Devices, systems, and methods for enhancing breathing in neurodegenerative disease

Abstract

Provided herein is a method of improving or preserving respiration, speech, or swallowing in a patient, including delivering, with one or more implanted leads, an electrical stimulation to the patient's spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech, or swallowing in the patient.

Description

DEVICES, SYSTEMS, AND METHODS FOR ENHANCING BREATHING IN NEURODEGENERATIVE DISEASECROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 677,486, filed July 31 , 2024, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTIONField of the Invention

[0002] Provided herein are devices, systems, and methods for modulating breathing in a patient, and, in particular, devices, systems and methods for modulating breathing in patients with degenerative and / or neuromuscular diseases, by delivering electrical stimulation to the patient’s spinal canal.Description of Related Art

[0003] Many neurodegenerative and / or neuromuscular diseases can result in loss of motor neuron function, which can negatively impact the ability of patients with such conditions to engage in a number of activities. Critically, as these conditions progress, control over breathing can be impacted. Currently, electrotherapeutic approaches use phrenic nerve and diaphragm pacers; however, these approaches have not improved breathing control, or mortality outcomes in patients with neurodegenerative and / or neuromuscular disease. Accordingly, there is a need in the field for improved devices, systems, and methods for modulating breathing function in patients with such conditions.SUMMARY OF THE INVENTION

[0004] Provided herein is a method of improving or preserving respiration, speech or swallowing in a patient, including delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech or swallowing in the patient.

[0005] Also provided herein is a system including at least one pulse generator, at least one electrode configured to be positioned within a patient’s spinal canal, and at least one processor configured to control the pulse generator to deliver electrical stimulation to the patient’s spinal canal, wherein the processor is configured to controlthe pulse generator to deliver stimulation at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech or swallowing in the patient.

[0006] Also provided herein is a method of improving respiration, speech, or swallowing in a patient with a neurodegenerative disease, including delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve respiration, speech or swallowing in the patient.

[0007] Also provided herein is a method of preserving respiration, speech, or swallowing in a patient with a neurodegenerative disease, including delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to preserve respiration, speech, or swallowing in the patient.

[0008] Further non-limiting embodiments are set forth in the following numbered clauses:

[0009] 1 . A method of improving or preserving respiration, speech, or swallowing in a patient, comprising delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech, or swallowing in the patient.

[0010] 2. The method of clause 1 , wherein the electrical stimulation is delivered to the patient’s spinal canal at one or more locations within C1 -C8, or T1 -T10.

[0011] 3. The method of clause 1 or clause 2, wherein the electrical stimulation is delivered to the patient’s spinal canal at C3.

[0012] 4. The method of any of clauses 1 -3, wherein the electrical stimulation is delivered at an intensity of 0.01 mA to 10 mA and / or 1 mV to 10,000 mV.

[0013] 5. The method of any of clauses 1 -4, wherein the electrical stimulation is delivered at a frequency of 1 Hz to 1 kHz.

[0014] 6. The method of any of clauses 1 -5, wherein the electrical stimulation comprises electrical pulses with a pulse width of 1 ps to about 500 ps.

[0015] 7. The method of any of clauses 1 -6, wherein the electrical stimulation comprises electrical pulses that are charge-balanced.

[0016] 8. The method of any of clauses 1 -7, wherein the electrical stimulation comprises electrical pulses that are symmetric or asymmetric.

[0017] 9. The method of any of clauses 1 -8, wherein the electrical stimulation is delivered for a period of from 1 minute to 4 weeks.

[0018] 10. The method of any of clauses 1 -9, wherein the electrical stimulation is delivered for about 4 hours a day, about 5 days a week, for about 4 weeks.

[0019] 1 1 . The method of any of clauses 1 -10, wherein the electrical stimulation is delivered for a predetermined amount of time per day, ranging from 0.5 to 24 hours.

[0020] 12. The method of any of clauses 1 -1 1 , further comprising administering to the patient an additional therapy.

[0021] 13. The method of any of clauses 1 -12, wherein the additional therapy is continuous positive airway pressure therapy.

[0022] 14. The method of any of clauses 1 -13, wherein the additional therapy is a pharmaceutical therapy, a gene therapy, and / or a cell therapy.

[0023] 15. The method of any of clauses 1 -14, wherein the patient has a neurodegenerative disease.

[0024] 16. The method of any of clauses 1 -15, wherein the patient has spinal muscular atrophy.

[0025] 17. The method of any of clauses 1 -16, wherein the patient has central apnea and / or obstructive sleep apnea.

[0026] 18. The method of any of clauses 1 -17, wherein the electrical stimulation improves one or more physiological parameters in the patient.

[0027] 19. The method of any of clauses 1 -18, wherein the one or more physiological parameters is tidal volume.

[0028] 20. The method of any of clauses 1 -19, wherein the one or more physiological parameters is electromyography (EMG).

[0029] 21. The method of any of clauses 1 -20, wherein the one or more physiological parameters is diaphragm EMG.

[0030] 22. A system comprising at least one pulse generator, at least one electrode configured to be positioned within a patient’s spinal canal, and at least one processor configured to control the pulse generator to deliver electrical stimulation to the patient’s spinal canal, wherein the processor is configured to control the pulse generator to deliver stimulation at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech, or swallowing in the patient.

[0031] 23. A method of improving respiration, speech, or swallowing in a patient with a neurodegenerative disease, comprising delivering, with one or more implantedleads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve respiration, speech, or swallowing in the patient.

[0032] 24. The method of clause 23, wherein the patient has Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington’s Disease, spinal muscular atrophy, muscular dystrophy, progressive muscular atrophy, glycogen storage disease, fatty acid metabolic disease, mitochondria myopathy and / or nucleotide metabolic disorder.

[0033] 25. The method of clause 23 or clause 24, wherein the patient has Alzheimer’s Disease and the method further comprises administering a stem cell therapy to the patient.

[0034] 26. A method of preserving respiration, speech, or swallowing in a patient with a neurodegenerative disease, comprising delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to preserve respiration, speech, or swallowing in the patient.

[0035] 27. The method of clause 26, wherein the patient has Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington’s Disease, spinal muscular atrophy, muscular dystrophy, progressive muscular atrophy, glycogen storage disease, fatty acid metabolic disease, mitochondria myopathy and / or nucleotide metabolic disorder.

[0036] 28. The method of clause 26 or clause 27, wherein the patient has Alzheimer’s Disease, and the method further comprises administering a stem cell therapy to the patient.BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1 is a schematic diagram of example components of one or more devices according to non-limiting embodiments described herein

[0038] FIG. 2 shows EMG latency in animals to which stimulation as described in non-limiting embodiments herein was delivered

[0039] FIGS. 3A-3B show EMG peak amplitude in animals to which stimulation as described in non-limiting embodiments herein was delivered

[0040] FIGS. 4A-4H show frequency-dependent suppression of EMG potentials in animals to which stimulation as described in non-limiting embodiments herein wasdelivered; y axis is pV and x axis is values (105);(A-B) 20 Hz stimulation; (C-D) 50 Hz stimulation (showing suppression); (E-F) 100 Hz (showing suppression); (G-H) 200 Hz (showing suppression).

[0041] FIG. 5 shows antibody staining and neuronal survival in animals to which stimulation as described in non-limiting embodiments herein was delivered.DESCRIPTION OF THE INVENTION

[0042] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word "about". In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For definitions provided herein, those definitions refer to word forms, cognates and grammatical variants of those words or phrases.

[0043] The figures accompanying this application are representative in nature, and should not be construed as implying any particular scale or directionality, unless otherwise indicated. For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal” and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.

[0044] As used herein, the term “comprising” and like terms are open-ended. The term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The term “consisting of” excludes any element, step, or ingredient not specified in the claim.

[0045] As used herein, the terms “a” and “an” refer to one or more.

[0046] As used herein, the term “patient” is any mammal, including humans, and a“human patient” is any human.

[0047] As used herein, the term "computing device" may refer to one or more electronic devices configured to process data. A computing device may, in some examples, include the necessary components to receive, process, and output data, such as a processor, a display, a memory, an input device, a network interface, and / or the like. A computing device may be a mobile device. As an example, a mobile device may include a cellular phone (e.g., a smartphone or standard cellular phone), a portable computer, a wearable device (e.g., watches, glasses, lenses, clothing, and / or the like), a personal digital assistant (PDA), and / or other like devices. A computing device may also be a desktop computer or other form of non-mobile computer.

[0048] As used herein, the terms “communication” and “communicate” refer to the receipt, transmission, or transfer of one or more signals, messages, commands, or other type of data. For one unit or device to be in communication with another unit or device means that the one unit or device is able to receive data from and / or transmit data to the other unit or device. A communication can use a direct or indirect connection, and can be wired and / or wireless in nature. Additionally, two units or devices can be in communication with each other even though the data transmitted can be modified, processed, routed, etc., between the first and second unit or device. For example, a first unit can be in communication with a second unit even though the first unit passively receives data and does not actively transmit data to the second unit. As another example, a first unit can be in communication with a second unit if an intermediary unit processes data from one unit and transmits processed data to the second unit. It will be appreciated that numerous other arrangements are possible. Any known electronic communication protocols and / or algorithms can be used such as, for example, TCP / IP (including HTTP and other protocols), WLAN (including 802.11 a / b / g / n and other radio frequency-based protocols and methods), analog transmissions, Global System for Mobile Communications (GSM), 3G / 4G / LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, and the like known to those of skill in the art.

[0049] As used herein, “electrical communication,” for example in the context of transmitting electrical pulses from a pulse generator to an electrode refers to sending an electrical pulse produced by a pulse generator to a skin surface electrode, an electrode lead, a magnetic coil, or like devices capable of generating electrical current to stimulate a nerve or neuron as described herein, typically through an electrically conductive lead, such as a wire.

[0050] The term “about” or “approximately” can mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean plus or minus 10%, per the practice in the art. Alternatively, “about” can mean a range of plus or minus 20%, plus or minus 10%, plus or minus 5%, or plus or minus 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, within 5-fold, or within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed. Also, where ranges and / or subranges of values are provided, the ranges and / or subranges can include the endpoints of the ranges and / or subranges.

[0051] The term “substantially” as used herein can refer to a value approaching 100% of a given value. In some cases, the term can refer to an amount that can be at least about 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 99.99% of a total amount. In some cases, the term can refer to an amount that can be about 100% of a total amount.

[0052] The terms “treat,” “treating”, “treatment,” “ameliorate” or “ameliorating” and other grammatical equivalents as used herein, can include alleviating, or abating a disease or condition symptoms, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by the disease or condition, or stopping symptoms of a disease or condition.

[0053] The term “preventing” can mean preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, and can include prophylaxis.

[0054] In some instances, “treat,” “treating”, “treatment,” “ameliorate” or “ameliorating” and other grammatical equivalents can include prophylaxis. “Treat,” “treating”, “treatment,” “ameliorate” or “ameliorating” and other grammatical equivalents can further include achieving a therapeutic benefit and / or a prophylactic benefit. Therapeutic benefit can mean eradication of the underlying disease being treated. Also, a therapeutic benefit can be achieved with the eradication of one or more of the physiological symptoms associated with the underlying disease such that animprovement can be observed in a subject notwithstanding that, in some embodiments, the subject can still be afflicted with the underlying disease.

[0055] The terms “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” as used herein, can refer to a sufficient amount of a compound being administered which will at least partially ameliorate a symptom of a disease or condition being treated.

[0056] The terms “co-administration”, “administered in combination with” and their grammatical equivalents or the like, as used herein, can encompass administration of stimulation as described herein and one or more selected therapeutic agents to a subject, and can include treatment regimens in which stimulation and a therapeutic agent are administered at the same or different times.

[0057] Provided herein are devices, systems, and methods for delivering electrical stimulation to the spinal cord of a patient, for modulating and / or preserving one or more parameters of the patient’s respiration, speech or swallowing. Such devices, systems, and methods provide an improvement to existing technology in terms of more rapid and effective treatment of breathing conditions, for example in individuals spinal muscular atrophy.

[0058] Suitable devices and systems may include a pulse generator in electrical communication with one or more electrode leads (which may be, in non-limiting embodiments, paddle leads). Suitable pulse generators and electrode leads are commercially available and are known to those of skill in the art, and may include, without limitation, those sold by A-M Systems (e.g., Model 2100 Isolated Pulse Stimulator), Rhythmlink (subdermal needle electrodes), and Medtronic (977A260 leads). One or more components of such a device or system may be implantable in the patient. In non-limiting embodiments, the pulse generator is implanted, as are the one or more leads. In non-limiting embodiments, skin surface electrodes (e.g., transcutaneous electrodes) are excluded from the device, and only implanted electrodes are used. In non-limiting embodiments, the one or more leads are implanted, and the pulse generator is arranged external to the patient, for example as a wearable device. Alternatively, the lead and pulse generator are both implanted and communication with the device is enabled through a separate external device that communicates through wireless technology. Useful pulse generators may include one or more processors or may be in communication with one or more processors or computing devices, to allow for control of electrical stimulation.

[0059] Any component of a pulse generator, or computing device in communication with a pulse generator, may have one or more elements of device 100 shown in FIG. 1 , which shows a diagram of example components of a device 100 according to nonlimiting embodiments. Device 100 may correspond to any element of a system (for example, a pulse generator, a pulse generator and a separate computing device, a separate computing device, a server, or various combinations thereof). In some nonlimiting embodiments, such systems or devices may include at least one device 100 and / or at least one component of device 100. The number and arrangement of components shown are provided as an example. In some non-limiting embodiments, device 100 may include additional components, fewer components, different components, or differently arranged components than those shown. Additionally, or alternatively, a set of components (e.g., one or more components) of device 100 may perform one or more functions described as being performed by another set of components of device 100.

[0060] As shown in FIG. 1 , device 100 (which may be a pulse generator and / or may be a computing device in communication with a pulse generator) may include a bus 202, a processor 204, memory 206, a storage component 208, an input component 210, an output component 212, and a communication interface 214. Bus 202 may include a component that permits communication among the components of device 100. In some non-limiting embodiments, processor 204 may be implemented in hardware, firmware, or a combination of hardware and software. For example, processor 204 may include a processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), an accelerated processing unit (APU), etc.), a microprocessor, a digital signal processor (DSP), and / or any processing component (e.g., a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), etc.) that can be programmed to perform a function. Memory 206 may include random access memory (RAM), read only memory (ROM), and / or another type of dynamic or static storage device (e.g., flash memory, magnetic memory, optical memory, etc.) that stores information and / or instructions for use by processor 204.

[0061] With continued reference to FIG. 1 , storage component 208 may store information and / or software related to the operation and use of device 100. For example, storage component 208 may include a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optic disk, a solid-state disk, etc.) and / or another type of computer-readable medium. Input component 210 may include a component thatpermits device 100 to receive information, such as via user input (e.g., a touch screen display, a keyboard, a keypad, a mouse, a button, a switch, a microphone, etc.). Additionally, or alternatively, input component 210 may include a sensor for sensing information (e.g., a global positioning system (GPS) component, an accelerometer, a gyroscope, an actuator, etc.). Sensors useful here may include biochemical sensors, electrochemical sensors, sensors for detecting autonomic tone, sensors for detecting sympathetic tone, and / or the like. Output component 212 may include a component that provides output information from device 100 (e.g., a display, a speaker, one or more light-emitting diodes (LEDs), etc.). Communication interface 214 may include a transceiver-like component (e.g., a transceiver, a separate receiver and transmitter, etc.) that enables device 100 to communicate with other devices, such as via a wired connection, a wireless connection, or a combination of wired and wireless connections. Communication interface 214 may permit device 100 to receive information from another device and / or provide information to another device. For example, communication interface 214 may include an Ethernet interface, an optical interface, a coaxial interface, an infrared interface, a radio frequency (RF) interface, a universal serial bus (USB) interface, a Wi-Fi® interface, a cellular network interface, and / or the like.

[0062] Device 100 may perform one or more processes described herein. Device 100 may perform these processes based on processor 204 executing software instructions stored by a computer-readable medium, such as memory 206 and / or storage component 208. A computer-readable medium may include any non-transitory memory device. A memory device includes memory space located inside of a single physical storage device or memory space spread across multiple physical storage devices. Software instructions may be read into memory 206 and / or storage component 208 from another computer-readable medium or from another device via communication interface 214. When executed, software instructions stored in memory 206 and / or storage component 208 may cause processor 204 to perform one or more processes described herein. Additionally, or alternatively, hardwired circuitry may be used in place of or in combination with software instructions to perform one or more processes described herein. Thus, embodiments described herein are not limited to any specific combination of hardware circuitry and software. The term “configured to,” as used herein, may refer to an arrangement of software, device(s), and / or hardware for performing and / or enabling one or more functions (e.g., actions, processes, stepsof a process, and / or the like). For example, “a processor configured to” may refer to a processor that executes software instructions (e.g., program code) that cause the processor to perform one or more functions.

[0063] One or more elements of device 100 may be received within a housing with, for example, pulse generator(s), which may in non-limiting embodiments be implantable or may be external to the patient. In non-limiting embodiments, device 100, including pulse generator(s) and electrodes and / or leads 110, is implanted in the patient. In non-limiting embodiments, device 100, including pulse generator(s) is arranged externally of the patient, while leads are implanted in the patient. In nonlimiting embodiments, one or more components of a system may be implanted, while others are external to the patient, and / or are distributed (e.g., one or more components of device 100 are implanted within patient and one or more components of device 100 are external to the patient).

[0064] In non-limiting embodiments, a system may include a pulse generator (which may include one or more components of device 100) which is implanted or is external to the patient, and which delivers stimulation to electrode lead(s) that are implanted at or adjacent to a region of interest (e.g., a region to be stimulated), and a distinct computing device that may be part of the system, which may include a controller app or software on a smartphone, tablet, laptop, smart watch, personal computer, workstation, server, and / or computer network. In non-limiting embodiments, device 100 is password protected, such that a patient may not alter any stimulation parameters (in non-limiting embodiments, a doctor may access device 100 to update stimulation parameters). In non-limiting embodiments, device 100, whether implantable or not, may include one or more power sources, which may be rechargeable, for example through inductive charging.

[0065] In non-limiting embodiments, device 100 may be in communication with one or more computing devices to allow a healthcare provider remote monitoring and updating of device 100, including updating of stimulation parameters.

[0066] As noted above, devices and systems described herein deliver electrical stimulation to a patient. Such devices may be programmed to deliver the stimulation without user input, and / or may allow for a user, for example a medical professional, or the patient, to adjust one or more parameters of the stimulation.

[0067] The electrical stimulation described herein can include electrical pulses that can have any suitable characteristic, so long as the stimulation is effective to achievethe desired physiological response, as described herein. As such, the terms "electrical stimulation" and "electrical pulses" are used interchangeably herein. As will be recognized by a person of skill in the art, characteristics of the electrical pulses, including, without limitation, amplitude (pulse strength, referring to the magnitude or size of a signal voltage or current), voltage, amperage, duration (e.g., pulse width), frequency, polarity, phase, relative timing (e.g., inter pulse width), and symmetry of positive and negative pulses in biphasic stimulation, and / or wave shape (e.g., square, sine, triangle, sawtooth, or variations or combinations thereof) may be varied in order to provide the desired physiological response, so long as other characteristics of the electrical signals (e.g., without limitation, amplitude, voltage, amperage, duration, polarity, phase, relative timing and symmetry of positive and negative pulses in biphasic stimulation, and / or wave shape) are within ranges sufficient to elicit the desired physiological response.

[0068] One characteristic of the electrical signals used to produce a desired response, as described above, is the frequency of the electrical pulse. Although effective ranges (e.g., frequencies able to produce a stated effect) may vary from subject-to-subject, and the controlling factor is achieving a desired physiological outcome, certain, non-limiting exemplary ranges may be as follows. In non-limiting embodiments, useful frequencies may range from about 1 Hz to about 1 MHz, about 1 Hz to about 20 Hz, about 1 Hz to about 10 Hz, about 20 Hz to about 200 Hz, about 20 Hz to about 50 Hz, about 50 Hz to about 100 Hz, about 100 Hz to about 200 Hz, 100 Hz to about 900 kHz, about 200 Hz to about 800 kHz, about 300 Hz to about 700 kHz, about 400 Hz to about 600 kHz, about 500 Hz to about 500 kHz, about 600 Hz to about 400 kHz, about 700 Hz to about 300 kHz, about 800 Hz to about 200 kHz, about 900 Hz to about 100 kHz, in non-limiting embodiments about 100 Hz to about 1 kHz, about 200 Hz to about 900 Hz, about 300 Hz to about 800 Hz, about 400 Hz to about 700 Hz, about 500 Hz to about 600 Hz, and / or all values and subranges therebetween inclusive.

[0069] In non-limiting embodiments, the electrical pulses are delivered with a pulse width (e.g., pulse duration) of about 1 ps to about 500 ps, all values and subranges there between inclusive.

[0070] Stimulation as described herein may be delivered in one or more patterns, for example, burst, continuous, tonic, pulsed, modulated, randomized, alternating, graded as increasing or decreasing, and / or sequential stimulation patterns.Stimulation, once delivered, may be delivered for any suitable period, for example, until one or more physiological responses are achieved, and indicate that stimulation should be changed (e.g., turned on, turned off, increased, decreased, and / or ramped). In some cases, stimulation may not elicit a detectable response during stimulation or immediately following, but rather elicit a response as demonstrated through delayed loss of physiological response or function.

[0071] A characteristic of electrical pulses is their intensity, which in a medium of stable or relatively stable resistance, such as mammalian tissue, can be characterized as relating to current (I, typically measured in mA), or voltage (V, typically measured in mV or V), based on Ohm's Law. It should, therefore, be understood that the intensity of the stimulation is a matter of both V and I, and as such, both are increased, e.g., proportionally or substantially proportionally, with increased intensity of stimulation.

[0072] A characteristic of the intensity of the pulses is voltage. Stimulation can be achieved in a typical range of from 1 mV to 20 V, all subranges and values there between inclusive. In non-limiting embodiments or aspects, the stimulation is delivered with electrical pulses having a voltage from about 0.8 V to about 16 V, about 2 V to about 16 V, about 4 V to about 16 V, about 6 V to about 16 V, about 0.9 V, about 1 V, about 2 V, about 3 V, about 4V, about 6 V, or any subrange or value therebetween.

[0073] Another characteristic of the intensity of pulses is amplitude. Suitable stimulation can be achieved in a typical range of from 0.001 mA to 10 mA, all values and subranges therebetween inclusive. A range of 0.001 mA to 1 mA may be effective in many instances.

[0074] As indicated above, the waveform of the pulses may vary, so long as the desired physiological response is realized. One skilled in the art will appreciate that other types of electrical stimulation may also be used in accordance with the present invention. Monophasic or biphasic stimuli, or a mixture thereof, may be used. Damage to nerves by the application of an electrical current may be minimized, as is known in the art, by application of biphasic pulses or biphasic waveforms to the nerve(s), as opposed to monophasic pulses or waveforms that can damage nerves in some instances of long-term use. "Biphasic current," "biphasic pulses," or "biphasic waveforms" refer to two or more pulses that are of opposite polarity that may be of equal or substantially equal net charge (hence, biphasic and charge balanced), and may be symmetrical, asymmetrical, or substantially symmetrical. This is accomplished, for example, by applying through an electrode one or more positivepulses, followed by one or more negative pulses, typically of the same amplitude and duration as the positive pulses, or vice versa, such that the net charge applied to the target of the electrode is zero, or approximately zero. For charge-balanced biphasic stimulation, the opposite polarity pulses may have different amplitudes, profiles, or durations, so long as the net applied charge by the biphasic pulse pair (the combination of the positive and negative pulses) is approximately zero.

[0075] The waveform may be of any useful shape, including without limitation: sine, square, rectangular, triangular, sawtooth, rectilinear, pulse, exponential, truncated exponential, or damped sinusoidal. In non-limiting embodiments, the waveform is rectangular.

[0076] The pulses may increase or decrease over the stimulation period. The pulses may be delivered continuously or intermittently as needed. For example, the stimulation may be delivered for short intervals (e.g., 0.1 -10.0 minutes, all values and subranges therebetween inclusive) or longer intervals (360 minutes or even longer, for example days, weeks, months, or even years, all values and subranges therebetween inclusive). In aspects, the stimulation is delivered for at least 5 minutes whether in a continuous approach or intervals separated by periods of non-stimulation. The periods of non-stimulation that separate stimulation intervals may range from 0.1 - 10.0 minutes, and all values and subranges therebetween inclusive. In non-limiting embodiments, intermittent stimulation may be followed by a period of continuous stimulation. In non-limiting embodiments, the physiological response may not be detected during stimulation but only elicited during conditional experiences that are revealed after the stimulation has stopped. The delay in physiological response may be minutes, hours, days, weeks or even years. In non-limiting embodiments, when the device starts and / or stops delivering stimulation, the physiological response is ramped up and / or down, during or beyond the stimulation period, rather than immediately ceasing or turning on to 100% intensity.

[0077] In non-limiting embodiments, biphasic stimulation may be delivered at the lowest intensity (e.g., amplitude) to evoke an EMG response within a targeted muscle group, with a pulse duration of about 400 ps, at a frequency of about 1 Hz. In nonlimiting embodiments, stimulation as described herein may include one or more periods of sub-threshold stimulation, where sensory afferent fibers are recruited, but motor fibers are not activated. As used herein, the term “sub-threshold depolarization” or “sub-threshold stimulation” means a stimulation sufficient to increase membranevoltage of a nerve or neuron from resting membrane potential (e.g., -70mV) to a level below the excitation threshold, such that the nerve or neuron does not become excited, e.g., no action potential is initiated or conducted. For example, sub-threshold stimulation may mean delivering stimulation having an amplitude that is 90% of the lowest amplitude sufficient to elicit visible muscle contraction or EMG response. Ranges for pulse duration include 1 ps to 10,000 ps, all values and subranges therebetween inclusive. In addition, Frequency includes 0.1 Hz to 10,000 Hz, all values and subranges therebetween inclusive. Stimulation can be delivered with variable pulse duration and frequency including burst patterns.

[0078] In non-limiting embodiments, during delivery of stimulation, pulses are delivered in bursts, with an intra-burst frequency of about 600 Hz and a burst duration of about 17 ms (e.g., about 10 pulses per burst) and an inter-burst frequency of about 30 Hz. Ranges for intra and inter-burst frequency range from 1 Hz to 10,000 Hz, all values and subranges therebetween inclusive. Burst duration ranges from 1 ms to 1 ,000 ms, all values and subranges therebetween inclusive.

[0079] In non-limiting embodiments, stimulation is delivered continuously. In non-limiting embodiments, stimulation is delivered each day, for one or more time periods each day; representing training periods or maintenance periods. For example, the training or maintenance periods may include stimulation delivered for 0.5 to 24 hours a day, for 1 to 7 days per week, for a duration of 1 to 52 weeks per year, all values and subranges therebetween inclusive. Currently existing stimulation paradigms include continuous stimulation; 24 hours a day for 7 days a week; stimulation provided for 0.5-8.0 hours a day for 1 -7 days a week; and all values in between. These stimulation periods may be separated by rest period with stimulation being non-continuous within a given day, week, month, or year.

[0080] As described above, stimulation delivered by devices and systems described herein may be delivered to the spinal cord, sensory nerve rootlets, or sensory dorsal root ganglion. In non-limiting embodiments, the stimulation may be delivered to the spinal canal. Suitable stimulation may be delivered to the spinal canal at the cervical (e.g., C1 -C8, including any 1 , 2, or more particular cervical levels) or thoracic (e.g., T1 -T12, including any 1 , 2, or more particular thoracic levels) levels. In non-limiting embodiments, stimulation may be delivered to the cervical spinal canal at C2-C6, C3-C6, C3-C5, C3-C4, and / or C3. In non-limiting embodiments, stimulation may be delivered to the thoracic spinal canal at T1 -T10 levels, and any subintervaltherebetween. Without wishing to be bound by the theory, it is believed that delivering stimulation to the spinal canal at one or more of the aforementioned levels stimulates dorsal sensory roots / rootlets, and / or sensory ganglions (e.g., stimulation at C3 may recruit C4, C5, and / or C6 nerve rootlets), causing a motor response in one or more muscle groups of interest, for example in muscles relating to inspiratory or expiratory respiration control. Moreover, those of skill in the art will appreciate that stimulation cannot be delivered at an anatomical location too remote from the aforementioned, and that the further from these levels (e.g., the further from C3) that the stimulation is delivered, the more intense and / or longer the stimulation must be delivered to achieve the desired outcome, which can negatively impact one or more physiological parameters and thus may be undesirable.

[0081] In non-limiting embodiments, a patient to which the stimulation described herein is delivered may have a condition such as obstructive sleep apnea, central sleep apnea, one or more motor deficits related to breathing, and / or a neurodegenerative disease, for example, and without limitation, spinal muscular atrophy (SMA), Parkinson’s Disease (PD), muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), progressive muscular atrophy, Huntington’s disease, glycogen storage diseases (e.g., von Gierke disease, Pompe disease, Cori disease, and / or McArdle disease), fatty acid metabolic diseases (e.g., medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiency, and very long-chain acyl-CoA dehydrogenase (VLCADD) deficiency), mitochondria myopathies (e.g., Kearns-Sayre syndrome, Leigh syndrome, MELAS syndrome, and / or MNGIE syndrome) and / or nucleotide metabolic disorders (e.g., Lesch-Nyhan syndrome, adenosine deaminase deficiency, Orotic aciduria, and / or phosphoribosylpyrophosphate synthetase superactivity). Those of skill in the art will appreciate that electrical stimulation parameters as described herein may be modified depending on the condition being treated.

[0082] In non-limiting embodiments, electrical stimulation as described herein is administered to the patient in conjunction with one or more additional interventions, including, without limitation, medications / pharmaceutical interventions (e.g., onasemnogene abeparvovec, nusinersen, risdiplam, levodopa, stem cell therapies (e.g., mesenchymal stem cell therapies, and / or gene therapies), gene therapy interventions, interventions that target alternative neural elements in conjugation with spinal sensory structures outlined above, including (brain structures, brainstemstructures, cerebellar structures or peripheral neural elements), continuous positive airway pressure (CPAP), and / or bilevel positive airway pressure (BiPAP). Such interventions may be administered in any amount effective to treat the condition (such as a condition described herein), and / or may be a sub-therapeutic dosage (for example, as a supplement to the electrical stimulation described herein). Dosages for therapeutics disclosed herein are generally known, and one of ordinary skill in the art can identify useful dosage forms (e.g., capsules, tablets, caplets, pills, troches, lozenges, powders, granules, liquids, suspensions, creams, ointments, jellies, pastes, lotions), ranges, frequencies (e.g., once, twice, or more times daily for any suitable amount of time), amounts (e.g., about 1 microgram (pg) to about 1000 mg, whether in terms of raw amount, amount per kg body weight of the patient, or amount per volume of an administered composition, all values and subranges therebetween inclusive), and routes of administration (e.g., orally, rectally, or parenterally) based on the identity of the therapeutic. The term "parenteral" as used herein can include subcutaneous, intravenous, intramuscular, or intrasternal injection and infusion techniques. Administration can include injection or infusion, including intra-arterial, intracardiac, intracerebroventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration.

[0083] Electrical stimulation as described herein, when delivered to a patient, may be sufficient to improve, preserve (e.g., in the context of progressive degenerative disease), and / or restore one or more physiological parameters in the patient. As used herein, “preserve” means that a physiological function or parameter is maintained at or about a level of the physiological function or parameter when the treatment is initiated. For example, and without limitation, electrical stimulation may improve, preserve (e.g., in the context of progressive degenerative disease), and / or restore a patient’s tidal volume, end-tidal CO2, respiratory rate, cough production, inspiratory force, expiratory force, speech, or swallowing and / or the like. In non-limiting embodiments, electrical stimulation delivered to the patient may be sufficient to improve (e.g., increase) an electromyograph (EMG) signal generated by one or more muscles related to respiration, speech or swallowing. For example, electrical stimulation may be sufficient to improve the patient’s diaphragm EMG, intercostalmuscles EMG, scalene muscles EMG, or EMG activity of additional muscles that facilitate inspiratory or expiratory airflow related to breathing. In addition, by impacting muscles related to respiration, non-respiratory activities that share similar anatomical structures to respiratory may be influenced (e.g., preserved, enhanced, or increased), for example and without limitation, speech and swallowing.ExampleImplantation

[0084] An epidural spinal cord stimulation lead is implanted so that the electrode is localized over the dorsal afferent rootlet of the corresponding muscle group.

[0085] Phrenic nerve controlling the diaphragm muscle; C3-C5

[0086] Thoracic intercostal nerves; T1 -T10

[0087] Selective, sensory afferent activation of isolated muscle groups is performed using a ramp stimulation protocol that employs trans-synaptic motor activation. Specifically, pulse amplitude is progressively increased until muscles are recruited, indirectly through sensory neuron activation, as confirmed with electromyography.

[0088] Pulse amplitude: lowest amplitude sufficient to evoke an EMG response within targeted muscle

[0089] Pulse duration: 400 ps (biphasic)

[0090] Pulse frequency: 1 HzTreatment (Training or Maintenance) Protocol

[0091] For a duration of 4 hours a day, 5 days a week for 4 weeks, animals are treated with "subthreshold stimulation" designed to recruit sensory afferent fibers without directly activating motor efferent fibers. Subthreshold stimulation amplitude is determined as the amplitude that is 90% of the lowest amplitude sufficient to elicit visible muscle contraction in a freely behaving mouse. Since the sensory afferent fibers are in closer proximity to the electrode than the motor efferent fibers, and since the stimulation amplitude is not sufficient to elicit a direct motor evoked output (as demonstrated by lack of EMG response), the treatment protocol is selectively activating sensory afferent fibers without directly stimulating the motor efferent fibers. This process is known to facilitate volitional (e.g. supraspinal derived) upper limb and lower limb motor activity in humans suffering from neuromuscular paralysis.

[0092] Pulse duration: 400 ps (biphasic)

[0093] Intra-burst frequency: 600 Hz

[0094] Burst duration: 17 ms (10 pulses per burst)

[0095] Inter-burst frequency: 30 HzConfirmation of selective sensory afferent activation

[0096] Selective activation of sensory afferent fibers is confirmed with frequency dependent stimulation. Specifically, mice are stimulated with the same pulse amplitude utilized during the "treatment protocol". When the EMG activity is evoked indirectly via trans-synaptic sensory afferent activation, EMG activity is suppressed during high frequency stimulation (greater than 20Hz) as the synapse propagation frequency tolerance is lower than the stimulation frequency. For example, at high stimulation rates (e.g. high frequencies), not all electrical pulses that are delivered to sensory fibers will elicit an EMG signal. The time delay for the post-synaptic motor neuron to reset its membrane potential is the rate limiting step in trans-synaptic signal propagation. To confirm trans-synaptic EMG activation, high frequency stimulation will lose 1 :1 EMG; otherwise known as frequency dependent suppression. Conversely, if the stimulation amplitude was directly activating motor efferent fibers or motor neurons through spinal cord stimulation, 1 :1 EMG activation would be observed during high frequency stimulation.

[0097] Pulse duration: 400 ps (biphasic)

[0098] Intra-burst frequency: 500 Hz

[0099] Burst duration: 10 ms (5 pulses per burst)

[0100] Inter-burst frequency: 10 / 20 / 40 Hz Results

[0101] EMG latency

[0102] As shown in FIGS. 2A-2B, diseased mice with neurodegenerative neuromuscular disease (in red) demonstrate variable prolongation in EMG latency, impacting the synchrony of muscle recruitment, which is highly associated with clinical weakness. Normal mice (in green) demonstrate closely clustered latencies that are short in duration. Diseased mice that have been treated / trained with spinal cord stimulation (in blue) demonstrate closely clustered latencies that are short in duration.

[0103] EMG peak amplitude

[0104] As shown in FIGS. 3A-3B, diseased mice (in red) demonstrate loss of the highest peak amplitude values, which is highly associated with clinical weakness. In respiratory control, this would result in loss of cough reflexes or high tidal volume breathing. Normal mice (in green) demonstrate high peak amplitude values expected of intact animals. Diseased mice that have been treated / trained with spinal cordstimulation (in blue) demonstrate some preservation of the highest peak amplitudes. Not demonstrated in the red group, but shown in the green group.

[0105] Frequency-Dependent Suppression

[0106] FIGS. 4A-4H show data demonstrating frequency dependent suppression of EMG potentials. This is a hallmark feature of indirect motor facilitation via sensory afferent stimulation (i.e. trans-synaptic motor neuron activation). Frequencydependent stimulation is not observed when spinal cord stimulation directly targets the spinal cord or efferent motor neurons (cell bodies, rootlets, or axons). Currently studied treatments utilizing phrenic nerve pacers and diaphragm pacers target motor neurons and / or muscles directly. In clinical trials, diaphragm pacers fail to preserve respiratory motor activity in degenerative neuromuscular disease. Frequency dependent suppression was not shown within other known methods, which represents a major gap in claims that such methods are targeting sensory afferent fibers.

[0107] Motor Neuron Survival

[0108] FIG. 5 shows spinal cord tissue stained with Chat antibody to highlight motor neurons. Normal tissue demonstrates a robust population of motor neurons within the spinal cord ventral horn. Diseased mice with neurodegenerative neuromuscular disease demonstrate near complete loss of motor neurons. Mice treated / trained with spinal cord stimulation demonstrate partial preservation of motor neurons.

[0109] While the present invention has been described in terms of the above detailed description, those of ordinary skill in the art will understand that alterations may be made within the spirit of the invention. Accordingly, the above should not be considered limiting, and the scope of the invention is defined by the appended claims.

Claims

THE INVENTION CLAIMED IS1. A method of improving or preserving respiration, speech, or swallowing in a patient, comprising delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech, or swallowing in the patient.

2. The method of claim 1 , wherein the electrical stimulation is delivered to the patient’s spinal canal at one or more locations within C1 -C8, or T1- T10.

3. The method of claim 1 , wherein the electrical stimulation is delivered to the patient’s spinal canal at C3.

4. The method of claim 1 , wherein the electrical stimulation is delivered at an intensity of 0.01 mA to 10 mA and / or 1 mV to 10,000 mV.

5. The method of claim 1 , wherein the electrical stimulation is delivered at a frequency of 1 Hz to 1 kHz.

6. The method of claim 1 , wherein the electrical stimulation comprises electrical pulses with a pulse width of 1 ps to about 500 ps.

7. The method of claim 1 , wherein the electrical stimulation comprises electrical pulses that are charge-balanced.

8. The method of claim 1 , wherein the electrical stimulation comprises electrical pulses that are symmetric or asymmetric.

9. The method of claim 1 , wherein the electrical stimulation is delivered for a period of from 1 minute to 4 weeks.

10. The method of claim 1 , wherein the electrical stimulation is delivered for about 4 hours a day, about 5 days a week, for about 4 weeks.11 . The method of claim 1 , wherein the electrical stimulation is delivered for a predetermined amount of time per day, ranging from 0.5 to 24 hours.

12. The method of claim 1 , further comprising administering to the patient an additional therapy.

13. The method of claim 12, wherein the additional therapy is continuous positive airway pressure therapy.

14. The method of claim 12, wherein the additional therapy is a pharmaceutical therapy, a gene therapy, and / or a cell therapy.

15. The method of claim 1 , wherein the patient has a neurodegenerative disease.

16. The method of claim 15, wherein the patient has spinal muscular atrophy.

17. The method of claim 1 , wherein the patient has central apnea and / or obstructive sleep apnea.

18. The method of claim 1 , wherein the electrical stimulation improves one or more physiological parameters in the patient.

19. The method of claim 18, wherein the one or more physiological parameters is tidal volume.

20. The method of claim 18, wherein the one or more physiological parameters is electromyography (EMG).21 . The method of claim 20, wherein the one or more physiological parameters is diaphragm EMG.

22. A system comprising at least one pulse generator, at least one electrode configured to be positioned within a patient’s spinal canal, and at least one processor configured to control the pulse generator to deliver electrical stimulation to the patient’s spinal canal, wherein the processor is configured to control the pulse generator to deliver stimulation at a frequency, intensity, and for a length of time sufficient to improve or preserve respiration, speech or swallowing in the patient.

23. A method of improving respiration, speech, or swallowing in a patient with a neurodegenerative disease, comprising delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to improve respiration, speech, or swallowing in the patient.

24. The method of claim 23, wherein the patient has Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Huntington’s Disease, spinal muscular atrophy, muscular dystrophy, progressive muscular atrophy, glycogen storage disease, fatty acid metabolic disease, mitochondria myopathy and / or nucleotide metabolic disorder.

25. The method of claim 23, wherein the patient has Alzheimer’s Disease and the method further comprises administering a stem cell therapy to the patient.

26. A method of preserving respiration, speech, or swallowing in a patient with a neurodegenerative disease, comprising delivering, with one or more implanted leads, an electrical stimulation to the patient’s spinal canal, wherein the stimulation is delivered at a frequency, intensity, and for a length of time sufficient to preserve respiration, speech, or swallowing in the patient.

27. The method of claim 26, wherein the patient has Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis,Huntington’s Disease, spinal muscular atrophy, muscular dystrophy, progressive muscular atrophy, glycogen storage disease, fatty acid metabolic disease, mitochondria myopathy and / or nucleotide metabolic disorder.

28. The method of claim 26, wherein the patient has Alzheimer’s Disease and the method further comprises administering a stem cell therapy to the patient.

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