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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. Copyright © 2009 by the American Congress of Rehabilitation Medicine [ABSTRACT FROM AUTHOR]

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. Copyright © 2009 by the American Congress of Rehabilitation Medicine [ABSTRACT FROM AUTHOR]

Patients with spinal cord injury have an increased risk of developing respiratory tract infections as the result of expiratory muscle paralysis and consequent inability to cough. We have developed a method by which the expiratory muscles can be activated via lower thoracic and upper lumbar spinal cord stimulation to produce an effective cough mechanism. In a tetraplegic patient who required frequent (8.57+/-2.3 times per week [mean+/-SEM]) caregiver assistance to facilitate airway clearance and expectoration of secretions, three epidural electrodes were applied in the T9, T11, and L1 spinal cord regions. During stimulation at the T9 and L1 levels, airway pressures were 90 and 82 cm H2O, respectively. Peak expiratory flow rates were 6.4 L/s and 5.0 L/s; respectively. During combined (T9+L1) stimulation, airway pressure and expiratory flow rate increased to 132 cm H2O and 7.4 L/s, respectively. Addition of the third lead did not result in further increases in pressure generation. These values are characteristic of those observed with a normal subject. Because the patient is able to trigger the device independently, he no longer requires caregiver support for airway management. If confirmed in additional patients, spinal cord stimulation may be a useful method to restore an effective cough mechanism in patients with spinal cord injury. [ABSTRACT FROM AUTHOR]

Approximately 5% of spinal cord-injured individuals suffer from respiratory muscle paralysis and require chronic mechanical ventilation. Unfortunately, this form of life support is associated with a number of undesirable side effects and discomforts. The only available alternative to mechanical ventilation is diaphragm pacing via bilateral phrenic nerve stimulation. This technique can provide patients with marked improvements in life quality and offers significant advantages compared to mechanical ventilation. Many patients, however, do not have bilateral phrenic function, or are not willing to accept the risks inherent with phrenic nerve pacing and therefore are not candidates for this technique. Two alternative methods to ventilate patients with ventilator-dependent tetraplegia are reviewed in this paper. In patients with only a single functional phrenic nerve who are therefore not candidates for phrenic nerve pacing, combined intercostal muscle and unilateral phrenic nerve stimulation has recently been shown to maintain ventilatory support. In patients with bilateral phrenic nerve function, on-going studies suggest that intramuscular diaphragm pacing may be a useful alternative to direct phrenic nerve pacing. By placing the electrodes into the diaphragm laparoscopically, this method allows for the diaphragm to be activated without manipulation of the phrenic nerve, need for thoracotomy, or hospitalization. Both techniques provide benefits similar to that derived from bilateral phrenic nerve pacing and hold promise as alternative methods of ventilatory support in selected populations groups. [ABSTRACT FROM AUTHOR]

Objectives: To determine caregiver burden and quality of life of primary family caregivers of participants with cervical SCI before and after use of the cough stimulation system (CSS)., Design: Prospective assessment at four timepoints via questionnaire responses., Setting: Out-patient hospital, United States., Participants: 15 primary family caregivers of participants with cervical SCI completed questionnaires including a respiratory care burden index ( n  = 15) and a commonly employed caregiver burden inventory ( n  = 9), before and at the 6-month, 1-year and 2-year timepoints following use of the CSS., Results: SCI participants had significant clinical improvements in terms of restoration of an effective cough and ability to manage airway secretions with use of the CSS. Restoration of expiratory muscle function with use of the CSS also resulted in less caregivers (CG) stress, greater control of their participants' breathing problems, and improvement in quality of life. Results of the caregiver burden inventory demonstrated marked reductions in caregiver burden in development items, physical health and social relationship. Overall caregiver burden fell from 43.4 ± 13.8 pre-implant to 32.4 ± 7.9 (P = 0.06), 31.7 ± 10.5 (P = 0.05), and 26.5 ± 9.3 (P = 0.01) at the 6-month, 1-year and 2-year timepoints., Conclusion: Use of the CSS by cervical SCI participants results in restoration of an effective cough with significant clinical benefits. While caregiver burden is very high in primary family caregivers, they derive marked improvement in caregiver burden and quality of life with implementation of this device. Trial registration: ClinicalTrials.gov identifier: NCT00116337. Trial registration: ClinicalTrials.gov identifier: NCT01659541.

Objective: HF-SCS is a novel technique of inspiratory muscle activation which results in coincident activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways and has the potential to provide respiratory support in ventilator dependent persons with spinal cord injury. The purpose of the present study was to examine the phrenic-to-intercostal reflex during HF-SCS., Methods: In 5 anesthetized and C2 spinalized dogs, electrical stimulation was applied via a stimulating electrode located on the ventral surface of the upper thoracic spinal cord at the T2 level. Fine wire recording electrodes were used to assess single motor unit (SMU) activity of the left and right external intercostal muscles (EI) in the 3rd interspace before and after sequential left and right phrenicotomy., Results: Mean control peak firing frequency of the right EI and left EI was 11.4 ± 0.3 Hz and 10.6 ± 0.3 Hz respectively. Following unilateral right phrenic nerve section, mean SMU peak firing frequency of right EI (ipsilateral to the section) was significantly greater when compared to control (15.9 ± 0.5 Hz vs 11.4 ± 0.3 Hz; p = 0.01). Mean SMU peak firing frequency of the contralateral left EI remained unchanged (10.2 ± 0.3 Hz vs 10.6 ± 0.3 Hz, p = 0.40). Subsequent, section of the left phrenic nerve resulted in significantly higher mean SMU peak firing frequency of the left EI (16.2 ± 0.5 Hz vs 10.2 ± 0.3 Hz) when compared to before section p = 0.01). Contralateral, right EI peak firing frequency was not different if compared to before left phrenic nerve section (16.9 ± 0.4 Hz vs. 15.9 ± 0.5 Hz; p = 0.14)., Conclusion: This study demonstrates that during HF-SCS: 1) unilateral diaphragmatic afferents reflexly inhibit motor activity to the ipsilateral EI muscles, 2) the neural circuitry mediating the phrenic-to-intercostal reflex is preserved at a spinal level and does not require supraspinal input and 3) unilateral compensatory increases were observed in EI muscle activation following ipsilateral diaphragm paralysis., Competing Interests: Conflict of interest A. DiMarco is a founder of and has a significant financial interest in Synapse BioMedical, a manufacturer of diaphragm pacing systems and holds patents for spinal cord stimulation to restore cough and respiration (nos. 5,678,535; 5,911,218; 5,999,855; and 8,751,004). A. DiMarco and K. Kowalski hold the U.S. patents for technology related to the content of this manuscript, Respiratory Muscle Activation by Spinal Cord Stimulation (no. 8,352,036)., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: High-frequency spinal cord stimulation (HF-SCS) is a potential method to provide natural and effective inspiratory muscle pacing in patients with ventilator-dependent spinal cord injuries. Experimental data have demonstrated that HF-SCS elicits physiological activation of the diaphragm and inspiratory intercostal muscles via spinal cord pathways. However, the activation thresholds, extent of activation, and optimal electrode configurations (i.e., lead separation, contact spacing, and contact length) to activate these neural elements remain unknown. Therefore, the goal of this study was to use a computational modeling approach to investigate the direct effects of HF-SCS on the spinal cord and to optimize electrode design and stimulation parameters., Materials and Methods: We developed a computer model of HF-SCS that consisted of two main components: 1) finite element models of the electric field generated during HF-SCS, and 2) multicompartment cable models of axons and motoneurons within the spinal cord. We systematically evaluated the neural recruitment during HF-SCS for several unique electrode designs and stimulation configurations to optimize activation of these neural elements. We then evaluated our predictions by testing two of these lead designs with in vivo canine experiments., Results: Our model results suggested that within physiological stimulation amplitudes, HF-SCS activates both axons in the ventrolateral funiculi (VLF) and inspiratory intercostal motoneurons. We used our model to predict a lead design to maximize HF-SCS activation of these neural targets. We evaluated this lead design via in vivo experiments, and our computational model predictions demonstrated excellent agreement with our experimental testing., Conclusions: Our computational modeling and experimental results support the potential advantages of a lead design with longer contacts and larger edge-to-edge contact spacing to maximize inspiratory muscle activation during HF-SCS at the T2 spinal level. While these results need to be further validated in future studies, we believe that the results of this study will help improve the efficacy of HF-SCS technologies for inspiratory muscle pacing., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine participant quality of life before and after use of the cough stimulation system (Cough System)., Design: Prospective assessment of life quality at 4 timepoints via questionnaire responses., Setting: Out-patient hospital, United States., Participants: 28 subjects with spinal cord injury (SCI) completed life quality assessment questionnaires before and at the 28- 40- and 52-week timepoints following use of the Cough System., Results: Each subject demonstrated significant clinical improvements in terms of restoration of an effective cough and ability to manage airway secretions with use of the Cough System. Positive airway pressures and peak expiratory airflows approached values associated with a normal cough. Related to cough/secretion management, use of this system also resulted less interference with family life and daily activities, less financial difficulties, less requirement for caregiver assistance, less stress, less embarrassment and greater control of their breathing problems (p < 0.01), for each comparison). There also significant improvements in that their overall health and quality of life (p < 0.01, for each comparison). Subjects also reported greater ease in breathing, restored ability to sneeze and enhanced mobility. The incidence of acute respiratory tract infections fell from 1.3 ± 0.3 to 0.2 ± 0.1 events/subject year (p < 0.01). Ten subjects developed mild hemodynamic effects consistent with autonomic dysreflexia that abated completely with continued use of the Cough System. Some subjects experienced mild leg jerks during SCS, which were well tolerated and abated completely with reduction in stimulus amplitude, No subjects reported bowel or bladder leakage., Conclusion: Use of the Cough System by SCI subjects is a safe and efficacious method which significantly improves life quality and has the potential to reduce the mortality and morbidity associated with SCI., Competing Interests: Dr. DiMarco holds two United States Patents for technology related to the content of this paper: Method and Apparatus for Electrical Activation of the Expiratory Muscles to Restore Cough (5,999,855); Bipolar Spinal Cord Stimulation to Activate the Expiratory Muscles to Restore Cough (8,751,004); System and Method for Activating Inspiratory and Expiratory Muscle Function (10,549,100). This investigation was approved by the Institutional Review Board of MetroHealth Medical Center (IRB98-00091 and RB15-00014)., (© 2022.)

Objective: To compare the safety and effectiveness of wire (WE) vs. disc (DE) electrodes to restore cough in subjects with spinal cord injury (SCI)., Design: Clinical trials assessing the effectiveness and clinical outcomes associated with two electrode systems to activate the expiratory muscles., Setting: Inpatient hospital setting for DE or WE electrode insertion; outpatient evaluation of cough efficacy and instructions for home use., Participants: Twenty-nine subjects with SCI; 17 participants with DE and 12 with WE implants., Intervention: Surgical implantation of WE or DE to restore cough. Daily application of spinal cord stimulation (SCS) at home., Main Outcome Measure(s): Airway pressure (P) and peak airflow (F) generation achieved with SCS; clinical parameters including ease in raising secretions, incidence of acute respiratory tract infections (RTI) and side effects., Results: P and F achieved with DE and WE were not significantly different. For example, at total lung capacity (TLC) with participant effort, P was 128 ± 12 cmH 2 O and 118 ± 14 cmH 2 O, with DE and WE, respectively. The degree of difficulty in raising secretions improved markedly in both groups. The incidence of RTI per year fell from 1.3 ± 0.3 and 1.3 ± 0.5-0.3 ± 0.1 and 0.1 ± 0.1 for DE and WE groups, respectively (P   < 0.01 for both when compared to pre-implant values and NS between DE and WE groups). The only significant side effect i.e. short-term autonomic dysreflexia was also similar between groups., Conclusions: The results of this investigation indicate that both DE and WE result in comparable degrees of expiratory muscle activation, clinical benefits and side effects. Importantly, SCS to restore cough can be achieved with use of WE which can be placed using minimally invasive techniques and associated reduction in cost, surgical time and overall risk. Trial registration: ClinicalTrials.gov identifier: NCT00116337., NCT01659541, FDA IDE: G980267.

Objective: To compare the effectiveness of wire versus disc electrodes to activate the inspiratory muscles via high frequency spinal cord stimulation., Design: Animal study., Setting: Research laboratory., Animals: Dogs (n = 5) INTERVENTIONS: In separate trials, spinal cord stimulation (SCS) was applied via disc (DE) and two parallel wire electrodes (WE) on the ventral epidural space at the T2-T3 spinal region., Main Outcome Measure(s): Airway pressure (P) and inspired volume (V) generation following stimulation with DE and WE were compared. Given our previous success with (DE), outcome variables with this electrode were used as our gold standard to which all comparisons were made., Results: Two configurations of WE using monopolar stimulation (MS) resulted in P and V that were similar to those generated with MS with DE. For example, MS with parallel WE connected together to function as a common cathode (Y-connection) and a 2-channel system (separate cathodes with a remote ground), resulted in P that were 91 ± 6 and 92 ± 4%, respectively, of those achieved with DE (NS for both). Bipolar stimulation with parallel WE using a Y-connection and with a 2-channel system, resulted in P that were 96 ± 4 and 94 ± 4%, of the P achieved with DE (NS for both)., Conclusion(s): These results suggest that specific configurations of WE, which can be placed via minimally invasive techniques, provide comparable activation of the inspiratory muscles compared to DE and may be a useful technique to restore ventilatory support in persons with spinal cord injury., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To systematically determine whether use of the spinal cord stimulation (SCS) system to restore cough may improve bowel management (BM) in individuals with spinal cord injury (SCI)., Design: Experimental studies (clinical trial)., Setting: Inpatient hospital setting for electrode insertion; outpatient setting for measurement of respiratory pressures; home setting for application of SCS., Participants: Participants (N=5) with cervical SCI., Intervention: A fully implantable SCS cough system was surgically placed in each subject. SCS was applied at home, 2-3 times/d, on a chronic basis, every time bowel regimen was performed and as needed for secretion management. Stimulus parameters were set at values resulting in near maximum airway pressure generation, which was used as an index of expiratory muscle strength. Participants also used SCS during their bowel routine., Main Outcome Measures: Airway pressure generation achieved with SCS. Weekly completion of Bowel Routine Log including BM time, mechanical measures, and medications used., Results: Mean pressure during spontaneous efforts was 30±8 cmH 2 O. After a period of reconditioning, SCS resulted in pressure of 146±21 cmH 2 O. The time required for BM routines was reduced from 118±34 minutes to 18±2 minutes (P<.05) and was directly related to the magnitude of pressure development during SCS. Mechanical methods for BM were completely eliminated in 4 patients. No patients experienced fecal incontinence as result of SCS. Each participant also reported marked overall improvement associated with BM., Conclusions: Our results of this pilot study suggest that SCS to restore cough may be a useful method to improve BM and life quality for both patients with SCI and their caregivers. Our results indicate that the improvement in BM is secondary to restoration of intra-abdominal pressure development., (Copyright © 2020 American Congress of Rehabilitation Medicine. All rights reserved.)

As the COVID-19 pandemic unfolds, emergency department (ED) personnel will face a higher caseload, including those with special medical needs such as persons living with spinal cord injuries and disorders (SCI/D). Individuals with SCI/D who develop COVID-19 are at higher risk for rapid decompensation and development of acute respiratory failure during respiratory infections due to the combination of chronic respiratory muscle paralysis and autonomic dysregulation causing neurogenic restrictive/obstructive lung disease and chronic immune dysfunction. Often, acute respiratory infections will lead to significant mucus production in individuals with SCI/D, and aggressive secretion management is an important component of successful medical treatment. Secretion management techniques include nebulized bronchodilators, chest percussion/drainage techniques, manually assisted coughing techniques, nasotracheal suctioning, and mechanical insufflation-exsufflation. ED professionals, including respiratory therapists, should be familiar with the significant comorbidities associated with SCI/D and the customized secretion management procedures and techniques required for optimal medical management and prevention of respiratory failure. Importantly, protocols should also be implemented to minimize potential COVID-19 spread during aerosol-generating procedures., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)

Background: Spinal cord injury (SCI) results in significant loss in pulmonary function secondary to respiratory muscle paralysis. Retention of secretions and atelectasis and, recurrent respiratory tract infections may also impact pulmonary function. Objective: To determine whether usage of lower thoracic spinal cord stimulation (SCS) to restore cough may improve spontaneous pulmonary function in individuals with chronic SCI. Design/Methods: 10 tetraplegics utilized SCS system on a regular daily basis. Spontaneous inspiratory capacity (IC), maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were measured at baseline prior to usage of the device and repeated every 4-5 weeks over a 20-week period. Maximum airway pressure generation (P) during SCS (40 V, 50 Hz, 0.2 ms) at total lung capacity (TLC) with subject maximal expiratory effort, at the same timepoints were determined, as well. Results: Following daily use of SCS, mean IC improved from 1636 ± 229 to 1932 ± 239 ml (127 ± 8% of baseline values) after 20 weeks (P < 0.05). Mean MIP increased from 40 ± 7, to 50 ± 8 cmH 2 O (127 ± 6% of baseline values) after 20 weeks, respectively (P < 0.05). MEP also improved from 27 ± 3.7 to 33 ± 5 (127 ± 14% of baseline values) (NS). During SCS, P increased from baseline in all participants from mean 87 ± 8 cmH 2 O to 117 ± 14 cmH 2 O at weeks 20, during TLC with subject maximal expiratory effort, respectively (P < 0.05). Each subject stated that they experienced much greater ease in raising secretions with use of SCS. Conclusion: Our findings indicate that use of SCS not only improves expiratory muscle function to restore cough but also results in improvement inspiratory function, as well.

Lower thoracic spinal cord stimulation is an effective method of restoring an effective cough in participants with complete spinal cord injury. The high voltage requirements however significantly limits this application in subjects with intact lower chest wall sensation. In anesthetized animals, we have shown that the expiratory muscles can also be effectively activated with low stimulus currents (1 mA) but with high stimulus frequencies (HF-SCS -500 Hz). In 3 intact, awake pigs the responses to HF-SCS, were evaluated. HF-SCS was associated with marked expansion of the abdominal wall and external oblique EMG activity without any associated changes in heart rate or vocalization. During a terminal procedure under general anesthesia, responses to HF-SCS were re-assessed. Abdominal movement and EMG were similar to that observed in the awake state. HF-SCS (1.5 mA) resulted in an airway pressure of 65 ± 2cmH 2 O. Our results indicate that lower thoracic HF-SCS may be a useful method to restore an effective cough in patients with intact chest wall sensation., (Copyright © 2019. Published by Elsevier B.V.)

High-frequency spinal cord stimulation (HF-SCS) applied at the T2 spinal level results in physiologic activation of the inspiratory muscles in C2 spinal-sectioned dogs. Although the bulbo-spinal fibers were cut, they likely survived the duration of acute experiments, and inspiratory muscle activation may have involved stimulation of these fibers. In two anesthetized, C2 paralyzed, intubated, and mechanically ventilated dogs, HF-SCS (300 Hz) was applied at the T2 level. The effectiveness of HF-SCS in generating inspired volume (V) and negative airway pressures (P) was evaluated over a period of 5 days during which time the bulbo-spinal fibers would have degenerated. Because the effectiveness of HF-SCS may be adversely affected by deterioration of these fibers and/or the condition of the animal, low-frequency (50 Hz) SCS (LF-SCS) was also performed and served as a control. All vital signs, oxygen saturation, and end-tidal Pco 2 remained stable over the 5-day period. V and P also remained stable over the study period. For example, mean V and P were 771 ± 25 ml and 64 ± 1 cmH 2 O with HF-SCS (3 mA) during the initial and 674 ± 59 ml and 63 ± 5 cmH 2 O on the final day. Comparable values during LF-SCS (8 mA) were 467 ± 12 ml and 48 ± 1 cmH 2 O during the initial and 397 ± 20 ml and 42 ± 2 cmH 2 O on the final day. Because V and P in response to HF-SCS remained stable over a 5-day period following which the bulbo-spinal fibers would have degenerated, the mechanism of HF-SCS does not depend upon the viability of these tracts. HF-SCS therefore may be a useful method to restore ventilation in chronic ventilator dependent tetraplegics. NEW & NOTEWORTHY This study indicates that the respiratory responses to high-frequency spinal cord stimulation applied at the T2 level results in activation of the inspiratory motoneuron pools via interneuronal circuits and/or the inspiratory motoneurons directly and does not depend upon activation of long descending inspiratory bulbo-spinal fibers. This method therefore, may provide an alternative method to restore ventilation in ventilator dependent spinal cord injured patients.

This article describes the application of neuromodulation in different ways to motor recovery, to replace lost function, or to improve function of organ systems for those who have experienced spinal cord injury or stroke. Multiple devices have been developed and are currently available for use whereas others are still in the experimental stage. Multiple uses of neuromodulation are described., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In animals, high-frequency spinal cord stimulation (HF-SCS) applied on the ventral epidural surface at the T 2 level results in negative airway pressure generation consistent with inspiratory muscle activation. In the present study, in anesthetized dogs, we found that ventral HF-SCS (500 Hz) applied at all thoracic levels resulted in negative airway pressure generation. In the region of the lower thoracic spinal cord, negative airway pressure generation was most pronounced at the T 9 level. At this level, airway pressure generation was monitored: 1) during ventral HF-SCS over a wide range of stimulus amplitudes (0.5-15 mA) and frequencies (50-1,000 Hz) and 2) following spinal sections at C 8 (to assess potential diaphragm activation) and subsequently at T 6 (to assess potential intercostal muscle activation). The application of low stimulus currents between 1 and 2 mA and high stimulus frequencies (>300 Hz) resulted in the development of large negative airway pressure generation. Stimulation with 1 mA, 500 Hz resulted in a highest negative airway pressure generation of 47 ± 2 cmH 2 O. Increasing stimulus current was associated with progressive reductions in the magnitude of negative airway pressure generation. HF-SCS (500 Hz) with 15 mA resulted in a negative airway pressure generation of 7 ± 3 cmH 2 O. C 8 section markedly reduced negative airway pressure generation, and subsequent T 6 section resulted in positive airway pressure generation after HF-SCS. Our results indicate the existence of pathways with connections to both the phrenic and inspiratory intercostal motoneuron pools in the ventral part of the lower thoracic spinal cord. We speculate that the circuits mediating the previously described excitatory intercostal-to-phrenic reflex mediate the observed responses. NEW & NOTEWORTHY This study suggests that, in contrast to dorsal high-frequency spinal cord stimulation at the T 9 spinal level, which results in positive pressure generation, ventral high-frequency spinal cord stimulation at the same spinal level results in large negative airway pressure generation with low stimulus currents. This method, therefore, may provide an alternative method to restore ventilation in ventilator-dependent spinal cord-injured patients.

Objectives: The aim of this study was to assess the safety and efficacy of complete restoration of respiratory muscle function in subjects with spinal cord injury., Methods: This was an interventional study investigating three subjects maintained on a diaphragm pacing system who were implanted with the spinal cord stimulation system to restore cough. Peak expiratory airflow and airway pressure generation were the primary physiologic outcome measures; an assessment of the degree of difficulty in raising secretions was the primary clinical outcome measure., Results: Mean peak expiratory airflow and airway pressure generation during spontaneous efforts were 1.7 ± 0.2 L/s and 31 ± 7 cmH2O, respectively. When spinal cord stimulation was applied after pacing volume associated with the subject's maximum inspiratory effort and synchronized with the subject's maximum expiratory effort, peak expiratory airflow and airway pressure generation were 9.0 ± 1.9 L/s and 90 ± 6 cmH2O, respectively (P < 0.05). Moreover, each subject experienced much greater ease in raising secretions and marked improvement in the ease in raising secretions compared with other methods., Conclusions: Complete restoration of respiratory muscle function can be safely and effectively achieved in the same individuals with spinal cord injury. Spinal cord stimulation results in peak expiratory airflow and airway pressure generation characteristic of a normal cough, whereas diaphragm pacing was successful in maintaining patients off mechanical ventilation.

Context: Spinal cord stimulation (SCS) via disc electrodes surgically placed via laminotomy incisions has been shown to restore an effective cough in subjects with spinal cord injury (SCI). The purpose of this study was to evaluate a new method of expiratory muscle activation utilizing spinal cord wire leads, which can be implanted with minimally invasive techniques., Methods: In a subject with SCI, parallel wire leads with two electrode contacts were inserted percutaneously through a needle, advanced to the T9, T11 spinal levels and connected to an implanted radiofrequency receiver. Stimulus parameters were set at values resulting in near maximum airway pressure generation (Paw) (40V, 50Hz, 0.2ms). Paw was measured at functional residual capacity (FRC) and total lung capacity (TLC) as an index of expiratory muscle strength., Results: Paw during spontaneous efforts was 20 cmH 2 O (8.6% predicted). Bipolar (T9-T11) SCS resulted in Paw of 84 and 103 cmH 2 O, at FRC and TLC respectively. Monopolar (T9 only) SCS resulted in Paw of 61 and 86 cmH 2 O, at FRC and TLC respectively. This subject experienced much greater ease in raising secretions with use of SCS and no longer required other methods of secretion management., Conclusion: SCS via wire leads, which can be implanted using minimally invasive techniques, may provide a new useful method to restore an effective cough and possibly reduce the morbidity and mortality associated with respiratory tract infections in patients with SCI.

Diaphragm pacing (DP) is a useful and cost-effective alternative to mechanical ventilation in patients with ventilator-dependent spinal cord injury and central hypoventilation syndrome. Patients with SCI should be carefully screened to assess the integrity of their phrenic nerves. In eligible patients, DP improves mobility, speech, olfaction, and quality of life. The stigma of being attached to a mechanical device and risk of ventilator disconnection are eliminated. There is also some evidence that DP results in a reduction in the rate of respiratory tract infections. DP is associated with infrequent side effects and complications, such as wire breakage, radiofrequency failure, and infection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In persons with spinal cord injury, lower thoracic low-frequency spinal cord stimulation (LF-SCS; 50 Hz, 15 mA) is a useful method to restore an effective cough. Unfortunately, the high-stimulus-amplitude requirements and potential activation of pain fibers significantly limit this application in persons with intact sensation. In this study, the mechanism of the expiratory muscle activation, via high-frequency SCS (HF-SCS; 500 Hz, 1 mA) was evaluated in dogs. In group 1, the effects of electrode placement on airway pressure generation (P) was evaluated. Maximal P occurred at the T9-T10 level with progressive decrements in P at more rostral and caudal levels for both LF-SCS and HF-SCS. In group 2, electromyographic (EMG) latencies of internal intercostal muscle (II) activation were evaluated before and after spinal root section and during direct motor root stimulation. Onset time of II EMG activity during HF-SCS was significantly longer (3.84 ± 1.16 ms) than obtained during direct motor root activation (1.61 ± 0.10 ms). In group 3, P and external oblique (EO) EMG activity, before and after sequential spinal section at the T11-T12 level, were evaluated. Bilateral dorsal column section significantly reduced EO EMG activity below the section and resulted in a substantial fall in P. Subsequent lateral funiculi section completely abolished those activities and resulted in further reductions in P. We conclude that 1) activation of the expiratory muscles via HF-SCS is dependent entirely on synaptic spinal cord pathways, and 2) HF-SCS at the T9 level produces a comparable level of muscle activation with that achieved with LF-SCS but with much lower stimulus amplitudes. NEW & NOTEWORTHY The findings in the present study suggest that lower thoracic high-frequency spinal cord stimulation with low stimulus currents results in sufficient activation of the expiratory muscles via spinal circuitry to produce large positive airway pressures sufficient to generate an effective cough mechanism. This method, therefore, may be applied in patient populations with intact sensation such as stroke and amyotrophic lateral sclerosis to restore an effective cough.

Numerous studies have demonstrated the effect of lung volume on prolongation of duration of expiration (TE) with limited understanding of the TE shortening and termination of expiration as observed in newborn. In 14 dogs, the effects of varied onset of lung inflation during expiration on the TE were evaluated. When lung inflation was applied in the first part of expiration (20-60% of TE) TE was lengthened. However, in the second portion (60-80% of TE) of expiration, lung inflation either terminated or prolonged TE; whereas in the last portion of expiration (80-90% of TE), lung inflation tended to terminate expiration prematurely. The effects were abolished after bilateral vagotomy. We postulate that prolongation of TE relates to the Breuer-Hering inflation reflex, which increases the time needed for a passive expiration; whereas the ability to shorten TE could relate to Head's paradoxical reflex acting to initiate inspiration or to activate inspiratory motor activity to brake expiratory flow as occurs in the newborn., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To determine if an implanted neuroprosthesis for restoration of an effective cough is less costly than conventional methods of respiratory management. Methods: Nonrandomized clinical trial of participants ( N = 14) with spinal cord injury (SCI) using the Cough Stimulator device in the inpatient hospital setting for Cough Stimulator implantation and outpatient hospital or residence for follow-up. A neuroprosthesis was implanted for restoration of an effective cough. The annual costs associated with respiratory management, without (pre implantation) and with (post implantation) the neuroprosthesis, were examined over a 4-year period. Results: The total cost related to implantation of the Cough Stimulator was $59,891, with no maintenance costs over subsequent years. The incidence of respiratory tract infections and the need for caregiver support fell significantly following implantation. The costs associated with respiratory tract infections fell significantly from a mean of $36,406 ± 11,855/year to $13,284 ± 7,035/year ( p < .05) pre and post implantation, respectively. Costs fell further to $8,817 ± 5,990 and $4,467 ± 4,404 following the 2nd and 3rd years post implantation ( p < .05), respectively. The costs associated with caregiver support fell significantly from $25,312 ± 8,019/year to $2,630 ± 2,233/year ( p < .05) pre and post implantation, respectively, and remained low in subsequent years ( p < .05). Other costs related to secretion management fell significantly and remained low in subsequent years ( p < .05). Break-even analysis demonstrated that this point was reached in the first year. Conclusion: The results of this investigation demonstrate that implantation and use of the Cough Stimulator resulted in significant reductions in the overall costs of respiratory management in this patient population.

Spinal cord stimulation (SCS, 50Hz) is a useful method to restore an effective cough in persons with spinal cord injury (SCI). However, high stimulus amplitudes and potential activation of pain fibers, significantly limits this application. It is our hypothesis that high frequency SCS (HF-SCS), with low stimulus amplitudes may provide the same level of expiratory muscle activation. In 6 dogs, the effects of SCS, with varying stimulus parameters on positive pressure (P) generation was evaluated. At any given level of stimulus current, mean P was largest at 500Hz, compared to all other stimulus frequencies. For example, with stimulation at 1mA and frequencies of 200, 500 and 600Hz, P were 25±3, 58±4, 51±6cmH2O, respectively. By comparison, P achieved with conventional SCS parameters was 61±5cmH2O. HF-SCS results in a comparable P compared to that achieved with conventional stimulus parameters but with much lower stimulus amplitudes. This method may be useful to restore cough even in subjects with intact sensation., (Published by Elsevier B.V.)

Background: It is our hypothesis that high intensity spinal cord stimulation (SCS) to restore an effective cough mechanism using wire leads, will result in significant activation of target neurons without tissue injury or electrode corrosion., Methods: Adult mini-pigs underwent chronic spinal cord compression, followed by implantation of parallel wire leads on the dorsal epidural surface of the spinal cord, with stimulation contacts at the T9 and T12, and control electrode contacts at the T2 and T5 levels. After 3 months of daily SCS, airway pressure generation (P), tissue in the area of the stimulating and control electrodes and electrode leads were examined. P was also assessed in acute animals, which served as controls., Results: Mean P at FRC was 54±5cmH2O and 109±11cmH2O in the control and chronically stimulated animals, respectively (p<0.05). There was minimal tissue reaction in the area of the stimulating and control electrodes. All sets of leads revealed no evidence of electrode corrosion., Comparison With Existing Methods: Previous porcine models of chronic spinal cord injury (SCI) were developed to study neurological and regenerative outcomes. Our method of chronic SCI porcine model was developed to evaluate the safety of electrical SCS to restore expiratory muscle function., Conclusion: Chronic SCS with wire lead electrodes results in significant increases in P without evidence of significant adverse tissue reaction, nor evidence of electrode corrosion. This method may be a safe and useful technique to restore a functional cough in spinal cord injured subjects., (Copyright © 2016 Elsevier B.V. All rights reserved.)

High-frequency spinal cord stimulation (HF-SCS) is a novel technique of inspiratory muscle activation involving stimulation of spinal cord pathways, which may have application as a method to provide inspiratory muscle pacing in ventilator-dependent patients with spinal cord injury. The purpose of the present study was to compare the spatial distribution of motor drive to the parasternal intercostal muscles during spontaneous breathing with that occurring during HF-SCS. In nine anesthetized dogs, HF-SCS was applied at the T2 spinal level. Fine-wire recording electrodes were used to assess single motor unit (SMU) pattern of activation in the medial bundles of the 2nd and 4th and lateral bundles of the 2nd interspaces during spontaneous breathing and HF-SCS following C1 spinal section. Stimulus amplitude during HF-SCS was adjusted such that inspired volumes matched that occurring during spontaneous breathing (protocol 1). During HF-SCS mean peak SMU firing frequency was highest in the medial bundles of the 2nd interspace (17.1 ± 0.6 Hz) and significantly lower in the lateral bundles of the 2nd interspace (13.5 ± 0.5 Hz) and medial bundles of the 4th (15.2 ± 0.7 Hz) (P < 0.05 for each comparison). Similar rostrocaudal and mediolateral gradients of activity were observed during spontaneous breathing prior to C1 section. Since rib cage movement was greater and peak discharge frequencies of the SMUs higher during HF-SCS compared with spontaneous breathing, stimulus amplitude during HF-SCS was adjusted such that rib cage movement matched that occurring during spontaneous breathing (protocol 2). Under this protocol, mean peak SMU frequencies and rostrocaudal and mediolateral gradients of activity during HF-SCS were not significantly different compared with spontaneous breathing. This study demonstrates that 1) the topographic pattern of electrical activation of the parasternal intercostal muscles during HF-SCS is similar to that occurring during spontaneous breathing, and 2) differential spatial distribution of parasternal intercostal activation does not depend upon differential descending synaptic input from supraspinal centers., (Copyright © 2015 the American Physiological Society.)

Spinal cord injuries (SCI) can disrupt communications between the brain and the body, resulting in loss of control over otherwise intact neuromuscular systems. Functional electrical stimulation (FES) of the central and peripheral nervous system can use these intact neuromuscular systems to provide therapeutic exercise options to allow functional restoration and to manage medical complications following SCI. The use of FES for the restoration of muscular and organ functions may significantly decrease the morbidity and mortality following SCI. Many FES devices are commercially available and should be considered as part of the lifelong rehabilitation care plan for all eligible persons with SCI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

After cervical spinal cord injuries, many patients are unable to sustain independent ventilation because of a disruption of diaphragm innervation and respiratory functioning. If phrenic nerve function is preserved, the patient may be able to tolerate exogenous pacing of the diaphragm via electrical stimulation. Previously this was accomplished by stimulation directly to the phrenic nerves, but may be accomplished less invasively by percutaneously stimulating the diaphragm itself. The benefits, when compared with mechanical ventilation, include a lower rate of pulmonary complications, improved venous return, more normal breathing and speech, facilitation of eating, cost-effectiveness, and increased patient mobility., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To determine the long-term effects of the cough stimulation system., Design: Nonrandomized clinical trial of subjects using the study device well beyond the period of close follow-up., Setting: Use of the study device in the home setting., Participants: Subjects (N = 10) implanted with the device for a minimum of 2 years (mean 4.6 ± 0.6 years)., Interventions: Application of daily stimulation., Outcome Measures: Airway pressure generation and other clinical assessments including ease in raising secretions, life quality, caregiver support, and incidence of respiratory tract infections were measured at 1 year and mean 4.6 years after implantation., Results: Each subject continued to use the device on a regular basis. During SCS, mean maximum airway pressures were 103.1 ± 20.4 and 107.7 ± 23.0 cm H₂O at the 1-year and mean 4.6-year follow-up points, respectively (P < 0.05 compared with pre-implant and not significantly different (NS) compared with 1-year follow-up). Benchmarks related to ease in raising secretions and improvements in life quality related to respiratory care were maintained at the mean 4.6 year follow-up. The need for trained caregivers to provide other means of secretion management remained significantly below the pre-implant values (P < 0.05). The incidence of acute respiratory tract infections remained low at 0.2 ± 0.1 events/year, which is significantly below the pre-implant value of 1.4 ± 0.3 events/year (P < 0.05)., Conclusion: Subjects continued to use the system on a long-term basis beyond the period of close follow-up and to continued derive significant clinical benefits.

Diaphragm pacing is a clinically useful modality providing artificial ventilatory support in patients with ventilator dependent spinal cord injury. Since this technique is successful in providing full-time ventilatory support in only ~50% of patients, better methods are needed. In this paper, we review a novel method of inspiratory muscle activation involving the application of electrical stimulation applied to the ventral surface of the upper thoracic spinal cord at high stimulus frequencies (300 Hz). In an animal model, high frequency spinal cord stimulation (HF-SCS) results in synchronous activation of both the diaphragm and inspiratory intercostal muscles. Since this method results in an asynchronous pattern of EMG activity and mean peak firing frequencies similar to those observed during spontaneous breathing, HF-SCS is a more physiologic form of inspiratory muscle activation. Further, ventilation can be maintained on a long-term basis with repetitive stimulation at low stimulus amplitudes (<1 mA). These preliminary results suggest that HF-SCS holds promise as a more successful method of inspiratory muscle pacing., (Copyright © 2013 Elsevier B.V. All rights reserved.)

As demonstrated in a canine model, high frequency spinal cord stimulation (HF-SCS) is a novel and more physiologic method of electrical activation of the inspiratory muscles compared to current techniques. The dog model, however, has significant limitations due to cost and societal concerns. Since the rodent respiratory system is also a relevant model for the study of neuronal circuitry function, the aims of the present study were to a) assess the effects of HF-SCS and b) determine the methodology of application of this technique in rats. In 9 Sprague Dawley rats, diaphragm multiunit and single motor unit EMG activity were assessed during spontaneous breathing and HF-SCS applied on the ventral epidural surface of the spinal cord at the T2 level following C1 spinal section. As in dogs, HF-SCS results in the activation of the diaphragm at physiological firing frequencies and the generation of large inspired volumes. Mean maximum firing frequencies of the diaphragm during spontaneous breathing and HF-SCS were 23.3 ± 1.4 Hz (range: 9.8-51.6 Hz) and 26.6 ± 1.3 Hz; range: 12.0-72.9 Hz, respectively, at comparable inspired volumes. Moreover, HF-SCS was successful in pacing these animals over a 60-min period without evidence of system fatigue. Our results suggest that, similar to the dog model, HF-SCS in the rat results in the activation of spinal cord tracts which synapse with the phrenic motoneuron pool, allowing the processing of the stimulus and consequent physiologic activation of the inspiratory muscles. The rat may be a useful model for further studies evaluating phrenic motoneuron physiology., (Copyright © 2013 Elsevier Inc. All rights reserved.)

High frequency spinal cord stimulation (HF-SCS) is a method of inspiratory muscle activation resulting in phrenic motoneuron activation via stimulation of spinal cord pathways. The specific pathways mediating this response, however, are unknown. The aim of this study was to assess the potential role of upper cervical (C1-C4) pre-phrenic interneurons (UCI) and localize the pathways in the thoracic spinal cord mediating activation of phrenic motoneurons during HF-SCS. In 7 anesthetized, spinalized (C1 level) dogs, HF-SCS was applied at the T2 level. Diaphragm EMG, inspired volume and airway pressure generation were monitored before and following sequential spinal cord sections at the C4 and C8 levels. Section at the C4 level and dorsal columns at C8 resulted in no significant changes. However, lateral funiculi section (C8 level) resulted in significant reductions in each parameter. We conclude that during upper thoracic HF-SCS, the phrenic motoneuron pools are activated via spinal pathways located in the lateral funiculus but UCI are not involved., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: Respiratory complications account for a major cause of morbidity and mortality in subjects with spinal cord injury (SCI) due to paralysis of the expiratory muscles and the consequent inability to generate effective cough. We demonstrated previously that effective cough can be restored in SCI via spinal cord stimulation (SCS) with disc leads positioned on the lower thoracic and upper lumbar spinal cord via laminotomy incisions. In this study, the effectiveness of wire leads, which can be placed using minimally invasive techniques, to activate the expiratory muscles was evaluated., Design: Animal study., Setting: Research laboratory., Animals: Dogs (n = 8)., Interventions: In separate trials, disc and wire leads were inserted onto the dorsal epidural space at the T9, T11, and L1 spinal cord levels. Effects of electrical stimulation with disc, single wire, and two wire leads placed in parallel were compared., Outcome Measures: Airway pressure generation following stimulation with disc and various configurations of wire leads were compared., Results: Several different configurations of wire leads resulted in airway pressures that were similar to those generated with monopolar stimulation with disc leads (MSDLs). For example, combined monopolar stimulation with parallel wire leads at the T9 + T11 and T9 + L1 levels resulted in airway pressures that were 103.5 ± 6.4 and 101.9 ± 7.0%, respectively, of those achieved with MSDL. Bipolar stimulation with parallel wire leads at T9-T11 and T9-L1 resulted in airway pressures that were 94.2 ± 3.4 and 96.8 ± 5.0%, respectively, of the pressures achieved with MSDL. Other wire configurations were also evaluated, but were generally less effective., Conclusion: These results suggest that specific configurations of wire leads, which can be placed via minimally invasive techniques, result in comparable activation of the expiratory muscles compared to disc leads and may be a useful technique to restore cough in persons with SCI.

In contrast to previous methods of electrical stimulation of the inspiratory muscles, high frequency spinal cord stimulation (HF-SCS) results in more physiological activation of these muscles. The spatial distribution of activation to the external intercostal muscles by this method is unknown. In anaesthetized dogs, multiunit and single motor unit (SMU) EMG activity was monitored in the dorsal portion of the 3rd, 5th and 7th interspaces and ventral portion of the 3rd interspace during spontaneous breathing and HF-SCS following C2 spinal section. Stimulus amplitude during HF-SCS was adjusted such that inspired volumes matched spontaneous breathing (Protocol 1). During HF-SCS, mean peak SMU firing frequency was highest in the 3rd interspace (dorsal) (18.8 ± 0.3 Hz) and significantly lower in the 3rd interspace (ventral) (12.2 ± 0.2 Hz) and 5th interspace (dorsal) (15.3 ± 0.3 Hz) (P <0.05 for each comparison). Similar rostrocaudal and dorsoventral gradients of activity were observed during spontaneous breathing prior to C2 section. No significant activity was observed in the 7th interspace during either spontaneous breathing or HF-SCS. Since peak discharge frequencies of the SMUs were higher and rib cage movement greater during HF-SCS compared to spontaneous breathing, stimulus amplitude during HF-SCS was adjusted such that rib cage movement matched (Protocol 2). Under these conditions, mean peak SMU frequencies and rostrocaudal and dorsoventral gradients of activity during HF-SCS were not significantly different compared to spontaneous breathing. These results indicate that (a) the topographic pattern of electrical activation of the external intercostal muscles during HF-SCS is similar to that occurring during spontaneous breathing and (b) differential descending synaptic input from supraspinal centres is not a required component of the differential spatial distribution of external intercostal muscle activation. HF-SCS may provide a more physiological method of inspiratory muscle pacing.

High frequency spinal cord stimulation (HF-SCS) is a novel and more physiologic method of inspiratory muscle activation which involves stimulation of spinal cord pathways. In the present study, we determined if activation of the inspiratory intercostal muscles alone by this technique could be utilized to maintain artificial ventilation. In 7 anesthetized dogs, following C2 spinal cord section and bilateral phrenicotomy, trains of electrical stimulation (12 times/min) were applied at the T2 level. Eucapnea was maintained during an initial 5.5h period of continuous stimulation. During a subsequent 0.5h period, stimulus parameters were increased to induce hyperventilation resulting in a sustained fall in end-tidal P(CO(2)) to 29.3 + or - 0.4 mmHg. Single motor unit peak firing frequencies of the intercostal muscles during HF-SCS were similar to those occurring during spontaneous breathing. This technique holds promise as a method to restore ventilation in ventilator-dependent tetraplegics who do not have adequate phrenic nerve function for diaphragm pacing., (Copyright 2010 Elsevier B.V. All rights reserved.)

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.

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.

Following spinal cord injury, the expiratory muscles develop significant disuse atrophy characterized by reductions in their weight, fiber cross-sectional area, and force-generating capacity. We determined the extent to which these physiological alterations can be prevented with electrical stimulation. Because a critical function of the expiratory muscles is cough generation, an important goal was the maintenance of maximal force production. In a cat model of spinal cord injury, short periods of high-frequency lower thoracic electrical spinal cord stimulation (SCS) at the T(10) level (50 Hz, 15 min, twice/day, 5 days/wk) were initiated 2 wk following spinalization and continued for a 6-mo period. Airway pressure (P)-generating capacity was determined by SCS. Five acute, spinalized animals served as controls. Compared with controls, initial P fell from 43.9 +/- 1.0 to 41.8 +/- 0.7 cmH(2)O (not significant) in the chronic animals. There were small reductions in the weight of the external oblique, internal oblique, transverses abdominis, internal intercostal, and rectus abdominis muscles (not significant for each). There were no significant changes in the population of fast muscle fibers. Because prior studies (Kowalski KE, Romaniuk JR, DiMarco AF. J Appl Physiol 102: 1422-1428, 2007) have demonstrated significant atrophy following spinalization in this model, these results indicate that expiratory muscle atrophy can be prevented by the application of short periods of daily high-frequency stimulation. Because the frequency of stimulation is similar to the expected pattern of clinical use for cough generation, the daily application of electrical stimulation could potentially serve the dual purpose of maintenance of expiratory muscle function and airway clearance.

Lower thoracic spinal cord stimulation (SCS) results in the generation of large positive airway pressures. The potential effects of diaphragm co-activation during SCS were investigated in 10 anesthetized dogs. Diaphragm compound action potentials (CMAPs) were present during SCS at the T10 and T12 levels. In group 1, airway (Paw) and trans-diaphragmatic (Pdi) pressures were monitored during supramaximal SCS before and after phrenicotomy. In group 2, pressures were monitored before and after C2 section to evaluate the potential influence of supraspinal centers. Following phrenicotomy in group 1, the reduction in Pdi during SCS was associated with increases in Paw. In group 2, diaphragm CMAPs and active Pdi increased following C2 section, while Paw fell. Following phrenicotomy, Paw increased significantly. In intact animals therefore, changes in Paw during SCS are affected by the interaction between inhibitory and excitatory influences on diaphragm activation. We conclude that lower thoracic SCS results in substantial diaphragm co-activation and secondary reductions in airway pressure generation.

Following spinal cord injury, muscles below the level of injury develop variable degrees of disuse atrophy. The present study assessed the physiological changes of the expiratory muscles in a cat model of spinal cord injury. Muscle fiber typing, cross-sectional area, muscle weight, and changes in pressure-generating capacity were assessed in five cats spinalized at the T(6) level. Airway pressure (P)-generating capacity was monitored during lower thoracic spinal cord stimulation before and 6 mo after spinalization. These parameters were also assessed in five acute animals, which served as controls. In spinalized animals, P fell from 41 +/- l to 28 +/- 3 cm H2O (means +/- SE; P < 0.001). Muscle weight of the external oblique, internal oblique, transversus abdominis, and internal intercostal muscles decreased significantly (P < 0.05 for each). Muscle weight of the external oblique, internal oblique, transversus abdominis, and internal intercostal, but not rectus abdominis (RA), correlated linearly with P (r > 0.7 for each; P < 0.05 for each). Mean muscle fiber cross-sectional area of these muscles was significantly smaller (P < 0.05 for each; except RA) and also correlated linearly with P (r > 0.55 for each; P < 0.05 for each, except RA). In spinalized animals, the expiratory muscles demonstrated a significant increase in the population of fast muscle fibers. These results indicate that, following spinalization, 1) the expiratory muscles undergo significant atrophy and fiber-type transformation and 2) the P-generating capacity of the expiratory muscles falls significantly secondary to reductions in muscle mass.

The effects of pulse lung inflation (LI) on expiratory muscle activity and phase duration (Te) were determined in anesthetized, spontaneously breathing dogs (n = 20). A volume syringe was used to inflate the lungs at various times during the expiratory phase. The magnitude of lung volume was assessed by the corresponding change in airway pressure (Paw; range 2-20 cmH(2)O). Electromyographic (EMG) activities were recorded from both thoracic and abdominal muscles. Parasternal muscle EMG was used to record inspiratory activity. Expiratory activity was assessed from the triangularis sterni (TS), internal intercostal (IIC), and transversus abdominis (TA) muscles. Lung inflations <7 cmH(2)O consistently inhibited TS activity but had variable effects on TA and IIC activity and expiratory duration. Lung inflations resulting in Paw values >7 cmH(2)O, however, inhibited expiratory EMG activity of each of the expiratory muscles and lengthened Te in all animals. The responses of expiratory EMG and Te were directly related to the magnitude of the lung inflation. The inhibition of expiratory motor activity was independent of the timing of pulse lung inflation during the expiratory phase. The inhibitory effects of lung inflation were eliminated by bilateral vagotomy and could be reproduced by electrical stimulation of the vagus nerve. We conclude that pulse lung inflation resulting in Paw between 7 and 20 cmH(2)O produces a vagally mediated inhibition of expiratory muscle activity that is directly related to the magnitude of the inflation. Lower inflation pressures produce variable effects that are muscle specific.

Respiratory dysfunction is a major cause of morbidity and mortality in spinal cord injury (SCI), which causes impairment of respiratory muscles, reduced vital capacity, ineffective cough, reduction in lung and chest wall compliance, and excess oxygen cost of breathing due to distortion of the respiratory system. Severely affected individuals may require assisted ventilation, which can cause problems with speech production. Appropriate candidates can sometimes be liberated from mechanical ventilation by phrenic-nerve pacing and pacing of the external intercostal muscles. Partial recovery of respiratory-muscle performance occurs spontaneously. The eventual vital capacity depends on the extent of spontaneous recovery, years since injury, smoking, a history of chest injury or surgery, and maximum inspiratory pressure. Also, respiratory-muscle training and abdominal binders improve performance of the respiratory muscles. For patients on long-term ventilation, speech production is difficult. Often, practitioners are reluctant to deflate the tracheostomy tube cuff to allow speech production. Yet cuff-deflation can be done safely. Standard ventilator settings produce poor speech quality. Recent studies demonstrated vast improvement with long inspiratory time and positive end-expiratory pressure. Abdominal binders improve speech quality in patients with phrenic-nerve pacers. Recent data show that the level and completeness of injury and older age at the time of injury may not be related directly to mortality in SCI, which suggests that the care of SCI has improved. The data indicate that independent predictors of all-cause mortality include diabetes mellitus, heart disease, cigarette smoking, and percent-of-predicted forced expiratory volume in the first second. An important clinical problem in SCI is weak cough, which causes retention of secretions during infections. Methods for secretion clearance include chest physical therapy, spontaneous cough, suctioning, cough assistance by forced compression of the abdomen ("quad cough"), and mechanical insufflation-exsufflation. Recently described but not yet available for general use is activation of the abdominal muscles via an epidural electrode placed at spinal cord level T9-L1.

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.

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.

Objective: To evaluate the usefulness of combined intercostal and diaphragm pacing to maintain independence from mechanical ventilation., Design: A prospective trial., Setting: Clinical research center at a large tertiary hospital., Participants: Four ventilator-dependent subjects with spinal cord injury with only unilateral phrenic nerve function., Intervention: During an initial surgical procedure, a multipolar epidural disk electrode was positioned on the ventral surface of the upper-thoracic spinal cord via a hemilaminectomy to activate the inspiratory intercostal muscles. A phrenic nerve electrode was implanted unilaterally via the thoracic approach., Main Outcome Measures: Inspired volume production and duration that subjects could be comfortably maintained when off mechanical ventilatory support., Results: Initial maximum inspired volumes from combined intercostal and diaphragm stimulation ranged between .23 and .93L and significantly increased over the course of reconditioning period to between 0.55 and 1.31L; subjects could be maintained off mechanical ventilation between 16 and 24 hours a day., Conclusions: Combined intercostal and unilateral diaphragm pacing may be a useful therapeutic modality capable of maintaining long-term ventilatory support in patients with only unilateral phrenic nerve function.