WO2025019832A1

WO2025019832A1 - Systems and methods for treating parkinson's disease using neuromodulation

Info

Publication number: WO2025019832A1
Application number: PCT/US2024/038883
Authority: WO
Inventors: John Morriss
Original assignee: Boomerang Medical Inc
Current assignee: Boomerang Medical Inc
Priority date: 2023-07-20
Filing date: 2024-07-19
Publication date: 2025-01-23
Anticipated expiration: 2026-01-20

Abstract

Systems and methods for treating Parkinson's Disease (PD) using neuromodulation are described herein. For example, PD can be treated by delivering an electrical signal to one or more sacral nerves of a patient via an implanted signal delivery device positioned proximate one or more of the patient's sacral nerves.

Description

SYSTEMS AND METHODS FOR TREATING PARKINSON’S

DISEASE USING NEUROMODULATION

CROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63/514,751 , filed July 20, 2023, the disclosure of which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

[0002] The present technology is directed toward electrically modulating nervous tissue to treat a patient condition.

BACKGROUND

[0003] Parkinson’s Disease (PD) is a progressive neurological disorder characterized by motor dysfunction, including tremor, bradykinesia, rigid muscles, and the like. In addition to motor dysfunction, many patients with PD also have overactive bladder (OAB) and/or gastrointestinal (Gl) dysfunction. Typically, the OAB and Gl dysfunction present before the motor dysfunction. The incidence of Parkinson’s Disease is steadily increasing, with nearly 1 million PD patients in the United States and 10 million PD patients worldwide. Despite this, treatment options remain limited and/or ineffective. For example, the most common PD treatment includes administering drugs that attempt to increase the dopamine levels in the patient to reduce symptoms. Another PD treatment includes deep brain stimulation, which includes implanting electrodes into the patient’s brain to provide electrical stimulation to specific neural targets in the patient’s brain.

BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1A is a partially schematic illustration of an implantable sacral neuromodulation system positioned at a patient’s sacral region to deliver electrical signals in accordance with some embodiments of the present technology.

[0005] Figure 1 B illustrates an embodiment of the sacral neuromodulation system of Figure 1A with multiple signal delivery devices for providing bilateral sacral stimulation and configured in accordance with some embodiments of the present technology.

[0006] Figure 1 C illustrates another embodiment of the sacral neuromodulation system of Figure 1 A with multiple signal delivery devices for stimulating different target structures and configured in accordance with some embodiments of the present technology.

[0007] Figure 1 D illustrates two sacral neuromodulation systems implanted at a patient’s sacral region to independently deliver electrical signals and configured in accordance with some embodiments of the present technology

[0008] Figure 1 E illustrates sacral nerve anatomy of a patient, along with a portion of a signal delivery device of the system of Figures 1A-1 D shown as implanted at a representative location in accordance with some embodiments of the present technology.

[0009] Figure 2A is a partially schematic illustration of an electrical signal generated in accordance with some embodiments of the present technology.

[0010] Figure 2B is a partially schematic illustration of another electrical signal generated in accordance with some embodiments of the present technology.

[0011] Figures 3A and 3B are front and back views of a leg of a patient with a plurality of sensors coupled thereto for measuring patient parameters and configured in accordance with select embodiments of the present technology.

[0012] Figure 4 is a partially schematic illustration of a transdermal sacral neuromodulation system positioned proximate a patient’s sacral region to deliver electrical signals in accordance with some embodiments of the present technology.

DETAILED DESCRIPTION

A. Introduction

[0013] The present technology is directed to treating Parkinson’s Disease (PD) and/or symptoms suggestive of PD using neuromodulation. For example, many of the embodiments described herein include electrically stimulating one or more sacral nerves or other neural targets proximate the sacral nerves of a patient to treat symptoms of and/or symptoms suggestive of the patient’s PD. As described in detail throughout this Detailed Description, the electrical signal can be delivered via an implanted signal delivery device positioned proximate one or more of the patient’s sacral nerves. The electrical signal can modulate the activity of the sacral nerve(s) and/or other nerves, which may in turn treat, reduce, or ameliorate one or more symptoms associated with and/or suggestive of PD. For example, in some embodiments the sacral neuromodulation described herein is expected to treat overactive bladder (OAB) and/or gastrointestinal (Gl) symptoms associated with and/or suggestive of PD. These OAB- and Gl-related symptoms often predate other symptoms associated with PD (e.g., motor symptoms). These symptoms therefore may be suggestive of PD in certain patients, even if the patient has not been diagnosed with PD. Embodiments of the present technology are expected to useful in treating these early symptoms suggestive of PD, even in patients that have not formally been diagnosed with PD.

[0014] In some embodiments, the sacral neuromodulation described herein is expected to treat other symptoms, in addition to or in lieu of the OAB and/or Gl symptoms. For example, the sacral neuromodulation described herein may improve motor symptoms associated with PD, such as reducing gait dysfunction, reducing tremor, or the like. In some embodiments, the sacral neuromodulation described herein may slow the progression of PD and/or delay the onset of certain symptoms associated with PD (e.g., delay the onset of motor symptoms). As described throughout this Detailed Description, the sacral neuromodulation delivered in accordance with the present technology may have additional benefits in the treatment of PD.

[0015] Unless otherwise stated, the terms “generally,” “about,” and “approximately” refer to values within 10% of a stated value. For example, the use of the term “about 100” refers to a range of 90 to 110, inclusive. In instances in which relative terminology is used in reference to something that does not include a numerical value, the terms are given their ordinary meaning to one skilled in the art.

[0016] As used herein, and unless otherwise noted, the terms “modulate,” “modulation,” “stimulate,” and “stimulation” refer generally to electrical signals that have an inhibitory, excitatory, and/or other effect on a target neural population. Accordingly, a sacral nerve “stimulator” can have an inhibitory effect and/or an excitatory effect on certain neural populations. [0017] As used herein, the terms “electrical therapy signal,” “electrical signal,” “therapy signal,” “signal,” and other associated terms are used interchangeably and generally refer to an electrical signal that can be characterized by one more parameters, such as frequency, pulse width, and/or amplitude.

[0018] As used herein, “proximate a target neural population” refers to the placement of a signal delivery element such that it can deliver electrical stimulation to the target neural population. For example, if the target population includes the third sacral spinal nerve, “proximate the target neural population” includes, but is not limited to, the relative lead positions described and shown in Figure 1 E, as well as other positions not expressly described herein.

[0019] Specific details of certain embodiments of the disclosure are described below with reference to methods for modulating one or more target neural populations (e.g., nerves) or sites of a patient, and associated implantable structures for providing the modulation. Although selected embodiments are described below with reference to modulating the sacral nerves, the modulation may in some instances be directed to other neurological structures and/or target neural populations and/or other neurological tissues throughout the body. For example, some embodiments may include modulating the vagus nerve, the splenic nerve, the splanchnic nerve, and/or other peripheral nerves. Some embodiments can have configurations, components, and/or procedures different than those described herein, and other embodiments may eliminate particular components and/or procedures. A person of ordinary skill in the relevant art, therefore, will understand that the present disclosure may include other embodiments with additional elements, and/or may include other embodiments without several of the features shown and described below with reference to Figures 1 A-4.

B. Representative Embodiments of the Present Technology

[0020] Figure 1A schematically illustrates a sacral neuromodulation system 100 (“the system 100”) implanted to stimulate a patient’s sacral nerves and configured in accordance with embodiments of the present technology. The system 100 includes a signal generator 110 and a signal delivery device 120. The signal generator 110 can be implanted and/or implantable subcutaneously within the patient P. For example, in the illustrated embodiment the signal generator 110 is implanted subcutaneously at the lower back/upper buttock area of the patient P (e.g., adjacent but posterior to the iliac crest IC and/or iliac fossa IF). In other embodiments, the signal generator 110 can be positioned subcutaneously within or proximate the sacral pocket, the glute, the abdomen, the upper thigh, or another position relatively close to the sacral nerves. In other embodiments, such as described below with reference to Figure 4, the signal generator 110 can remain external to the patient during operation.

[0021] The signal delivery device 120 extends from the signal generator 110 and can be implanted within the patient P proximate a target neural population. In some embodiments, the target neural population includes one or more of the sacral spinal nerves (e.g., the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve and/or the S4 sacral nerve). Accordingly, in some embodiments the signal delivery device 120 can extend through one of the sacral foramen S1 -S4 (the illustrated embodiment depicts the signal delivery device 120 extending through the sacral foramen S1 ) and adjacent one or more sacral spinal nerves when implanted. More specifically, the signal delivery device 120 can be implanted proximate the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve, and/or the S4 sacral nerve. In other embodiments, the signal delivery device 120 can be implanted proximate other target neural structures adjacent the sacral nerves, such as other sensory or motor neurons within the pelvic or upper thigh regions. Other target neural structures can include, for example, the femoral and/or obturator nerves. The signal delivery device 120 can carry features configured to administer therapy to the target neural population. For example, the signal delivery device 120 can include one or more lead(s) or lead bodies 122 extending from the signal generator 110 toward the target neural population (e.g., toward the S3 sacral nerve). As described in greater detail with reference to Figure 1 E, the lead 122 can include or carry one or more electrical contacts or electrodes (e.g., ring electrodes, cuff electrodes, and/or other suitable electrical contacts) that deliver electrical signals to the target neural population.

[0022] In operation, the signal generator 110 can generate and transmit signals (e.g., electrical signals) to the signal delivery device 120. In turn, the signal delivery device 120 can deliver the electrical signals to the target neural population, e.g., to electrically modulate neurons within the target neural population to induce a therapeutic effect in the patient. Representative electrical signals that can be generated by the signal generator 110 and delivered to the patient P via the signal delivery device 120 are described in greater detail below with reference to Figures 2A and 2B. [0023] The signal generator 110 can include a machine-readable (e.g., computer- readable) medium containing instructions for generating and transmitting electrical signals. Accordingly, generating electrical signals in accordance with the methods described herein can include executing computer-executable instructions contained by, on, or in computer-readable media located within the signal generator 110. The signal generator 110 can also include one or more processors for executing the machine- readable instructions, memory unit(s), batteries (rechargeable and/or non- rechargeable), communication devices (e.g., an antenna), and/or other software or hardware-based components. As shown in Figure 1A, the signal generator 110 can include a single housing for storing some or all of the foregoing components, although in other embodiments some or all of the foregoing components can be stored in separate housings.

[0024] In some embodiments, the signal generator 110 can be configured to communicate with one or more external controllers. For example, the signal generator 110 can wirelessly communicate with a physician controller (not shown) that is external to the patient P. A physician or other healthcare provider can use the physician controller to program the signal generator 110, e.g., to select parameters for the electrical signal to be generated by the signal generator 110. In some embodiments, the signal generator 110 can also communicate with a patient controller that is external to the patient P. The patient P can use the patient controller to control various aspects of the therapy provided by the signal generator 110. For example, the patient may be able to start and stop electrical stimulation therapy using the patient controller, switch between different stimulation waveforms, and/or control certain parameters (e.g., amplitude) of the electrical stimulation using the patient controller. In some embodiments, the signal generator 110 can transmit data to the physician controller and/or the patient controller for user review. For example, the signal generator 110 may periodically (or on demand) transmit data associated with one or more of electrode impedance, battery power, program settings (e.g., current signal parameters), historical program settings (e.g., historical signal parameters), program/parameter changes, usage data (e.g., stimulation start and stop times), or the like. The physician controller and the patient controller can include a dedicated controller device, or be implemented as an application on a smartphone, tablet, etc. [0025] In some embodiments, the system 100 can be implanted in the patient P to treat PD or an associated condition. For example, the system 100 can deliver electrical signals to one or more sacral nerves of the patient to electrically stimulate the one or more sacral nerves. As described in detail throughout this Detailed Description, the electrical signal can treat, reduce, and/or ameliorate one or more symptoms of, or symptoms suggestive of, PD, and/or delay the onset or progression of one or more symptoms of PD. For example, the electrical signal may treat PD by reducing one or more of PD-related OAB symptoms, Gl symptoms, motor symptoms, cognitive symptoms, or other PD-related symptoms Additional details of electrical signals and stimulation regimes for treating PD are described below with reference to Figures 2A and 2B.

[0026] In some embodiments, prior to receiving the signal generator 110, the patient P undergoes a trial period during which the patient P receives electrical stimulation to determine whether the patient P responds favorably to stimulation therapy. During the trial period, the patient P may use a temporary, external trial stimulator that generates and transmits electrical signals to the target neural population via the signal delivery device 120 or another implanted signal delivery element. If the patient responds favorably during the trial period, the patient may elect to have the signal generator 110 implanted to facilitate chronic stimulation therapy. In some embodiments, the trial period can be omitted, and the signal generator 110 can be implanted without the patient previously receiving stimulation from a temporary external signal generator.

[0027] In some embodiments, the system 100 can include multiple signal delivery devices 120 positioned proximate different target neural populations. For example, Figure 1 B illustrates an embodiment of the system 100 with multiple signal delivery devices for providing bilateral sacral stimulation and configured in accordance with some embodiments of the present technology. In particular, in addition to the signal delivery device 120 (“the first signal delivery device 120”), the system 100 further includes a second signal delivery device 130 in the embodiment depicted in Figure 1 B. The second signal delivery device 130 can be the same as or generally similar to the first signal delivery device 120. For example, the second signal delivery device 130 can include a lead or lead body 132 extending from the signal generator and carrying one or more electrodes or electrical contacts positionable proximate a target neural population. In the illustrated embodiments, for example, the first signal delivery device 120 extends through the S1 sacral foramen on a first side of the patient’s spinal midline, and the second signal delivery device 130 extends through the S1 sacral foramen on a second side of the patient’s spinal midline. Although shown as extending through sacral foramen at the same level, in other embodiments the first signal delivery device 120 can extend through a different level (e.g., the S3 sacral foramen) than the second signal delivery device 130.

[0028] The signal generator 110 can be programmed to transmit electrical signals to the first signal delivery device 120, the second signal delivery device 130, and/or both the first signal delivery device 120 and the second signal delivery device 130. For example, in some embodiments the signal generator 110 can simultaneously deliver an electrical signal to the first signal delivery device 120 and the second signal delivery device 130 to provide bilateral sacral stimulation to the patient (e.g., simultaneous bilateral stimulation). In other embodiments, the signal generator can alternate between delivering electrical signals to the first signal delivery device 120 and the second signal delivery device 130 (e.g., alternating bilateral stimulation). The electrical signal delivered to the first signal delivery device 120 can be the same as, or different than, the electrical signal delivered to the second signal delivery device 130.

[0029] Figure 1 C illustrates another embodiment of the system 100 with multiple signal delivery devices for stimulating different target structures and configured in accordance with some embodiments of the present technology. More specifically, in the illustrated embodiment, the system 100 includes the signal delivery device 120 (“the first signal delivery device 120”), the second signal delivery device 130, a third signal delivery device 140, and a fourth signal delivery device 150. Each of the signal delivery devices 120-150 can include a corresponding lead. For example, the first signal delivery device 120 includes the lead 122 as previously described, the second signal delivery device 130 includes the second lead 132, the third signal delivery device 140 includes a third lead 142, and the fourth signal delivery device 150 includes a fourth lead 152. Each of the leads 122-152 can extend from the signal generator 110 and include one or more electrodes or electrical contacts positionable proximate a target neural population. Each of the signal delivery devices 120-150 can be positioned proximate a different target neural population (e.g., to stimulate different sacral nerves or other neural structures proximate the sacral nerves, such as other sensory or motor neurons within the pelvic or upper thigh regions). Although illustrated as all being positioned on a same side of the patient (e.g., to provide unilateral stimulation), in some embodiments one or more of the signal delivery devices 120-150 extend across the patient’s midline (e.g., to provide bilateral stimulation). Moreover, although illustrated as having four signal delivery devices, in some embodiments the system 100 can include more or fewer signal delivery devices, such as one, two, three, five, six, seven, or eight.

[0030] As described above with reference to Figure 1 B, the signal generator 110 can be programmed to transmit electrical signals to each of the signal delivery devices 120-150. For example, in some embodiments the signal generator 110 can simultaneously deliver electrical signals to each of the signal delivery devices 120-150. In other embodiments, the signal generator can alternate between delivering electrical signals to individual ones of, or subsets of, the signal delivery devices 120-150. A user (e.g., healthcare provider) can program the signal generator 110 to deliver an electrical signal only to one, or only to a subset of, the signal delivery devices 120-150, e.g., based on a desired stimulation target. That is, a user can select which signal delivery devices 120-150 to activate based on which neural structure(s) are proximate the signal delivery devices 120-150. The electrical signals delivered to individual signal delivery devices can be the same as, or different than, electrical signals delivered to other individual signal delivery devices. For example, the electrical signal may be specific to the target neural structure associated with the corresponding signal delivery device.

[0031] In some embodiments, the patient P may receive multiple independent sacral stimulation systems. For example, Figure 1 D illustrates two sacral neuromodulation systems implanted in the patient P and configured to independently provide sacral stimulation in accordance with some embodiments of the present technology. More specifically, Figure 1 D illustrates the system 100 (“the first system 100”) as shown and described with reference to Figure 1A implanted to stimulate a first side of the patient, and a second sacral neuromodulation system 160 (“the second system 160”) implanted to stimulate a second side of the patient across the spinal midline from the first side. Similar to the first system 100, the second system 160 can include an implantable signal generator 170 and one or more signal delivery devices 180. The signal generator 170 and the signal delivery device 180 can be the same as or generally similar to the signal generator 110 and the signal delivery device 120 described previously. The first system 100 and the second system 160 can be independently programmed and operated.

[0032] Figure 1 E is an illustration of a sacral plexus SP of a patient, along with a distal portion of the lead 122 shown as implanted at a representative location. The sacral plexus SP includes four sacral spinal nerves: the first sacral nerve S1 , the second sacral nerve S2, the third sacral nerve S3, and the fourth sacral nerve S4. The lead 122 is shown as extending along (e.g., proximate to) the third sacral nerve S3 such that it can electrically stimulate the third sacral nerve S3. In other embodiments, however, the lead 122 can be positioned proximate other sacral spinal nerves, and/or proximate other nerve fibers of the sacral plexus SP, to electrically stimulate other target tissue. In yet other embodiments, the lead 122 can be positioned proximate other neural structures of the sacral plexus SP.

[0033] Figure 1 E also shows a plurality of electrodes or electrical contacts 124a-d carried by the lead 122, as described previously. Electrical signals generated by the signal generator 110 and transmitted through the lead 122 can be delivered to the target neural population via the electrodes 124a-d. Although shown as having four electrodes, the lead 122 can have more or fewer electrodes, such as one, two, three, four, five, six, seven, eight, or more.

[0034] In some embodiments, test stimulation may be administered to a patient during a procedure to implant the signal delivery device 120. This can be done to ensure adequate placement of the lead 122, e.g., to ensure that the electrical signals delivered via the lead 122 are applied to the target neural population. In some embodiments, test stimulation is administered at or above a sensory threshold during an implant procedure such that the patient can give intraoperative feedback about the location of the sensation, and thus the location of the lead 122. In some embodiments, test stimulation is administered at or above a motor threshold during the implant procedure, and a motor response to the test stimulation is observed to determine the location of the lead 122. In other embodiments, however, placement of the lead 122 can be confirmed using other techniques (e.g., imaging), such that intraoperative test stimulation is not required.

[0035] Figure 2A is a partially schematic illustration of a representative electrical signal waveform 200 (“the signal 200”) generated in accordance with embodiments of the present technology. The signal 200 can be generated by the system 100 (e.g., by the signal generator 110) described above with respect to Figures 1A-1 E, or by another sacral neuromodulation system. As described throughout this Detailed Description, the signal 200 can be delivered to a patient’s sacral region to treat a patient condition such as PD.

[0036] The signal 200 includes repeating pulse periods 201 , with each pulse period 201 having a biphasic pulse 202 followed by an interpulse interval 212. Each pulse 202 includes a first pulse phase 203 having a first polarity followed by a second pulse phase 204 having a second polarity that is opposite the first polarity. For example, in the illustrated embodiment the first pulse phase 203 is an anodic pulse phase and the second pulse phase 204 is a cathodic pulse phase, although in other embodiments the anodic pulse phase and the cathodic pulse phase can be reversed, such that the cathodic pulse phase is the first pulse phase and the anodic pulse phase is the second pulse phase. In other embodiments, the signal 200 includes monophasic pulses. In such embodiments, the signal 200 includes repeating pulses of the same polarity.

[0037] In some embodiments, the first pulse phase 203 is separated from the second pulse phase 204 by an interphase interval 208. During the interphase interval 208, the amplitude of the signal 200 can return to baseline (e.g., zero or about zero), although in other embodiments the amplitude of the signal 200 during the interphase interval 214 can be a non-zero value. In some embodiments, the interphase interval 208 is omitted, and the signal 200 transitions directly from the first pulse phase 203 to the second pulse phase 204.

[0038] The first pulse phase 203 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 2 milliseconds. For example, the first pulse phase 203 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 1.5 milliseconds, or from about 100 microseconds to about 1 millisecond, or from about 100 microseconds to about 800 microseconds, or from about 200 microseconds to about 700 microseconds, or from about 200 microseconds to about 600 microseconds, or from about 300 microseconds to about 700 microseconds, or from about 300 microseconds to about 600 microseconds, or from about 300 microseconds to about 500 microseconds, or from about 400 microseconds to about 600 microseconds, or from about 400 microseconds to about 500 microseconds. For example, in some embodiments the pulse width 206 can be about 100 microseconds, about 150 microseconds, about 200 microseconds, about 250 microseconds, about 300 microseconds, about 350 microseconds, about 400 microseconds, about 450 microseconds, about 500 microseconds, about 550 microseconds, about 600 microseconds, about 650 microseconds, or about 700 microseconds. The foregoing pulse width ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have pulse width values outside the foregoing ranges.

[0039] In some embodiments, the second pulse phase 204 has the same or about the same pulse width as the first pulse phase 203. Accordingly, the second pulse phase 204 can have any of the pulse widths recited above with respect to the first pulse phase 203. In other embodiments, however, the second pulse phase 204 can have a different pulse width than the first pulse phase 203. For example, if the first pulse phase 203 has a pulse width of 400 microseconds or less, the second pulse phase 204 may have a pulse width of 600 microseconds or more. Likewise, if the first pulse phase 203 has a pulse width of 600 microseconds or more, the second pulse phase 204 may have a pulse width of 400 microseconds or less.

[0040] Regardless of whether the first pulse phase 203 and the second pulse phase 204 have the same pulse width, a total charge delivered during the second pulse phase 204 can be equal or approximately equal in magnitude and opposite in polarity from the total charge delivered during the first pulse phase 203. In this way, the second pulse phase 204 is a charge balancing pulse that prevents or at least reduces charge buildup at the electrode used to deliver the signal 200. Accordingly, in embodiments for which the first pulse phase 203 and the second pulse phase 204 have an equal or approximately equal pulse width, the first pulse phase 203 and the second pulse phase 204 can have an equal or approximately equal and opposite amplitude. In embodiments in which the first pulse phase 203 and the second pulse phase 204 have different pulse widths, the first pulse phase 203 and the second pulse phase 204 can have different amplitudes such that the total charge delivered during the first pulse phase 203 and the second pulse phase 204 remains approximately the same. In other embodiments, the pulse 202 can be charge imbalanced, such that the first pulse phase 203 and the second pulse phase 204 do not deliver charges of the same magnitude. In such embodiments, charge buildup at the electrode may passively dissipate. [0041] The interpulse interval 212 is a quiescent period between sequential pulses 202. During the interpulse interval 212, the signal 200 can return to a baseline amplitude (e.g., zero or about zero) such that little to no charge is administered to the patient. In some embodiments, the interpulse interval can be within an interpulse interval range of from about 1 millisecond to about 1 second, such as from about 5 milliseconds to about 500 milliseconds, or from about 50 milliseconds to about 500 milliseconds, or from about 100 milliseconds to about 300 milliseconds. The foregoing interpulse interval ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have interpulse interval values outside the foregoing ranges. In some embodiments, the duration of the interpulse interval 212 can be set independently from the duration of the pulses 202. In other embodiments, the duration of the interpulse interval 212 is set based on a selected pulse 202 duration and desired signal frequency.

[0042] The duration of the pulse period 201 determines the frequency of the signal 200. For example, if the duration of the pulse period 201 is 200 milliseconds, then the frequency of the signal is 5 Hz (i.e. , five pulse periods 201 are delivered per second). The signal 200 can have a frequency between about 0.5 Hz and about 50 Hz. For example, the signal 200 can have a frequency within a frequency range of from about 1 Hz to about 40 Hz, or from about 1 Hz to about 30 Hz, or from about 1 Hz to about 25 Hz, or from about 1 Hz to about 20 Hz, or from about 1 Hz to about 15 Hz, or from about 5 Hz to about 15 Hz, or from about 1 Hz to about 12 Hz, or from about 1 Hz to about 10 Hz, or from about 2 Hz to about 8 Hz, or from about 3 Hz to about 7 Hz, or from about 4 Hz to about 6 Hz, or from about 4.5 Hz to about 5.5 Hz, or from about 4.8 Hz to about 5.2 Hz. In other embodiments, the signal 200 can have a frequency of about 0.5 Hz, about 1 Hz, about 2 Hz, about 3 Hz, about 4 Hz, about 5 Hz, about 6 Hz, about 7 Hz, or about 8 Hz. In some embodiments, the signal 200 can have a frequency of about 4.2 Hz, about 4.4 Hz, about 4.6 Hz, about 4.8 Hz, about 5.0 Hz, about 5.2 Hz, about 5.4 Hz, about 5.6 Hz, or about 5.8 Hz. The foregoing frequency ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have frequency values outside the foregoing ranges.

[0043] The pulses 202 can have a current amplitude between about 0.1 mA and about 20 mA. For example, in some embodiments the pulses 202 have a current amplitude within a current amplitude range of from about 0.5 mA to about 15 mA, or from about 1 mA to about 12 mA, or from about 2 mA to about 12 mA, or from about 3 mA to about 10 mA. The pulses 202 can also have a voltage amplitude between about 0.1 V and 15 V. For example, in some embodiments the pulses 202 have a voltage amplitude within a voltage amplitude range of from about 0.1 V to about 10 V, or from about 0.2 V to about 8 V, or from about 0.5 V to about 4 V. In some embodiments, the amplitude (e.g., the current amplitude and/or the voltage amplitude) of the signal 200 is set based on an individual patient’s sensory threshold and/or motor threshold. For example, in some embodiments the pulses 202 have a peak amplitude that is below the sensory or perception threshold of the patient. In such embodiments, the patient generally cannot actively feel the signal 200 as it is being administered. For example, the pulses 202 may have an amplitude that is 50% of sensory threshold, 60% of sensory threshold, 70% of sensory threshold, 80% of sensory threshold, 90% of sensory threshold, or 95% of sensory threshold. In other embodiments, the pulses 202 have an amplitude that is at or above the sensory threshold, such that the patient can perceive the signal 200 being delivered. In yet other embodiments, the pulses 202 have an amplitude that is below the motor threshold of the patient. In such embodiments, the signal 200 itself does not induce clinically discernable movement (e.g., muscle twitching) in the patient while being administered. Indeed, as described above, the signal 200 may quiet abnormal motor function (e.g., tremor) that occurs in the absence of signal administration, even when administered below the motor threshold. For example, the pulses 202 may have an amplitude that is 50% of motor threshold, 60% of motor threshold, 70% of motor threshold, 80% of motor threshold, 90% of motor threshold, or 95% of motor threshold. In other embodiments, the pulses 202 have an amplitude that is at or above the motor threshold.

[0044] In some embodiments, electrical signals generated in accordance with the present technology can have one more ramped parameters. For example, Figure 2B illustrates an electrical signal 250 (“the signal 250”) with a ramped amplitude in accordance with some embodiments of the present technology. The signal 250 shown in Figure 2B can be generally similar to the signal 200 shown in Figure 2A, and can have any of the parameters and parameter values described above in connection with the signal 200. However, relative to the signal 200, an amplitude of the of the signal 250 can be ramped such that a peak amplitude of the signal 250 changes over time. In the illustrated embodiment, for example, the signal 250 includes a plurality of pulses 252 (five pulses 252a-252e are shown), with each sequential pulse 252 having a different amplitude than the preceding pulse 252. More specifically, the amplitude of the signal 250 increases from pulse 252a to pulse 252c, and then decreases from pulse 252c to pulse 252e. This pattern can then be repeated. In some embodiments, the signal 250 includes multiple pulses 252 at a common amplitude before being ramped up or down to a different amplitude (e.g., multiple pulses are delivered with an amplitude equal to the pulse 252a before the signal 250 is ramped to delivering pulses with an amplitude equal to the pulse 252b). Although shown as being ramped in two directions, in other embodiments the signal 250 is ramped only in a single direction (e.g., the amplitude is either increased or decreased, but not both), until a maximum or minimum amplitude is reached.

[0045] In some embodiments, other parameters of the signal 250 (e.g., pulse width, interpulse interval, frequency, etc.) can remain constant (e.g., unchanged) as the amplitude of the pulses 252 is ramped. In other embodiments, one or more other parameters can be ramped, in addition to the amplitude being ramped. For example, in some embodiments both a pulse width and an amplitude of the pulses 252 is ramped. In such embodiments, the pulse width of the pulses 252 may be inversely ramped with the amplitude, such that as the amplitude increases, the pulse width decreases, and vice versa. Moreover, in some embodiments the pulse width, frequency, or other parameter is ramped instead of the amplitude.

[0046] The electrical signals described herein (e.g., the signal 200 of Figure 2A and the signal 250 of Figure 2B) can be administered intermittently or continuously. Continuous stimulation refers to delivering the electrical signals without interruption. Intermittent stimulation refers to cycling between “on” times during which the signal is being administered, and “off” times during which the signal is not being administered. In some embodiments, the “on” time can be between about 1 second and about 30 minutes, and the “off” time can be between about 1 second and about 30 minutes. Representative examples of suitable intermittent stimulation schedules include 10 seconds on, 10 seconds off; 10 seconds on, 30 seconds off; 10 seconds on, 60 seconds off; 10 seconds on, 90 seconds off; 30 seconds on, 30 seconds off; 30 seconds on, 60 seconds off; 30 seconds on, 90 seconds off; 1 minute on, 1 minute off; 10 minutes on, 10 minutes off, 15 minutes on, 15 minutes off, etc. The on times and off times are provided by way of example only — in some embodiments, the electrical signals described herein may be applied according to different on times and off times.

[0047] Regardless of whether the signal is administered intermittently or continuously, the signal can be administered according to a duty cycle of between about 0.1 % and about 100%. As used herein, and referring again to Figure 2A, the term duty cycle refers to the fraction of a single pulse period 201 (which consists of a single pulse 202 and a single interpulse interval 212) in which the pulse 202 is being actively delivered. That is, for a single pulse period, the duty cycle can be expressed as: (pulse width/duration of pulse period) x 100. For example, if a pulse period comprises (1 ) a biphasic pulse with no interphase interval and with each phase of the pulse having a pulse width of 500 microseconds, followed by (2) an interpulse interval having a duration of 99 milliseconds (e.g., before the following pulse period begins), the duty cycle is 1 % (1 millisecond combined pulse width/100 millisecond pulse period duration, x 100). In this way, the term duty cycle is different than the term intermittent, which generally refers to delivering sequential pulse periods in a row for a first duration (e.g., 10 seconds), followed by a quiescent period during which no pulse periods are delivered for a second duration (e.g., for 90 seconds).

[0048] In some embodiments, the electrical signals are administered during discrete stimulation sessions or periods that have a duration less than 24 hours. For example, the stimulation sessions may have a duration of between about 5 minutes and about 12 hours, such as between about 15 minutes and about 6 hours, or between about 15 minutes and about 4 hours, or between about 15 minutes and about 3 hours, or between about 15 minutes and about 2 hours, or between about 30 minutes and about 3 hours, or between about 30 minutes and about 2 hours, or between about 30 minutes and about 1.5 hours, or between about 45 minutes and about 1.5 hours. In some embodiments, the stimulation sessions can have a duration of about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours. During the stimulation sessions, the electrical signals can be administered continuously or intermittently, and/or according to a duty cycle, as described above. The patient can receive one or more stimulation sessions per day. For example, in some embodiments the patient receives a single stimulation session per day. In other embodiments, the patient receives multiple (e.g., two, three, four, etc.) discrete stimulation sessions per day. During periods between stimulation sessions, the patient generally does not receive any stimulation, or at least any clinically meaningful stimulation. The foregoing representative stimulation period durations are provided by way of example only — in some embodiments, the electrical signals described herein may be applied during stimulation sessions having different durations. In some embodiments, electrical stimulation is applied for 24 hours per day.

[0049] The number and/or duration of stimulation sessions can be associated with various patient events or activities. In a first representative example, the stimulation sessions may occur while the patient is active, and/or during times of the day that the patient is typically active (e.g., to improve gait). Administering the stimulation sessions while the patient is ambulatory is expected to improve patient gait while reducing battery drain during periods in which the patient is not active. As described below with reference to FIGS. 3A and 3B, sensors can be used to automatically detect patient ambulation and trigger the start of a stimulation session. In a second representative example, the stimulation sessions may occur during or after the patient is prandial (e.g., to reduce Gl-related symptoms). In yet another representative example, the electrical stimulation may be delivered during short (e.g., 5-minute) stimulation sessions that occur each hour the patient is awake and/or active. For any of the foregoing examples, the signals can be applied using any of the signal parameters described for the signal 200 with reference to Figure 2A and the signal 250 with reference to Figure 2B. The foregoing examples are also provided by way of example only — the stimulation sessions can be applied at other times throughout the day, tied to other patient events, and/or according to other intervals beyond those described above.

[0050] In some embodiments, the patient can control when they receive the stimulation session and/or the type of stimulation they receive. For example, the patient may have access to a patient controller that can control operation of the signal generator (e.g., the signal generator 110 shown in Figure 1A) to initiate a stimulation session. Providing the patient with control over the timing of the stimulation sessions may be beneficial because the patient can initiate stimulation during a convenient time, during patient activity, and/or when the patient experiences certain PD-related symptoms (e.g., OAB, Gl dysfunction, tremor, gait dysfunction, etc.). In a representative example, the patient may select to initiate the stimulation session during the day (e.g., as opposed to at night), while avoiding certain activities (e.g., driving, periods of concentration, etc.), and/or during or after periods or activities that may lead to an increase in symptoms or an increased perception of symptoms (e.g., during or after consuming food, while walking, etc.). The patient may also be able to select between different stimulation waveforms, adjust certain stimulation parameters such as signal amplitude, or the like. In this way, the patient can tailor the stimulation therapy based on the severity of symptoms they are experiencing. For example, if the patient is experiencing increased tremor, or increased Gl symptoms, the patient may elect to select a “stronger” stimulation waveform and/or increase the amplitude of the signal.

[0051] In other embodiments, a signal generator can be programmed to automatically administer the stimulation session during predetermined intervals. For example, the signal generator can be programmed to automatically deliver a stimulation session every day at 1 PM or another selected time. As another example, the signal generator can be programmed to automatically deliver a stimulation session timed with certain patient activities. For example, the signal generator can be programmed to automatically deliver a stimulation session at a time the patient typically eats a meal (e.g., 8AM, 12PM, and/or 6PM), e.g., to reduce Gl dysfunction, or goes on a walk (e.g., 10AM and 4PM), e.g., to improve gait. Additionally or alternatively, the signal generator can be programmed to automatically deliver a stimulation session at a time that the patient’s symptoms are typically the worst, which can be determined using patient feedback such as questionnaires, symptoms logs, etc. As yet another example, the signal generator can be programmed to automatically deliver a stimulation session based on a time the patient takes other medication (e.g., concurrent with taking medication, a specified duration before taking medication, or a specified duration after taking medication). Programming the signal generator to automatically administer the stimulation session may be advantageous because it eliminates the possibility of a patient forgetting to initiate therapy, and therefore may provide a more consistent therapy.

[0052] In some embodiments, the signal can be initiated, terminated, or adjusted based on one or more sensed parameters. For example, Figures 3A and 3B are front and back views, respectively, of a right leg of patient P with a plurality of sensors 350 attached thereto in accordance with embodiments of the present technology. As shown in Figure 3A, four pairs of sensors 350 can be positioned on the front of the leg over the vastus lateralis muscle, the rectus femoris muscle, the vastus medialis muscle, and the tibialis anterior muscle. As shown in Figure 3B, four pairs of sensors 350 can also be positioned on the back of the leg over the semitendinosus muscle, the biceps femoris muscle, and the gastrocnemius muscle. As one skilled in the art will appreciate, the foregoing are provided by way of example only — in some embodiments, there can be more or fewer sensors 350, and the sensors can be placed on or adjacent different muscle groups. Moreover, although Figures 3A and 3B only illustrate a right leg of the patient P, in some embodiments the sensors 350 can be positioned on a left leg of the patient P, in addition to or in lieu of placing the sensors 350 on the right leg of the patient. Similarly, one or more sensors 350 can be positioned on a left foot and/or right foot of the patient P, in addition to or in lieu of placing the sensors 350 on the illustrated leg muscles.

[0053] Referring collectively to Figures 3A and 3B, the sensors 350 can be configured to measure one or more patient parameters associated with motor function of the patient, including, but not limited to, electromyography (EMG), motor neuron conduction, muscle contraction, muscle twitching, leg motion, gait, etc. Accordingly, in some embodiments the sensors 350 can be electrodes, accelerometers, or other suitable sensors. In embodiments in which the sensors are electrodes, the sensors 350 can be surface electrodes, needle (e.g., intramuscular) electrodes, or other suitable electrodes. Although shown as being positioned on the patient’s skin, the sensors 350 can alternatively be partially or fully implanted, such as implanted within the housing of a stimulator system (e.g., the system 100 of FIGS. 1A-1 D) or at another location.

[0054] In some embodiments, the sensors 350 are configured to measure muscle depolarization during muscle contraction. In such embodiments, two electrodes are positioned proximate one another and adjacent a central region of the target muscle, with a first electrode configured as an anode and a second electrode configured as a cathode. A third electrode can be positioned proximate a bony landmark and configured as a reference electrode. The measured voltage differential during muscle depolarization corresponds to an EMG signal for the muscle. The detected EMG signal for the muscle can then be analyzed to determine a pathological state of the patient. For example, in some embodiments, EMG signals in muscles at rest may indicate abnormal fasciculations or fibrillation potentials. [0055] One or more stimulation parameters (e.g., for the signal 200 shown in Figure 2A and/or the signal 250 shown in Figure 2B) can be selected based on the sensed parameters. For example, an amplitude of the signal 200 can be increased with the patient at rest until motor neuron/muscle activity is detected by the sensors 350. The amplitude can then be decreased so that it is set just under the motor threshold. In this way, the stimulation dose can be maximized while avoiding unwanted activation of motor neurons/muscles.

[0056] The sensors 350 and the sacral neuromodulation system 100 (Figures 1A- 1 E) can operate as a closed loop system to provide adaptive sacral nerve stimulation. In particular, the sensors 350 can transmit data indicative of one or more sensed parameters (e.g., EMG) to a controller 360 associated with the system 100, which can then determine, based on the data, whether stimulation should be started, stopped, or adjusted. For example, in response to EMG data indicating that a patient is ambulatory, the controller 360 may automatically direct the signal generator 110 (Figures 1 A-1 D) of the system 100 to initiate stimulation therapy, e.g., to improve gait. As another example, in response to EMG data indicating that a patient’s gait is abnormal, the controller 360 may direct the signal generator 110 to adjust one or more signal parameters of stimulation (e.g., increase an amplitude, increase a frequency, etc.). Stimulation may also be given in a pattern that corresponds to the muscle activation within the gait cycle. As yet another example, in response to EMG data indicating a patient’s left leg is functioning abnormally but a patient’s right leg is functioning normally, the controller 360 may direct the signal generator 110 to apply unilateral stimulation only on the left side. As yet another example, in response to EMG data indicating the patient is resting, the controller 360 may direct the signal generator 110 to cease stimulation therapy, e.g., to preserve battery. The controller can be coupled to the sensors via a wired or wireless connection. In some embodiments, the controller is part of the signal generator 110 (Figures 1A-1 D), a physician programmer/controller, a patient programmer/controller, or another computing device.

[0057] In addition to or in lieu of operating as a closed loop system, the sensors 350 can also transmit data indicative of the one or more sensed parameters to an external device (e.g., a physician programmer or controller, a patient controller such as a mobile phone application, etc.) that enables the patient and/or physician to review the sensed parameters. Based on the sensed parameters, the patient and/or physician can start, stop, or adjust stimulation therapy. The sensor 350 can transmit the data for display regardless of whether the sensors 350 are part of a closed loop system as described above. That way, the patient and/or physician can monitor the sensed parameters to determine whether to adjust stimulation therapy.

[0058] In some embodiments, the sensors 350 continuously measure and transmit the one or more sensed parameters. In other embodiments, the sensors 350 periodically measure and transmit the one or more sensed parameters, such as once per hour, once per day, once per week, etc. In some embodiments, the sensors 350 are used to take on-demand measurements of the one or more sensed parameters, in addition to or in lieu of automatically measuring the parameter at periodic intervals.

[0059] In some embodiments, two or more electrical signals (e.g., the signal 200 described with reference Figure 2A and/or the signal 250 described with reference to Figure 2B) can be delivered concurrently. For example, in some embodiments a first signal is delivered continuously or intermittently for 24 hours per day as a base signal, and a second signal is delivered during discrete stimulation sessions (e.g., any of the stimulation sessions described previously). The first signal and the second signal can have any of the signal parameters described for the signal 200 and the signal 250 with reference to Figures 2A and 2B. However, the first signal may have a first set of signal delivery parameters (e.g., frequency, pulse width, amplitude, duty cycle, etc.), and the second signal may have a second set of signal delivery parameters that at least partially differ from the first set of signal delivery parameters. As a first example, the first signal may have a frequency of about 1 Hz, and the second signal may have a frequency of about 5 Hz. As another example, the first signal may be applied at a duty cycle of about 1 %, and the second signal can be applied at a duty cycle of about 50%. The foregoing are provided by way of example only, and the first signal can differ from the second signal in other ways. In some embodiments, the second signal can be programmed to be automatically administered at various time intervals, e.g., to correspond to various patient events or activities as described previously. In other embodiments, the second signal can be an “on-demand” signal that the patient can initiate, e.g., in response to an increase in PD symptoms.

[0060] In embodiments in which multiple electrical signals are delivered to the patient, the first signal and the second signal can be delivered in cycles. For example, the first signal can be administered for a first period of time (e.g., a first stimulation session), and the second signal can be administered for a second period of time (e.g., a second stimulation session) after the first period of time. In such embodiments, the first period of time may partially overlap with the second period of time, although in other embodiments the first period of time does not overlap with the second period of time. In some embodiments, the timing of the first signal and the second signal can be set based on patient patterns. For example, the patient may receive a first (e.g., stronger) signal during one or more portions of the day during which the patient is typically active, a second (e.g., weaker) signal during one or more portions of the day during which the patient is typically less active, and no stimulation during one or more portions of the day the patient is typically asleep. As another example, the timing of the first signal and the second signal can be based upon one or more sensed parameters obtained using the sensor 350. As yet another example, the first signal and second signal can be administered in cycles to separate targets on opposite sides of the patient’s midline, such as to alternate between triggering the left leg and the right leg to improve gait. In this way, multiple electrical signals can be administered to the patient to coordinate activity at different neural and/or muscular groups.

[0061] The first signal and the second signal can be generated by the same signal generator (e.g., the signal generator 110 described with reference to Figure 1A) or by different signal generators (e.g., the first signal generator 110 and the second signal generator 170, respectively, as described with reference to Figure 1 D). Likewise, the first signal and the second signal can be administered via the same signal delivery device (e.g., the signal delivery device 120 described with reference to Figure 1A), or via different signal delivery devices (e.g., the signal delivery device 120 and the signal delivery device 130 described with reference to Figure 1 B). In embodiments in which the first signal and the second signal are delivered via the same signal delivery device, the first signal and the second signal can be delivered by different electrodes of the same signal delivery device (e.g., to enable concurrent delivery of the first signal and the second signal, if desired). In embodiments in which delivery of the first signal and the second signal do not temporally overlap, the first signal and the second signal may be delivered by the same combination of electrodes.

[0062] Although the foregoing describes using an implanted system to electrically stimulate the patient’s sacral region to treat PD, in other embodiments a transdermal sacral neuromodulation system can be used to electrically stimulate the patient’s sacral region to treat PD. For example, Figure 4 illustrates another sacral neuromodulation system 400 (“the system 400”) for stimulating a patient’s sacral nerves and configured in accordance with some embodiments of the present technology. The system 400 can include a signal generator 410 and a signal delivery device 420. Similar to the system 100 described with reference to Figures 1A and 1 B, the signal generator 410 can generate and transmit electrical signals to the signal delivery device 420, which can deliver the electrical signals to patient tissue. However, unlike the system 100 described with reference to Figures 1A-1 E, the signal generator 410 and signal delivery device 420 remain external to the patient. That is, neither the signal generator 410 nor the signal delivery device 420 are implanted in the patient. Electrical signals are instead transmitted through the patient’s skin and other tissue toward the target neural population (e.g., the sacral spinal nerves). In such embodiments, the signal parameters can be adjusted such that the effective therapy provided at the target neural population is equivalent to the therapy provided in the embodiments described above. This may include, e.g., increasing an amplitude of the electrical signal to account for signal dissipation, providing a carrier signal to promote delivery of the therapy signal to the target neural population, etc. In some embodiments, the signal delivery device 420 can include a patch electrode or other energy delivery interface for delivering transdermal stimulation to the patient. In other embodiments, the signal delivery device 420 includes one or more coils for transmitting electromagnetic signals into the patient. The system 400 can therefore be configured to provide Transcutaneous Electrical Nerve Stimulation (“TENS”), Transcutaneous Magnetic Stimulation, or other transdermal stimulation therapies. In some embodiments, a stimulation system may include some implanted components and some external components. For example, a stimulation system may include an external signal generator and an implanted signal delivery device. In such embodiments, the external signal generator can transmit electrical signals to the signal delivery via a wireless or wired connection device for delivery to a target neural population. In yet other embodiments, the sacral region can be stimulated using electroacupuncture or other techniques known for delivering electrical stimulation to patient tissue.

[0063] In some embodiments, the sacral neuromodulation described herein can be administered in combination with additional therapies. For example, the sacral neuromodulation described herein can be administered in addition to drug therapy (e.g., L-Dopa therapy). As another example, the sacral neuromodulation described herein can be administered in combination with deep brain stimulation (DBS). In such embodiments, the timing of administering the sacral neuromodulation can be coordinated with the timing of the other therapy (e.g., timed to overlap with the other therapies, timed to precede the other therapies timed to follow the other therapies, etc.).

[0064] Without being bound by theory, the sacral neuromodulation described herein is expected to be a useful therapy in treating PD. This is particularly true because sacral neuromodulation is expected to address multiple symptoms of PD. For example, the sacral neuromodulation described herein may treat OAB- and/or Gl-related symptoms of PD in addition to treating motor symptoms (e.g., gait dysfunction). In some embodiments, the sacral neuromodulation may delay the onset of motor symptoms. Thus, because Gl-related symptoms often appear before motor symptoms, sacral neuromodulation can be administered relatively early in disease progression and can (1 ) address Gl-related symptoms, while simultaneously (2) delaying the onset of motor symptoms. Moreover, once motor symptoms begin, the sacral neuromodulation can continue to be administered to reduce the seventy of the motor symptoms (e.g., by synchronizing stimulation with patient gait). This is expected to be particularly beneficial because it will not require an additional surgery to implant another stimulator at another location. That is, because the sacral stimulation described herein can address multiple PD symptoms from a single implant location, the patient is less likely to need additional surgical interventions as new symptoms arise during the progression of their PD.

C. Representative Mechanisms of Action

[0065] An emerging body of evidence suggests that chronic inflammation is a key aspect of the pathophysiology underlying PD progression, including the progressive degeneration of the dopamine-producing neurons in the substantia nigra. For example, PD is associated with upregulated neuroinflammatory mediators, increased serum levels of pro-inflammatory cytokines (e.g., TNF-a, IL-1 , IL-18, etc.), mutations in LRRK2 (which regulates inflammatory processes), elevated fecal calprotectin levels, and increased intestinal inflammation.

[0066] Without intending to be bound by theory, one potential mechanism of action underlying the treatment of PD with sacral neuromodulation as described herein includes reducing chronic inflammation by altering activity of the autonomic nervous system. The autonomic nervous system has a fundamental role in mediating inflammation. For example, the autonomic nervous system can control release of various immunomodulatory substances (e.g., pro-inflammatory cytokines, antiinflammatory cytokines, etc.) to mediate inflammation. This is largely controlled by the sympathetic nervous system and the parasympathetic nervous system. When activated, the sympathetic nervous system may induce release of pro-inflammatory substances (e.g., pro-inflammatory cytokines such as TNF-a, IL-1 , IL-18, etc.), whereas the parasympathetic nervous system may induce release of anti-inflammatory substances (e.g., anti-inflammatory cytokines such as IL-4, IL-10, etc.). Normally, the sympathetic and parasympathetic systems work in sync to promote immune responses and modulate healing. However, in certain patients, the sympathetic and parasympathetic systems may be imbalanced or dysfunctional, which may contribute to chronic inflammation. Such patients may have a chronic imbalance between serum levels of pro-inflammatory cytokines and anti-inflammatory cytokines. An example of a chronic condition in which patients may have an imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines includes PD.

[0067] The cholinergic anti-inflammatory pathway (CAP) is a neural mechanism that inhibits pro-inflammatory cytokine release. For example, when activated, the CAP inhibits synthesis of certain pro-inflammatory molecules (e.g., TNF) in the liver and spleen and reduces the amount of circulating pro-inflammatory molecules. CAP receives inputs from multiple peripheral nerves, including the vagus nerve, the splenic nerve, and the sacral nerve. It has been previously demonstrated that stimulating the vagus nerve activates the CAP, which in turn has been shown to decrease pro- inflammatory cytokine production/release and reduce inflammation.

[0068] Without being bound by theory, one potential mechanism of action underlying the treatment of PD with sacral nerve stimulation includes activating the CAP. In some embodiments, this may occur via activation of afferent nerve fibers, which can transmit signals from the sacral nerve toward the brain, which in turn may activate the CAP. In other embodiments, this may occur via direct activation of the CAP, without involvement of the central nervous system. Regardless, activating the CAP may cause T cells within the spleen to release the neurotransmitter acetylcholine, which may bind to a7 nicotinic acetylcholine receptors on macrophages in the spleen. This may reduce the ability to release inflammatory cytokines, including, for example, TNF-a, IL-6, and/or IL-1 [3. Activating the CAP may also cause direct release of acetylcholine from one or more local nerves (e.g., the splenic nerve, the sacral nerve), bypassing the need for the T-cell intermediary. The reduction in pro-inflammatory cytokines may help restore the balance between pro-inflammatory cytokines and anti-inflammatory cytokines. This in turn may normalize the balance between the sympathetic and parasympathetic nervous systems, leading to reduced inflammation and improvement in PD-related symptoms.

[0069] Another potential mechanism of action involves activation of efferent nerve fibers that extend from the sacral nerves toward the gastrointestinal tract (e.g., the colon). For example, activating efferent nerve fibers that innervate the distal bowel may promote the release of acetylcholine from myenteric neurons. The secreted acetylcholine can then bind to receptors (e.g., a7 nicotinic acetylcholine receptors) on macrophages proximate the gastrointestinal tract. The binding of acetylcholine to a7 receptors on the macrophages can reduce the release of pro-inflammatory cytokines and/or block pro-inflammatory cytokines, as described above. The reduction in pro- inflammatory cytokines may reduce inflammation of the gastrointestinal tract, leading to an improvement in certain PD-related symptoms.

[0070] The foregoing mechanisms of action are provided as potential explanations underlying the efficacy of using sacral nerve stimulation to treat PD. However, the benefit of sacral nerve stimulation in patients with PD may arise through alternative mechanisms, in addition to or in lieu of the mechanism described herein. For example, although the foregoing mechanisms largely involve reducing and/or blocking pro- inflammatory cytokines, other mechanisms may include increasing and/or promoting anti-inflammatory cytokines. Moreover, sacral neuromodulation may treat PD through mechanism that are not related to modulating inflammation, such as by modulating neurons and/or neural pathways involved in controlling movement (e.g., to improve gait, reduce tremor, etc.). Accordingly, the present technology is not limited to a particular mechanism of action, unless expressly stated otherwise.

D. Representative Examples

[0071] The following examples are provided to further illustrate embodiments of the present technology and are not to be interpreted as limiting the scope of the present technology. To the extent that certain embodiments or features thereof are mentioned, it is merely for purposes of illustration and, unless otherwise specified, is not intended to limit the present technology. It will be understood that many variations can be made in the procedures described herein while still remaining within the bounds of the present technology. Such variations are intended to be included within the scope of the presently disclosed technology.

1. A method of treating a patient with Parkinson’s Disease (PD) and/or symptoms suggestive of PD, the method comprising: generating an electrical signal having a frequency within a frequency range of from about 0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve of the patient, wherein the electrical signal reduces OAB- and/or Gl-related symptoms associated with and/or suggestive of PD.

2. The method of example 1 wherein the electrical signal improves motor related symptoms associated with or suggestive of PD in addition to reducing the OAB- and/or Gl-related symptoms.

3. The method of example 2 wherein the motor related symptoms include gait dysfunction.

4. The method of example 1 wherein the electrical signal delays an onset of motor related symptoms associated with the patient’s PD in addition to reducing the OAB- and/or Gl-related symptoms.

5. The method of example 1 wherein the electrical signal slows a progression of motor related symptoms associated with or suggestive of PD in addition to reducing the OAB- and/or Gl-related symptoms. 6. The method of any of examples 1 -5 wherein the signal delivery device is a first signal delivery device positioned proximate a first sacral nerve of the patient and the electrical signal is a first electrical signal, and wherein the method further comprises: generating a second electrical signal; and delivering the second electrical signal to a second sacral nerve of the patient via a second implanted signal delivery device positioned adjacent the second sacral nerve of the patient.

7. The method of example 6 wherein the first sacral nerve and the second sacral nerve are contralateral.

8. The method of example 6 wherein the first sacral nerve and the second sacral nerve are ipsilateral.

9. The method of any of examples 1 -8 wherein the operations of generating and delivering are done in response to the patient having PD and/or having symptoms suggestive of PD.

10. A system for treating a patient with Parkinson’s Disease (PD) and/or symptoms suggestive of PD, the system comprising: an implantable signal delivery device positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal having a frequency within a frequency range of from about 0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA, and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, wherein the electrical signal, when delivered to the sacral nerve, reduces OAB- and/or Gl-related symptoms associated with and/or suggestive of PD. 11. The system of example 10 wherein the signal delivery device is a first signal delivery device and the sacral nerve is a first sacral nerve, and wherein the system further comprises a second implantable signal delivery device positionable proximate a second sacral nerve of the patient.

12. The system of example 11 wherein the electrical signal is a first electrical signal, and wherein the second implantable signal delivery device is configured to be coupled to the signal generator to receive a second electrical signal therefrom.

13. The system of example 12 wherein the second electrical signal has the same parameters as the first electrical signal.

14. The system of example 12 wherein the second electrical signal has different parameters than the first electrical signal.

15. The system of example 11 wherein the signal generator is a first signal generator and the electrical signal is a first electrical signal, and wherein the system further comprises a second signal generator programmed with instructions that, when executed, cause the second signal generator to generate and deliver a second electrical signal to the second sacral nerve via the second implantable signal delivery device.

16. The system of example 15 wherein the second electrical signal has the same parameters as the first electrical signal.

17. The system of example 15 wherein the second electrical signal has different parameters than the first electrical signal.

18. A method of treating a patient with Parkinson’s Disease (PD), the method comprising: identifying a patient is ambulatory via one or more sensors positioned external to or implanted within the patient; in response to identifying the patient is ambulatory, automatically generating an electrical signal having a frequency within a frequency range of from about 0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve of the patient, wherein the electrical signal improves gait dysfunction associated with the patient’s PD.

19. The method of example 18, further comprising: identifying the patient is non-ambulatory via the one or more sensors; and in response to identifying the patient is non-ambulatory, ceasing generation and delivery of the electrical signal.

20. The method of example 18 or example 19, further comprising: measuring one or more parameters associated with the patient’s ambulation via the one or more sensors; and based on the one or more measured parameters, adjust at least one signal delivery parameter of the electrical signal.

21 . The method of example 20 wherein the one or more parameters include electromyography, motor neuron conduction, muscle contraction, muscle twitching, and/or leg motion.

22. The method of example 20 or example 21 wherein the one or more signal delivery parameters include frequency, pulse width, amplitude, and/or duty cycle.

23. A system for treating a patient with Parkinson’s Disease (PD), the system comprising: one or more sensors positionable on and/or within the patient, wherein the one or more sensors are configured to (a) identify when the patient is ambulatory, and (b) in response to identifying that the patient is ambulatory, transmit a signal indicating that the patient is ambulatory; an implantable signal delivery device positionable proximate a sacral nerve of the patient; and a signal generator configured to receive the signals transmitted from the one or more sensors, wherein in response to receiving the signal indicating that the patient is ambulatory, the signal generator is programmed to automatically generate an electrical signal having a frequency within a frequency range of from about 0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA, and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, wherein the electrical signal improves gait dysfunction associated with the patient’s PD.

24. The system of example 23 wherein the one or more sensors are further configured to measure one or more additional parameters associated with the patient.

25. The system of example 24 wherein the one or more additional parameters include electromyography, motor neuron conduction, muscle contraction, muscle twitching, and/or leg motion.

26. The system of example 24 or example 25 wherein: the signal is a first signal, the sensors are further configured to transmit a second signal indicative of the measured one or more additional parameters, and the signal generator is further configured to receive the second signal and, in response to receiving the second signal, adjusts at least one signal delivery parameter.

27. The system of any of examples 23-26 wherein the one or more sensors include an accelerometer. 28. The system of any of examples 23-26 wherein the one or more sensors include an electrode.

29. The system of any of examples 23-26 wherein the one or more sensors are configured to be coupled to an external surface of the patient’s body.

E. Conclusion

[0072] From the foregoing, it will be appreciated that specific embodiments of the disclosed technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. For example, electrical signals described herein can be delivered at combinations of parameter values within the foregoing ranges at values that are not expressly disclosed herein. Certain aspects of the technology described in the context of particular embodiments may be combined or eliminated in other embodiments. Further, while advantages associated with certain embodiments of the disclosed technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the present technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.

[0073] The use of “and/or,” as in “A and/or B” refers to A alone, B alone, and both A and B. Additionally, the term “comprising” is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and/or additional types of other features are not precluded. It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein. [0074] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, to between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

Claims

CLAIMS I/We claim:

2. The method of claim 1 wherein the electrical signal improves motor related symptoms associated with or suggestive of PD in addition to reducing the OAB- and/or Gl-related symptoms.

3. The method of claim 2 wherein the motor related symptoms include gait dysfunction.

4. The method of claim 1 wherein the electrical signal delays an onset of motor related symptoms associated with the patient’s PD in addition to reducing the OAB- and/or Gl-related symptoms.

5. The method of claim 1 wherein the electrical signal slows a progression of motor related symptoms associated with or suggestive of PD in addition to reducing the OAB- and/or Gl-related symptoms.

6. The method of claim 1 wherein the signal delivery device is a first signal delivery device positioned proximate a first sacral nerve of the patient and the electrical signal is a first electrical signal, and wherein the method further comprises: generating a second electrical signal; and delivering the second electrical signal to a second sacral nerve of the patient via a second implanted signal delivery device positioned adjacent the second sacral nerve of the patient.

7. The method of claim 6 wherein the first sacral nerve and the second sacral nerve are contralateral.

8. The method of claim 6 wherein the first sacral nerve and the second sacral nerve are ipsilateral.

9. The method of claim 1 wherein the operations of generating and delivering are done in response to the patient having PD and/or having symptoms suggestive of PD.

10. A system for treating a patient with Parkinson’s Disease (PD) and/or symptoms suggestive of PD, the system comprising: an implantable signal delivery device positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal having a frequency within a frequency range of from about 0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA, and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, wherein the electrical signal, when delivered to the sacral nerve, reduces OAB- and/or Gl-related symptoms associated with and/or suggestive of PD.

11 . The system of claim 10 wherein the signal delivery device is a first signal delivery device and the sacral nerve is a first sacral nerve, and wherein the system further comprises a second implantable signal delivery device positionable proximate a second sacral nerve of the patient.

12. The system of claim 11 wherein the electrical signal is a first electrical signal, and wherein the second implantable signal delivery device is configured to be coupled to the signal generator to receive a second electrical signal therefrom.

13. The system of claim 12 wherein the second electrical signal has the same parameters as the first electrical signal.

14. The system of claim 12 wherein the second electrical signal has different parameters than the first electrical signal.

15. The system of claim 10 wherein the signal generator is a first signal generator and the electrical signal is a first electrical signal, and wherein the system further comprises a second signal generator programmed with instructions that, when executed, cause the second signal generator to generate and deliver a second electrical signal to the second sacral nerve via the second implantable signal delivery device.

16. The system of claim 15 wherein the second electrical signal has the same parameters as the first electrical signal.

17. The system of claim 15 wherein the second electrical signal has different parameters than the first electrical signal.

18. A method of treating a patient with Parkinson’s Disease (PD), the method comprising: identifying a patient is ambulatory via one or more sensors positioned external to or implanted within the patient; in response to identifying the patient is ambulatory, automatically generating an electrical signal having a frequency within a frequency range of from about

0.5 Hz to about 50 Hz, a pulse width in a pulse width range of from about 100 microseconds to about 2 milliseconds, and an amplitude within an amplitude range of from about 0.5 mA to about 15 mA; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve of the patient, wherein the electrical signal improves gait dysfunction associated with the patient’s PD.

19. The method of claim 18, further comprising: identifying the patient is non-ambulatory via the one or more sensors; and in response to identifying the patient is non-ambulatory, ceasing generation and delivery of the electrical signal.

20. The method of claim 18, further comprising: measuring one or more parameters associated with the patient’s ambulation via the one or more sensors; and based on the one or more measured parameters, adjust at least one signal delivery parameter of the electrical signal.

21. The method of claim 20 wherein the one or more parameters include electromyography, motor neuron conduction, muscle contraction, muscle twitching, and/or leg motion.

22. The method of claim 20 wherein the one or more signal delivery parameters include frequency, pulse width, amplitude, and/or duty cycle.

24. The system of claim 23 wherein the one or more sensors are further configured to measure one or more additional parameters associated with the patient.

25. The system of claim 24 wherein the one or more additional parameters include electromyography, motor neuron conduction, muscle contraction, muscle twitching, and/or leg motion.

26. The system of claim 24 wherein: the signal is a first signal, the sensors are further configured to transmit a second signal indicative of the measured one or more additional parameters, and the signal generator is further configured to receive the second signal and, in response to receiving the second signal, adjusts at least one signal delivery parameter.

27. The system of claim 23 wherein the one or more sensors include an accelerometer.

28. The system of claim 23 wherein the one or more sensors include an electrode.

29. The system of claim 23 wherein the one or more sensors are configured to be coupled to an external surface of the patient’s body.