CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63/280,652, filed on November 18, 2022, the entirety of which is incorporated by reference herein.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates generally to systems and methods for treating neurological disorders. More particularly, the present disclosure relates to systems and methods for wirelessly driving an interferential current neurostimulator for peripheral nerves to treat epilepsy.

BACKGROUND OF THE DISCLOSURE

[0003] Pharmaceutical intervention to treat epilepsy can be successful, but in the case of refractory epilepsy, these pharmaceutical interventions are not effective. Many refractory epilepsy patients turn to implantable neurostimulator devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS;) however, these devices have their own limitations including finite battery life, large size, and the negative side effects caused by the tethered cuff electrode.

SUMMARY

[0004] In accordance with an aspect of the present disclosure, an interferential cuff electrode is disclosed. The interferential cuff electrode includes an annular body configured to be positioned at least partially around a nerve in a patient. The interferential cuff electrode also includes a plurality of contacts coupled to the body. The contacts are configured to apply first and second demodulated signals to the nerve. The first and second demodulated signals differ from one another by an interference frequency, a phase angle, or both. The first and second demodulated signals are configured to stimulate the nerve at the interference frequency.

[0005] In another embodiment, the interferential current stimulator (ICS) is disclosed. The ICS may be used for stimulating a peripheral nerve in a patient to treat a neurological disorder. The ICS may include one or more signal generators configured to generate a first modulated signal and a second modulated signal. The first modulated signal includes a carrier signal that is modulated by a first frequency, a first phase, or both. The second modulated signal includes the carrier signal modulated by a second frequency, a second phase, or both. The first and second frequencies differ from one another by an interference frequency. The first and second phases differ from one another by a phase angle. The ICS also includes one or more transmitters configured to wirelessly transmit the first and second modulated signals. The one or more signal generators and the one or more transmitters are positioned outside of the patient. The ICS also includes one or more receivers configured to wirelessly receive the first and second modulated signals via magnetic resonance coupling, inductive coupling, capacitive coupling, or a combination thereof. The ICS also includes one or more passive demodulation circuits configured to demodulate the first and second signals to produce first and second demodulated signals. The first demodulated signal is at the first frequency and/or phase. The second demodulated signal is at the second frequency and/or phase. The ICS also includes an interferential cuff electrode configured to receive the first and second demodulated signals. The one or more receivers, the one or more passive demodulation circuits, and the interferential cuff electrode are positioned within the patient. The interferential cuff electrode includes an annular body that is configured to be positioned at least partially around the peripheral nerve. The interferential cuff electrode also includes a first set of contacts coupled to the body. The contacts in the first set are circumferentially offset from one another around the body. The interferential cuff electrode also includes a second set of contacts coupled to the body. The contacts in the second set are circumferentially offset from one another around the body. The first and second sets of contacts are axially offset from one another with respect to the body. The interferential cuff electrode is configured to apply the first and second demodulated signals to the peripheral nerve via the first and second sets of contacts, which is configured to stimulate the peripheral nerve and cause the peripheral nerve to conduct at the interference frequency.

[0006] A method for stimulating a peripheral nerve in a patient is also disclosed. The method includes generating first and second modulated signals. The method also includes wirelessly transmitting the first and second modulated signals to an interferential cuff electrode that is positioned at least partially around a nerve in a patient. The method also includes demodulating the first and second modulated signals using the interferential cuff electrode to produce first and second demodulated signals. The method also includes applying the first and second demodulated signals to the nerve via a plurality of contacts on the interferential cuff electrode. The first and second demodulated signals differ from one another by an interference frequency and/or phase. The first and second demodulated signals are configured to stimulate the nerve at the interference frequency.

BRIEF DESCRIPTION OF THE FIGURES

[0007] Figures 1A-1G illustrate envelopes produced by various stimulation methods, according to an embodiment.

[0008] Figures 2A-2C illustrate perspective views of different electrodes, according to an embodiment.

[0009] Figure 3 illustrates a schematic of at least part of a wireless ICS system (e.g., including the electrode from Figure 2C), according to an embodiment.

[0010] Figure 4 illustrates a flowchart of a method for stimulating a nerve, according to an embodiment.

[0011] Figures 5A-5H illustrate data processing from experiments, according to an embodiment.

[0012] Figure 6 illustrates a modulated RF signal, according to an embodiment.

[0013] Figure 7 illustrates a demodulated signal (e.g., the modulated RF signal after being demodulated), according to an embodiment.

[0014] Figure 8 illustrates an EMG in response introducing the demodulated signal to a nerve, according to an embodiment.

[0015] Figure 9 illustrates a graph showing a spectrum of signals including the modulated RF signal, the demodulated signal, and the EMG, according to an embodiment.

[0016] Figures 10A-10G illustrate a new rotatable geometry, according to an embodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The presently disclosed subject matter now will be described more fully hereinafter with reference to the accompanying Drawings, in which some, but not all embodiments of the disclosures are shown. Like numbers refer to like elements throughout. The presently disclosed subject matter may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0018] The system and method described herein may apply electrical stimulation to a target (e.g., a peripheral nerve or carotid body). The system and method are also robust enough to work without damaging the system or the patient if the patient moves. The system and method may apply a plurality of signals (e.g., two or more signals, three or more signals, etc.), including new types of interference and modulation. The system and method may include a modular electrode array with a plurality of electrode contacts (e.g., twelve contacts) that allows the creation and transmission of spatially complex signals. The system and method may also include a feedback algorithm that can determine predetermined (e.g., optimal) stimulation parameters. The system and method may be (e.g., completely) passive and/or wireless such that stimulation may be applied without an implanted stimulator device (e.g., signal generator).

[0019] The system and method may target new, smaller, more delicate structures to be placed anywhere in the patient. The system and method may pull from a large (e.g., several orders of magnitude or larger) set of possible signal combinations, and steer the signal(s) in new ways that are safer for the patient. The system and method may iterate over many simulation settings to determine a predetermined (e.g., optimal) setting for the patient. As described below, the system and method may include a wireless, unpowered device that may increase the lifetime of the device and decrease the side effects caused by the device. The system and method have broad applicability in medicine and neuroscience. For example, the system and method can be used to treat neurological disorders such as epilepsy.

[0020] Interferential current stimulation (ICS) of peripheral nerves via an implanted electrode intended for chronic use

[0021] A benefit of deep brain stimulation (DBS) devices, or rather a detriment of vagal nerve stimulator (VNS) devices, is that the skull is a rigid, fixed surface. The brain may move slightly inside the skull. This security of location means that an electrode that is rigidly affixed to the skull does not move around a lot, with regards to its target location. This stability is good, because the electrode is hard and sharp, and brain tissue is not, and movement (e.g., from walking and/or exercising) may cause the electrode to damage the tissue. This stability is not present in peripheral nerve applications like the VNS device. Both the target and the electrode are constantly moving around. If the electrode is hard and rigid, then tissue damage may occur. Even if the electrode is soft and flexible (as is the case for peripheral nerve stimulators), then if the target moves around inside the electrode, it is also moving around inside the stimulation region - which varies with geometry. As a result, the device may unintentionally apply more or less stimulation than intended, either causing a lack of effect (e.g., resulting in a seizure), or tissue damage from over-stimulation. For VNS devices, the electrode may be tied around the nerve and connected to the stimulation circuitry. This tethering of the electrode can damage the nerve by putting tension on it.

[0022] Applicant has applied the system and method herein to peripheral nerves because the ICS operates on a soft, flexible substrate, and the target and electrodes may move. The geometry of the stimulation field that is desirable may change. In one embodiment, the system and method may target the sciatic nerve, but from a cuff electrode that is placed very close to the nerve. The region of stimulation may be 30-90% of the total volume encompassed by the cuff electrode, while in conventional applications, it may only be 5-10%. Those differences change the techniques that may be used to create the stimulation region. Specifically, in small-volume-ratio applications, the two electrodes of one of the channels (e.g., 1+ and 1-) may be close to one another, but far from the other channel (e.g., 2+ and 2-). However, in a large-volume-ratio application, the four electrodes may be substantially evenly spaced. In addition, the differences may change the waveforms that are selected. In a small-volume -ratio application, the signal may be selected to decay over distance faster than a predetermined threshold, while in the large-volume case, the opposite may be selected. In addition, a peripheral nerve is substantially cylindrical, while the conventional techniques create a spherical volume of stimulation. The system and method herein create a substantially cylindrical region of stimulation, which is inherently more efficient for a cylindrical target. For example, the cylindrical region may achieve the same level of effect with less damage and side effects.

[0023] Selecting the electrodes and the signals to make specialized regions of stimulation

[0024] A 1990 Hz, 2000 Hz, and 2010 Hz combination, where the amplitude of the 2000 Hz signal is greater than (e.g., twice as large as) the others, produces something that is a 10 Hz interference pattern. As far as nerves are concerned, a higher frequency stimulation region with a 10 Hz envelope will have a similar effect as a region which is exactly 10 Hz. However, the addition of a third signal dramatically changes the geometry of the stimulation field, as shown in Figures 1A-1D below.

[0025] More particularly, Figures 1A-1D illustrate envelopes produced by various stimulation methods, according to an embodiment. Figure 1A is a domain embodiment that shows the geometry of the model, a large cylindrical 2D surface, a smaller cylindrical surface (e.g., a nerve), and 6 low impedance cylinders circumscribing the nerve. In each case, the 6 contacts are modeled as constant voltage boundaries at ± IV.

[0026] Figure IB is a bipolar embodiment in which the 6 contacts are all +1 V (and 6 located further into the z-direction into the page are -IV). As used herein, bipolar stimulation refers to a stimulation technique in which a single signal is conducted between a pair of electrode contacts. In bipolar simulation, the frequency of the signal applied is the same as the frequency of the desired effect. The field produced in the center of the target cylinder is small and low amplitude.

[0027] Figure 1C shows two, two channel ICS embodiments having two pairs (each 180° apart). As used herein, two channel ICS stimulation refers to the use of two stimulators operating across two pairs of electrode contacts to create a stimulation region. The two stimulators output signals that are too low amplitude to stimulate the nerve on their own, and/or too high frequency to produce phasic firing, but in the region in which they interfere, they produce an interference signal with a lower frequency envelope at a sufficient amplitude to produce phasic nerve firing. There are at least four contacts and at least two signals. The two sinusoids have specified frequencies and amplitudes. By changing which signal has a larger amplitude, a user can recruit different muscles preferentially, demonstrating selectivity. The animal data shown demonstrates how such an embodiment may allow target selectivity, one of the goals for improving patient outcomes.

[0028] Figure ID two, three channel ICS embodiment having three pairs (each 120° apart). As used herein, three channel ICS stimulation refers to the use of three stimulators operating across three pairs of electrode contacts to create a stimulation region. The three stimulators output signals that are too low amplitude to stimulate the nerve on their own, and/or too high frequency to produce phasic firing, but in the region in which they interfere, they produce one or more interference signals with a lower frequency envelope at a sufficient amplitude to produce phasic nerve firing. In one embodiment, the cuff electrode may have two rings of six electrodes that are 60 degrees apart. This geometry produces a large target region with higher amplitude. Two channel ICS stimulation and three channel ICS stimulation are only a subset of the potential techniques allowed by the cuff electrode and the channels used and are included as non-exhaustive examples. The three sinusoids have specified frequencies and amplitudes. By changing which signal has a larger amplitude, a user can recruit different muscles preferentially, demonstrating selectivity. The animal data shown demonstrates how such an embodiment may allow target selectivity, one of the goals for improving patient outcomes.

[0029] Figure IE shows two, three channel ICS embodiments in which the signals differ by not one, but two beat frequencies. The three stimulators output signals that are too low amplitude to stimulate the nerve on their own, and/or too high frequency to produce phasic firing, but in the region in which they interfere, they produce one or more interference signals with a lower frequency envelope at a sufficient amplitude to produce phasic nerve firing. The three sinusoids have specified frequencies and amplitudes. By changing the geometric locations of signals, a user can recruit different muscles preferentially, demonstrating selectivity. The animal data shown demonstrates how such an embodiment may allow target selectivity, one of the goals for improving patient outcomes.

[0030] Figure IF shows two, one channel ICS embodiments in which the signal in question has an asymmetric envelope - with the bottom envelope achieving larger amplitude negative values than the top envelope achieves positive values. While the embodiment shows one channel, geometrically, the signal in question is the sum of 5 sinusoids, all applied to the same two electrodes. Such an embodiment may be applied to a plurality of (e.g., 10 or more) electrodes; however, this figure only elects two to demonstrate the premise of the technique more simply. Figure IF shows embodiment in which the sum of many sines is applied between an anode and a cathode. The signal in question has an asymmetric envelope behavior. By switching the anode and cathode, a user can recruit different muscles preferentially, demonstrating selectivity. The signal in question is: Frequency: 2000 Hz, 2020 Hz, 4020 Hz, 6020 Hz, 8040 Hz. Amplitudes (ratio): 1, 1, 1.25, 1.67, 2. Phase: 0, 0, pi/4, pi/2, pi. The animal data shown demonstrates how such an embodiment may allow target selectivity, one of the goals for improving patient outcomes. [0031] Figure 1G shows a three channel ICS embodiment in which the signals in question are changed in phase, and not frequency, amplitude, or geometric orientation. Such an embodiment may also change these parameters to optimize performance, but this figure elects to keep these parameters fixed in order to demonstrate the premise of the technique more simply. The signals have specified frequencies and phases. By changing the phase of a signal, a user can recruit different muscles preferentially, demonstrating selectivity. The animal data shown demonstrates how such an embodiment may allow target selectivity, one of the goals for improving patient outcomes.

[0032] By using multiple types of signals (e.g., up to 6 independent signals, and up to 11 dependent signals), the system can create geometries which are more complex than conventional geometries. A complex geometry may be better because it allows the system to only stimulate the desired part of the nerve, while not stimulating other parts of the nerve. In contrast, with only two signals, the geometry only has four possible shapes. Higher order interference patterns (i.e., interference patterns based on more signals, more types of signals (not just sine waves), and/or more types of interference (phase modulation)) may enable more targeted stimulation, more activation at the target, and less side effects.

[0033] Modular, 12 contact electrode array in a near-nerve cuff electrode

[0034] Nerves are substantially cylindrical and behave similar to wires. Nerves have subbundles called fascicles, and inside the fascicles are individual neurons, which are the smallest unit of nerve signaling. Fascicles and neurons also behave similar to wires. For example, if a neuron runs from the bottom of the spine to the bottom of the foot, it doesn’t really matter if that nerve is stimulated at the ankle or at the knee, it’s going to have the same effect. When stimulating the cylinder, having a stimulation region that is large in the axial direction may not cause side effects, while having a region that is large in the transverse direction may cause side effects. In the first case, the field is only stimulating one neuron, and just stimulating a larger portion of that neuron, which doesn’t change the outcome. In the second case, the field is stimulating multiple neurons, and only for a short distance of each neuron. However, it only takes a very short distance of stimulation on each neuron to activate it, so this second case may cause side effects. Therefore, the shape of the stimulation geometry can be designed (e.g., optimized) so that it is smaller in the transverse plane, and larger in the axial direction. The electrode design may use electrodes that run parallel to the nerve, as this design increases (e.g., maximizes) the transverse- axial efficiency. [0035] Figures 2A-2C illustrate perspective views of electrodes, according to an embodiment. More particularly, Figure 2A illustrates a design for bipolar stimulation using circumferential contacts, with electrical current driven parallel to the axis of the nerve. The electrode 200A includes a substantially cylindrical body 210A and one or more circumferential/annular electrode contacts (two are shown: 220A, 222A) that are positioned around the body 210A. The contacts 220A, 222A may be spaced axially apart with respect to a central longitudinal axis through the body 210A.

[0036] Figure 2B illustrates a design for two channel ICS stimulation using axial electrode contacts, with the current driven perpendicular to the axis of the nerve. The electrode 200B includes a substantially cylindrical body 210B and one or more axial electrode contacts (three are shown: 220B, 222B, 224B) that are positioned along the body 21 OB. The contacts 220B, 222B, 224B circumferentially offset from one another around the body 21 OB. The contacts 220B, 222B, 224B may be parallel with respect to a central longitudinal axis through the body 210B.

[0037] Figure 2C illustrates a cuff design. The electrode 200C includes a substantially annular body 210C that is configured to be positioned around a target (e.g., a nerve) 212C. The electrode 200C may also include a plurality of discrete electrode contacts (e.g., 12) that can be arranged to approximate ideal geometries for bipolar stimulation, two channel ICS, three channel ICS, or a combination thereof. In this example, a first set of contacts (e.g., 6 contacts) 220C is circumferentially offset from one another, and a second set of contacts (e.g., 6 contacts) 222C is circumferentially offset from one another. The first and second sets 220C, 222C are axially offset with one another with respect to a central longitudinal axis through the body 210C.

[0038] The electrode 200C in Figure 2C is efficient because it uses an optimized spatial arrangement of contacts 220C, 222C to create ICS stimulation regions. More particularly, the electrode 200C includes 2 electrode sets (also referred to as contact sets) 220C, 222C, with 6 contacts in the first set positioned toward the proximal side of the nerve, and 6 contacts in the second set positioned toward the distal side of the nerve. Each set of 6 is radially distributed, about 60 degrees apart. This arrangement is both versatile enough to allow the creation of many different types of ICS waveforms and efficient enough to be practical. It allows the creation of efficient, effective ICS patterns and no more. Further, the individual electrodes are long in the axial direction, which may be optimal for ICS geometries on peripheral nerves.

[0039] An integrated algorithm to determine the simulation settings

[0040] The cuff electrode 200C may have a subset of possible ICS geometries - not so complicated that the cuff is impractical to implant, and not so simple that the technology is limited. The cuff electrode 200C and the nerve 212C inside may move around as the patient moves. As the cuff 200C and the nerve 212C move, the target moves with respect to the contacts 220C, 222C, and the stimulation geometry also changes. Because a single cuff may allow many types of ICS, the algorithm may search for the optimal stimulation geometry. The algorithm may have a model of the geometry of the cuff electrode 200C, the nerve 212C, and/or the target, and by recording the output of the stimulation (e.g., from an EMG of the muscles contracting in response to the stimulated nerve), the algorithm can then build a model of its environment and attempt to choose and steer the signal toward the target.

[0041] Steering refers to changing settings on the stimulator (e.g., signal generator) without physically moving the cuff electrode 200C (e.g., contacts 220C, 222C), which moves the stimulation region around within the volume enclosed by the cuff electrode 200C. In one embodiment, the stimulation region may be steered by selectively changing the contacts 220C, 222C that receive the signals, which can be used to effectively “rotate” the stimulation region. With 12 contacts and three or more signals, there are many different, nonredundant ways to apply the same stimulation geometry. Not all ICS geometries are symmetric about the axial direction. If the same relative connections on the contacts 220C, 222C are maintained, but they are rotated by one contact (e.g., not physically moving the cuff electrode 200C, but by using switches on the stimulator, changing which contact 220C, 222C receives which signal), then the stimulation region can be rotated around the target 212C. In contrast, conventional steering is only in one direction, across the line which connects channel #1 to channel #2. Using rotations, steering may be around the 360 degrees of the cuff electrode 200C. By using three or more signals, steering may be achieved in more directions, for example, the line between channel #1 and #2, the line connecting channels #2 and #3, and finally #1 and #3. Therefore, this technique is versatile as it allows a stimulation region to be steered with flexibility and control. Steering may also be achieved by changing parameters of the signals (e.g., their number, amplitude, frequency, phase, types of interference, and more) to create different regions of stimulation.

[0042] A passive system with no implanted stimulator

[0043] The system can be operated wirelessly, with the stimulator source (e.g., signal generator) placed outside of the patient. Using signal modulation, the (two, or three, or more) ICS signals can be coupled onto a high frequency carrier signal (e.g., 10 MHz), which can penetrate tissue with no side effects. A coil on the electrode cuff 200C can receive this wireless signal. Small electrical components integrated on the electrode cuff 200C can demodulate the ICS signals from the wireless signal, and then the contacts 220C, 222C can apply the demodulated signals to the target 212C. These small demodulation circuits and their contacts may not be placed directly on the target 212C. Rather, they can be placed anywhere around the target 212C as they produce the signals that then interfere to create the desired ICS pattern. The design utilizes passive circuit components, such that stimulation only occurs when the wireless signal is present. This also allows for a lower power consumption of the circuit itself. An overview of the signals at different points in the system can be seen in Figure 3.

[0044] More particularly, Figure 3 illustrates a schematic of at least part of a wireless ICS system 300, according to an embodiment. The system 300 may include a signal generator 310. The signal generator 310 may be configured to generate amplitude-modulated radio-frequency (RF) signals. The RF signals may include the carrier signal in the megahertz (MHz) range modified by a frequency in the kilohertz (kHz) range. The signal generator 310 may be coupled to a transmitter (Tx) 320. The transmitter 320 may be configured to wirelessly transmit the amplitude-modulated RF signals to a receiver (Rx) 330. The transmitter 320 and/or the receiver 330 may be or include coils. The receiver 330 may be coupled to a (e.g., passive) demodulation circuit 340, which may demodulate the amplitude-modulated RF signals to produce demodulated RF signals. The demodulation circuit 340 may be coupled to an interferential cuff electrode 350, which may introduce the demodulated signals to the target. The cuff electrode 350 may be the same as, or different from, the cuff electrode 200C described above. The signal generator 310 and the transmitter 320 may be positioned outside of the patient, and the receiver coil 330, the demodulation circuit 340, the interferential cuff electrode 350, or a combination thereof may be positioned within (e.g., implanted in) the patient (e.g., an animal or human).

[0045] Figure 4 illustrates a flowchart of a method 400 for stimulating a nerve, according to an embodiment. The method 400 may use the system 300 (or two or more systems 300 in parallel). A first signal generator 310A may generate a first signal 315A, and a second signal generator 310B may generate a second signal 315B. The signals 315A, 315B may be or include amplitude- modulated radio frequency (RF) signals. The signals 315A, 315B may be modulated by different frequencies. In one example, the first signal 315A may be modulated by 2 kHz, and the second signal 315B may be modulated by 2.01 kHz.

[0046] The first signal 315A may be (e.g., wirelessly) transmitted from a transmitter coil 320A to a receiver coil 33OA, and the second signal 315B may be (e.g., wirelessly) transmitted from a transmitter coil 320B to a receiver coil 33OB. For example, the system may use magnetic resonance coupling, inductive coupling, and/or capacitive coupling to transmit the signals 315A, 315B in the MHz range (e.g., 10 MHz) modulated by the selected kHz frequency signal for ICS.

[0047] A first (e.g., passive) demodulation circuit 340A may demodulate the first signal 315A to produce a first demodulated signal 345A, and a second (e.g., passive) demodulation circuit 340B may demodulate the second signal 315B to produce a second demodulated signal 345B. In an example, the first demodulated signal 345A may be a 2 kHz sine wave, and the second demodulated signal 345B may be a 2.01 kHz sine wave. The interferential cuff electrode 350 may apply the first and/or second demodulated signal(s) 345A, 345B to a nerve in the patient. In other words, the demodulation circuits 340A, 340B may demodulate the signals 315A, 315B to produce only the kHz signals 345A, 345B at the cuff electrode 350. The two signals 345A, 345B may generate a predetermined stimulation (e.g., 10 Hz) in the patient that is the difference in frequency between the two signals 345 A, 345B. These kHz frequency signals 345 A, 345B are applied to the tissue through the electrode 350 and interfere as previously discussed.

[0048] Figure 4 depicts a 2 channel ICS embodiment, but it may be expanded to 3 or more channels. To do so, the same process would be repeated utilizing a third set of the same components (e.g., signal generator, transmitter, receiver, demodulation circuit) operating with the desired signals and frequencies required to produce the desired interference pattern. More particularly the third set may cause the cuff electrode 350 to apply a third demodulated signal in addition to the first and second demodulated signals. Using three or more demodulated signals allows new, more focused shapes to be created, since there are a limited number of ways that two signals can interfere.

[0049] When three demodulated signals are applied, there may be four different types of interference: the interference between signal 1 and signal 2, the interference between signal 1 and signal 3, the interference between signal 2 and signal 3, and the interference between signals 1, 2, and 3. Using the example above with demodulated signals at 1990 Hz, 2000 Hz, and 2010 Hz, this may result in interferences at: 10 Hz, 20 Hz, 10 Hz, and 10 Hz (with this one having the largest amplitude). The three different 10 Hz interferences may be in sync with one another, so they add up to one large 10 Hz interference, or they may occur at different times, resulting in different parts of the nerve being stimulated at different moments in time. However, the frequencies of the demodulated signals may be selected to optimize the interference. For example, the demodulated signals of 1990 Hz, 2000 Hz, and 2010 may have the vast majority of interference at the main, desired frequency (e.g., 10 Hz), with a much smaller amount of interference being at the other frequency (e.g., 20 Hz).

[0050] Figures 5A-5H illustrate data processing from experiments, according to an embodiment. The experiments verified the efficacy of a wired stimulation system including the cuff electrode 350 on the sciatic nerve. For example, in 7 animals, 9 legs, 63 techniques, 81 recruitment curves, and 2025 stimulation trials, it was demonstrated that the ICS techniques described herein are statistically significantly more selective in their activation compared to conventional techniques.

[0051] As mentioned above, the system may create a small region of activity inside the nerve, activating some parts of the nerve, but not others. This is clinically relevant because most nerves do many different things, and conventional electrodes can only stimulate the whole nerve, or none of it. In the experiments of Figures 5A-5H, a motor nerve (e.g., the sciatic nerve) was the target. This nerve goes to many different muscles in the leg, but the experiments focused on the biceps femoris and the soleus. A conventional electrode activates both muscles at the same time. The experiments tried many different parameters with regular stimulation, and with the new ICS technique, and compared how strongly each of the two muscles was activated. The ability to activate one muscle, and not the other (and then do the opposite), is referred to herein as "selectivity." The set of images in Figures 5A-5H show the experimental progression. The data was processed to determine how "selective" each technique was. The graphs show that over multiple experiments, the ICS technique provides more selectivity. In other words, based on the settings, the ICS technique can activate only the biceps femoris, only the soleus, or both, while regular stimulation techniques cannot.

[0052] A series of models may be generated to visualize what each geometry accomplishes, and how to pick the best strategy for a particular application. These models feed into an algorithm. With two or three sine-based signals, it may be determined what the stimulation region should look like. However, as the number of signals increases, and/or the signals become more complex, the model(s) may be used to predict what the stimulation region will look like.

[0053] The efficacy of the wireless ICS system has been demonstrated in a plurality of animals. Two or more wireless carrier signals may be generated in the MHz frequency range, and each may be modulated with a different signal in the kHz range. The carrier signals may be the same or different. Figure 6 illustrates a modulated RF signal, according to an embodiment. These modulated signals (e.g., signals 315A, 315B) are then wirelessly transmitted using (e.g., magnetic resonance coupling) to receivers 33OA, 33OB and then passed to the demodulation circuits 340A, 340B. The demodulation circuits 340A, 340B then demodulate these two RF signals 315A, 315B to produce the two signals in the kHz range (e.g., 2kHz and 2.01kHz sine waves) referred to as the intermediate frequency (IF) signals 345 A, 345B.

[0054] Figure 7 illustrates a (single) demodulated sine wave at the IF of 2 kHz, according to an embodiment. These IF signals (e.g., signals 345A, 345B) may then be applied to the sciatic nerve in a patient (e.g., an anesthetized rat) using an interferential cuff electrode 350. An electromyogram (EMG) may be recorded to measure the muscle contraction in response to the nerve stimulation. Muscle contraction may be seen when both signals 345A, 345B are applied. The contractions occurred at the interference frequency (e.g., 10Hz). Figure 8 illustrates an EMG of the muscle contraction, according to an embodiment. Figure 9 illustrates a graph showing a spectrum of signals including the modulated RF signal, the demodulated sine wave (IF), and the EMG, according to an embodiment.

[0055] Figures 10A-10G illustrate a new rotatable geometry, according to an embodiment. More particularly, Figure 10A illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target- specific optimization. Figure 10B illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target- specific optimization. Figure 10C illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target- specific optimization. Figure 10D illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target- specific optimization. Figure 10E illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target-specific optimization. Figure 10F illustrates an embodiment which targets a radial section of the nerve. Together, with other radial sections, selectivity is achieved, and the location of targets within the nerve may be estimated, demonstrating both selectivity and target- specific optimization. Figure 10G provides a summary of Figures 10A-10F. For example, Figure 10G includes an embodiment which targets a radial slice of the nerve. With repetitions of the embodiment at different radial slices, an estimation of the target muscles within the nerve can be generated. The embodiment demonstrates how the technique might be used for patient specific nerve mapping and optimization.

[0056] In a series of experiments, one of the ICS geometries was selected that made an off- center interference pattern, and this was “rotated” around the sciatic nerve. As used herein, an “off-center interference pattern” refers to an interference pattern from the signals that is not aligned with a central longitudinal axis through the nerve. The sciatic nerve innervates several muscles in the leg, and by rotating the stimulation region around the nerve, different muscles can be activated. Using ICS style waveforms, the stimulation parameters were changed, which changed the activated muscle. This achieved better muscle selectivity than conventional techniques. These results demonstrate how interferential techniques can create a region of stimulation which has functional benefits - when the contacts are placed around a nerve which controls both foot and calf contractions, by trying multiple parameters, a user is able to control whether the foot, the calf, or both contract in response to stimulations. By quantifying and comparing the relative contractions in the foot and calf, it can be determined which techniques are better at differentiating between the two. With this data, the interferential techniques described herein can be used to target small, delicate sub-structures in ways that the standards of the field cannot. Such an embodiment is demonstrated in figures 10A-10G.

[0057] As mentioned above, the cuff electrode may include axially long electrode contacts that may be optimized for ICS in a peripheral nerve. The cuff electrode may include two rings of multiple (e.g., 6) evenly radially spaced electrode contacts, which optimizes ICS geometries for a cylinder which occupies a significant portion of the electrode-enclosed volume. The ICS waveform techniques may implement 1) more spatially complex arrangements of two signals (enabled by the cuff electrode), and/or 2) spatially complex (or simple) arrangements of 3-11 signals. ICS steering may be based on 1) spatially complex amplitude steering of two signals, 2) spatially complex (or simple) amplitude steering of three or more signals, and 3) steering based on switching the active and inactive electrodes, while maintaining the same fundamental geometry. The system may use interference techniques using sine and/or non-sine waveforms, and amplitude and/or non-amplitude modulation techniques, like phase and/or frequency modulation. The ICS waveforms may be applied using an implanted, unpowered, entirely passive cuff electrode, driven by an external coil, by using high frequency (e.g., 2 MHz) modulation. The algorithm may be used to optimize, in real time, the ideal stimulation parameters for a particular situation, based on the algorithm’s awareness of 1) the cuff electrode array 2) candidate ICS techniques based on simulations 3) its own environment, and where the cuff electrode and the target exist in that environment, and/or 4) feedback, from a measured bio signal of the patient.

[0058] Previously, it was thought that nerves extracted envelopes. For example, for a stimulus of a sum of a 2000 Hz sine and a 2020 Hz sine, there is a 20 Hz envelope. The envelope is not "real." There is 2000 Hz energy, 2020 Hz energy, but no 20 Hz energy. Certain circuit elements (e.g., diodes, rectifiers), or nonlinear functions (e.g., absolute value) can transform the sum of a 2000 Hz sine and a 2020 Hz sine to produce a new signal which has 20 Hz energy. When the sum of 2000 / 2020 is applied to a nerve, it fires at 20 Hz. Nerves can't fire at more than 1000 Hz at most (and usually 300-400 is a reasonable maximum). Thus, it was a reasonable assumption that nerves could act like a diode or rectifier and produce 20 Hz energy.

[0059] Thus, "envelope extraction" has been a presumed property of neurons for the last 70 years. However, applicant’s data conclusively proves that this property does not exist. Instead, neurons are simply responding to the 2000 / 2020 energies in a manner that looks like 20 Hz. However, Applicant’s data proves 20 Hz energy is not generated nor predictive of firing.

[0060] This change in explanation fundamentally changes the "shapes" of stimulation. When viewing images and/or heat maps of simulation intensity, the previous images/heat maps showed the shape of 20 Hz energy, not the shape of 2000 or 2020Hz energy. However, the new shapes are radically different. More particularly, the ability of the technique to target really deep structures in the brain (e.g., how it's being used in 15 ongoing human clinical trials) is poor. The technique is still very good at precise control of targets near electrodes for a peripheral nerve target.

[0061] Although the present disclosure has been described in connection with preferred embodiments thereof, it will be appreciated by those skilled in the art that additions, deletions, modifications, and substitutions not specifically described may be made without departing from the spirit and scope of the disclosure as defined in the appended claims.