are the gold standard in preclinical studies. Therefore, well-characterized and well-described models are crucial for the development and validation of innovative therapies. 
Partial ligation of the sciatic nerve (pSNL) is a procedure that induces chronic neuropathic pain in mice, characterized by mechanical and thermal hypersensitivity, ongoing pain, and changes in limb temperature, making this model a great fit to study neuropathic pain preclinically. pSNL is an advantageous model to study neuropathic pain as it reproduces many symptoms observed in humans with neuropathic pain. Furthermore, the surgical procedure is relatively fast and straightforward to perform. Unilateral pSNL of one limb allows for comparison between the ipsilateral and contralateral paws, as well as evaluation of central sensitization. 
To induce chronic neuropathic hypersensitivity, a 9-0 non-absorbable nylon thread is used to ligate the dorsal third of the sciatic nerve. This article describes the surgical procedure and characterizes the development of chronic neuropathic pain through multiple commonly used behavioral tests. As a plethora of innovative therapies are now being investigated to treat chronic pain, this article provides crucial concepts for standardization and an accurate description of surgeries required to induce neuropathic pain.

Partial sciatic nerve ligation induces long-lasting chronic neuropathic pain, characterized by exaggerated responses to thermal and mechanical stimuli. This mouse model of neuropathic pain is commonly used to study innovative therapies for pain management. This article describes in detail the surgical procedure to improve standardization and reproducibility.

Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. ...

Gastric Ultrasound Technique for Mitigating Peri-Procedural Aspiration Risk

Gastric Point of Care Ultrasound in Adults: Image Acquisition and Interpretation

Over the past two decades, diagnostic point-of-care ultrasound (POCUS) has emerged as a rapid and non-invasive bedside tool for addressing clinical inquiries related to gastric content. One emerging concern pertains to patients about to undergo sedation and/or endotracheal intubation: the elevated risk of aspiration from the patient&#39;s stomach contents. Aspiration of gastric contents into the lungs poses a serious and potentially life-threatening complication. This occurs more frequently when the stomach is considered &#34;full&#34; and can be affected by the techniques employed for airway management, making it potentially preventable. To mitigate the risk of peri-procedural aspiration, two distinct medical specialties (anesthesiology and critical care medicine) have independently developed techniques to utilize ultrasonography for identifying patients requiring &#34;full stomach&#34; precautions. Due to these separate specialties, the work of each group remains relatively unfamiliar outside its respective field. This article presents descriptions of both techniques for gastric ultrasound. Furthermore, it explains how these approaches can complement each other when one of them falls short. Regarding image acquisition, the article covers the following topics: indications and contraindications, selection of the appropriate probe, patient positioning, and troubleshooting. The article also delves into image interpretation, complete with example images. Additionally, it demonstrates how one of the two techniques can be employed to estimate gastric fluid volume. Lastly, the article briefly discusses medical decision-making based on the findings of this examination.

Author Spotlight: Point-of-Care Ultrasound for Gastric Content Assessment and Risk Stratification in Perioperative Care 

This protocol introduces two methods for image acquisition in gastric ultrasonography. Additionally, tips are provided for interpreting this information to assist in medical decision-making.

Over the past two decades, diagnostic point-of-care ultrasound (POCUS) has emerged as a rapid and non-invasive bedside tool for addressing clinical ...

Assessing the Efficacy of Cranial Electrical Stimulation in Fibromyalgia

A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive disturbances, and other somatic complaints. Available therapies are often insufficient in treating symptoms, with inadequate pain control commonly leading to opioid usage for attempted management. Cranial electrical stimulation (CES) is a promising non-pharmacologic treatment option for pain conditions that uses pulsed electrical current stimulation to modify&#160;brain function via transcutaneous electrodes. These neural mechanisms and the applications of CES in fibromyalgia symptom relief require further exploration.
A total of 50 participants from the Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosed with fibromyalgia were enrolled and then block-randomized into either a placebo plus standard therapy or active CES plus standard therapy group. Baseline assessments were obtained prior to the start of treatment. Both interventions occurred over 12 weeks, and participants were assessed at 6 weeks and 12 weeks after treatment initiation. The primary outcome investigated whether pain and functional improvements occur with the application of CES. Additionally, baseline and follow-up resting state functional connectivity magnetic resonance imaging (rs-fcMRI) were obtained at the 6-week and 12-week time points to assess for clinical applications of neural connectivity biomarkers and the underlying neural associations related to treatment effects.
This is a randomized, placebo-controlled trial to determine the efficacy of CES for improving pain and function in fibromyalgia and further develop rs-fcMRI as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Author Spotlight: Methodologies and Advancements of Chronic Pain Management Research

The current study is a randomized, placebo-controlled trial to determine the efficacy of cranial electrical stimulation (CES) for improving pain and function in fibromyalgia and further develop resting functional connectivity magnetic resonance imaging (rs-fcMRI) as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive ...

RPNI Surgery for Treating Postamputation Pain

Regenerative Peripheral Nerve Interface: Surgical Protocol for a Randomized Controlled Trial in Postamputation Pain

Surgical procedures, including nerve reconstruction and end-organ muscle reinnervation, have become more prominent in the prosthetic field over the past decade. Primarily developed to increase the functionality of prosthetic limbs, these surgical procedures have also been found to reduce postamputation neuropathic pain. Today, some of these procedures are performed more frequently for the management and prevention of postamputation pain than for prosthetic fitting, indicating a significant need for effective solutions to postamputation pain. One notable emerging procedure in this context is the Regenerative Peripheral Nerve Interface (RPNI). RPNI surgery involves an operative approach that entails splitting the nerve end longitudinally into its main fascicles and implanting these fascicles within&#160;free denervated and devascularized muscle grafts. The RPNI procedure takes a proactive stance in addressing freshly cut nerve endings, facilitating painful neuroma prevention and treatment by enabling the&#160;nerve to regenerate and innervate an end organ, i.e., the free muscle graft. Retrospective studies have shown RPNI&#39;s effectiveness in alleviating postamputation pain and preventing the formation of painful neuromas. The increasing frequency of utilization of this approach has also given rise to variations in the technique. This article aims to provide a step-by-step description of the RPNI procedure, which will serve as the standardized procedure employed in an international, randomized controlled trial (ClinicalTrials.gov, NCT05009394). In this trial, RPNI is compared to two other surgical procedures for postamputation pain management, specifically, Targeted Muscle Reinnervation (TMR) and neuroma excision coupled with intra-muscular transposition and burying.

Author Spotlight: Regenerative Peripheral Nerve Interface (RPNI) Surgery in Postamputation Pain Management

Here, we describe the surgical procedure to perform Regenerative Peripheral Nerve Interface (RPNI) surgery for treating postamputation neuropathic pain in the context of an international, randomized controlled trial (RCT) (ClinicalTrials.gov, NCT05009394). The RCT compares RPNI with two other surgical techniques, namely, Targeted Muscle Reinnervation (TMR) and neuroma excision combined with intra-muscular transposition.

Surgical procedures, including nerve reconstruction and end-organ muscle reinnervation, have become more prominent in the prosthetic field over the past ...