Spinal cord stimulation for conditioning respiratory muscles

Abstract

Systems and methods for conditioning the patient's respiratory muscles are described. In some variations, the method for conditioning the patient's respiratory muscles can include providing a stimulation signal to a thoracic spinal cord region of the patient, the stimulation signal being effective to maintain strength of one or more respiratory muscles by increasing and / or sustaining activation of the one or more respiratory muscles of the patient. In some variations, the method includes providing the stimulation signal via one or more sensors or the like in response to detecting an inspiration phase of the patient.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority to U.S. Provisional Patent Application No. 63 / 174,979, filed April 14, 2021, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to the field of spinal cord stimulation therapy to improve respiratory function. [Background technology]

[0003] Thousands of patients suffer from respiratory failure or disorder each year in the United States, the causes of which are believed to be due to a wide range of conditions, including illness or injury. For example, acute respiratory distress syndrome (ARDS) is a potentially fatal respiratory failure that affects approximately 200,000 patients annually in the United States, resulting in approximately 75,000 deaths per year. Approximately 10% of intensive care unit (ICU) admissions worldwide are ARDS patients, equating to more than 3 million patients per year. The best way to address such respiratory failure is invasive mechanical ventilation (e.g., ventilation through an endotracheal tube, or tracheotomy, where breaths are delivered by a ventilator), which compensates for the lack of oxygen supply. However, although mechanical ventilation is highly effective, it can cause significant complications and is not sufficient to avoid morbidity and mortality. Importantly, under prolonged intubation, patients typically experience ventilator-induced diaphragm dysfunction and / or other respiratory muscle tissue atrophy, which is measurable within 1-2 days of initiating mechanical ventilation. This loss of respiratory function prevents rapid weaning and removal from mechanical ventilation, increases ventilation-related complications, and reduces quality of life. Furthermore, prolonged intubation occupies limited hospital resources, limiting access to care, which can have devastating effects at a time when ventilatory equipment is greatly needed, as evidenced by the recent COVID-19 pandemic. Summary of the Invention

[0004] In general, in some variations, the method of conditioning the patient's respiratory muscles can include providing a stimulation signal to one or more of the patient's cervical, thoracic, and lumbar spinal cord, the stimulation signal being effective to maintain strength of the one or more respiratory muscles by increasing and / or sustaining activation of the one or more respiratory muscles of the patient. In some variations, the spinal cord stimulation may be combined with cortical stimulation associated with the one or more respiratory muscles. In some variations, the method may include detecting an inhalation phase of the patient from one or more sensors and providing a stimulation signal during the detected inhalation phase. In some variations, the method may further include detecting an exhalation phase of the patient from one or more sensors and ceasing to provide the stimulation signal during the detected exhalation phase. The thoracic spinal cord stimulation can be configured to activate the one or more respiratory muscles by activating motor neurons at a segmental level of the spinal cord. In some variations, the stimulation signal may be provided to a posterior column of the thoracic spinal cord. In some variations, the method may include providing a second stimulation signal to the patient's cervical spinal cord region, the second stimulation signal being effective to activate the patient's respiratory drive. In some variations, the method may include applying a third stimulation signal to a lumbar spinal region of the patient, the third stimulation signal effective to activate a respiratory drive of the patient.

[0005] In some variations, the system for conditioning muscles may include a controller configured to detect an inhalation phase of the patient based on a sensor signal from the one or more sensors, and a stimulator configured to provide a stimulation signal to one or more of the patient's cervical, thoracic, and lumbar spinal cord during the detected inhalation phase. The stimulation signal may be effective to maintain strength of the one or more respiratory muscles by activating the one or more respiratory muscles of the patient during the inhalation phase. In some variations, the spinal cord stimulation may be combined with cortical stimulation associated with the one or more respiratory muscles. In some variations, the system may include a second stimulator configured to provide a second stimulation signal to the patient's cervical spinal cord, the second stimulation signal being effective to activate a respiratory drive of the patient. In some variations, the system may include a third stimulator configured to provide a third stimulation signal to the patient's lumbar spinal cord region, the third stimulation signal being effective to activate a respiratory drive of the patient. [Brief description of the drawings]

[0006] [Figure 1A] 1 shows a flowchart illustrating a variation of a method for conditioning the patient's respiratory muscles. [Figure 1B] 1 shows diaphragmatic EMG and respiratory pressure traces illustrating diaphragmatic activation during the inspiratory phase of a subject's breathing. [Figure 1C] An exemplary signal set is shown indicating airway pressure, thoracic excursion assessed by a chest belt, a spinal cord stimulation signal synchronized with inhalation and exhalation phases determined from the thoracic excursion, and a paraspinal EMG signal measuring stimulation resulting from the stimulation signal. [Diagram 2] 1 shows a schematic diagram of a variation of a system for conditioning muscles through spinal cord stimulation. [Figure 3A] The experimental setup for an example study investigating the effects of cervical epidural stimulation during the reversal of opioid-induced respiratory depression in human subjects is shown. The spinal column levels are shown on the side of the spinal fixation device, with the stimulation electrodes in direct contact with the dorsolateral surface of the spine. [Figure 3B]Two stimulation protocols according to the relevant study are shown in Figure 3A. [Figure 4A] Control and experimental epidural stimulation at C3 / C4 in the example study associated with Figures 3A and 3B are shown. Specifically, representative tracings of EMG activity of the genioglossus, left and right intercostal muscles, and left and right sides of the diaphragm during the ON state (subject's spontaneous, voluntary breathing) are shown. [Figure 4B] Control and experimental epidural stimulation at C3 / C4 during the example study associated with Figures 3A and 3B are shown. Representative tracings of EMG activity of the genioglossus, left and right intercostal muscles, and left and right sides of the diaphragm during the off state (complete suppression of spontaneous respiratory activity induced by remifentanil) are shown. [Figure 5A] In the example study related to Figures 3A and 3B, epidural electrical stimulation (EES) at different cervical spinal cord levels induced breathing pattern changes during the ON state. Specifically, Figure 5A shows the changes in breathing rate (a), tidal volume (b), and end-tidal PCO2 (c) induced by EES at cervical spinal cord levels (C2-C7) during the ON state. Filled dots represent outcomes during the stimulation test, whereas open dots represent outcomes after the control or stimulation test. Respiratory rate and tidal volume values ​​during the ON state are expressed as a ratio of respiratory rate or tidal volume measured during the stimulation or post-stimulation condition to the respective baseline condition. Thus, no response corresponds to 1.0. End-tidal PCO2 is expressed in mmHg as the change from the baseline value measured during the pre-stimulation condition. The mean and standard error of the mean across subjects are shown. "*" indicates when the mean response was significantly different from the corresponding control no-stimulus condition (p<0.05), and "**" indicates when the p-value was <0.01. [Figure 5B]In the example study related to Figures 3A and 3B, EES at different cervical levels induced breathing pattern changes during the OFF state. Specifically, Figure 5B shows changes in respiratory rate (d), tidal volume (e), and end-tidal PCO2 (f) as a function of cervical level stimulated during the OFF state. Filled dots represent outcomes during the stimulation test, whereas open dots represent outcomes in the control or after the stimulation test. No response corresponds to 0, since respiratory rate and tidal volume were absent during the OFF state before stimulation. End-tidal PCO2 is expressed in mmHg as the change from baseline values ​​measured during the pre-stimulation condition. The mean and standard error of the mean across subjects are shown. "*" indicates when the mean response was significantly different (p<0.05) from the corresponding control no-stimulation condition, and "**" indicates when p-value <0.01. [Figure 5C] FIG. 3B shows a graphical summary of the respiratory responses (number of patient responses / total number of patients tested*100%) at different stimulation sites in the example study associated with FIG. 3A and FIG. 3B. [Figure 6A] Figure 3A and Figure 3B show respiratory oscillation phase shifts induced by cervical spinal cord EES in the example study associated with them. Specifically, the phase transition curves of the phase comparison between the old phase before stimulation and the new phase after stimulation are shown. The 95% confidence intervals of the new and old phases when no stimulation was delivered are shown to indicate spontaneous fluctuations in phase angle in the absence of resetting. [Figure 6B] Respiratory oscillation phase shifts induced by cervical EES in the example study associated with Figures 3A and 3B are shown. The percentage of responses with and without a phase shift is shown among all cases tested with sham, 5 Hz, or 30 Hz stimulation. [Figure 6C]Respiratory oscillation phase shifts induced by cervical spinal cord EES in the example study related to Figures 3A and 3B. Comparison of paired spontaneous and stimulation / sham induced phase shifts is shown. Repeated measures two-way ANOVA and multiple comparisons with paired t-tests were applied to analyze the differences between the phase shifts induced by the intervention and the spontaneous phase shifts observed during the pre-stimulation baseline. Means and standard error of the mean (SEM) were plotted. ****p<0.0001. [Figure 7] Definitions of respiratory phase resetting are shown as referenced with respect to Figures 6A-6C. Figure 7 shows representative traces of ventilation pressure ("airway pressure") and EMG of the genioglossus, left and right intercostal muscles, and left and right sides of the diaphragm ("EMG genioglossus", "EMG left intercostal muscles", "EMG right intercostal muscles", "EMG left diaphragm", and "EMG right diaphragm", respectively). Below these traces is a time-aligned representation of the inspiratory phase shift ("respiratory onset") after the end of the EES. Dark bars indicate the inspiratory phase, white spaces indicate the expiratory phase. The original control respiratory phase is shown below the actual respiratory phase for comparison ("original onset respiratory phase"). [Figure 8] Figure 8 shows combined cell distribution maps from five subjects showing SST+ / NK1R+ cells in the example study. Specifically, in (panels a1-a4), Figure 8 shows pictures at 40x magnification of NK1R and SST double positive cells in spinal tissue samples, including NK1R expression, SST expression, cell nucleus location, and SST+ / NK1R+ expression. Arrows are superimposed to indicate the location of cell bodies. In (panels b-h), Figure 8 shows 2D mapping matrices of seven spinal levels averaged across five subjects. In (panel i), Figure 8 shows histograms of SST+ / NK1R+, SST+ / NK1R-, and SST- / NK1R+ cell counts (*, p<0.05; **, p<0.01; ***, p<0.005, ****, p<0.0001). [Figure 9] A-C show muscle evoked potentials (EVPs) elicited by non-invasive transcutaneous electrical stimulation (TES) to access respiratory spinal motor neurons in a study example. [Figure 10]A-D show exemplary results of modifying a patient's respiratory response with transcutaneous electrical stimulation in an example study. [Figure 11] An example study shows transcutaneous electrical stimulation at C2 / 3 eliciting coordinated spontaneous respiratory activity in anesthetized humans. [Figure 12] We demonstrate transcutaneous electrical stimulation to induce spontaneous respiratory activity via central pattern generation in the respiratory muscles during an existing non-breathing patient state. [Figure 13] 1 shows transcutaneous electrical stimulation to induce respiratory muscle activation through stimulation that provides central respiratory pattern generation. [Figure 14] We demonstrate transcutaneous electrical stimulation to preserve muscle integrity in mechanically ventilated patients through stimulation that provides respiratory central pattern generation. [Figure 15] FIG. 1 shows tidal volume heat maps of epidural electrical stimulation (EES) respiratory responses in mice, providing central respiratory pattern generation. [Figure 16] FIG. 1 shows frequency heatmaps of epidural electrical stimulation (EES) respiratory responses in mice, providing central respiratory pattern generation. [Figure 17] FIG. 13 shows minute ventilation heat maps of epidural electrical stimulation (EES) respiratory responses in mice, providing central respiratory pattern generation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Non-limiting examples of various aspects and variations of the present invention are described herein and illustrated in the accompanying drawings.

[0008] Described herein are spinal cord stimulation methods and systems for conditioning respiratory muscles, such as for preventing, delaying, or treating respiratory muscle atrophy in patients. Spinal cord stimulation can be given, for example, to patients (e.g., acute, chronic) undergoing mechanical ventilation, and can be useful for preventing respiratory muscle atrophy in such patients. Mechanical ventilation can unload the respiratory muscles (e.g., reduce the force required for the muscles to perform ventilation), which can cause muscle atrophy, since force generation by the muscles at least maintains muscle mass. After intubation and initiation of mechanical ventilation, many patients require the use of large amounts of sedatives to tolerate ventilation at low tidal volumes (lung protection). The need for the use of sedatives (e.g., opioids, propofol) can often cause or contribute to the rapid onset of diaphragmatic atrophy and delayed liberation from mechanical ventilation, as respiratory muscles weaken, as well as delayed weaning. However, patients undergoing mechanical ventilation may benefit from spinal cord stimulation as described herein by maintaining or strengthening the respiratory muscles, thereby shortening the time on mechanical ventilation and / or reducing ventilator-related complications. For example, spinal cord stimulation (e.g., CPG) may induce respiratory activity in the absence of activity (respiratory muscle groups are activated, including upper airway muscles such as genioglossus, hypoglossus, etc.) and increase respiratory rate when respiratory activity is present. Additionally, the methods and systems described herein may condition the respiratory muscles to facilitate the process of weaning from mechanical ventilation, thereby reducing the patient's reliance on mechanical ventilation and / or shortening the duration of mechanical ventilation. This improves access to care by allowing more patients to be treated with mechanical ventilation, maximizing valuable hospital resources.

[0009] In some variations, spinal cord stimulation may be given to patients who are intubated with a ventilator or similar support device as described above, although spinal cord stimulation may be given to patients in other situations. For example, in some variations, spinal cord stimulation as described herein may be given to patients who are not intubated with a ventilator, and spinal cord stimulation may be given to delay or prevent the need for mechanical ventilation. In some variations, spinal cord stimulation as described herein may be given to hospitalized patients to reduce or prevent skeletal and / or respiratory muscle atrophy due to bed rest, or to patients in an ICU setting to reduce or prevent skeletal and / or respiratory muscle atrophy due to bed rest and / or mechanical ventilation. In some variations, patients in rehabilitation (e.g., in hospital, at home) may receive spinal cord stimulation as described herein to reduce or prevent skeletal and / or respiratory muscle atrophy, promote muscle recovery, etc. As another example, in some variations, spinal cord stimulation as described herein may be administered to patients undergoing venovenous extracorporeal membrane oxygenation (vvECMO) where respiratory muscles are inactive due to lack of respiratory drive (pCO2). In some variations, ECMO may serve as bridge therapy for patients suffering from severe cardiac and respiratory failure before and after surgery (e.g., lung transplant). For example, respiratory muscles may be severely atrophied after lung transplant and may benefit from spinal cord stimulation as described herein.

[0010] The methods and systems described herein can be used to treat any suitable patient, such as a patient having respiratory failure or impairment (e.g., any condition in which the respiratory muscles are inactive and require acute or chronic mechanical ventilation). For example, the respiratory failure can be caused, at least in part, by respiratory distress syndrome (ARDS, COVID ARDS), ECMO (e.g., vvECMO), ventilator-induced diaphragm dysfunction, critical illness myopathy, chronic obstructive pulmonary disease (COPD), stroke, spinal cord injury, heart failure, trauma, pneumonia, sepsis, aging, neurodegenerative disease (e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), congenital central hypoventilation syndrome (CCHS), primary lateral sclerosis (PLS), dystonia, cerebral palsy, Guillain-Barré syndrome, chronic inflammatory polyneuropathy, etc.), or any combination thereof.

[0011] Spinal Cord Stimulation Methods In some variations, the method for conditioning the respiratory muscles may include providing a stimulation signal to the patient's cervical, thoracic, and / or lumbar spinal cord, the stimulation signal being effective to increase and / or sustain activation of the patient's respiratory muscles, thereby maintaining and / or improving the strength of the respiratory muscles. The stimulation may be configured to activate motor neurons, nerve roots, and / or interneurons at the spinal level targeted by the respiratory muscles to prevent muscle atrophy. For example, the stimulation may function to activate local neural circuits that induce spinal motor responses in the intercostal muscles and / or diaphragm. Such stimulation may include subthreshold stimulation (i.e., stimulation that does not directly trigger an action potential because it does not reach the threshold required for firing) and suprathreshold stimulation.

[0012] One or more strategies can be used to help prevent muscle atrophy. For example, stimulation of the cervical, thoracic, and / or lumbar spinal cord may result in spinal segments activating respiratory muscles (e.g., activating diaphragm muscle-specific neuro-respiratory substrates) and conditioning respiratory muscles without interfering with mechanical ventilation (if present). As another example, stimulation of the cervical, thoracic, and / or lumbar spinal cord may result in activation of a wide range of respiratory muscles via the central respiratory pattern generation (CPG) of the medulla (e.g., more global, CPG-dependent respiratory muscle activation).

[0013] Spinal cord stimulation can be applied to any spinal cord region. For example, in some variations, the method may include applying stimulation to a thoracic spinal cord region selected from the group consisting of T7-T7, T7-T8, T7-T9, T8-T8, T8-T9, T9-T9, and T1-11. These thoracic spinal cord regions are associated with spinal cord segments that activate respiratory muscles including intercostal muscles (e.g., external intercostal muscles) and diaphragm muscles. Generally, in some variations, the thoracic spinal cord stimulation signal may have a stimulation frequency of at least about 20 Hz, between about 20 Hz and about 100 Hz, between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, or between about 1 Hz and about 5 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz. Stimulation frequencies up to about 5 Hz may correspond to spinal cord segment stimulation, but higher frequencies may access CPG activity regardless of stimulation site. In some variations, spinal cord stimulation in the motor pool of the respiratory musculature may be configured to condition muscles with supra-motor threshold stimulation. In some variations, stimulation as described herein may be provided during the inspiration phase.

[0014] Additionally or alternatively, spinal cord stimulation may be applied to an appropriate cervical spinal cord region. For example, in some variations, the method may include applying stimulation to a cervical spinal cord region selected from the group consisting of C1-C1, C1-C2, C1-C3, C1-C4, C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, C4-C4, C3, C4, and C5. These cervical spinal cord regions are also associated with spinal cord segments that activate respiratory muscles, including the intercostal muscles and primary inspiratory muscles (e.g., the diaphragm muscle). Generally, in some variations, the cervical spinal cord stimulation signal may have a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, or at least about 20 Hz, between about 20 Hz and about 100 Hz, or between about 1 Hz and about 5 Hz. In some variations, the cervical spinal cord stimulation has a stimulation frequency of about 30 Hz. In some variations, the method may include providing stimulation at a frequency of at least about 20 Hz to the C3 / 4 cervical spinal cord region. In some variations, the cervical spinal cord stimulation may be similar to that described below with respect to CPG activation. For example, cervical spinal cord stimulation may be provided for muscle conditioning and / or CPG activation. In some variations, the stimulation described herein may be provided during the inspiration phase.

[0015] Additionally or alternatively, spinal cord stimulation may be applied to an appropriate lumbar spinal cord region. For example, in some variations, the method may include applying stimulation to a lumbar spinal cord region selected from the group consisting of L1-L2, L3-L4, and L4-L5. Generally, in some variations, the lumbar spinal cord stimulation signal may have a stimulation frequency of at least about 20 Hz, between about 20 Hz and about 100 Hz, between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, or between about 1 Hz and about 5 Hz.

[0016] In some variations of this method, two or more stimulation signals may be provided to a spinal cord region at slightly offset frequencies during a time-interference (TI) stimulation scheme (e.g., coherent stimulation). For example, stimulation of the cervical, thoracic, and / or lumbar spinal cord may be performed using two stimulation waveforms offset by a frequency difference ranging between about 1 Hz and about 10 Hz, between about 1 Hz and about 5 Hz, or between about 1 Hz and about 2 Hz (e.g., a 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, or 10 Hz difference in frequency between the two waveforms). For example, thoracic spinal cord stimulation for conditioning respiratory muscles and / or avoiding respiratory muscle atrophy may be provided by two separate stimulation sources (e.g., electrodes) providing stimulation at 1 Hz and 2 Hz, respectively. As another example, cervical spinal cord stimulation for conditioning respiratory muscles and / or avoiding respiratory muscle atrophy may be provided by two separate stimulation sources (e.g., electrodes) providing stimulation at 30 Hz and 31 Hz (or 5000 Hz and 5001 Hz), respectively. The offset frequency may induce an interfering stimulation pattern at a predetermined frequency (e.g., about 1 Hz). Without being bound to any particular theory, it is believed that TI stimulation may activate neurons via the offset or beat frequency of the two waveforms, reducing stimulation of overlying anatomical structures not of interest. In some variations, TI stimulation may be applied to transcutaneous spinal cord stimulation and / or spinal cord stimulation using needle electrodes. In some variations, the two or more stimulation signals may have a stimulation frequency as described herein of at least about 20 Hz, between about 20 Hz and about 100 Hz, between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, or between about 1 Hz and about 5 Hz.

[0017] In some variations of the method, two or more stimulation signals may be provided to the spinal cord region, including a first stimulation signal (e.g., monophasic signal, biphasic signal) having a first frequency and an overlapping second stimulation signal having a second frequency higher than the first frequency. For example, stimulation of the cervical, thoracic, and / or lumbar spinal cord may be performed using two overlapping stimulation waveforms, with a first stimulation signal having a frequency between about 0.5 Hz and about 100 Hz and a second stimulation signal having a frequency between about 5 kHz and about 10 kHz. In some variations, the stimulation may be monopolar or bipolar and may further include an amplitude between about 0.5 mA and about 200 mA, and a pulse duration between about 0.5 ms and about 3.0 ms. In some variations, the first stimulation signal may have a frequency of at least about 20 Hz, or between about 20 Hz and about 100 Hz, or between about 1 Hz and about 50 Hz, or between about 0.5 Hz and about 30 Hz, or between about 0.5 Hz and about 10 Hz, or between about 0.5 Hz and about 5 Hz. In some variations, the amplitude of the stimulation signal may range from about 30 mA, or about 40 mA, or about 50 mA, or about 60 mA, or about 70 mA, or about 80 mA up to about 200 mA, or up to about 200 mA, or up to about 150 mA.

[0018] In some variations, the method may include combining the cervical, thoracic, and / or lumbar spinal stimulation described herein with cortical stimulation associated with one or more respiratory muscles. The cortical stimulation signal may, for example, help to enhance synaptic plasticity of neural circuits associated with the function of those respiratory muscle(s). For example, in some variations, the method may include combining the cervical, thoracic, and / or lumbar spinal stimulation described herein with cortical stimulation of the diaphragm muscle to help improve or maintain diaphragm function. The cortical stimulation may be applied to the motor cortex, and the accompanying cervical, thoracic, and / or lumbar stimulation may be timed to reach the cervical, thoracic, and / or lumbar synapses, respectively, substantially simultaneously (at a predetermined interval thereafter) with the cortical stimulation pulse(s) reaching the cervical, thoracic, and / or lumbar synapses. That is, the cortical stimulation activating the affected muscle can be induced to be temporally simultaneous with the spinal cord stimulation, such that a second stimulus for the spinal cord stimulation arrives at the spinal motor neuron at approximately the same time that a first stimulus applied to the cortical motor neuron arrives at the spinal motor neuron. In some variations, the location of the cortical stimulation may be based on (e.g., the amount of) the premotor or motor homunculus (e.g., the cortical representation of the relevant muscles, including the diaphragm) (e.g., the amount of) the cortical stimulation may be determined and adjusted.

[0019] In some variations, spinal cord-related plasticity can be used to increase voluntary motor output. For example, transcranial magnetic stimulation applied in combination with cervical spinal cord stimulation can increase the force of one or more target muscles. In some variations, transcutaneous cervical spinal cord stimulation pulses applied at subthreshold intensity can be combined with magnetic pulses applied to the motor cortex at suprathreshold intensity to be configured to converge in time within the cervical spinal cord to enhance hand responses. For example, paired stimulation of the cortex and spinal cord allows the cortical pulse to reach the cervical spinal cord by about 5 milliseconds before the spinal cord pulse, enhancing hand responses.

[0020] Additionally, stimulation may be provided bilaterally to muscles on both sides, or unilaterally to affect muscles on the opposite side. In some variations, for autonomic functions such as respiratory function, stimulation may be coordinated with muscle contraction such that stimulation is activated during inspiration. In some variations, cortical stimulation may be provided alone or in combination with spinal cord stimulation to condition one or more muscles and / or prevent muscle atrophy.

[0021] In some variations, the cortical stimulation may be configured to activate respiratory muscles by descending inputs to condition one or more muscles through one or more of the following: activation of the CPG, direct or indirect activation of spinal motor neurons (e.g., by direct pathways from the cortex or lumbar spinal cord to spinal motor neurons, regardless of stimulation site, or activation by the respiratory CPG; these pathways exist in parallel). In some variations, the CPG activation may be configured to activate (and strengthen) respiratory muscles through innervation connected via the CPG in proportion to the intensity of the CPG stimulation. Furthermore, direct spinal motor activation may include locally distributed stimulation patterns (e.g., thoracic stimulation at T8 may activate motor neurons at T6-12 with a bell-shaped curve of activation descending from the spinal motor neuron activation peak).

[0022] In some variations, the spinal cord stimulation may be timed to arrive at an associated set of synapses at an interval ranging between about 0 ms and about 10 ms after the arrival of a cortical stimulation pulse at the same. Such an interval may be, for example, about 1 ms, about 2 ms, about 3 ms, about 4 ms, about 5 ms, about 6 ms, about 7 ms, about 8 ms, about 9 ms, or about 10 ms after the arrival of the cortical stimulation pulse. For example, a controller such as controller 210 described in more detail herein may be configured to control the timing of the cortical-spinal cord stimulation as described herein.

[0023] Cortical stimulation may be applied transcranially and may include transcutaneous electrical stimulation, minimally invasive transcutaneous electrical stimulation, and / or magnetic stimulation, as described in more detail below.

[0024] Stimulation of the cervical, thoracic, and / or lumbar spinal cord regions may be performed using a dorsal and / or ventral approach. For example, in some variations, at least one stimulation signal may be provided to the posterior columns of the cervical, thoracic, and / or lumbar spinal cord. For example, a dorsal approach may be easier to access and less likely to interfere with other medical devices, such as those associated with ventilators.

[0025] In some variations, the stimulation signal can be applied using a combination of dorsal and ventral approaches. For example, in variations where percutaneous, minimally invasive, or epidural electrical stimulation is applied to a target stimulation location for respiratory muscle conditioning, one or more electrodes can be placed on the posterior region of the patient and one or more electrodes can be positioned on the anterior region of the patient. For example, percutaneous, minimally invasive, or epidural electrical stimulation of the cervical spinal cord for respiratory muscle conditioning may be applied using a posteroanterior configuration in which at least one electrode (e.g., a cathode) is positioned over the upper thoracic spinous processes and at least one electrode (e.g., an anode) is positioned on the anterior surface of the patient's cervical spinal cord region. For example, it is believed that this posteroanterior electrode configuration may elicit muscle responses across multiple cervical myotomes through activation of sensory afferent and motor efferent circuits, with lower stimulation intensities activating primarily sensor afferent circuits and higher stimulation intensities activating primarily motor efferent circuits.

[0026] In some variations, a method for conditioning a patient's respiratory muscles can include providing a stimulation signal including two alternating pulses of opposite polarity separated by a predetermined delay to form a delayed biphasic pulse waveform. In some variations, the predetermined delay can be up to about 1 μs, between about 1 μs and about 1 μs, between about 1 μs and about 100 μs, or between about 100 μs and about 500 μs. For example, the delayed pulses can include a biphasic carrier pulse of a first frequency (e.g., about 10 kHz) and a burst pulse of a second frequency (e.g., about 30 Hz), each pulse having a pulse width of about 1 ms. In some variations, the delayed pulses of the stimulation signal can be applied using transcutaneous electrical spinal neuromodulation (TESCoN) (e.g., with an adhesive electrode between C3-C4, C5-C6, or T1-T2 acting as the cathode and two adhesive electrodes on both shoulders as the anodes).

[0027] In some variations, the methods may include administering the stimulation signal during one or more treatment sessions, which may have a duration ranging, for example, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, or about 15 minutes.

[0028] The patient may receive multiple therapy sessions at any suitable frequency, such as periodically. For example, the method may include providing a stimulation signal every hour, every 90 minutes, every 2 hours, every 3 hours, or every 5 hours in a therapy session. The repeated therapy sessions may each have the same duration or may have different durations. The therapy sessions may be repeated as needed to maintain and / or improve respiratory muscle strength. For example, in a variation in which the patient is sedated or unconscious and intubated on a ventilator, the therapy sessions may be repeated until the patient regains consciousness. As another example, in a variation in which the patient is on bed rest or in rehabilitation, the therapy sessions may be repeated until the patient is no longer on bed rest or may be repeated during one of the multiple rehabilitation therapy sessions until the patient is sufficiently rehabilitated.

[0029] In an exemplary variation, a method for conditioning a patient's respiratory muscles includes applying a stimulation signal to the patient's thoracic spinal cord region during hourly treatment sessions, each treatment session having a duration of about 15 minutes. In a variation in which the method is performed on a sedated patient, the treatment sessions can be repeated until the patient regains consciousness.

[0030] Stimulation Modalities and Parameters Spinal cord stimulation can be applied by any suitable non-invasive or invasive method. For example, in some variations, the stimulation signal can be applied percutaneously, minimally invasively percutaneously, or epidurally. In some variations, spinal cord stimulation can be electrical or magnetic.

[0031] Transcutaneous Electrical Stimulation In some variations, the method of conditioning the respiratory muscles may include applying a transcutaneous electrical stimulation signal to the cervical, thoracic, and / or lumbar spinal regions, as described above. The transcutaneous electrical stimulation may be applied, for example, via one or more surface electrodes.

[0032] The transcutaneous electrical stimulation signal may have a frequency and amplitude suitable for eliciting a motor response in the targeted respiratory muscles (e.g., intercostal muscles, diaphragm). In some variations, the method may include providing a transcutaneous electrical stimulation signal to the thoracic spinal cord region having a stimulation frequency of between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, between about 1 Hz and about 5 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz. Additionally or alternatively, in some variations, the method may include providing a transcutaneous electrical stimulation signal to the cervical or lumbar spinal cord region having a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the cervical or lumbar spinal cord stimulation has a stimulation frequency of about 30 Hz.

[0033] Additionally or alternatively, the method may include applying a transcutaneous electrical stimulation signal having an amplitude between about 5 mA and about 300 mA, or between about 5 mA and about 250 mA, or between about 5 mA and about 200 mA, between about 5 mA and about 150 mA, or between about 5 mA and about 100 mA, or between about 5 mA and about 80 mA, or between about 5 mA and about 60 mA, or between about 5 mA and about 50 mA.

[0034] In some variations, the transcutaneous electrical stimulation signal may be superimposed on a high frequency carrier signal. The high frequency carrier signal may range, for example, between about 3 kHz and up to about 30 kHz, or up to about 20 kHz, or up to about 15 kHz. In certain embodiments, the carrier signal is about 10 kHz. In some variations, the carrier frequency amplitude may range from about 30 mA, or about 40 mA, or about 50 mA, or about 60 mA, or about 70 mA, or about 80 mA to up to about 300 mA, or up to about 200 mA, or up to about 150 mA.

[0035] Minimally Invasive Transcutaneous Stimulation In some variations, the method of conditioning the respiratory muscles may include applying a minimally invasive transcutaneous electrical stimulation signal to the cervical, thoracic, and / or lumbar spinal cord regions, as described above. The minimally invasive transcutaneous stimulation can be applied, for example, via one or more needle electrodes.

[0036] The minimally invasive transcutaneous electrical stimulation signal may have a frequency and amplitude suitable for eliciting a motor response of targeted respiratory muscles (e.g., intercostal muscles, diaphragm). In some variations, the method may include providing a minimally invasive transcutaneous electrical stimulation signal to the thoracic spinal cord region having a stimulation frequency of between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, between about 1 Hz and about 5 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz. Additionally or alternatively, in some variations, the method may include providing a minimally invasive transcutaneous electrical stimulation signal to the cervical or lumbar spinal cord region having a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the cervical or lumbar spinal cord stimulation has a stimulation frequency of about 30 Hz.

[0037] Additionally or alternatively, the method may include applying a minimally invasive transcutaneous electrical stimulation signal having an amplitude between about 5 mA and about 300 mA, or between about 5 mA and about 250 mA, or between about 5 mA and about 200 mA, between about 5 mA and about 150 mA, or between about 5 mA and about 100 mA, or between about 5 mA and about 80 mA, or between about 5 mA and about 60 mA, or between about 5 mA and about 50 mA.

[0038] In some variations, the minimally invasive transcutaneous electrical stimulation signal may be superimposed on a high-frequency carrier signal. The high-frequency carrier signal may range, for example, between about 3 kHz and up to about 30 kHz, or up to about 20 kHz, or up to about 15 kHz. In certain embodiments, the carrier signal is about 10 kHz. In some variations, the carrier frequency amplitude may range from about 30 mA, or about 40 mA, or about 50 mA, or about 60 mA, or about 70 mA, or about 80 mA to up to about 300 mA, or up to about 200 mA, or up to about 150 mA.

[0039] epidural stimulation In some variations, the method of conditioning the respiratory muscles may include applying an epidural electrical stimulation signal to the cervical, thoracic, and / or lumbar spinal cord regions, as described above. The epidural stimulation may be applied, for example, via one or more implanted electrodes placed at an epidural site.

[0040] The epidural stimulation signal may have a frequency suitable to elicit a motor response of targeted respiratory muscles (e.g., intercostal muscles, diaphragm). In some variations, the method may include administering to the thoracic spinal cord region an epidural stimulation signal having a stimulation frequency of between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, between about 1 Hz and about 5 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz. Additionally or alternatively, in some variations, the method may include providing an epidural electrical stimulation signal to the cervical or lumbar spinal cord region having a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the cervical or lumbar spinal cord stimulation has a stimulation frequency of about 30 Hz.

[0041] Additionally or alternatively, the method may include providing an epidural stimulation signal having an amplitude between about 5 mA and about 300 mA, or between about 5 mA and about 250 mA, or between about 5 mA and about 200 mA, between about 5 mA and about 150 mA, or between about 5 mA and about 100 mA, or between about 5 mA and about 80 mA, or between about 5 mA and about 60 mA, or between about 5 mA and about 50 mA.

[0042] Magnetic stimulation In some variations, the method of conditioning respiratory muscles may include providing a stimulation signal, elicited by a magnetic signal, to the cervical, thoracic, and / or lumbar spinal cord regions, as described above. The magnetic signal may be provided, for example, via one or more magnetic coils (e.g., a magnetic wand).

[0043] The stimulation signal induced by the magnetic signal may have a frequency suitable to induce a motor response in the targeted respiratory muscles (e.g., intercostal muscles, diaphragm). In some variations, the method may include applying a stimulation signal to the thoracic spinal cord region having a stimulation frequency of between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, between about 1 Hz and about 5 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz. Additionally or alternatively, in some variations, the method may include providing a stimulation signal to the cervical or lumbar spinal cord region having a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the cervical or lumbar spinal cord stimulation has a stimulation frequency of about 30 Hz.

[0044] In some variations, the stimulation is provided by generating a magnetic field strength of up to about 10 Tesla, up to about 8 Tesla, up to about 6 Tesla, up to about 5 Tesla, up to about 4 Tesla, up to about 3 Tesla, up to about 2 Tesla, or up to about 1 Tesla.

[0045] The stimulation signal may have a frequency and amplitude suitable to elicit a motor response of the targeted respiratory muscles (e.g., intercostal muscles, diaphragm). In some variations, the method may include providing a stimulation signal having a stimulation frequency of between about 1 Hz and about 50 Hz, between about 1 Hz and about 30 Hz, between about 1 Hz and about 10 Hz, or between about 1 Hz and about 5 Hz. In some variations, the stimulation frequency is about 1 Hz or about 2 Hz.

[0046] CPG activation Breathing involves a complex network of circuits involving central pattern generation (CPG) across the brainstem and cervical spinal cord to generate respiratory rhythm. In some variations, the method may additionally or alternatively include activating the respiratory network by providing stimulation to the patient's cervical spinal cord region to activate respiratory drive.

[0047] Thus, in some variations, the method for conditioning the respiratory muscles may include providing a second stimulation signal to the patient's cervical spinal cord, the second stimulation signal being effective to activate the patient's respiratory drive. The second stimulation signal may, for example, activate a rostrally directed sensor input to the brainstem respiratory circuit, increasing widespread activation of the respiratory muscles. The second stimulation signal to the cervical spinal cord may be provided simultaneously with a stimulation signal to the thoracic and / or lumbar spinal cord, for example, as described above. Stimulation of the cervical, thoracic, and / or lumbar spinal cord may be performed in conjunction to more effectively condition the respiratory muscles (e.g., to facilitate weaning from a ventilator).

[0048] Similarly, in some variations, the method for conditioning the respiratory muscles may include providing a third stimulation signal to the patient's lumbar spinal cord, the third stimulation signal being effective to activate the patient's respiratory drive. The second stimulation signal may, for example, activate a rostrally directed sensor input to the brainstem respiratory circuit, increasing widespread activation of the respiratory muscles. The third stimulation signal to the lumbar spinal cord may be provided simultaneously with the stimulation signal to the thoracic and / or cervical spinal cord, for example, as described above. To more effectively condition the respiratory muscles (e.g., to facilitate weaning from a ventilator or when the respiratory muscles are inactive due to vvECMO), cervical, thoracic, and / or lumbar stimulation may be performed in conjunction.

[0049] In some variations, applying the third stimulation signal may be performed during the detected inspiration phase. In some variations, the third stimulation signal may be applied to a region selected from the group consisting of L1-L2, L3-L4, and L4-L5.

[0050] The cervical spinal cord stimulation, in some variations, may be similar to that described in U.S. Patent Publication No. 2018 / 0185642 entitled "Accessing Spinal Network to Enable Respiratory Function" and / or U.S. Patent Publication No. 20190381313 entitled "Accessing Spinal Network to Enable Respiratory Function," each of which is incorporated herein by reference in its entirety. For example, in some variations, cervical spinal cord stimulation may be provided to a region selected from the group consisting of C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, and C4-C4. Further, the cervical spinal cord stimulation signal may have a stimulation frequency ranging from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz, up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, at least about 20 Hz, or between about 20 Hz and about 100 Hz. In some variations, the cervical spinal cord stimulation has a stimulation frequency of about 30 Hz.

[0051] Similar to the thoracic and lumbar stimulation discussed above, cervical spinal cord stimulation may be in the form of transcutaneous electrical stimulation, minimally invasive transcutaneous electrical stimulation, epidural stimulation, and / or stimulation induced by magnetic signals.

[0052] Closed Loop Stimulation In some variations, spinal cord stimulation may be applied in a manner that is coordinated in time with respiratory activity. For example, to properly condition the respiratory muscles, the method may include stimulating one or more regions of the cervical, thoracic, and / or lumbar spinal cord in phase with the patient's inhalation phase. Thus, in some variations, as shown in FIG. 1A, a method 100 for conditioning the patient's respiratory muscles includes detecting (110) the patient's inhalation phase and applying (120) a stimulation signal to one or more of the patient's cervical, thoracic, and / or lumbar spinal cord during the detected inhalation phase. Additionally, the method 100 may include detecting (130) the patient's exhalation phase and ceasing (140) applying the stimulation signal during the detected patient's exhalation phase.

[0053] Similar to those described above, thoracic and / or lumbar stimulation signals may be effective to maintain the strength of one or more respiratory muscles of a patient by increasing and / or sustaining activation of the one or more respiratory muscles during the inspiration phase. Additionally or alternatively, cervical stimulation signals may be effective to activate the patient's respiratory drive. The stimulation signal(s) provided in response to a detected inspiration phase may be similar to any of the stimulation signals described above.

[0054] FIG. 1B shows an example of respiratory pressure traces and diaphragm EMG associations with spontaneous breathing in a human subject. Specifically, waveform (B) shows a respiratory pressure trace over several respiratory cycles, with the peak increase in pressure correlating with the inhalation phase of breathing. Waveform (A) shows an EMG trace (measured by an EMG sensor) of the diaphragm muscle. As shown by the alignment of the active segments of waveform (A) with the inhalation phase of waveform (B), the diaphragm muscle is activated throughout the inhalation phase of breathing. In a variation of method 200 in which cervical and / or thoracic spinal cord stimulation is performed in a biomimetic closed-loop manner based on detection of the inhalation phase, conditioning of the diaphragm muscle can be configured to emulate the EMG activity of waveform (A).

[0055] The patient's inhalation phase can be detected based on one or more sensor signals, since the sensor signal(s) can provide feedback in a closed-loop stimulation method to indicate the patient's inhalation, exhalation, and / or other respiratory activity. For example, the sensor signal from the sensor is configured to detect chest wall expansion or other movement and provide a sensor signal indicative thereof. As described in more detail below, examples of such sensors include devices (e.g., inductance bands, strain gauge bands, accelerometers) that can be attached to the patient and measure the patient's thoracic impedance or rib cage movement. Thus, cervical and / or thoracic stimulation can be provided in phase with the inhalation phase detected based on one or more such sensor signals.

[0056] In variations in which the patient is undergoing mechanical ventilation, cervical, thoracic and / or lumbar stimulation provided to the patient may be coordinated with the mechanical ventilation. As described further below, an output signal from the ventilator indicating the ventilatory cycle or phase may be provided and analyzed to determine the timing of the patient's inspiration phase induction. Thus, cervical, thoracic and / or lumbar stimulation may be provided in phase with the ventilator activity.

[0057] For example, FIG. 1C shows a variation of how closed-loop transcutaneous spinal electrical stimulation is performed in response to chest motion assessed by an optional chest belt. Chest wall motion is captured by a PVDF chest wall sensor ("thoracic excursion"), and the signal is processed to determine the inspiration phase. Cervical spinal stimulation ("stim") is applied at a stimulation frequency of 30 Hz during the early inspiration phase. FIG. 1C also shows how the resulting stimulation can be captured by a paraspinal EMG ("paraspinal EMG") placed next to the stimulation electrode. The resulting stimulation is responsive to various breathing intervals and is closed loop. A closed-loop stimulation system can be applied by terminating stimulation at the end of inspiration and the beginning of expiration until the next inspiration cycle. It should be understood that while FIG. 1C shows a particular variation of stimulation and thresholds, the stimulation activation and termination thresholds can be altered in any suitable manner. Additionally, the closed-loop nature of the stimulation can be extended to apply to other suitable cervical, thoracic, and / or lumbar stimulation signals (e.g., modalities, various slopes of the stimulation ramp-up and ramp-down, frequencies, intensities, pulse widths, etc.), such as any of the cervical, thoracic, and / or lumbar stimulation modalities or parameters described above.

[0058] Spinal Cord Stimulation Systems 2, a spinal cord stimulation system 200 for conditioning respiratory muscles can include a controller 210, at least one pulse generator 220, and at least one stimulator 230. The controller 210 can be communicatively coupled to one or more sensors 240, which can collect one or more sensor signals, such as sensor signals indicative of a patient's inspiration, expiration, and / or other respiratory activity.

[0059] Additionally, system 200 may include circuit elements (not shown) suitable for powering electronic components of system 200 to enable network connectivity (e.g., data communication), and / or other suitable elements. In some variations, at least a portion of system 200 may be implantable. In variations in which at least a portion of system 200 is implanted, system 200 may include wireless power transmission elements, such as antennas or coils, for providing wireless power to the implanted electronics (e.g., via inductive coupling, radiative coupling, etc.), or wired power transmission via a conductive connection. In some variations, system 200 may include a power storage element, such as a battery or capacitor. In some variations, system 200 may comprise a ventilator configured for one or more of invasive and non-invasive ventilation of a patient.

[0060] controller In various embodiments, the controller 210 functions to modulate stimulation pulses provided to the patient through the stimulator(s) 230. For example, the controller 210 may adjust stimulation parameters generated by the stimulator(s) 230 and / or control the on / off timing of stimulation provided by the stimulator(s) 230. The controller 210 may be separate from the stimulator(s) 230 or may be integrated with one or more of the stimulator(s) 230. The controller 210 may include, or be operably coupled to, one or more memory devices that store instructions for controlling the stimulation signal(s) and may include one or more processors for performing analysis (e.g., analyzing sensor signals), determining instructions to send to the stimulator for signal generation, determining the timing of such instructions, etc.

[0061] As described above, the controller 210 may be communicatively coupled to one or more sensors 240, such as to receive one or more sensor signals indicative of respiratory activity. The controller 210 may receive such sensor signals, analyze the sensor signals to determine inhalation phase, exhalation phase, and / or other suitable characteristics of the patient's respiratory activity, control the ramp-up / ramp-down of the stimulation signal(s), and / or adjust stimulation parameters, as described above. In some variations, stimulation by the stimulator 230 may be modulated based on the patient's measured respiratory phase monitored by the one or more sensors 240.

[0062] Sensor(s) In some variations, the system 200 may include one or more sensors 240 configured to provide a sensor signal indicative of respiratory activity. For example, the system 200 may include one or more sensors configured to detect chest wall expansion or other chest motion. A variety of sensor technologies may be suitable for detecting chest wall expansion or other chest motion. For example, chest motion may be measured using an inductance or strain gauge band placed around the rib cage (e.g., just below the armpits). In some variations, the one or more sensors may be part of an inductance band, where chest expansion may be determined by changes in the inductance of the band induced by expansion / contraction of the band. Similarly, in some variations, the one or more sensors may be part of a strain gauge band, where changes in the resistance / conductance of the strain gauge caused by expansion / contraction of the band may be readily measured using methods known to those skilled in the art. As another example, chest wall expansion and / or motion may be monitored using a sensor that measures chest impedance. In some variations, respiratory phase may be estimated by sensors measuring one or more of airway flow and end tidal CO2.

[0063] Additionally or alternatively, the sensor 240 may include an accelerometer attached to the surface of the body (e.g., using a wearable band or other garment, adhesive, etc.), although in other variations the accelerometer may be implanted within the body. Signals from the accelerometer may be analyzed to determine respiratory activity, for example, by mapping chest wall movement and / or timing of chest wall movement.

[0064] stimulator In various embodiments, the system 200 may include one or more stimulators 230 configured to provide stimulation to a spinal cord region. Each stimulator 230 may include a pulse generator and one or more stimulation elements configured to provide stimulation according to pulses generated by the pulse generator. The pulse generator and one or more stimulation elements may be housed together or separately (and may be connected to each other, e.g., by a lead).

[0065] In some variations, the stimulation element of the stimulator 230 may be configured to provide transcutaneous electrical stimulation. The stimulator 230 may include, for example, one or more surface electrodes that can be applied to the patient's skin proximate a target spinal location (e.g., thoracic, cervical, lumbar, etc.). In some variations, the one or more surface electrodes may be adhesive so as to be removably attached to the skin. Alternatively, in some variations, the stimulation element for providing transcutaneous electrical stimulation may include one or more surface electrodes on a housing (e.g., a handheld device, a wearable device, etc.) that can be held or secured relative to the patient such that the surface electrodes are in contact with the skin.

[0066] In some variations, the stimulation elements of the stimulator 230 may be configured to provide minimally invasive percutaneous electrical stimulation. The stimulator 230 may include, for example, one or more needle electrodes that may be inserted into one or more target stimulation locations. For example, a minimally invasive percutaneous lead may include two or more spaced electrodes (e.g., evenly or non-equally spaced electrodes) that are placed above the dura layer (e.g., through the use of a Touhy-like needle). For insertion, the Touhy-like needle may be passed through the skin between the desired vertebrae and opened above the dura layer.

[0067] In some variations, the stimulation elements of the stimulator 230 may be configured to provide epidural stimulation. The stimulator 230 may include, for example, an implantable electrode array. In some variations, the implantable electrode array may be a high-density electrode array prepared using suitable microfabrication techniques to arrange a large number of electrodes in an array configuration on a flexible substrate. The electrode array may include one or more biocompatible metals (e.g., gold, platinum, chromium, titanium, iridium, tungsten, and / or oxides and / or alloys thereof) arranged on a flexible material. Examples of suitable flexible materials include Parylene A, Parylene C, Parylene AM, Parylene F, Parylene N, Parylene D, silicon, and other flexible substrate materials, or combinations thereof. The implantable electrode array may be implanted using any of a number of methods (e.g., laminectomy procedures) as known to those skilled in the art. For example, in some embodiments, electrical energy is delivered through electrodes positioned outside the dural layer surrounding the spinal cord. Superficial (subdural) stimulation of the cord is also contemplated; for example, stimulation can be applied to the dorsal columns and dorsal root entries.

[0068] In some variations, the implantable electrodes may also be provided with an implantable controller 210 and / or an implantable power source. The implantable controller 210 may be programmed / reprogrammed using an external device (e.g., using a handheld device that communicates with the control circuitry through the skin). Programming may be repeated as many times as necessary.

[0069] In some variations, electrodes for electrical stimulation (percutaneous, minimally invasive percutaneous, epidural) may be operably coupled to the controller 210, which allows selection of electrode(s) to activate / stimulate and / or controls the frequency and / or pulse width and / or amplitude of the stimulation. In some variations, electrode selection, frequency, amplitude, and pulse width may be independently selectable, e.g., at different times, different electrodes may be selected. At any time, different electrodes may provide different stimulation frequencies and / or amplitudes. In some variations, different or all electrodes may operate in monopolar and / or bipolar modes, using constant current or constant voltage delivery of stimulation.

[0070] In some variations, the stimulation elements of the stimulator 230 may be configured to provide stimulation induced by a magnetic signal. The stimulator 230 may include, for example, one or more elements configured to generate a magnetic field that induces a current in a region of interest in the spinal cord. In some variations, effective neural stimulation is achieved within about 10 8 A / s of transient current can be achieved. In a particular variant, this current is obtained by switching a current through an electronic switching component (e.g., a thyristor or an insulated gate bipolar transistor (IGBT)).

[0071] In some variations, the magnetic stimulator may include a high current pulse generator that generates a discharge current (e.g., 5,000 amp or more) and a stimulator coil that generates a magnetic pulse (e.g., with a magnetic field strength of up to 4, 6, 8, or even 10 Tesla), with pulse durations typically ranging from about 100 μs to 1 ms or more depending on the type of stimulator. In some variations, the stimulator coil may include one or more well-insulated copper windings along with a temperature sensor and a safety switch. A voltage source (such as a battery) may charge a capacitor or other storage element via a charging circuit under the control of a control circuit (such as a microprocessor) that receives information such as the capacitor voltage, the power settings by the user, and various safety interlocks within the device to ensure proper operation, and the capacitor may then be connected to the coil by an electronic switching component when stimulation is applied. The control circuit may be operated to receive user input and / or sensor signal(s) via a controller interface and adjust stimulation parameters accordingly.

[0072] Upon activation, a discharge current is passed through the coil, inducing a magnetic flux. A fast discharge time is important for the efficiency of the stimulator, as it is the rate of change of the magnetic field that generates currents in the tissue. Thus, currents are generated in the tissue, which in turn cause depolarization of cell membranes, resulting in stimulation of the target nerve.

[0073] Since the magnetic field strength falls off as the square of the distance from the stimulation coil, the stimulation intensity is highest near the coil surface. The stimulation characteristics of the magnetic pulse, such as the depth of penetration, intensity and accuracy, depend on the rise time, peak electrical energy delivered to the coil, and the spatial distribution of the field. While the rise time and peak coil energy are governed by the electrical properties of the magnetic stimulation device and the stimulation coil, the spatial distribution of the induced electric field depends on the coil geometry and the anatomy of the region through which the induced current flows.

[0074] As discussed above, in various embodiments, the system 200 can include multiple stimulators (or multiple stimulation elements). For example, the system 200 can include a first stimulator configured to provide thoracic spinal stimulation, a second stimulator configured to provide cervical spinal stimulation, and a third stimulator configured to provide lumbar spinal stimulation. In some variations with multiple stimulators, the first, second, and / or third stimulators can be of substantially identical construction (e.g., having the same modality, both stimulators providing transcutaneous electrical stimulation, minimally invasive transcutaneous electrical stimulation, epidural stimulation, or magnetic stimulation). Alternatively, in some variations with multiple stimulators, the first, second, and / or third stimulators can be different (e.g., having different stimulation modalities). Additionally, it should be understood that the system 200 can include any suitable number of stimulators, such as 1, 2, 3, 4, 5, or more stimulators.

[0075] Glutamate agonists Somatostatin (SST) and neurokinin 1 receptors (NK1R) in the cervical spinal cord are involved in gating afferent inputs and may be related to the generation of breathing patterns (i.e., respiratory drive) in the brainstem (see Example 3 below). Glutamate may be an excitatory neurotransmitter that helps improve the organization of SST+ / NK1R+ neurons in the cervical spinal cord.

[0076] Thus, the spinal cord stimulation methods described herein may be used in combination with one or more agents, such as glutamatergic agents, to further enhance respiratory function (e.g., enhance the CPG of respiratory drive, and in some variations improve the combined enhancement of a patient's respiratory function.

[0077] These agents can be administered alone or in combination with spinal cord stimulation as described herein. For example, glutamatergic agents can be administered in combination with transcutaneous electrical stimulation, minimally invasive transcutaneous electrical stimulation, epidural electrical stimulation, and / or magnetic stimulation of the cervical and / or thoracic spinal cord as described herein. This combination of approaches can help place the spinal cord in an optimal physiological state for activating and / or improving respiratory drive and / or enhancing other respiratory functions (e.g., conditioning of the respiratory muscles as described herein).

[0078] In some variations, the glutamatergic agent(s) may be administered systemically, although additionally or alternatively, the glutamatergic agent(s) may be administered locally (e.g., to a particular region of the spinal cord, such as the cervical spinal cord). The glutamatergic agent(s) may be administered or delivered by injection (e.g., subcutaneously, intravenously, intramuscularly), orally, rectally, inhaled, or in any suitable manner. EXAMPLES

[0079] The following examples are offered to illustrate, but not to limit, the claimed invention.

[0080] Example 1 - Activation of the respiratory center by EES Opioid overdoses can lead to death as a result of suppression of brainstem respiratory circuits. We tested the hypothesis that exogenous stimulation of the cervical spinal cord can activate respiratory centers in the ventral medulla and increase ventilation in humans. To determine whether neuromodulation can reverse opioid-induced respiratory depression (OIRD), we applied epidural electrical stimulation (EES) dorsally to cervical spinal cord levels C2 to C7 in 17 anesthetized human subjects whose breathing was suppressed after administration of the synthetic opioid analgesic remifentanil, using commercially available electrodes approved for intraoperative monitoring. One subject was tested only in the control no-stimulation condition. We administered remifentanil to the test subjects at two doses: a low dose of 0.01–0.03 mcg / kg / min and a high dose of 0.03–0.1 mcg / kg / min. The low dose of remifentanil partially suppressed breathing. High doses of remifentanil induced respiratory depression and caused apnea.

[0081] Figure 3A shows the experimental setup with a typical example of the exposed surface of the spine labeled at the vertebral levels. Stimulation electrodes are shown in direct contact with the dorsolateral surface of the spine. Constant current epidural stimulation was given using an ES-IX 2 stimulator (Cadwell, Kennewick, USA) via a disposable double ball-tip direct nerve stimulator probe (Cadwell #302431). A ground needle was placed on the tissue surface close to the surgical incision. Constant current stimulation consisted of square-wave monophasic pulses at 5 Hz or 30 Hz, each with a pulse width of 500 μsec. Optimal stimulation intensity ranged from 3 mA to 5 mA. Stimulation was applied for 30, 60, or 90 s at each cervical location in the on or off state. We defined optimal stimulation intensity as 80% of the current required to elicit a minimal perceptible motor response in the deltoid muscle of either arm. Thus, all stimulation current levels were below the threshold for deltoid muscle activation. Stimulation settings were applied that are within the range commonly used for clinical neurophysiological assessments and that can be safely used during patient surgery. The effects of epidural electrical stimulation were compared to those of a control non-stimulation procedure (sham). The sham experiment consisted of placing a stimulating electrode on the dorsolateral dura surface of the spinal cord, applying the same movements and pressures as during real stimulation, but without delivering any electrical current.

[0082] We defined the subject's spontaneous, voluntary breathing as the ON state and the complete suppression of spontaneous respiratory activity (remifentanil-induced apnea) as the OFF state. Seventeen subjects were tested in the ON state, eight of whom were tested in both the ON and OFF states. EMG recordings measured the extent to which the EES influenced respiratory muscle activity. We evaluated two frequencies of constant-current monopolar EES applied to seven locations in the subject's ON and OFF states to determine optimal stimulation parameters (Figure 3B).

[0083] In voluntarily breathing patients, 5 Hz EES was found to increase respiratory rate, whereas 30 Hz EES was found to increase respiratory amplitude. Among subjects tested in the ON state (Figure 4A, Figure 5A), 30 Hz EES at the level of the fourth cervical segment (C4) significantly increased respiratory tidal volume (p=0.0164, Intra / Pre) and decreased end-tidal carbon dioxide (ΔP) compared to control unstimulated values ​​at the same cervical level in the same subjects. ETCO2 , p=0.017, Post / Pre).

[0084] 5 Hz EES stimulation at cervical segments C5, C6, and C7 increased respiratory rate compared to control values ​​(C5, p = 0.0356; C6, p = 0.0061; and C7, p = 0.0092) but did not significantly increase tidal volume or ΔP ETCO2 However, the increase in respiratory rate induced by 5 Hz stimulation at all three cervical levels persisted after stimulation was stopped and decayed over 60–90 s. ETCO2 Given that pulse oximetry oxygen saturation (SpO2) remained stable (indicating no change in the chemical drive to breathe), we believe that the EES initiated a short-term enhancement in respiratory rate that persisted after the EES was stopped and that this enhancement decayed over 60-90 seconds.

[0085] The stimulation intensity of EES was below the motor activation threshold. Deltoid EMG activity did not respond to 5 or 30 Hz EES at any cervical spinal cord level tested in ON-state subjects, including the C5-C6 level where the motor neurons innervating the deltoid reside. We observed genioglossus EMG activation in 73% of tests eliciting a respiratory response, from which we infer that the EES activated the hypoglossal nucleus in the brainstem. Furthermore, genioglossus EMG activity was coordinated with diaphragm and intercostal EMG activation and preceded the activation of these "pump muscles," as it normally does during restful breathing. These observations indicate that pacing of motor neurons was not the underlying cause of the responses we measured, but rather that dorsal cervical EES activated neurons that enhanced the activity of the intrinsic respiratory control system in the brainstem, resulting in an increase in respiratory rate or magnitude of respiratory muscle activation.

[0086] When voluntary breathing was suppressed by a high dose of remifentanil, 30 Hz stimulation evoked a sustained respiratory response. Eight of the 17 subjects were tested in the off-state, without any voluntary breathing (Figure 5B). 30 Hz stimulation had its greatest effect between cervical spinal cord levels 3 and 4 (C3 / 4), with respiratory muscle activation evident in six subjects (75%), and three of these six subjects continued to breathe after stimulation had ceased. A significant decrease in PETCO2 was recorded in these subjects, indicating effective alveolar gas exchange. In the example off-state response in Figure 4B, there was an immediate increase in genioglossus and left external intercostal muscle EMG activity. Intercostal and diaphragm EMG activity began on the left side of the spine targeting C3 / 4, and as EES continued, phasic EMG activation appeared on both sides of the diaphragm. Sequential activation of sublingual and pump muscle EMG activity was present only after phasic EMG activity had developed. This rhythmic breathing pattern was initiated in five of six subjects, including all three subjects whose respiratory activation persisted after EES cessation.

[0087] 5 Hz stimulation in subjects in the OFF state slightly decreased PETCO2 after stimulation but failed to elicit meaningful respiratory activity (Figure 5B). We observed changes in tonic EMG activity of the genioglossus, intercostal, and diaphragm muscles, but no changes in phasic activity were recorded (Figure 5B(d)). Compared with 5 Hz EES, 30 Hz stimulation more effectively induced respiratory activation during the OFF state (Figure 5G). However, in the ON state, different cervical spinal cord levels responded differently to 30 Hz or 5 Hz EES. 5 Hz EES more frequently produced larger respiratory responses at C5–C7, whereas 30 Hz more effectively initiated respiratory responses at more rostral cervical spinal cord levels (C2–C4) (Figure 5B).

[0088] Cervical EES reset the respiratory cycle. Further analysis of inspiration onset in the ON state showed that cervical EES reset the respiratory cycle, which was assessed using phase transition analysis of the respiratory cycle (Figure 6A). Phase transition was measured by recording the change (or no change) in phase when EES was applied at different times in the respiratory cycle. To account for spontaneous variations in respiratory phase duration, we calculated the old phase (φold) as the ratio of the two cycles before stimulation was delivered. The stimulated phase (φstim) was defined as the ratio of the interval between the onset of inspiration and the onset of EES divided by the phase duration of the previous unstimulated breath, and defines when in the respiratory cycle the EES was initiated. To capture the effect of EES on the phase relationship of stimulated breathing (breath duration), we defined the new phase as the ratio of stimulated breath duration to the duration of the breath preceding stimulus delivery (φnew) (Figure 7). All ratios were converted to degrees. The new phase φnew and the old phase φold (vertical axis; Fig. 6A) were plotted as a function of the stimulation phase φstim (horizontal axis). To show the effect of spontaneous phase variations during the respiratory cycle without EES, we plotted the 95% confidence interval of φold (shaded area, Fig. 6A). φnew lying outside this range likely represents phase resetting (Fig. 6B). Although respiratory cycle resetting was more common during 5 or 30 Hz EES than during sham stimulation (Fig. 3B and Fig. 3C), resetting could have either accelerated or delayed the respiratory cycle, and the angles were not normally distributed. Therefore, we obtained the absolute value of the change in phase angle and transformed the absolute value of the change in phase angle using a Box-Cox transformation, resulting in homoscedasticity of the data, consistent with the assumptions of the parametric statistical analysis we used. The EES-induced phase angle changes observed after the onset of 5 Hz and 30 Hz EES were significantly larger than the spontaneous fluctuations in phase angle in the sham condition (p<0.0001 for both sham vs. 5 Hz and sham vs. 30 Hz, Fig. 3B). This finding is consistent with the resetting observed after a single pulse of epidural stimulation, where resetting was frequently observed after dorsal cervical spinal cord EES (but not ventral EES).We infer from this analysis that the pathways of cervical neurons or axons activated by EES interact with and resynchronize with central respiratory pattern generators in the brainstem, which is consistent with the pattern of upper airway and pump muscle activation observed during dorsal cervical EES.

[0089] We therefore studied the ability of EES to modulate the rhythmic breathing pattern itself in a setting where communication with effector motoneurons in the ventral spinal cord was intact but activity of the respiratory rhythm / pattern generator was suppressed. We observed that 30 Hz EES at C3 / 4 increased minute tidal volume in spontaneously breathing patients and induced periodic respiratory activity in apneic patients after remifentanil administration. The effect of EES persisted after EES cessation, suggesting that EES at the dorsal cervical spinal cord induced a short-term potentiation of the respiratory pattern generator that decayed within 60–90 s after EES cessation. The cervical spinal circuit can be considered as an effector of respiratory muscle activation downstream of the more rostral ponto-bulbar network that generates rhythmic respiratory activity. We observed that cervical EES not only increased the amplitude of breathing but also actively modulated the oscillation of the respiratory rate. 5 Hz stimulation at C5-C7 regions increased respiratory rate and often induced a phase shift of the respiratory cycle at the onset of EES, whereas 30 Hz stimulation increased tidal volume during EES at the C4 level. The dual effects of dorsal cervical EES at different spinal locations suggest that different sets of cervical spinal neurons or axon pathways express different frequency-dependent activation patterns and that different sets of activated neurons or axons communicate with different parts of the respiratory central pattern generator, controlling respiratory rate (likely more rostral pontine-bulbar elements of the respiratory pattern generating network) and tidal volume (likely more ventral bulbar elements of the respiratory central pattern generator or spinal phrenic motoneurons).

[0090] Example 2 - Administration of glutamatergic drugs to enhance respiratory function Characterizing the distribution of somatostatin (SST) and neurokinin 1 receptor (NK1R)-containing cells in the cervical spinal cord may lead to a better understanding of respiratory neuroregulatory mechanisms. Both SST+ and NK1R+ neurons in the spinal cord are involved in gating afferent inputs, and SST+ / NK1R+ neurons are associated with the generation of respiratory patterns in the brainstem. We performed immunohistochemical analysis to identify the distribution of SST+ and NK1R+ neurons in cervical spinal cord regions of five human cadavers. Levels C3 / 4, C6, and C7 contained significantly higher densities of SST and NK1R double-positive neurons in layers III-IX (LIII-IX) compared with the staining of SST and NK1R at the C2 level of the spinal cord (Figure 8). These levels are also the spinal cord levels most responsive to EES. The correlation between cervical SST+ / NK1R+ neurons in postmortem human tissue samples and their responsiveness to in vivo cervical EES raises the possibility that cervical neurons have similar neuronal properties to brainstem neurons that affect respiration. Therefore, given these results, administering glutamatergic drugs to patients may be useful in enhancing respiratory function.

[0091] Example 3 - Segmental activation of respiratory muscles by TES We investigated non-invasive neuromodulation of the respiratory spinal circuitry specifically using transcutaneous electrical stimulation (TES), which has a substantial safety profile with no TES-related side effects in more than 50 subjects with a total of >50,000 hours of treatment.

[0092] As shown in Figures 9A-C, bilateral, monophasic, 1 Hz transcutaneous electrical stimulation was tested with bipolar configuration electrode placements (C2 / 3+T1 / 2, C2 / 3+T7 / 8, and T1 / 2+T7 / 8). Each electrode configuration was tested in both polarity directions (anode and cathode placement). Muscle evoked potentials (EVPs) were recorded in the respiratory muscles, genioglossus, bilateral intercostal muscles, and bilateral diaphragm muscles to evaluate the efficiency of specific electrode configurations in recruiting and accessing respiratory motoneurons. Muscle EVPs in the right lower extremity were recorded as an apneic control. In this representative patient, the transcutaneous stimulation configurations that elicited the most prominent EVP activation (early phase) in the diaphragm and intercostal muscles are highlighted as effective settings (especially C2 / 3 cathode, T7 / 8 anode, " * "). In the cohort of eight patients, the T1 / 2 cathode, C2 / 3 anode configuration was significantly higher than the other configurations at 5.375 ± 1.43 mV (p<0.05). One-way ANOVA, p<0.0005 by post hoc Tukey. The criterion for efficacy was the maximum amplitude of respiratory muscle EVP at the lowest intensity stimulation within a 100 ms window of stimulation. An average of 15 EVPs were performed and averaged. It should be understood that the patient positions shown in Figures 9A-C are for illustrative purposes only and stimulation can be performed with the patient in any suitable position, such as supine, prone, or lateral.

[0093] 10A-10D show exemplary results of modifying a patient's respiratory response by transcutaneous electrical stimulation. TES targeted to the C2 / 3 spinal cord modified spontaneous breathing in a representative patient intubated in preparation for elective surgery (A-C, "on state") and in another representative patient without spontaneous breathing (D, "off state, showing 30 Hz"). During the recordings, the ventilator setting was switched to off and the patient breathed through a breathing tube. Breaths per minute (bpm) and airway pressure (cmH20) were measured in three phases: before, during, and after stimulation. Maximum respiratory rate and maximum airway pressure were calculated based on the maximum values ​​reached during each phase. Vertical lines demarcate the boundaries of the changes made to the stimulator. In each of FIGS. 10A-10D, the leftmost line demarcates the ramp-up of the stimulator, the middle line indicates reaching the maximum intensity of the stimulator (100 mA), and the rightmost line indicates switching off the stimulation. In a sample of patients with pre-existing spontaneous breathing, increases in respiratory rate and airway pressure of up to 20% and 45%, respectively, were observed. Comparing respiratory rates in the ON state within a cohort of 10 subjects treated with 30 Hz stimulation, 9.3 bpm (± 1.77) were observed before stimulation, 11.4 bpm (± 1.43) during stimulation, and 8.75 bpm (± 1.59) after stimulation. Pre-stimulation vs. stimulation, p<0.05; stimulation vs. post-stimulation, p<0.01. One-way ANOVA, p<0.005 by post hoc Tukey. In patients without spontaneous breathing, respiratory activity could be induced during stimulation up to 4 breaths per minute and -7.5 cmH20. Comparing respiration rates within the off-state cohort of 10 subjects treated with 30 Hz stimulation, 0 bpm (±0), 4.5 bpm (±1.96), and 5.9 ±2.42 bpm were observed pre-stimulation vs. post-stimulation, p<0.01. One-way ANOVA, p<0.0005 by post-hoc Tukey. No significant responses were observed with control 5 Hz stimulation in either the on or off state (p>0.05). Bpm=breaths per minute; Hz=hertz; sec=seconds. Positive deflections are expiration and negative deflections are inspiration of air (±standard deviation). Similar results were observed in 10 subjects.

[0094] Further, FIG. 11 shows transcutaneous electrical stimulation at C2 / 3 eliciting coordinated spontaneous respiratory activity in anesthetized humans. EMG activity was acquired with the patient under anesthesia (remifentanil and propofol) before the start of elective surgery. Changes in airway pressure and EMG pattern were assessed during 2 min of control sham stimulation (not shown) in the absence of obvious respiratory and EMG activity. A 30 Hz TES was applied to the dorsal neck surface (C2 / 3 spinal level) using hydrogel electrodes. Constant current stimulation was delivered by square wave, 30 Hz, biphasic pulses at an optimal current of 75 mA. Before the 30 s of stimulation, no respiratory pressure or muscle EMG activity was evident. During 30 Hz stimulation at the C2 / 3 level, respiratory activity was evident, with bursts of activity in the diaphragm (indicated by arrows) and intercostal muscles, despite the electrical noise induced by the stimulation. Furthermore, there was no discernible activity in the deltoid muscle, which is not a respiratory muscle. Similar results were observed in 9 other subjects.

[0095] Overall, spinal TES was shown to activate spinal motor neurons associated with intercostal and diaphragm muscles (Figures 9A-C). Spinal TES was shown to reset respiratory rhythm and increase both respiratory depth and rate during remifentanil-induced respiratory depression (Figures 10B, C), and to induce spontaneous respiratory activity in the absence of pre-existing breathing (Figures 10D, D, E). Thus, if a restricted region of the dorsal cervical spinal cord is targeted using specific stimulation parameters, TES may activate respiratory muscles at the medulla oblongata, and in the medulla, if stimulation is sufficient to reset and activate the respiratory CPG, TES may activate all respiratory muscles, including those innervated by cranial nerves. It is hypothesized that TES functions by 1) activating local neural circuits to elicit medulla motor responses (Figures 9A-C), or 2) by activating rostrally directed sensory inputs to the brainstem respiratory circuit, thereby increasing widespread activation of respiratory muscles (CPG). These two stimulation methods allow for a reduction in the time of mechanical ventilation by reducing respiratory muscle atrophy. Given the enormous potential impact of our stimulation protocol for improving respiratory muscle function, we recognize the need to introduce this technology into the clinic and the market.

[0096] FIG. 12 shows transcutaneous electrical stimulation inducing spontaneous breathing activity by CPG activation of respiratory muscles during a pre-existing non-breathing patient state. Specifically, four patients using mechanical ventilation had no respiratory drive and no spontaneous breathing (off state). Bilateral, monophasic, 30 Hz transcutaneous electrical stimulation (TES) was applied targeting the upper cervical spinal cord. Minute ventilation (tidal volume x frequency) was assessed in three phases: before ("Pre"), during ("Intra"), and after ("Post") stimulation. TES induced spontaneous breathing when stimulation was present (Intra, p=0.00926), and breathing was sustained after stimulation (Post, p=0.00987). P-values ​​of p<0.01 were calculated by one-way ANOVA and post-hoc Dunnett's multiple comparison test.

[0097] FIG. 13 shows transcutaneous electrical stimulation inducing respiratory muscle activation through stimulation providing central respiratory pattern generation. Specifically, cervical TES modulated minute tidal volume (L) in a stimulation frequency-dependent manner in seven spontaneously breathing (ON) patients. Minute ventilation during 30 Hz stimulation ("Intra") or post-stimulation ("Post") phases was calculated compared to the average before stimulation ("Pre") to reflect the respiratory changes induced by TES. Minute ventilation was significantly elevated after stimulation (30 Hz Post / Pre, p=0.0277). P-value of p<0.05 was calculated based on two-way ANOVA and Sidak's multiple comparison test.

[0098] Figure 14 shows transcutaneous electrical stimulation preserving muscle integrity in mechanically ventilated patients through stimulation providing respiratory central pattern generation. Specifically, a 72-year-old elderly patient with COVID and ARDS was intubated for acute respiratory failure and treated daily with TES (bipolar stimulation at C3 and T8 positions for 60 minutes once a day at 30 Hz, gated to turn on during inspiration). The stimulation protocol included dual-channel, bipolar stimulation at C3 and T8 performed in a closed-loop manner gated to the inspiration phase, at a frequency of 30 Hz at submotor threshold intensity (75 mA). Assessment of right diaphragm muscle thickness was performed daily for 5 days within 4 hours of the start of mechanical ventilation (rectangular data point markers). There was no evidence of a decrease in diaphragm muscle thickness throughout the 5 days of mechanical ventilation. In contrast, a control subject with a similar clinical profile (circular data point marker) (an older COVID and ARDS patient aged 68 years) who did not receive TES treatment had a clear reduction in respiratory muscle thickness throughout the period of mechanical ventilation, losing more than 30% of the diaphragm muscle thickness. Thus, compared to control subjects who did not receive TES treatment during mechanical ventilation, patients who received TES treatment appeared to benefit with no evidence of diaphragm muscle atrophy.

[0099] Example 4 - CPG activation of respiratory muscles by epidural electrical stimulation of the lumbar spinal cord. Figures 15-17 are plots of epidural electrical stimulation (EES) respiratory responses in mice corresponding to CPG activation of respiratory muscles. One set of EES locations included rostral lumbar (L1L2), mid-lumbar (L3L4), and caudal lumbar (L5L6) spinal segments. Stimulation locations were verified by examining corresponding postmortem tissues. Physiological parameters were measured before, during, and after stimulation. In particular, respiratory pressure was measured and EMG sensors were used to measure left and right diaphragms, respectively. Measured signal data was processed to generate estimated respiratory features including expiratory peak, inspiratory trough, expiratory onset, and inspiratory onset.

[0100] A set of surface plots of the phase of the EES-induced respiratory response and stimulus intensity were generated for a set of time points including pre-stimulus baseline, during stimulation, immediately after stimulation, 3 min after stimulation, and 6 min after stimulation (not shown). In addition, plots were generated for the change in the percentage of tidal volume in response to EES applied at spinal levels L1L2, L3L4, and L5L6, the change in the percentage of frequency in response to EES applied at spinal levels L1L2, L3L4, and L5L6, and the change in the percentage of minute ventilation in response to EES applied at spinal levels L1L2, L3L4, and L5L6. Stimulation was performed at 30 Hz. It should be noted that since humans do not have an L6 spinal level, the L6 spinal level in mice is considered to correspond to the L5 spinal level in humans.

[0101] FIG. 15 shows a set of heat maps of EES-evoked tidal volumes providing respiratory central pattern generation, where the mean percent change in respiratory parameters compared to pre-stimulus baseline is plotted and is given by the following Equation 1:

number

[0102] Changes near a given threshold (P<0.05) are darker and changes below the given threshold are brighter in Figure 15. L5 / 6 provided the most robust changes in tidal volume, but L1 / 2 at an intensity of 0.5 mA was chosen as the stimulation parameter because the EES of L5 / 6 was associated with animal movement and muscle contraction.

[0103] FIG. 16 shows a set of heatmaps of EES-evoked respiration rates providing central respiratory pattern generation, plotting the average percent change in respiratory parameters compared to pre-stimulus baseline given by Equation 1. In FIG. 16, changes near a given threshold (P<0.05) are darker and changes below the given threshold are lighter. EES at L1 / 2 produced the largest power response.

[0104] Figure 17 shows a set of heat maps of EES-evoked minute ventilation providing respiratory central pattern generation, plotting the mean percent change in respiratory parameters compared to pre-stimulus baseline as given by Equation 1. In Figure 17, changes near a given threshold (P<0.05) are darker and changes below the given threshold are lighter.

[0105] Enumeration of embodiments Various embodiments provided herein may include, but are not necessarily limited to, one or more of the following.

[0106] Embodiment A1. A method for conditioning the respiratory muscles of a patient, comprising: detecting an inspiratory phase of the patient from one or more sensors; applying a stimulation signal to one or more of the patient's cervical, thoracic, and lumbar spinal cord during the detected inspiration phase; Including, The method, wherein the stimulation signal is effective to maintain strength of one or more respiratory muscles of the patient by enhancing and / or sustaining the activation of the one or more respiratory muscles during the inhalation phase.

[0107] Embodiment A2. The method of embodiment A1, wherein the stimulation signal activates the one or more respiratory muscles by activating motor neurons at the segmental level of the spinal cord.

[0108] Embodiment A3. The method of embodiment A1 or embodiment A2, wherein the stimulation signal is applied to the dorsal columns of the thoracic spinal cord.

[0109] Embodiment A4. The method of any one of embodiments A1-A3, wherein the stimulation signal is applied to a region selected from the group consisting of C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, C4-C4, C3, C4, C5, C2-C7, T1, T1-T12, T7-T7, T7-T8, T7-T9, T8-T8, T8-T9, T9-T9, L1-L2, L3-L4, and L4-L5.

[0110] Embodiment A5. The method of any one of embodiments A1-A4, wherein the stimulation signal has a stimulation frequency between about 20 Hz and 100 Hz.

[0111] Embodiment A6. The method of embodiment A5, wherein the stimulation signal has a stimulation frequency between about 1 Hz and about 50 Hz.

[0112] Embodiment A7. The method of embodiment A6, wherein the stimulation signal has a stimulation frequency between about 1 Hz and about 10 Hz.

[0113] Embodiment A8. The method of any one of embodiments A1-A7, wherein the stimulation signal is superimposed on a radio frequency carrier signal.

[0114] Embodiment A9. The method of embodiment A8, wherein the high frequency carrier signal has a frequency of about 3 kHz, or about 5 kHz, or about 8 kHz up to about 30 kHz, or up to about 20 kHz, or up to about 15 kHz.

[0115] Embodiment A10. The method of embodiment A9, wherein the high frequency carrier signal has a frequency of about 10 kHz.

[0116] Embodiment A11. The method of any one of embodiments A1-A10, wherein the stimulation signal is an electrical stimulation signal.

[0117] Embodiment A12. The method of any one of embodiments A1 to A11, wherein the stimulation signal has an amplitude between about 5 mA and about 300 mA, or between about 5 mA and about 250 mA, or between about 5 mA and about 200 mA, between about 5 mA and about 150 mA, or between about 5 mA and about 100 mA, or between about 5 mA and about 80 mA, or between about 5 mA and about 60 mA, or between about 5 mA and about 50 mA.

[0118] Embodiment A13. The method of any one of embodiments A1-A11, wherein the stimulation signal is applied transcutaneously.

[0119] Embodiment A14. The method of any one of Embodiments A1-A11, wherein the stimulation signal is delivered epidurally.

[0120] Embodiment A15. The method of any one of embodiments A1-A11, wherein the stimulation signal is delivered percutaneously.

[0121] Embodiment A16. The method of any one of embodiments A1-A11, wherein the stimulation signal is induced by a magnetic signal.

[0122] Embodiment A17. The method of any one of embodiments A1-A16, wherein the one or more respiratory muscles include the intercostal muscles, the diaphragm, or both.

[0123] Embodiment A18. The method of any one of embodiments A1-A17, further comprising applying a second stimulation signal to the patient's cervical spinal cord, the second stimulation signal being effective to activate the patient's respiratory drive.

[0124] Embodiment A19. The method of embodiment A18, wherein the administering of the second stimulation signal is performed during the detected inspiration phase.

[0125] Embodiment A20. The method of embodiment A18 or embodiment A19, wherein the second stimulation signal is applied to a region selected from the group consisting of C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, C4-C4, and C3, C4, C5.

[0126] Embodiment A21. The method of any one of embodiments A1-A20, further comprising applying a third stimulation signal to the patient's lumbar spinal cord, the third stimulation signal being effective to activate the patient's respiratory drive.

[0127] Embodiment A22. The method of embodiment A21, wherein the administering of the third stimulation signal is performed during the detected inspiration phase.

[0128] Embodiment A23. The method of embodiment A21 or A22, wherein the third stimulation signal is applied to regions selected from the group consisting of L1-L2, L3-L4, and L4-L5.

[0129] Embodiment A24. The method of any one of embodiments A18-A20, wherein the second stimulation signal has a stimulation frequency from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, or between about 20 Hz and about 100 Hz.

[0130] Embodiment A25. The method of any one of embodiments A21-A23, wherein the third stimulation signal has a stimulation frequency from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, or between about 20 Hz and about 100 Hz.

[0131] Embodiment A26. The method of any one of embodiments A1-A25, further comprising detecting an exhalation phase of the patient and ceasing application of the stimulation signal during the detected exhalation phase.

[0132] Embodiment A27. The method of any one of embodiments A1-A26, wherein the stimulation signal is provided to prevent respiratory muscle atrophy in the patient.

[0133] Embodiment A28. The method of any one of embodiments A1-A26, wherein the stimulation signal is provided to treat respiratory muscle atrophy in the patient.

[0134] Embodiment A29. The method of any one of embodiments A1-A28, wherein the patient is intubated on a ventilator and the stimulation signal is administered to promote ventilator weaning.

[0135] Embodiment A30. The method of any one of embodiments A1-A28, wherein the patient is not intubated on a ventilator and the stimulation signal is administered to delay or prevent the need for mechanical ventilation.

[0136] Embodiment A31. The method of any of embodiments A1-A30, wherein the patient has respiratory failure or impairment.

[0137] Embodiment A32. The method of embodiment A29, wherein the respiratory failure or respiratory disorder is caused by any one or more of acute respiratory distress syndrome (ARDS), ECMO, ventilator-induced diaphragmatic dysfunction, critical illness myopathy, chronic obstructive pulmonary disease (COPD), stroke, spinal cord injury, cardiac failure, trauma, pneumonia, sepsis, aging, and neurodegenerative disease.

[0138] Embodiment A33. The method of embodiment A32, wherein the neurodegenerative disease is associated with a condition selected from the group consisting of Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), congenital central hypoventilation syndrome (CCHS), primary lateral sclerosis (PLS), dystonia, cerebral palsy, Guillain-Barré syndrome, and chronic inflammatory polyneuropathy.

[0139] Embodiment A34. The method of any one of embodiments A1-A33, further comprising administering to said patient a glutamatergic agent.

[0140] Embodiment A35. A stimulation device configured to provide the stimulation signal of any one of embodiments A1 to A34.

[0141] Embodiment B1. A system for conditioning muscles of a patient, comprising: a controller configured to detect an inspiration phase of the patient based on sensor signals from one or more sensors; a stimulation device configured to apply a stimulation signal to one or more of the patient's cervical, thoracic, and lumbar spinal cord during the detected inspiration phase; Including, The system, wherein the stimulation signal is effective to maintain strength of one or more respiratory muscles of the patient by activating the one or more respiratory muscles during the inspiration phase.

[0142] Embodiment B2. The system of embodiment B1, wherein the one or more sensors include a sensor configured to detect chest wall expansion.

[0143] Embodiment B3. The system of embodiment B1 or embodiment B2, wherein the one or more sensors include a sensor coupled to a ventilator treating the patient.

[0144] Embodiment B4. The system of any one of embodiments B1-B3, wherein the stimulation signal activates the one or more respiratory muscles by activating motor neurons at the segmental level of the spinal cord.

[0145] Embodiment B5. The system of any one of embodiments B1-B4, wherein the stimulation signal is provided to the dorsal columns of the thoracic spinal cord.

[0146] Embodiment B6. The system of any one of embodiments B1-B5, wherein the stimulation signal is provided to a region selected from the group consisting of C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, C4-C4, C3, C4, C5, C2-C7, T1, T1-T12, T7-T7, T7-T8, T7-T9, T8-T8, T8-T9, T9-T9, L1-L2, L3-L4, and L4-L5.

[0147] Embodiment B7. The system of any one of embodiments B1-B5, wherein the stimulation signal has a stimulation frequency between about 1 Hz and 50 Hz.

[0148] Embodiment B8. The system of embodiment B7, wherein the stimulation signal has a stimulation frequency between about 20 Hz and about 100 Hz.

[0149] Embodiment B9. The system of embodiment B8, wherein the stimulation signal has a stimulation frequency between about 1 Hz and about 50 Hz.

[0150] Embodiment B10. The system of any one of embodiments B1-B9, wherein the stimulation signal is superimposed on a radio frequency carrier signal.

[0151] Embodiment B11. The system of embodiment B10, wherein the high frequency carrier signal has a frequency of about 3 kHz, or about 5 kHz, or about 8 kHz up to about 30 kHz, or up to about 20 kHz, or up to about 15 kHz.

[0152] Embodiment B12. The method of embodiment B11, wherein the high frequency carrier signal has a frequency of about 10 kHz.

[0153] Embodiment B13. The system of any one of embodiments B1-B12, wherein the stimulator is an electrical stimulator.

[0154] Embodiment B14. The system of embodiment B13, wherein the stimulation signal has an amplitude between about 5 mA and about 300 mA, or between about 5 mA and about 250 mA, or between about 5 mA and about 200 mA, between about 5 mA and about 150 mA, or between about 5 mA and about 100 mA, or between about 5 mA and about 80 mA, or between about 5 mA and about 60 mA, or between about 5 mA and about 50 mA.

[0155] Embodiment B15. The system of any one of embodiments B1-B14, wherein the stimulator is configured to provide transcutaneous stimulation.

[0156] Embodiment B16. The system of embodiment B15, wherein the stimulator comprises one or more adhesive stimulators.

[0157] Embodiment B17. The system of any one of embodiments B1-B14, wherein the stimulator is configured to provide epidural stimulation.

[0158] Embodiment B18. The system of any one of embodiments B1-B14, wherein the stimulator is configured to provide minimally invasive transcutaneous stimulation.

[0159] Embodiment B19. The system of any one of embodiments B1-B12, wherein the stimulator is a magnetic stimulator.

[0160] Embodiment B20. The system of any one of embodiments B1-B19, further comprising a second stimulator configured to apply a second stimulation signal to the patient's cervical spinal cord, the second stimulation signal being effective to activate the patient's respiratory drive.

[0161] Embodiment B21. The system of embodiment B20, wherein the second stimulator is configured to apply the second stimulation signal during the detected inspiration phase.

[0162] Embodiment B22. The system of embodiment B20 or embodiment B21, wherein the second stimulation signal is applied to a region selected from the group consisting of C2-C2, C2-C3, C2-C4, C3-C3, C3-C4, C4-C4, and C3, C4, C5.

[0163] Embodiment B23. The system of any one of embodiments B1-B22, further comprising a third stimulator configured to apply a third stimulation signal to a lumbar spinal region of the patient, the third stimulation signal being effective to activate a respiratory drive of the patient.

[0164] Embodiment B24. The system of embodiment B23, wherein the third stimulator is configured to apply the third stimulation signal during the detected inspiration phase.

[0165] Embodiment B25. The method of claim B23 or B24, wherein the third stimulator is configured to apply the third stimulation signal to areas selected from the group consisting of L1-L2, L3-L4, and L4-L5.

[0166] Embodiment B26. The system of any one of embodiments B20-B22, wherein the second stimulation signal has a stimulation frequency from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, or between about 20 Hz and about 100 Hz.

[0167] Embodiment B27. The system of any one of embodiments B23-B25, wherein the third stimulation signal has a stimulation frequency from about 1 Hz, or from about 2 Hz, or from about 3 Hz, or from about 4 Hz, or from about 5 Hz, or from about 10 Hz, or from about 10 Hz, or from about 10 Hz, up to about 500 Hz, or up to about 400 Hz, or up to about 300 Hz, or up to about 200 Hz up to about 100 Hz, or up to about 90 Hz, or up to about 80 Hz, or up to about 60 Hz, or up to about 40 Hz, or from about 3 Hz, or from about 5 Hz to about 80 Hz, or from about 5 Hz to about 60 Hz, or up to about 30 Hz, or between about 20 Hz and about 100 Hz.

[0168] Embodiment B28. The system of any one of embodiments B1-B27, wherein the controller is further configured to detect an exhalation phase of the patient based on a second sensor signal from one or more sensors, and the stimulator is configured to cease applying the stimulation signal during the detected exhalation phase.

[0169] Embodiment B29. The system of any one of embodiments B1-B28, wherein the system is configured for use by a patient who is intubated on a ventilator, and the stimulation signal is provided to promote ventilator weaning.

[0170] Embodiment B30. The system of any one of embodiments B1-B28, wherein the system is configured for use with a non-intubated patient and the stimulation signal is provided to delay or prevent the need for mechanical ventilation.

[0171] It is noted that the term "patient" as used herein can refer to a human or non-human mammal under the care of a physician. However, the methods provided herein can also be applied to subjects not under the control or care of a physician. Thus, the terms "subject," "individual," and "patient" may be used interchangeably and may generally refer to a mammal, and in certain embodiments, to a human or non-human primate. It will be recognized that although these methods are described herein for use in humans, in certain embodiments, they are also suitable for use in animals, e.g., veterinary medicine. Thus, certain exemplary subjects include, but are not limited to, humans, non-human primates, dogs, horses, cats, pigs, ungulates, lagomorphs, and the like. Certain embodiments contemplate the methods described herein for use in domestic mammals (e.g., dogs, cats, horses), laboratory mammals (e.g., mice, rats, rabbits, hamsters, guinea pigs, pigs), and agricultural mammals (e.g., horses, cows, pigs, sheep), and the like. The term "subject" does not require the subject to have any particular status (e.g., inpatient, research participant, etc.) with respect to a hospital, clinic, or research facility. Thus, in various embodiments, a subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, boy, girl) under the care of a physician or other medical practitioner at a hospital, psychiatric facility, as an outpatient, or other clinical setting. In certain embodiments, a subject may not be under the care of a physician or medical practitioner, and in certain embodiments, may self-prescribe and / or self-administer the methods provided herein.

[0172] The foregoing description, for purposes of explanation, used specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required to practice the present invention. The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously, many modifications and variations are possible in light of the above teachings. The embodiments were chosen and described in order to explain the principles of the invention and its practical application, and thereby enable others skilled in the art to utilize the invention and various embodiments with various modifications as suitable for the particular use contemplated. It is intended that the following claims and their equivalents define the scope of the present invention.

Claims

1. 1. A method for controlling a stimulator during conditioning of a patient's respiratory muscles, comprising: receiving an indication of a detection of an inspiratory phase of the patient from one or more sensors; selecting a stimulation signal to be applied by the stimulation device to one or more of the patient's cervical, thoracic and lumbar spinal cord during the detected inspiration phase; Including, The method, wherein the stimulation signal is effective to maintain strength of the one or more respiratory muscles of the patient by increasing and / or sustaining activation of the one or more respiratory muscles during the inspiration phase.

2. The method of claim 1 , wherein the stimulation signal is configured to activate the one or more respiratory muscles by activating motor neurons at a segmental level of the spinal cord.

3. The method of claim 1 , wherein the stimulation signal is configured to be applied transcutaneously.

4. The method of claim 1 , wherein the stimulation signal is configured to be delivered epidurally or minimally invasively percutaneously.

5. The method of claim 1 , wherein the stimulation signal is induced by a magnetic signal. selecting a second stimulation signal configured to be applied to the patient's cervical spinal cord, the second stimulation signal configured to activate the patient's respiratory drive; or The method of claim 1 , further comprising selecting a third stimulation signal configured for application to the patient's lumbar spinal cord.

7. The method of claim 1 , wherein the stimulation signal is configured to prevent respiratory muscle atrophy in the patient.

8. 10. The method of claim 1, wherein the patient is intubated on a ventilator and the stimulation signal is configured to promote ventilator weaning.

9. 10. The method of claim 1, wherein the patient is not intubated on a ventilator and the stimulation signal is configured to delay or prevent the need for mechanical ventilation.

10. The method of claim 8, wherein the patient has respiratory failure or impairment caused by any one or more of acute respiratory distress syndrome (ARDS), ECMO, ventilator-induced diaphragmatic dysfunction, critical illness myopathy, chronic obstructive pulmonary disease (COPD), stroke, spinal cord injury, heart failure, trauma, pneumonia, sepsis, aging, and neurodegenerative disease.

11. 1. A system for conditioning a muscle of a patient, comprising: a controller configured to detect an inhalation phase of the patient based on sensor signals from one or more sensors; a stimulation device configured to apply a stimulation signal to one or more of the patient's cervical, thoracic, and lumbar spinal cord during the detected inspiration phase; Including, The system, wherein the stimulation signal is effective to maintain strength of one or more respiratory muscles of the patient by activating the one or more respiratory muscles during the inspiration phase.

12. 12. The system of claim 11, wherein the one or more sensors include a sensor configured to detect chest wall expansion, or at least one sensor of the one or more sensors is coupled to a ventilator treating the patient.

13. The system of claim 11 , wherein the stimulus signal is superimposed on a high frequency carrier signal.

14. The system of claim 11 , wherein the stimulator is an electrical stimulator.

15. The system of claim 11 , wherein the stimulator comprises one or more adhesive stimulators.

16. A second stimulator configured to provide a second stimulation signal to the patient's cervical spinal cord, the second stimulation signal being effective to activate the patient's respiratory drive; or 12. The system of claim 11, further comprising a third stimulator configured to apply a third stimulation signal to a lumbar spinal region of the patient.

17. 12. The system of claim 11, wherein the controller is further configured to detect an exhalation phase of the patient based on a second sensor signal from one or more sensors, and the stimulator is configured to cease applying the stimulation signal during the detected exhalation phase.

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