Restoration of respiratory muscle function following spinal cord injury. Review of electrical and magnetic stimulation techniques

Respiratory complications are a leading cause of morbidity and mortality in patients with spinal cord injury. Several techniques, currently available or in development, have the capacity to restore respiratory muscle function allowing these patients to live more normal lives and hopefully reduce the incidence of respiratory complications. Bilateral phrenic nerve pacing, a clinically accepted technique to restore inspiratory muscle function, allows patients with ventilator dependent tetraplegia complete freedom from mechanical ventilation. Compared to mechanical ventilation, phrenic nerve pacing provides patients with increased mobility, improved speech, improved comfort level and reduction in health care costs. The results of clinical trials of laparoscopically placed intramuscular diaphragm electrodes suggest that diaphragm pacing can also be achieved without the need for a thoracotomy and associated long hospital stay, and without manipulation of the phrenic nerve which carries a risk of phrenic nerve injury. Other clinical trials are being performed to restore inspiratory intercostal function. In patients with only unilateral phrenic nerve function who are not candidates for phrenic nerve pacing, combined intercostal and unilateral diaphragm pacing appears to provide benefits similar to that of bilateral diaphragm pacing. Clinical trials are also underway to restore expiratory muscle function. Magnetic stimulation, surface stimulation and spinal cord stimulation of the expiratory muscles are promising techniques to restore an effective cough mechanism in this patient population. These techniques hold promise to reduce the incidence of respiratory tract infections, atelectasis and respiratory failure in patients with spinal cord injury and reduce the morbidity and mortality associated with these complications.     

Ventilatory support by pacing of the conditioned diaphragm in quadriplegia

We provided full-time ventilatory support in five patients with respiratory paralysis accompanying quadriplegia by continuous electrical pacing of both hemidiaphragms simultaneously for 11 to 33 months through the application to the phrenic nerves of a low-frequency stimulus. The strength and endurance of the diaphragm muscle increased with pacing. Biopsy specimens taken from two patients who had uninterrupted stimulation for 6 and 16 weeks showed changes suggestive of the development of fatigue-resistant muscle fibers. When we compared these results with those of our earlier experience with intermittent unilateral stimulation of the diaphragm in 17 patients with respiratory paralysis, we found that continuous bilateral pacing using low-frequency stimulation appeared to be superior because of more efficient ventilation of both lungs, fewer total coulombs required to effect the same ventilation, and absence of myopathic changes in the diaphragm muscle. For patients with respiratory paralysis and intact phrenic nerves, continuous simultaneous pacing of both hemidiaphragms with low-frequency stimulation and a slow respiratory rate is a satisfactory method of providing full-time ventilatory support.     

Substance P-like immunoreactivity in the phrenic nerve and diaphragm: axonal transport of substance P in the phrenic nerve

Substance P-like immunoreactivity was demonstrated in the phrenic nerve of rat in quantities similar to that found in vagus and sciatic nerves. In the diaphragm, the peptide was concentrated in the motor endplate zone. A surgical cut of the phrenic nerve was followed by disappearance of substance P from the motor endplate zone. In addition we could demonstrate axonal transport of substance P in the phrenic nerve after transection of the nerve.     

Transcutaneous,dual channel phrenic nerve stimulator for diaphragm pacing

An electrical stimulation system for bilateral diaphragm pacing was constructed. The stimulator instrument comprises a transmitter and two implantable receivers and nerve electrodes. An optimised transcutaneous link system is described which utilises a radio frequency coupling to transmit both power and stimulus information to the receiver. The receiver unit was constructed in thick-film hybrid technology using bipolar and c.m.o.s. circuits and was packaged in a hermetically sealed metal case. The construction of the transmitter allows a high reliability, low power consumption and flexibility of the stimulus parameter control. A complete, bilateral phrenic nerve pacing system was implanted into a patient suffering from tetraplegia. It is concluded that electrical phrenic nerve stimulation to pace the diaphragm is capable of being used in clinical therapy.     

5-Hydroxytryptamine in the phrenic nerve diaphragm: evidence for its existence and release

Evidence is presented for the existence of 5-hydroxytryptamine (5-HT) within the phrenic nerve of the rat and its release following electrical stimulation. Contents of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the phrenic nerve and the indoleamine released into the bathing fluid were estimated fluorimetrically after isolation on Sephadex G-10 and/or solvent-solvent extraction. Bioassays of 5-HT were done on rat fundus strip. The phrenic nerve and the end-plate zone contains high levels of 5-HT (1.9 micrograms/g wet weight) and 5-HIAA (1.5 micrograms/g wet weight). The resting release of around 1 ng 5-HT/diaphragm/min was enhanced by 50% (1.5 ng 5-HT/diaphragm/min) upon supramaximal (2-4 V) electrical stimulation of 5 Hz. Phrenic nerve diaphragm prepared from the denervated and p-chlorophenylalanine (300 mg/kg/day i.p. for 3 days) treated rats failed to release 5-HT confirming the neuronal origin and the identity of the indoleamine respectively. Furthermore, methysergide, an antagonist of 5-HT in rat fundus strip, blocked the response obtained by the sample on it. A modulatory role of 5-HT in the phrenic nerve diaphragm of the rat is envisaged from the present study.     

Cartography of human diaphragmatic innervation: preliminary data

In humans, anatomy indicates that the phrenic nerve mainly arises from the C4 cervical root, with variable C3 and C5 contributions. How this translates into functional innervation is unknown. The diaphragm response to electrical stimulation of C3, C4 and C5 was described in three patients undergoing surgical laryngeal reinnervation with an upper phrenic root (surface chest electrodes at anterior, lateral and posterior sites; oesophageal and gastric pressures (Pes and Pga) to derive transdiaphragmatic pressure (Pdi)). Anatomically, the phrenic nerve predominantly originated from C4. Phrenic stimulation elicited motor responses at the three sites in the three patients, as did C4 stimulation. It produced Pdi values of 9, 11, and 14cmH(2)O in the three patients, respectively, vs. 9, 9, and 7cmH(2)O for C4. C3 stimulation produced modest Pdi responses, whereas C5 stimulation could produce Pdi responses close to those observed with C4 stimulation. These singular observations confirm the dominance of C4 in diaphragm innervation but suggest than C5 can be of importance.     

Phrenic nerve stimulation in patients with spinal cord injury

Phrenic nerve pacing (PNP) is a clinically useful technique to restore inspiratory muscle function in patients with respiratory failure secondary to cervical spinal cord injury. In this review, patient evaluation, equipment, methods of implementation, clinical outcomes, and the complications and side effects of PNP are discussed. Despite considerable technical development, and clinical success, however, current PNP systems have significant limitations. Even in patients with intact phrenic nerve function, PNP is successful in achieving full-time support in ～50% of patients. Inadequate inspired volume generation may arise secondary to incomplete diaphragm activation, reversed recruitment order of motor units, fiber type conversion resulting in reduced force generating capacity and lack of coincident intercostal muscle activation. A novel method of pacing is under development which involves stimulating spinal cord tracts which synapse with the inspiratory motoneuron pools. This technique results in combined activation of the intercostal muscles and diaphragm in concert and holds promise to provide a more physiologic and effective method of PNP.     

Augmentation of muscle nociceptive respiratory reflex facilitation by vagal afferents

Vagal influence on the facilitation of phrenic neural activity during respiratory phase-locked, gastrocnemius muscle nerve nociceptive electrical stimulation was examined in anesthetized, glomectomized, paralyzed, and artificially ventilated cats. (1) In the vagi-intact state, respiratory reflex facilitation was characterized by a sharp rise in peak amplitude, maximum rate of rise or slope, and mean rate of rise of integrated phrenic nerve activity. This was greater during inspiratory phase-locked (T1-locked) muscle nerve electrical stimulation than during expiratory phase-locked (TE-locked) muscle nerve electrical stimulation. "Evoked post-inspiratory phrenic activity" during the early expiratory phase was also observed during TE-locked muscle nerve electrical stimulation. (2) Bilateral vagotomy significantly attenuated the respiratory facilitation during both T1- and TE-locked muscle nerve electrical stimulation. In particular, the "evoked post-inspiratory phrenic activity" during TE-locked muscle nerve electrical stimulation was also attenuated or almost completely abolished. (3) Conditioning electrical stimulation of the vagus nerve revealed facilitatory reflexes which co-exist with inspiratory inhibitory reflexes. (4) The "evoked post-inspiratory phrenic activity" during TE-locked muscle nerve electrical stimulation, which was attenuated or abolished after vagotomy, was restored after vagal T1-locked conditioning stimuli combined with TE-locked muscle nerve electrical stimulation. The results suggest that vagal facilitatory reflexes augment the respiratory reflex facilitation during muscle nociceptive stimulation.     

Role of the ventrolateral region of the nucleus of the tractus solitarius in processing respiratory afferent input from vagus and superior laryngeal nerves

Summary The role of respiratory neurons located within and adjacent to the region of the ventrolateral nucleus of the tractus solitarius (vlNTS) in processing respiratory related afferent input from the vagus and superior laryngeal nerves was examined. Responses in phrenic neural discharge to electrical stimulation of the cervical vagus or superior laryngeal nerve afferents were determined before and after lesioning the vlNTS region. Studies were conducted on anesthetized, vagotomized, paralyzed and artificially ventilated cats. Arrays of 2 to 4 tungsten microelectrodes were used to record neuronal activity and for lesioning. Constant current lesions were made in the vlNTS region where respiratory neuronal discharges were recorded. The region of the vlNTS was probed with the microelectrodes and lesions made until no further respiratory related neuronal discharge could be recorded. The size and placement of lesions was determined in subsequent microscopic examination of 50 m thick sections. Prior to making lesions, electrical stimulation of the superior laryngeal nerve (4–100 A, 10 Hz, 0.1 ms pulse duration) elicited a short latency increase in discharge of phrenic motoneurons, primarily contralateral to the stimulated nerve. This was followed by a bilateral decrease in phrenic nerve discharge and, at higher currents, a longer latency increase in discharge. Stimulation of the vagus nerve at intensities chosen to selectively activate pulmonary stretch receptor afferent fibers produced a stimulus (current) dependent shortening of inspiratory duration. Responses were compared between measurements made immediately before and immediately after each lesion so that changes in response efficacy due to lesions per se could be distinguished from other factors, such as slight changes in the level of anesthesia over the several hours necessary in some cases to complete the lesions. Neither uni- nor bi-lateral lesions altered the efficacy with which stimulation of the vagus nerve shortened inspiratory duration. The short latency excitation of the phrenic motoneurons due to stimulation of the superior laryngeal nerve was severely attenuated by unilateral lesions of the vlNTS region ipsilateral to the stimulated nerve. Neither the bilateral inhibition nor the longer latency excitation due to superior laryngeal nerve stimulation was reduced by uni- or bi-lateral lesions of the vlNTS region. These results demonstrate that extensive destruction of the region of the vlNTS: a) does not markedly affect the inspiratory terminating reflex associated with electrical stimulation of the vagus nerve in a current range selective for activation of pulmonary stretch receptor afferents, and b) abolishes the short-latency increase, but not the bilateral decrease or longer latency increase in phrenic motoneuronal discharge which follows stimulation of the superior laryngeal nerve. We conclude that respiratory neurons in the region of the vlNTS do not play an obligatory role in the respiratory phase transitions in this experimental preparation. Neurons in the vlNTS region may participate in other reflexes, such as the generation of augmented phrenic motoneuronal discharge in response to activation of certain superior laryngeal or vagus nerve afferents.     

Bilateral reflex effects on phrenic nerve activity in response to single-shock vagal stimulation

The bilateral reflex actions of vagus nerve afferent signals on phrenic efferent activity have been tested by unilateral graded single shock electrical stimulation. An early excitation (latency 3–5 msec) was more prominent in the phrenic nerve contralateral to the stimulated vagus. Spinal cord hemisection at C₃ eliminated both contralateral and ipsilateral responses: thus, both were mediated via descending tracts in the contralateral cord. A bilaterally symmetrical early inhibition (latency 8–12 msec) followed the early excitation. The electrical thresholds for evoking the early responses and the temperature for blocking these responses during graded vagal cooling were closely similar to the threshold and blocking temperature for pulmonary stretch receptor afferents. Higher stimulus strengths evoked a strong, bilaterally similar, late excitation (latency 12–20 msec) followed by a late inhibition. At very high stimulus strengths a third excitation (latency 25–30 msec) could appear. Sometimes these responses were followed by lowered phrenic activity for the remainder of inspiration. Single shock stimulation of the intact vagus nerve or of the peripheral end of the cut recurrent laryngeal nerve provoked. by the contraction of laryngeal muscles, a strong, short latency (12 msec) inhibition of phrenic activity mediated by superior laryngeal nerve afferents. The implications of these results with respect to the reflex pathways of the different responses and their possible integration in the central respiratory control mechanisms are discussed.     

Right-sided vagus nerve stimulation inhibits induced spinal cord seizures

We have previously shown that left-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. To test our hypothesis that right-sided vagus nerve stimulation will also abort seizure activity, we have initiated seizures in the spinal cord and then performed right-sided vagus nerve stimulation in an animal model. Four pigs were anesthetized and placed in the lateral position and a small laminectomy performed in the lumbar region. Topical penicillin, a known epileptogenic drug to the cerebral cortex and spinal cord, was next applied to the dorsal surface of the exposed cord. With the exception of the control animal, once seizure activity was discernible via motor convulsion or increased electrical activity, the right vagus nerve previously isolated in the neck was stimulated. Following multiple stimulations of the vagus nerve and with seizure activity confirmed, the cord was transected in the midthoracic region and vagus nerve stimulation performed. Right-sided vagus nerve stimulation resulted in cessation of spinal cord seizure activity in all animals. Transection of the spinal cord superior to the site of seizure induction resulted in the ineffectiveness of vagus nerve stimulation in causing cessation of seizure activity in all study animals. As with left-sided vagus nerve stimulation, right-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. Additionally, the effects of right-sided vagus nerve stimulation on induced spinal cord seizures involve descending spinal pathways. These data may aid in the development of alternative mechanisms for electrical stimulation for patients with medically intractable seizures and add to our knowledge regarding the mechanism for seizure cessation following peripheral nerve stimulation.     

Enhanced recognition memory following vagus nerve stimulation in human subjects

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.     

Diaphragmatic effects of selective resection of the upper phrenic nerve root in dogs

The aim of this study was to evaluate the effects on the diaphragm of upper phrenic nerve root resections in dogs. During laryngeal reinnervation, selective resections of the upper phrenic nerve root (C5) were performed unilaterally (right side, n=7; Group A) and bilaterally (n=6; Group B) and compared to non denervated animals (n=5). After 8 months, a diaphragmatic evaluation was performed: X-ray, EMG, transdiaphragmatic pressure (Pdi) after ipsi- and bilateral tetanic stimulation of the phrenic nerves and a bilateral histological study of five hemidiaphragmatic regions. EMG alterations were significantly more severe in Group B than in Group A, for the left (p<0.05) and right hemidiaphragms (p<0.01). No differences in the X-rays were noted between the three groups. The Pdi of the three groups after occlusion and phrenic nerve stimulations (unilateral and bilateral) were not statistically different. Histological data demonstrated that there were no differences in fibre irregularity, predominant fibre type or fibrosis between the three groups. Macroscopic and microscopic atrophy, which was mainly present on the anterior regions of the hemidiaphragms, was significantly higher in Group B than in Group A and undenervated dogs (p<0.05). In conclusion, resection of the upper phrenic nerve root of one phrenic nerve (right side) have limited effect on the diaphragm in dogs. However, resection of the upper phrenic nerve root on both sides resulted in a significant effect on the EMGs and histology of the entire diaphragm without any significant consequences on transdiaphragmatic pressure.     

Diaphragmatic pacing stimulation in spinal cord injury: anesthetic and perioperative management

OBJECTIVE:

The standard therapy for patients with high-level spinal cord injury is long-term mechanical ventilation through a tracheostomy. However, in some cases, this approach results in death or disability. The aim of this study is to highlight the anesthetics and perioperative aspects of patients undergoing insertion of a diaphragmatic pacemaker.

METHODS:

Five patients with quadriplegia following high cervical traumatic spinal cord injury and ventilator-dependent chronic respiratory failure were implanted with a laparoscopic diaphragmatic pacemaker after preoperative assessments of their phrenic nerve function and diaphragm contractility through transcutaneous nerve stimulation. ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01385384","term_id":"NCT01385384"}}NCT01385384.

RESULTS:

The diaphragmatic pacemaker placement was successful in all of the patients. Two patients presented with capnothorax during the perioperative period, which resolved without consequences. After six months, three patients achieved continuous use of the diaphragm pacing system, and one patient could be removed from mechanical ventilation for more than 4 hours per day.

CONCLUSIONS:

The implantation of a diaphragmatic phrenic system is a new and safe technique with potential to improve the quality of life of patients who are dependent on mechanical ventilation because of spinal cord injuries. Appropriate indication and adequate perioperative care are fundamental to achieving better results.     

A new choice for the treatment of epilepsy: electrical auricula-vagus-stimulation

Preliminary reports have suggested that chronic, intermittent electrical stimulation of the cervical vagus nerve (VNS) is an effective treatment for patients who suffered from medically refractory epilepsy. But the traditional VNS is an invasive and implantable procedure that will bring some injury to the patient. Anatomic studies have confirmed the existence of auricular branch of the vagus nerve—Arnold nerve. The Arnold nerve mainly consists of afferent fibers and the superficial sites of the Arnold nerve are optimal for electrical stimulation. We hypothesized that electrical auricula-vagus-stimulation could be a new choice for the treatment of epilepsy.     

Motor responses of the urinary bladder and skeletal muscle in Botulinum intoxicated rats

1. Type A or type D botulinum toxin administered to rats did not produce a generalized paralysis of skeletal muscles at the time of ventilatory arrest. However, if survival was extended by artificial ventilation complete blockade of neuromuscular transmission developed 6.5 hr after 100 MLD of type D and 5 hr after 1000 MLD of type A toxin. The onset of paralysis of a muscle was shortened by repetitive stimulation of the motor nerves.2. There was no consistent blockade of parasympathetically innervated viscera in animals dying after type A toxin. Animals given type D toxin displayed mydriasis and urinary retention before death.3. Motor responses to electrical stimulation, of bladder preparations in vitro were more vulnerable to type D than to type A toxin. When somatic paralysis was complete in animals treated with type A or type D toxin the excised bladders produced pressure elevations 45 and 25%, respectively, of control preparations.4. During electrical stimulation of bladder preparations nearly paralysed by either toxin, the ACh release was significantly diminished from controls. In the rat bladder botulinum toxin specifically disrupted the liberation of mediator from post-ganglionic nerve endings.     

Persistence of the cardio-inhibitory response to brain stem ischaemia after destruction of the area postrema and the dorsal vagal nuclei

1. In anaesthetized cats, in which the carotid arterial bifurcation had been denervated and the spinal cord transected at the cervical level, reversible bradycardia mediated by the vagus nerves was elicited by temporary arrest of the cranial circulation. Methoxamine was infused intravenously to maintain peripheral vascular resistance, and artificial ventilation was given to avert systemic asphyxia.2. The bradycardia persisted in cats subjected to one or more of the following acute surgical procedures: left vagotomy, mid-collicular decerebration, decerebellation, bulbar transections at the acoustic striae and inferior fovea, and destruction of the area postrema and the underlying dorsal vagal nuclei. Ischaemia-induced bradycardia was invariably abolished after bilateral vagotomy or the administration of atropine.3. Bradycardia could not be elicited by electrical stimulation of the dorsal vagal nuclei, but was evoked by stimulation of deep structures in the vicinity of the nucleus ambiguus even after destruction of the dorsal vagal nuclei.4. Simultaneous application of ischaemia and electrical stimulation of the medullary cardio-decelerator locus produced convergent occlusion of the vagal response. The effect of ischaemia was inhibited by stimulation of a neighbouring region in the medial reticular formation. These interactions indicate that an interneuronal link is involved in the mechanism of ischaemia-induced bradycardia.5. It is concluded that the cardio-decelerator response to ischaemia is initiated upstream to the primary efferent vagal motor neurones and that the cardio-inhibitory fibres do not originate in the dorsal vagal nuclei.     

膈神经的解剖及临床应用研究进展

目的:为膈神经移位治疗臂丛根性撕托伤,提供应用解剖学资料.方法:查阅与膈神经移位治疗臂丛根性撕托伤相关的解剖与临床文献资料,分析其应用价值和意义.结果:提供膈神经在颈部、胸腔内和膈肌内的走行、位置、毗邻及分支分布资料.结论:膈神经移位是用来治疗臂丛根性撕托伤的主要动力神经;臂丛探索仍是诊断臂丛损伤的全标准.     

Responses of ventral respiratory neurones in the rat to vagus stimulation and the functional division of expiration.

In anaesthetized rats, extracellular and intracellular recordings were taken from 106 respiratory neurones in the intermediate region of the nucleus ambiguus. We observed unprovoked shortening of expiratory time accompanied, in all classes of respiratory neurone, by the elimination of the changes in membrane potential that were characteristic of stage II expiration. The demonstration of the elimination of stage II expiration in both the rat and cat strongly supports the functional division of expiration into stage I expiration (post-inspiration) and stage II expiration. In order to identify the neurones in the rat that receive inputs from vagal afferents and modulate the central respiratory rhythm, we examined whether any respiratory neurones responded to stimulation of the vagus nerve. Some post-inspiratory and stage II expiratory neurones responded. The short latency (< 2 ms) of four of the responses indicates that some vagal afferents act on post-inspiratory neurones via a disynaptic pathway. While repetitive stimulation of the vagus nerve could inhibit the phrenic rhythm, it appears that most inspiratory neurones in the intermediate region of the nucleus ambiguous complex are not directly involved in integrating the information from vagal afferents with the central respiratory rhythm.     

Idiopathic diaphragmatic paralysis—Satisfactory improvement of inspiratory muscle function by inspiratory muscle training

Daily inspiratory muscle strength and endurance training (IMT) was performed in a 44-year-old patient with idiopathic bilateral diaphragmatic paralysis (BDP) in addition to nocturnal non-invasive ventilation (NIV). After 4 months of training inspiratory muscle function improved satisfactorily whereas phrenic nerve latency remained pathological. Due to the improvement of inspiratory muscle capacity nocturnal NIV could be stopped without inducing nocturnal respiratory insufficiency.