Anthony F. DiMarco

Clinical Applications of Electrical Stimulation After Spinal Cord Injury

Abstract Summary: During the last one-half century, electrical stimulation has become dinically significant for improving health and restoring useful function afterspinal cord injury. Short-term stimulation can be provided by electrodes on the skin or percutaneous fine wires, but implanted systems are preferable for long-term use. Electrical stimulation of intact lower motor neurons can exercise paralyzed musdes and reverse wasting; improve strength, endurance, and cardiovascular fitness; and may reduce the progression of osteoporosis. Other potential therapeutic uses being investigated indude reduction of spasticity, prevention of deep vein thrombosis, and improvement of tissue health. Pacing of intact phrenic nerves in high tetraplegia can produce effective respiration without mechanical ventilation, allowing improved speech, increased mobility, and increased sense of well-being. lmprovement of cough has also been demonstrated. Stimulation of intact sacral ne.rves can produce effective micturition and reduce urinary tract infection; it can also improve bowel function and erection. lt is usually combined with posterior sacral rhizotomy to improve continence and bladder capacity, and the combination has been shown to reduce costs of care. Electroejaculation can now produce semen in most men with spinal cord injury. Significant achievements have also been made in restoring limb function . Useful hand grasp can be provided in CS and C6 tetraplegia, reducing dependence on adapted equipment and assistants. Standing, assistance with transfers, and walking for short distances can be provided to selected persons with paraplegia, improving their access to objects, places, and opportunities that are inaccessible from a wheelchair. This review summarizes the current state of therapeutic and neuroprosthetic applications of electrical stimulation afterspinal cord injury and identifies some future directions of research and dinical and commercial development.

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.

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 approximately 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.

Inspiratory Muscle Pacing in Spinal Cord Injury: Case Report and Clinical Commentary

Abstract Background/Objective: A significant fraction of patients with cervical spinal cord injury suffer from respiratory muscle paralysis and dependence on chronic mechanical ventilation. In selected patients, diaphragm pacing (DP) through electrical stimulation of the phrenic nerves provides an alternative to mechanical ventilation with significant advantages in life quality. Methods: A case report of an individual who successfully underwent DP using intramuscular diaphragm electrodes. A brief review of the state of the art of DP including the clinical benefits of DP, patient selection and evaluation, description of equipment, methods of transition from mechanical ventilation to DP, potential complications and side effects, long-term outcome, and potential future developments in this field is included. Results: Several available DP systems are available, including conventional ones in which electrodes are positioned directly on the phrenic nerves through thoracotomy and less invasive systems in which electrodes are placed within the diaphragm through laparoscopy. For patients with only unilateral phrenic nerve function, a combined intercostal and unilateral diaphragm pacing system is under development. Conclusions: In patients with ventilator-dependent tetraplegia, there are alternative methods of ventilatory support, which offer substantial benefits compared to mechanical ventilation.

High-frequency spinal cord stimulation of inspiratory muscles in dogs: a new method of inspiratory muscle pacing

Despite clinically available methods of diaphragm pacing, most patients with ventilator-dependent tetraplegia are still dependent on mechanical ventilation. Given the significant disadvantages of these devices, additional pacing options are needed. The objective of this study was to evaluate a novel and potentially more physiological method of inspiratory muscle activation, which involves the application of high-frequency (>200 Hz) stimulation to the ventral surface of the spinal cord in the high thoracic region. Studies were performed in 13 anesthetized dogs. High-frequency spinal cord stimulation (HF-SCS) results in the activation of both the diaphragm and inspiratory intercostal muscles, in concert, at physiological firing frequencies and the generation of large inspired volumes. Mean maximum firing frequencies of motor units in the parasternal (2nd interspace), the external intercostal (3rd interspace), and the diaphragm muscles were 10.6 +/- 0.4, 11.7 +/- 0.4, and 10.4 +/- 0.3 Hz, respectively. These values were not significantly different from those occurring during spontaneous breathing at comparable inspired volumes. Maximum inspired volume was 0.93 +/- 0.01 liter, which approximates the inspiratory capacity of these animals. Moreover, ventilation can be maintained on a chronic basis by this method (6 h) without evidence of system fatigue. Our results suggest that HF-SCS results in activation of spinal cord tracts that synapse with the inspiratory motoneuron pools, allowing processing of the stimulus and consequent physiological activation of the inspiratory muscles. HF-SCS has the potential to provide an effective method of inspiratory muscle pacing.

Lower Thoracic Spinal Cord Stimulation to Restore Cough in Patients With Spinal Cord Injury: Results of a National Institutes of Health–Sponsored Clinical Trial. Part I: Methodology and Effectiveness of Expiratory Muscle Activation

OBJECTIVE Evaluation of the capacity of lower thoracic spinal cord stimulation (SCS) to activate the expiratory muscles and generate large airway pressures and high peak airflows characteristic of cough, in subjects with tetraplegia. DESIGN Clinical trial. SETTING Inpatient hospital setting for electrode insertion; outpatient setting for measurement of respiratory pressures; home setting for application of SCS. PARTICIPANTS Subjects (N=9; 8 men, 1 woman) with cervical spinal cord injury and weak cough. INTERVENTIONS A fully implantable electrical stimulation system was surgically placed in each subject. Partial hemilaminectomies were made to place single-disk electrodes in the epidural space at the T9, T11, and L1 spinal levels. A radiofrequency receiver was placed in a subcutaneous pocket over the anterior portion of the chest wall. Electrode wires were tunneled subcutaneously and connected to the receiver. Stimulation was applied by activating a small portable external stimulus controller box powered by a rechargeable battery to each electrode lead alone and in combination. MAIN OUTCOME MEASURES Peak airflow and airway pressure generation achieved with SCS. RESULTS Supramaximal SCS resulted in high peak airflow rates and large airway pressures during stimulation at each electrode lead. Maximum peak airflow rates and airway pressures were achieved with combined stimulation of any 2 leads. At total lung capacity, mean maximum peak airflow rates and airway pressure generation were 8.6+/-1.8 (mean +/- SE) L/s and 137+/-30 cmH2O (mean +/- SE), respectively. CONCLUSIONS Lower thoracic SCS results in near maximum activation of the expiratory muscles and the generation of high peak airflow rates and positive airway pressures in the range of those observed with maximum cough efforts in healthy persons.

Effects of volume and frequency of mechanical ventilation on respiratory activity in humans

This study evaluated the interaction between respiratory chemical drive and non-chemical factors related to the frequency and level of thoracic displacement during mechanical ventilation in shaping respiratory activity. Ten normal subjects were artificially hyperventilated with a positive-pressure mechanical respirator to a baseline end-tidal PCO2 of approximately 30 Torr. Thereafter, in separate trials, the end-tidal PCO2 was increased by (a) progressively raising the concentration of CO2 in the inspired gas (FICO2) while holding tidal volume (VT) and breathing frequency (f) constant, (b) lowering f while holding VT and FICO2 constant, and (c) lowering VT while maintaining a constant f and FICO2. Initially, as the PCO2 rose above baseline levels with increases in FICO2, there was no change in inspiratory muscle activity, as measured by the peak inspiratory airway pressure, until the PCO2 reached 40 Torr. This PCO2 threshold for a change in respiratory activity was significantly reduced when the tidal volume or frequency of mechanical ventilation was lowered. These results suggest that non-chemical drives related to the frequency and level of thoracic displacement interact with chemical stimuli in shaping respiratory activity.

Lower Thoracic Spinal Cord Stimulation to Restore Cough in Patients with Spinal Cord Injury: Results of a National Institutes of Health-Sponsored Clinical Trial. Part II: Clinical Outcomes

OBJECTIVE To evaluate the clinical effects of spinal cord stimulation (SCS) to restore cough in subjects with cervical spinal cord injury. DESIGN Clinical trial assessing the clinical outcomes and side effects associated with the cough system. SETTING Outpatient hospital or residence. PARTICIPANTS Subjects (N=9; 8 men, 1 woman) with cervical spinal cord injury. INTERVENTIONS SCS was performed at home by either the subjects themselves or caregivers on a chronic basis and as needed for secretion management. MAIN OUTCOME MEASURES Ease in raising secretions, requirement for trained caregiver support related to secretion management, and incidence of acute respiratory tract infections. RESULTS The degree of difficulty in raising secretions improved markedly, and the need for alternative methods of secretion removal was virtually eliminated. Subject life quality related to respiratory care improved, with subjects reporting greater control of breathing problems and enhanced mobility. The incidence of acute respiratory tract infections fell from 2.0+/-0.5 to 0.7+/-0.4 events/subject year (P<.01), and mean level of trained caregiver support related to secretion management measured over a 2-week period decreased from 16.9+/-7.9 to 2.1+/-1.6 and 0.4+/-0.3 times/wk (P<.01) at 28 and 40 weeks after implantation of the device, respectively. Three subjects developed mild hemodynamic effects that abated completely with continued SCS. Subjects experienced mild leg jerks during SCS, which were well tolerated. There were no instances of bowel or bladder leakage. CONCLUSIONS Restoration of cough via SCS is safe and efficacious. This method improves life quality and has the potential to reduce the morbidity and mortality associated with recurrent respiratory tract infections in this patient population.

Distribution of electrical activation to the external intercostal muscles during high frequency spinal cord stimulation in dogs

Non‐technical summary  Normal breathing is controlled by specialized neurons in the central nervous system including the brainstem and spinal cord. Signals generated in the brainstem and transmitted to the major inspiratory muscles, including the diaphragm and intercostal muscles, are necessary to sustain life. However, we show that the specific pattern of intercostal muscle activation during breathing does not require input from the brainstem. In other words, the neural circuitry controlling this pattern of activation exists within the spinal cord. This knowledge furthers our understanding of the mechanisms that control breathing and has implications for patients with certain disease states such as cervical spinal cord injury.

Functional magnetic stimulation of the respiratory muscles in dogs

This study assessed the ability of functional magnetic stimulation (FMS) to activate the respiratory muscles in dogs. With the animal supine, FMS of the phrenic nerves using a high‐speed magnetic stimulator was performed by placing a round magnetic coil (MC) at the carotid triangle. Following hyperventilation‐induced apnea, changes in volume (ΔV) and airway pressure (ΔP) against an occluded airway were determined. FMS of the phrenic nerves produced substantial inspired function (ΔV = 373 ± 20.5 mL and ΔP = −20 ± 2.0 cm H2O). After bilateral phrenectomies, maximal inspired ΔV (219 ± 12.2 mL) and ΔP (−10 ± 1.0 cm H2O) were produced when the MC was placed near the C6–C7 spinous processes, while maximal expired ΔV (−199 ± 22.5 mL) and ΔP (11 ± 2.3 cm H2O) were produced following stimulation near the T9–T10 spinous processes. We conclude: (1) FMS of either the phrenic or upper intercostal nerves results in inspired volume production; (2) FMS of the lower intercostal nerves generates expired volume production; and (3) FMS of the respiratory muscles may be a useful noninvasive tool for artificial ventilation and assisted cough in patients with spinal cord injuries or other neurological disorders.