Neural interface device for stimulating nerves and measuring impedance

Abstract

A system for stimulating a nerve and measuring impedance. The system includes: a neural interface device including a plurality of electrodes for electrically contacting the nerve; a voltage or current source operably connected to at least a subset of the electrodes, wherein the voltage or current source is configured to generate an electrical signal to be applied to the electrodes; an impedance measurement module operably connected to at least a subset of the electrodes, wherein the impedance measurement module is configured to measure impedance between the electrodes; and a controller arranged to determine the amplitude of an action potential induced in the nerve via the electrical signal based on the measured impedance, and to adjust the electrical signal so as to induce an action potential having a target amplitude.

Description

Technical Field

[0001] The present disclosure relates to neural interface devices, systems, methods, computer programs, and computer-readable media for stimulating nerves and measuring impedance. Background Art

[0002] Typically, devices for stimulating nerves (i.e., neuromodulation devices) require components that ensure that stimulation is delivered at the correct level. For example, it may be necessary to ensure that stimulation is delivered to the nerve at a specific amplitude or for a specific duration. In other words, it may be necessary to ensure that the correct "dose" of stimulation is delivered to the nerve.

[0003] In order to monitor the dose of stimulation provided to the nerve by the neuromodulatory device, some form of feedback is required. However, direct feedback is not available for rheumatoid arthritis (RA) treatment. This is because immune system modulation and the associated effects on RA symptoms are only visible hours, days or months after stimulation, rather than being immediately observable. Cytokine analysis does not provide rapid (or real-time) feedback on the activation of the nerve.

[0004] Therefore, there is a need to estimate the amount of neural actuation or stimulation induced in the nerve. In addition, there is a need to ensure that the electrical charge delivered to the nerve associated with the splenic artery induces an action potential of a sufficient level that will produce a therapeutic effect. Summary of the invention

[0005] In one aspect, there is a system for stimulating a nerve and measuring impedance, the system comprising: a neural interface device including a plurality of electrodes for electrically contacting the nerve; a voltage or current source operably connected to at least a subset of the electrodes, wherein the voltage or current source is configured to generate an electrical signal (also referred to as a stimulation electrical signal) to be applied to the electrodes; an impedance measurement module operably connected to at least a subset of the electrodes, wherein the impedance measurement module is configured to measure the impedance between the electrodes; and a controller arranged to determine a quantitative indication of a change in the amplitude of an action potential induced in the nerve or a downstream effect caused by the action potential induced in the nerve via the electrical signal based on the measured impedance, and to adjust the electrical signal so as to induce an action potential having a target amplitude or a target change in the downstream effect caused by the action potential. An action potential may refer to a compound action potential induced by a pulse or a train of pulses (electrical signal).

[0006] In other words, there is a system for stimulating a nerve and monitoring a stimulation dose response based on impedance, the system comprising: a neural interface device comprising a plurality of electrodes for electrically contacting the nerve; a voltage or current source operably connected to at least a subset of the electrodes, wherein the voltage or current source is configured to generate an electrical signal to be applied to the electrodes; an impedance measurement module operably connected to at least a subset of the electrodes, wherein the impedance measurement module is configured to measure the impedance between the electrodes; and a controller arranged to determine a dose response caused by the electrical signal based on the measured impedance, and adjust the electrical signal so as to cause a target dose response.

[0007] On the other hand, there is a neural interface device for stimulating nerves and measuring impedance, the device comprising: a stimulation electrode pair for inducing electrical signals in the nerve; an impedance measuring electrode pair for measuring impedance between the impedance measuring electrodes; wherein the stimulation electrode pair is spaced apart from each other in a longitudinal direction about the nerve; wherein the impedance measuring electrode pair is spaced apart from each other in a direction perpendicular to the longitudinal direction about the nerve.

[0008] On the other hand, there is a system for stimulating nerves and measuring impedance, the system comprising: one or more neural interface devices described herein; and a voltage or current source operably connected to each pair of stimulation electrodes of each neural interface device described herein, wherein the voltage or current source is configured to generate an electrical signal to be applied to the nerve via the stimulation electrodes; and an impedance measurement module operably connected to each pair of impedance measurement electrodes, wherein the impedance measurement module is configured to measure the impedance between the pairs of impedance measurement electrodes.

[0009] On the other hand, there is a method for stimulating nerves and measuring impedance, the method comprising: providing one or more neural interface devices described herein; generating an electrical signal to be applied to the nerve via the stimulation electrodes of the neural interface device by at least one voltage or current source operably connected to the stimulation electrodes; and measuring the impedance between the impedance measurement electrodes of the neural interface device by at least one impedance measurement module operably connected to the impedance measurement electrodes.

[0010] On the other hand, there is a computer program comprising a code portion, which, when loaded and run on a computing device, causes the computing device to: generate an electrical signal to be applied to a nerve via the stimulation electrodes of the neural interface device described herein by at least one voltage or current source operably connected to the stimulation electrodes; and measure the impedance between the impedance measurement electrodes of the neural interface device described herein by at least one impedance measurement module operably connected to the impedance measurement electrodes.

[0011] In some embodiments, with respect to the aspects discussed above, the controller may be arranged to adjust the electrical signal based on the measured impedance without determining the amplitude of the action potential induced in the nerve. Instead, the expected (predetermined) indication of the correlation between the downstream effect of the compound action potential or dose response and the impedance is determined by the controller instead. For example, the controller may access a data table including the correlation data between the measured impedance (or indication of the impedance) value and the dose response (which may include various physiological responses), and based on the correlation data, the controller may determine the expected impedance value for the target dose response. Based on this, the stimulation electrical signal may be adjusted to meet the target dose response. Various other correlation data may be predetermined (or / and in some cases, the correlation data may be collected during use or installation of the system) for use in a similar manner. In other examples, in addition to or instead of using a table, other established relationship definitions (e.g., functions) may be used to determine the correlation, and thereby adjust the electrical signal based on the measured impedance. These are merely examples, and other methods that utilize the relationship between different elements may be used to determine the change in the stimulation signal to achieve the target dose response, target amplitude, or downstream effect of the applied electrical signal.

[0012] In other words, impedance is used to infer the recruitment of compound action potentials caused by the stimulation electrical signal. Downstream effects are associated with compound action potential activity. Therefore, impedance is used to infer downstream effects associated with compound action potential activity. This inferred downstream effect can be quantified, and the stimulation electrical signal can be adjusted based on the relative change in the quantified indicated downstream effect in order to induce an action potential with a desired (or target) downstream effect or a target dose response.

[0013] Thus, the controller need not determine the amplitude of the induced action potential, but instead determines an indication of the downstream effect caused by its action potential (e.g., splenic artery flow, mean arterial blood pressure, heart rate). Given the correlation between the downstream effect and the measured impedance, the electrical signal can also be adjusted to induce the desired downstream effect.

[0014] In other words, an electrical dose response system is provided for monitoring a dose response and adjusting an electrical signal to meet a target dose response, which may include inducing an action potential having a target amplitude or a downstream effect caused by an action potential having a target amplitude.

[0015] Measurement of electrical dose response may include response to a sequence of electrical pulses of increasing charge (e.g., stimulating electrical signals) applied in a fixed intermittent manner consisting of ON and OFF phases, wherein the ON phase may include a fixed number of stimulation pulses at a fixed stimulation frequency, and wherein the OFF phase may include no stimulation pulses for a fixed duration or a subthreshold pulse sequence known not to elicit a physiological response that allows the neurovascular bundle to return to baseline.

[0016] The impedance measurement module may be configured to measure a relative change in impedance in response to an applied dose of an electrical signal comprising a stimulation pulse train, wherein the relative change in impedance is a change in impedance relative to a baseline impedance prior to application of the electrical signal.

[0017] Thus, the impedance measurement module can measure real-time changes in impedance due to an applied dose comprising a stimulation pulse sequence.

[0018] The relative change in impedance relative to baseline may represent a measure of the response resulting from local activation of neural fascicles resulting from the applied dose, wherein such local neural activation is an indirect measure of desired target engagement for neuromodulation therapy.

[0019] Impedance measurements, as a representative measure of the response to an applied dose, are at least proportionally related to such dose. Thus, a means can be provided to quantify the relative response to any applied dose of fixed magnitude by increasing the magnitude of the dose and measuring the resulting change in impedance for each dose in real time to produce a complete dose-response curve.

[0020] A complete dose-response may include a response to a train of electrical pulses of increasing charge applied in a fixed intermittent pattern consisting of ON and OFF phases, wherein the ON phase may include a fixed number of stimulation pulses at a fixed stimulation frequency, and wherein the OFF phase may include a fixed duration with no stimulation pulses or a subthreshold pulse train known not to elicit a physiological response that allows the target to return to baseline.

[0021] Access resistance and polarization capacitance as components included in the impedance can be directly measured from the differential voltage induced across the stimulation electrodes.

[0022] The electrode-tissue interface access resistance can be extracted from the voltage at the rising (or leading) edge of the stimulation pulse.

[0023] The polarization capacitance of the electrode-tissue interface can be extracted from the difference between the peak electrode voltage at the falling (or trailing) edge and the rising edge of the stimulation pulse.

[0024] Access resistance is strongly correlated with local activation of the neurovascular bundle beneath the electrode.

[0025] Impedance can also be extracted from the differential voltage measured across the stimulation electrodes while applying a subthreshold pulse train between two dose pulses.

[0026] Therefore, real-time changes in impedance measured across multiple stimulation electrodes can be used to assess dose response.

[0027] Impedance changes can be measured by extracting real-time changes in access resistance and / or polarization capacitance directly from the compliance voltage across multiple stimulation electrodes during stimulation pulses.

[0028] Impedance changes can be measured by detecting the impedance of a subthreshold signal injected between stimulation pulses across multiple stimulation electrodes.

[0029] The dose response can be determined from real-time changes in impedance, wherein the change in impedance is correlated with changes in arterial blood flow during the applied dose, wherein the change in impedance is correlated with changes in blood pressure during the applied dose, wherein the change in impedance is correlated with changes in heart rate during the applied dose, and wherein the change in impedance is correlated with changes in respiratory rate during the applied dose.

[0030] The dose response determined using impedance response measurements can be correlated to changes in blood flow, blood pressure, heart rate, respiratory rate, or other physiological variables, where the correlation is deterministic and repeatable to assess the effectiveness of electrical neuromodulation, where the measurements are used to titrate therapy over time, where the measurements are used as a diagnostic long-term tool, and where the measurements are used to assess the intraoperative effectiveness of electrical neuromodulation.

[0031] Although some of the above aspects relate to stimulation electrodes and impedance measurement electrodes, a single pair of electrodes may also be configured to function as both stimulation electrodes and impedance measurement electrodes. In other words, it is not necessary to use two separate pairs of electrodes so that each pair is used for stimulation and impedance measurement, respectively. In other words, a single pair of electrodes may be configured to function as both a stimulation electrode pair and an impedance measurement electrode pair.

[0032] Measuring impedance mentioned throughout the specification includes directly and indirectly measuring impedance. For example, measuring impedance can include measuring impedance indicating parameters and / or impedance components, such as voltage and / or current. Various examples are provided throughout the specification.

[0033] Thus, according to some aspects, a number of different methods of measuring (or assessing) impedance have been discussed above. In one method, the impedance is measured by establishing a voltage at the electrode during the stimulation period (TPW) and dividing it by the current amplitude ( ) to assess impedance. In another approach, impedance is measured by injecting subthreshold currents between stimulation pulses, where impedance is assessed by measuring the voltage generated across the electrodes and dividing it by the subthreshold current amplitude. The subthreshold waveform can be a sine wave or can be a square wave pulse with an amplitude below that required to induce neural activation. In another approach, impedance is assessed by simply measuring the polarization capacitance (ΔV) of the impedance change caused by the stimulation pulses and / or subthreshold stimulation. C ) or access resistance (ΔV R ) to measure impedance.

[0034] Measuring impedance using a subthreshold signal as described in the various embodiments above enables impedance measurement regardless of the stimulation state without causing any physiological response in the subject. In other words, using a subthreshold signal enables dose response monitoring without causing any physiological response in the subject. Therefore, constant and / or uninterrupted impedance measurement or dose response monitoring can be performed.

[0035] Subthreshold frequencies do not induce any action potentials. The frequency of such subthreshold frequencies can be between 100 Hz-5 kHz, and the amplitude of such subthreshold frequencies can be between, for example, 10 μA-6 mA or 10 μA-2 mA (but these ranges can vary depending on the sensitivity of the system / electrode). BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Embodiments of the present invention will be described by way of example with reference to the following drawings, in which:

[0037] Figure 1 A neural interface device is shown;

[0038] Figure 2A showing a cross section of a neural interface device mounted on a blood vessel in a non-contracted state;

[0039] Figure 2B showing a cross section of a neural interface device mounted on a blood vessel in a non-contracted state;

[0040] Figure 3A A graph illustrating the correlation of blood flow in the splenic artery with evoked compound action potentials (eCAPs) in the nerve is shown;

[0041] Figure 3B Graphs showing the effects of porcine splenic plexus stimulation on impedance, Rinf (circles), splenic artery flow (squares), mean arterial blood pressure (diamonds), heart rate (asterisks), and eCAP (half-solid diamonds) after 1 minute of 0.4 ms biphasic stimulation at 10 Hz;

[0042] Figure 3CGraphs showing the effects of porcine splenic plexus stimulation on subthreshold impedance, |Z| (circles), splenic artery flow (squares), mean arterial blood pressure (diamonds), and heart rate (asterisks) after 1 minute of 0.4 ms biphasic stimulation at 10 Hz;

[0043] Figure 4 A neural stimulation and impedance measurement system is shown;

[0044] Figure 5 Another neural stimulation and impedance measurement system is shown;

[0045] Figure 6 is a graphical representation of waveforms used to stimulate and assess dose response via impedance measurement following injection of a subthreshold current (sinusoidal carrier);

[0046] Figure 7 is another illustration of waveforms used to stimulate and assess dose response via impedance measurement after injection of subthreshold current (pulse); and

[0047] Figure 8 A wider system including a neural stimulation system is shown. DETAILED DESCRIPTION

[0048] The present disclosure relates to applying an electrical signal to a nerve (eg, a nerve supplying the spleen) and thereby modulating neural activity of the nerve (eg, a nerve supplying the spleen), wherein the nerve is associated with a neurovascular bundle. The nerve may be a splenic artery nerve.

[0049] Other embodiments involve applying an electrical signal to at least one of the splenic artery nerves and the splenic artery. In other embodiments, the invention may involve applying an electrical signal to all of the splenic artery nerves and the splenic artery.

[0050] The neural interface device disclosed herein includes a stimulation electrode pair and a separate impedance measurement electrode pair. The stimulation electrodes are longitudinally positioned relative to each other so as to induce a differential voltage along the nerve and thereby induce actuation of the nerve. As described in the Summary of the Invention section, in some examples, the stimulation electrodes and the impedance measurement electrodes are not provided as separate electrode pairs. Therefore, in some examples, the same electrode pair can be used as both a stimulation electrode and an impedance measurement electrode.

[0051] In one embodiment, the impedance measurement electrodes are positioned perpendicular to the longitudinal direction of the nerve. This ensures that the stimulation potential appears as a common mode signal in the measurement made between the impedance measurement electrode pair.

[0052] refer to Figure 1 and 4, the neural interface device 10 comprises an electrode arrangement 15. The electrode arrangement 15 is configured to be placed on or around a nerve when the neural interface device 10 is in use. The electrode arrangement 15 comprises a pair of stimulation electrodes 11, 12 which are spaced apart from each other so as to define a first gap between each of the stimulation electrodes 11, 12, wherein the first gap is positioned along the longitudinal axis LL of the nerve (i.e., in the direction of the longitudinal axis of the nerve). In addition, Figure 1 The electrode arrangement 15 comprises an impedance measuring electrode pair 13, 14, which is separated by a second gap between each of the impedance measuring electrodes 13, 14. The second gap is positioned along an axis perpendicular to the longitudinal axis LL of the nerve. In this example, the impedance measuring electrodes 13, 14 are located between the stimulation electrodes 11, 12. However, in alternative embodiments, the impedance measuring electrode pair 13, 14 can also be placed at a position away from or close to the two electrodes in the stimulation electrode pair 11, 12. In another example, the impedance measuring electrodes 13, 14 are located outside the stimulation electrodes 11, 12, in other words, not between the stimulation electrodes 11, 12. In one embodiment, the impedance electrode 13 is located outside the stimulation electrode 11, and the impedance electrode 14 is located outside the stimulation electrode 12. The impedance measuring electrodes 13 and 14 may partially surround the nerve or may completely surround the nerve. In an embodiment in which the impedance measuring electrodes 13 and 14 completely surround the nerve, the second gap is positioned along an axis parallel to the longitudinal axis LL of the nerve.

[0053] The neural interface device 10 according to the present disclosure is a device that is in physical contact with a nerve. When an electrical signal is applied to the nerve via the neural interface device 10, the neural interface device 10 causes stimulation of neural activity in the nerve, for example in a human or animal subject.

[0054] The first electrode 11 and the second electrode 12 are preferably cuff-type electrodes (eg, spiral cuffs, helical cuffs, or flat interfaces) that at least partially surround the nerve. Figure 1 The first electrode 11 and the second electrode 12 shown in the figure are flat interface cuff electrodes that completely surround the nerve. However, other types of electrodes known in the art are also suitable for use in the electrode device 15. For example, one or more of a flat interface electrode, a mesh electrode, a linear rod lead electrode, a paddle lead electrode, a disk contact electrode, a hook electrode, a sling electrode, an intrafascicular electrode, an intravascular electrode, a glass suction electrode, a paddle electrode, and a percutaneous cylindrical electrode can be used.

[0055] The first electrode 11 and the second electrode 12 can be made of a high charge capacity material, or partially or completely coated with a high charge capacity material, such as platinum black, iridium oxide, titanium nitride, tantalum, poly(ethylenedioxythiophene), poly(3,4-ethylenedioxythiophene): p-toluenesulfonate (PEDOT:PTS or PEDT) and suitable combinations thereof, such as platinum-iridium alloy.

[0056] Referring to Figure 3, it has been determined from in vivo experiments that blood flow in the splenic artery correlates with evoked compound action potentials (eCAPs). The devices, systems, and methods described herein provide a technique for measuring blood flow or vasoconstriction during stimulation and using it as a surrogate marker for evoked action potentials. This biomarker can be used to ensure that the correct level of action potentials is induced in the nerve and that effective treatment is delivered to the patient.

[0057] Figure 3B Graphs showing the effect of porcine splenic plexus stimulation on impedance (access resistance), splenic artery flow, mean arterial blood pressure, heart rate, and eCAP. Impedance was calculated from the rising phase of the voltage trace from each stimulation pulse. The change in impedance (access resistance) for a given stimulus was calculated with reference to the baseline resistance before the 1 mA stimulus. Figure 3B It can be seen that the measured impedance provides a dose-dependent response similar to other biomarkers of splenic nerve activation, including blood flow, mean arterial blood pressure, heart rate, and eCAP within the splenic nerve.

[0058] Figure 3C Graphs showing the effect of porcine splenic plexus stimulation on impedance (|Z|), splenic artery flow, mean arterial blood pressure, and heart rate. Impedance was calculated from the voltage envelope of a subthreshold (e.g., 0.5-2 mA at 500 Hz) sinusoidal carrier that was delivered continuously across the stimulation electrodes in conjunction with suprathreshold stimulation. The impedance change for a given stimulus was calculated with reference to the baseline resistance before 1 mA stimulation.

[0059] therefore, Figure 3B and 3C It was shown that impedance change measurements (likely a result of vasoconstriction) provided dose-response feedback and correlated strongly with other biomarkers of splenic nerve activation, including decreases in blood flow and increases in mean arterial blood pressure, heart rate, and eCAP within the splenic nerve.

[0060] Figure 3B and 3C The data were obtained using the following materials and methods:

[0061] Animals were sedated with ketamine and midazolam administered by intramuscular injection. An intravenous catheter was placed in one ear vein, and anesthesia was induced by intravenous administration of propofol.

[0062] The surgical approach to SpN cuff implantation includes the following steps: The spleen is removed and the splenic artery (SpA) is identified along its visceral surface. In the middle of the spleen, close to where the SpA branches into the left gastrointestinal artery, a small segment of the SpA is carefully dissected to remove surrounding soft tissue for placement of a 2 mm ultrasound flow probe. After placement of the probe, the spleen is repositioned into the abdomen. The cuff is placed around the SpA and the intact periarterial SpN network. Tension on the spleen and artery is then released. SpA and SpV (splenic vein) blood flow readings are tested.

[0063] Electrophysiological experiments were also performed. These usually required dissection and cuffing (using 500-600 μm diameter bipolar or tripolar CorTec cuffs) of one or a few discrete SpN bundles a few centimeters away from the stimulation cuff (closer to the spleen) to enable recording of evoked compound action potentials (eCAPs) during stimulation of the entire SpN plexus or a few bundles. In addition, different combinations of blocking neural signaling upstream or downstream of the stimulation site were performed (e.g., using local application of local anesthesia, or transection of the SpN bundle).

[0064] The recorded eCAPs were amplified and filtered (10–1000 Hz) using an 1800 2-channel microelectrode AC amplifier (AM Systems). Neural activity was continuously monitored using an oscilloscope and recorded into a computer using a sampling rate of 15–20 kHz. The eCAPs were typically averaged (8 pulses) and the peak-to-peak or area under the mean response curve (AUC) was quantified. The conduction velocity of the eCAP component of the SpN was calculated from the distance between the stimulation and recording sites and the latency of the eCAP signal.

[0065] Electrocardiogram (ECG), heart rate (HR), arterial blood pressure, respiratory rate (RR), pulse oximetry, capnography, spirometry, and splenic artery blood flow were monitored throughout the procedure. Body temperature was continuously recorded with an intranasal probe. Arterial blood gases were analyzed throughout the experiment to monitor pH, glucose, pO2 and pCO2, K+ levels. All physiological parameters were recorded on recording sheets as well as the level of sevoflurane used (every 5-10 minutes). Physiological data were also digitized. All parameters were typically sampled at a frequency between 0.1 and 2 kHz.

[0066] Constant current stimulation was delivered by a DS5 isolated bipolar current stimulator (digitizer) driven by a Powerlab voltage output channel. Symmetrical bipolar square pulses of 0.4 milliseconds were delivered at 10Hz for 1 minute. A sampling rate of 250kHz was used to digitize the voltage across the output neural implant. A sampling rate of 10-20kHz was used to digitize the current delivered by DS5. The electrode-tissue interface access resistance was extracted from the voltage trace at the rising (or leading) edge of the stimulation pulse, and changes from the baseline were monitored for each stimulation current. In some cases, a subthreshold constant current sinusoidal (500Hz) carrier waveform of 0.5-2mA was continuously delivered across the stimulation electrode before, during, and after the supramaximal square wave stimulation performed at 10Hz as described above. The carrier was generated with Analog Discovery 2 (Digilent) and converted into current with a model 2200 analog excitation isolator (AM system). The voltage envelope of the subthreshold carrier was digitized and changed from the baseline monitored for each stimulation current. Voltage, current, and envelope voltage were digitized.

[0067] In this embodiment, a current is injected between the stimulation electrodes during stimulation of the nerve. The stimulation can be provided by a voltage or current source 60 operably connected to each of the stimulation electrodes of each neural interface device. The voltage or current source is configured to generate an electrical signal to be applied to the nerve via the stimulation electrode. In addition, the system includes an impedance measurement module 70 operably connected to each pair of impedance measurement electrodes. The impedance measurement module 70 is configured to measure the impedance between the pair of impedance measurement electrodes 13, 14. The system also includes a controller 80, which is configured to receive the impedance measurement results from the impedance measurement module 70 and control the stimulation signal provided by the voltage or current source 60 based on the impedance measurement results.

[0068] The impedance measurement current can be an AC current below the actuation threshold of the nerve (i.e., subthreshold stimulation, including amplitudes that induce actuation in the nerve). In addition, the stimulation current can be at a different frequency than the current injected between the impedance measurement electrodes. Most stimulation artifacts appear as common-mode signals across the impedance measurement electrodes and can be rejected by the impedance measurement circuit. Blanking (e.g., by using a blanking circuit) can also be used to minimize or block stimulation artifacts.

[0069] Stimulation through vasculature constriction can cause blood vessels (e.g., the splenic artery) to Figure 2A The non-contracted state shown in Figure 2BThe contraction state shown in . This results in a change in the blood flow rate in the vessel. In addition, this contraction changes the current path between the impedance measuring electrodes and results in a decrease in impedance. The level of impedance reduction can be related to the amount of stimulation introduced into the splenic artery, for example via a lookup table or by an established transfer function. In this way, the dose of stimulation applied to the nerve can be determined. Therefore, the stimulation provided can be adjusted so as to achieve a specific target dose.

[0070] refer to Figure 4 , a voltage or current source 60 provides stimulation to the nerve, and an impedance measurement module 70 measures the impedance between the electrode pairs 13 and 14. The voltage or current source 60 is controlled to provide a stimulation signal corresponding to a specific target dose. For example, the signal may have a specific amplitude, duration, or pattern to provide a target dose. The impedance measurement module 70 measures the impedance and outputs the impedance value to the controller 80. As described above, the impedance value is related to the blood flow to determine the actual level of the action potential induced in the nerve. Therefore, the controller 80 can be configured to determine whether the stimulation provided by the voltage or current source 60 meets the target action potential or target dose. If the target is met, the controller 80 maintains the level of the stimulation provided. However, if the target is not met, the controller can appropriately increase or decrease the stimulation level to meet the target. This can be an iterative process using a feedback loop provided by the controller 80, the voltage / current source 60, and the impedance measurement module.

[0071] exist Figure 5 In another embodiment shown, the neural interface device 10 does not use the impedance measurement electrodes 13, 14, or the neural interface device is not provided with these electrodes 13, 14. In this embodiment, the stimulation electrodes 11, 12 are used for impedance measurement, and the stimulation current is provided by the voltage / current source 90. This is an exemplary embodiment in which a single pair of electrodes is used as both stimulation electrodes and impedance measurement electrodes. In some embodiments, the subject's body (or the body of the implant, CAN) is used as an electrode. In other words, a monopolar stimulation can be provided between either of the two electrodes 11 or 12 and the CAN, wherein the impedance is sensed across the two internal electrodes 11 and 12. In another embodiment, the subject's body (or the body of the implant, CAN) is used as an electrode so that a monopolar stimulation can be provided between either of the two electrodes 11 or 12 and the CAN, wherein the impedance is sensed across the remaining unused electrodes 11 or 12 and the CAN.

[0072] In this embodiment, the ratio of the compliance voltage to the stimulation current changes during stimulation. The compliance voltage is defined as the voltage required to provide the desired current for a given load impedance, where the load is a combination of the biological impedance and the electrode impedance. The level of the compliance voltage indicates the impedance of the electrodes 11, 12 plus the impedance of the artery. Due to the contraction of the artery during stimulation, the impedance will change along the artery due to the reduced cross-section of the current path. This can be related to the amount of stimulation current. The ratio of the compliance voltage to the subthreshold stimulation also changes during subthreshold stimulation. Therefore, the ratio of the compliance voltage to the subthreshold stimulation (AC current or pulse) can also be used as an indication of the impedance of the electrodes 11, 12 plus the arterial impedance.

[0073] In this embodiment, the voltage / current source 90 can provide stimulation, measure impedance, and adjust the stimulation signal based on the measured impedance. This can occur in a similar manner as explained above with reference to the voltage / current source 60, the impedance measurement module 70, and the controller 80.

[0074] The electrical signal applied to the nerve in the above-described system is ideally non-destructive. As used herein, a "non-destructive signal" refers to a signal that, when applied, does not irreversibly impair the basic neural signaling capability of the nerve. That is, application of the non-destructive signal maintains the ability of the nerve, or its fibers or other neural tissue to which the signal is applied, to conduct action potentials when application of the signal ceases, even if such conduction is actually artificially stimulated by application of the non-destructive signal.

[0075] Stimulation of neural activity of a nerve can be achieved using an electrical signal that is used to replicate the normal neural activity of the nerve (i.e., action potential). Thus, the electrical signal can be a pulse train that includes a plurality of pulses (e.g., the stimulation pulses can have a frequency of 1-10 Hz and an amplitude of 1-30 mA, 1-16 mA, these ranges can vary depending on the sensitivity of the system). The number of pulses per second in the pulse train is set by the frequency, and the duration of the pulses within each phase is determined by the pulse width. Thus, the pulse width refers to the width (or time duration) of the main phase of the waveform. In the case where the pulse includes a first phase as the main phase and a second phase (e.g., an anodic and / or cathodic phase) as a recovery phase, the pulse width refers to the width (or duration) of the first phase.

[0076] Although a square waveform is preferred for the stimulation pulse, the pulse may also have a square, sawtooth, sinusoidal, triangular, trapezoidal, or quasi-rhombus waveform.Other complex waveforms similar to that of an action potential are also suitable for the present disclosure.

[0077] The pulses may be biphasic pulses. The term "biphasic" refers to an electrical signal that causes each electrode in the electrode arrangement 15 to be positively and negatively charged over time. The biphasic pulses may be charge balanced. The term "charge balanced" in relation to a pulse train refers to the equal positive and negative charges applied by the signal over the duration of the pulse.

[0078] Each pulse may have a pulse width between 0.05 ms and 2.0 ms, and the current of the signal provided may be between 100 µA-50 mA, such as 10 mA, 30 mA. Subthreshold stimulation may have a current of <2 mA. In particular, the pulse may have a pulse width of at least one of: 0.1 ms, 0.2 ms, 0.4 ms, 0.6 ms, 0.8 ms, 1 ms, 1.2 ms, 1.4 ms, 1.6 ms, 1.8 ms, and 2 ms.

[0079] refer to Figure 5 , the neural interface device 10 and the voltage or current source 60, the neural stimulation system 50 may include one or more of the following components: a microprocessor 113; an implantable transceiver 110; a physiological sensor 111; a power source 112; a memory 114 (also referred to as a non-transitory computer-readable storage device); and a physiological data processing module 115.

[0080] The implantable device 106 may include one or more of the following components: a voltage or current source 60 90 , an impedance measurement module 70 , a controller 80 , a power source 112 ; a memory 114 ; a microprocessor 113 and a physiological data processing module 115 .

[0081] The microprocessor 113 may be responsible for triggering the start and / or end of the electrical signal to be applied to the nerve. Optionally, the microprocessor 113 may also be responsible for generating and / or controlling signal parameters, including pulse width.

[0082] The microprocessor 113 can be configured to operate in an open loop manner, where a predefined signal (e.g., as described above) is applied to the nerve at a given period (or continuously) and for a given duration (or indefinitely), with or without an external trigger, and without any control or feedback mechanism. Alternatively, the microprocessor 113 can be configured to operate in a closed loop manner, where the electrical signal is applied based on a control or feedback mechanism. As described elsewhere herein, the external trigger can be an external controller 101 that can be operated by an operator to initiate the application of the electrical signal.

[0083] The microprocessor 113 may be configured to generate, in use, a preconfigured and / or operator-selectable signal that is independent of any input. Alternatively, the microprocessor 113 may be responsive to an external signal, such as information (e.g., data) about one or more physiological parameters of a subject in which the neurostimulation system 50 is implanted.

[0084] Microprocessor 113 may be triggered upon receiving a signal generated by an operator (e.g., a physician) or a subject in which neurostimulation system 50 is implanted. To this end, neurostimulation system 50 may be part of a wider system 100 that additionally includes an external system 118 that includes controller 101. Examples of wider system 100 are described below.

[0085] The external system 118 of the wider system 100 is external to the neurostimulation system 50 and external to the subject and includes a controller 101. The controller 101 can be used to control the neurostimulation system 50 and / or to externally power it. To this end, the controller 101 may include a power supply unit 102 and / or a programming unit 103. The external system 118 may further include a power transmission antenna 104 and a data transmission antenna 105, as further described below.

[0086] The controller 101 and / or the microprocessor 113 may be configured to periodically or continuously apply electrical signals to the nerves. The periodic application of electrical signals may include (on-off) n The signal is applied in a mode where n>1. For example, the electrical signal may be applied continuously for a certain duration, before being stopped for a period of time, before being applied again continuously for a second duration, and so on.

[0087] The controller 101 and / or microprocessor 113 may apply the signal a certain amount of times per day. For example, the signal may be applied in bursts throughout the day.

[0088] The continuous application may continue indefinitely, for example permanently. Alternatively, the continuous application may continue for a minimum period of time, for example, the signal may be continuously applied for at least 5 days, or at least 7 days.

[0089] Regardless of whether the signal applied to the nerve is controlled by controller 101, or whether the signal is applied continuously directly by microprocessor 113, although the signal may be a series of pulses, the gaps between the pulses do not mean that the signal is not applied continuously.

[0090] The signal may be applied only when the subject is in a particular state, such as only when the subject is awake, only when the subject is asleep, before and / or after ingesting food, before and / or after the subject exercises, and the like.

[0091] The timing for stimulating neural activity in a nerve may be achieved using controller 101 .

[0092] The power source 112 may include a current source and / or a voltage source for powering the current or voltage source 50. The power source 112 may also power the implantable device 106 and / or other components of the neural stimulation system 50, such as the microprocessor 113, the memory 114, and the implantable transceiver 110. The power source 112 may include a battery, which may be rechargeable.

[0093] It should be appreciated that the availability of power is limited in implantable devices, and the present invention has been designed with this constraint in mind.The implantable device 106 and / or the neural stimulation system 50 may be powered by an inductively powered or rechargeable power source.

[0094] The memory 114 may store power data and data relating to one or more physiological parameters from the internal neurostimulation system 50. For example, the memory 114 may store data relating to one or more signals indicative of one or more physiological parameters detected by the physiological sensor 111, and / or one or more corresponding physiological parameters determined via the physiological data processing module 115. Additionally or alternatively, the memory 114 may store power data and data relating to one or more physiological parameters from an external system 118 via the implantable transceiver 110. To this end, the implantable transceiver 110 may form part of a communication subsystem of the wider system 100, as discussed further below.

[0095] The physiological data processing module 115 is configured to process one or more signals indicative of one or more physiological parameters in the subject detected by the physiological sensor 111 to determine one or more corresponding physiological parameters. The physiological data processing module 115 can be configured to reduce the size of data related to the one or more physiological parameters for storage in the memory 114 and / or transmission to an external system via the implantable transceiver 110. The implantable transceiver 110 may include one or more antennas. The implantable transceiver 100 may use any suitable signaling process, such as RF, wireless, infrared, etc., for transmitting signals outside the body, such as to a wider system 100 of which the neurostimulation system 50 is a part.

[0096] Alternatively or in addition, the physiological data processing module 115 can be configured to process signals indicative of one or more physiological parameters and / or process the determined one or more physiological parameters to determine the progression of a disease in the subject. In this case, the neurostimulation system 50, and in particular the implantable device 106, will include the ability to calibrate and tune signal parameters based on the one or more physiological parameters of the subject and the determined progression of the subject's disease.

[0097] The physiological data processing module 115 and the at least one physiological sensor 111 may form a physiological sensor subsystem, also referred to herein as a detector, as part of the neural stimulation system 50, as part of the implantable device 106, or external to the system.

[0098] Physiological sensor 111 includes one or more sensors, each of which is configured to detect a signal indicative of one of the above one or more physiological parameters. For example, physiological sensor 110 is configured to: detect biomolecule concentration using electrical, RF or optical (visible, infrared) biochemical sensors; detect blood flow using intravascular or perivascular vessels in or around arteries; detect neural activity of nerves using electrical sensors; or a combination thereof.

[0099] The physiological parameters determined by the physiological data processing module 115 can be used to trigger the microprocessor 113 to apply an electrical signal to the nerve via the electrode device 15. Upon receiving the signal indicative of the physiological parameter received from the physiological sensor 111, the physiological data processor 115 can determine the subject's physiological parameters and the course of the disease by performing calculations according to techniques known in the art.

[0100] The memory 114 may store physiological data related to normal levels of one or more physiological parameters. The data may be specific to the subject in which the neurostimulation system 50 is implanted and collected from various tests known in the art. Upon receiving a signal indicative of a physiological parameter received from the physiological sensor 111, or otherwise periodically or upon request from the physiological sensor 111, the physiological data processor 115 may compare the physiological parameter determined from the signal received from the physiological sensor 111 with the data related to normal levels of the physiological parameter stored in the memory 114, and determine whether the received signal indicates a deficiency or excess of a particular physiological parameter, and therefore indicates the progression of a disease in the subject.

[0101] The neural stimulation system 50 can be configured such that if and when the physiological data processor 115 determines that the level of a physiological parameter is insufficient or too high, the physiological data processor 115 triggers the application of an electrical signal to the nerve via the electrode device 15 in a manner described elsewhere herein. For example, if a physiological parameter indicating a worsening of any physiological parameter and / or disease is determined, the physiological data processor 115 can trigger the application of an electrical signal that inhibits the secretion of the corresponding biochemical substance, as described elsewhere herein. The specific physiological parameters relevant to the present invention are described above. When one or more signals indicative of one or more of these physiological parameters are received by the physiological data processor 115, the electrical signal can be applied to the nerve via the electrode device 15.

[0102] The controller 101 may be configured to regulate the operation of the neural stimulation system 50. The data may be specific to the patient in whom the device is implanted. The controller 101 may also be configured to regulate the operation of the power source 112, the signal generator 60, and the processing elements 113, 115 and / or the neural interface element 10 in order to tune the electrical signal applied to the nerve via the electrode device 15.

[0103] Figure 6 and 7 Waveforms are shown for stimulation achieved simultaneously with dose response via impedance measurement, particularly with subthreshold current injected between stimulation pulses. Figure 6 In , the subthreshold waveform is a sine wave. Figure 7 In the , subthreshold waveform is a square wave pulse. As mentioned earlier, subthreshold stimulation waveforms are those waveforms with amplitudes below the threshold, which is the amplitude that induces neural activation. Impedance can also be derived from the stimulation pulse ΔV R The access resistance is extracted.

[0104] exist Figure 6 and 7 In the figure, the injected current waveform (lighter colors in the gray scale) and the resulting voltage waveform (darker colors in the gray scale) are shown in an overlapping manner. and The asymmetric square wave pulse is the stimulation pulse and has a ΔV C (which indicates polarization capacitance) and ΔV R The resulting voltage waveform (which indicates access resistance) represents the impedance change seen across the stimulation electrodes. The impedance change caused by the electrical dose can be measured by extracting the real-time changes in access resistance and / or polarization capacitance directly from the compliance voltage across the stimulation electrodes during the stimulation pulse. As shown in the figure, the impedance change caused by the applied electrical dose can also be measured by detecting the impedance of the subthreshold signal injected between stimulation pulses across the stimulation electrodes.

[0105] More specifically, in the case of injected subthreshold current, an impedance response occurs similar to those seen for the stimulus current and impedance response. That is, in response to the subthreshold pulse portion, an impedance response occurs, such as in Figure 6 and 7 As shown in Figure 2, overlapping subthreshold pulses.

[0106] Thus, a number of different methods of measuring (or evaluating) impedance have been discussed above. In one method, the impedance is measured by measuring the initial rise phase of the stimulation cycle (TPW) ΔV R During this time, a voltage is established at the electrode and divided by the current amplitude ( ) to assess impedance. In another approach, impedance is measured by injecting subthreshold currents between stimulation pulses, where impedance is assessed by measuring the voltage generated at the electrode (rise phase, peak, envelope, phase) and dividing it by the subthreshold current amplitude. The subthreshold waveform can be a sine wave or can be a square wave pulse with an amplitude below that of the induced neural activation. In another approach, impedance is measured by simply measuring the polarization capacitance (ΔV) of the impedance change caused by the stimulation pulses and / or subthreshold stimulation. C ) or access resistance (ΔV R ) to measure impedance.

[0107] Measuring impedance using a subthreshold signal as described in the various embodiments above enables impedance measurement regardless of the stimulation state without causing any physiological response in the subject. In other words, using a subthreshold signal enables dose response monitoring without causing any physiological response in the subject. Therefore, constant and / or uninterrupted impedance measurement or dose response monitoring can be performed.

[0108] In some embodiments, subthreshold signals and / or stimulation signals may be injected by using electrodes 12 and 11, and the same electrodes 12 and 11 may be used to measure impedance using any of the above methods. In other embodiments, subthreshold signals and / or stimulation signals may also be inserted using electrodes 12 and 11, and impedance may be measured using any of the above methods using different electrodes 13 and 14. When the measuring electrode is different from the stimulation electrode, any effects of current injection may be reduced and / or eliminated, thereby obtaining more accurate measurements at the measuring electrode.

[0109] Wider system

[0110] refer to Figure 8 , the neurostimulation device may be part of a wider system 100 that includes a number of subsystems, such as an external system 118. The external system 118 may be used to power and program the neurostimulation system 50 through the human skin and underlying tissue.

[0111] In addition to the controller 101, the external subsystem 118 may include one or more of the following: a power supply unit 102 for wirelessly recharging a battery of a power source 112 for powering the implantable device 106; and a programming unit 103 configured to communicate with the implantable transceiver 110. The programming unit 103 and the implantable transceiver 110 may form a communication subsystem. The power supply unit 102 may be housed together with the programming unit 103; alternatively, they may be housed in separate devices.

[0112] The external subsystem 118 may also include one or more of the following: a power transmission antenna 104; and a data transmission antenna 105. The power transmission antenna 104 may be configured to transmit an electromagnetic field at a low frequency (e.g., from 30 kHz to 10 MHz). The data transmission antenna 105 may be configured to transmit data for programming or reprogramming the implantable device 106, and may be used together with the power transmission antenna 104 to transmit an electromagnetic field at a high frequency (e.g., from 1 MHz to 10 GHz). During operation of the power transmission antenna 104, the temperature in the skin will not increase by more than 2 degrees Celsius over the surrounding tissue. At least one antenna of the implantable transceiver 110 may be configured to receive power from the external electromagnetic field generated by the power transmission antenna 104, which power may be used to charge the rechargeable battery of the power source 112.

[0113] The power transmitting antenna 104, the data transmitting antenna 105, and at least one antenna of the implantable transceiver 110 have certain characteristics, such as resonant frequency and quality factor (Q). One implementation of the (one or more) antennas is a coil with or without a ferrite core that forms an inductor with a defined inductance. The inductor can be coupled with a resonant capacitor and a resistive loss to form a resonant circuit. The frequency is set to match the frequency of the electromagnetic field generated by the power transmitting antenna 105. The second antenna of the at least one antenna of the implantable transceiver 110 can be used in the neural stimulation system 50 for data reception and transmission from / to the external system 118. If more than one antenna is used in the neural stimulation system 50, the antennas are rotated 30 degrees with respect to each other to achieve a better degree of power transfer efficiency during slight misalignment with the power transmitting antenna 104.

[0114] The external system 118 may include one or more external body-worn physiological sensors 121 (not shown) to detect signals indicative of one or more physiological parameters. The signals may be transmitted to the neurostimulation system 50 via at least one antenna of the implantable transceiver 110. Alternatively or in addition, the signals may be transmitted to the external neurostimulation system 50 via at least one antenna of the implantable transceiver 110 and then to the neurostimulation system 50. As with the signals indicative of one or more physiological parameters detected by the implanted physiological sensors 111, the signals indicative of one or more physiological parameters detected by the external sensors 121 may be processed by the physiological data processing module 115 to determine the one or more physiological parameters, and / or stored in the memory 114 to operate the neurostimulation system 50 in a closed-loop manner. In addition to or as an alternative to the physiological parameters determined via the signals received from the implanted physiological sensors 111, the physiological parameters of the subject determined via the signals received from the external sensors 121 may also be used.

[0115] The wider system 100 may include safety precautions that interrupt electrical stimulation of the nerve in the following exemplary events: abnormal operation of the neurostimulation system 50 (e.g., overvoltage); abnormal readings from implanted physiological sensors 111 (e.g., temperature rise exceeding 2 degrees Celsius or excessively high or low electrical impedance at the electrode-tissue interface); abnormal readings from external body-worn physiological sensors 121 (not shown); or abnormal responses to stimulation detected by an operator (e.g., a physician or a subject). The safety precautions may be implemented via the controller 101 and communicated to the neurostimulation system 50, or implemented internally within the neurostimulation system 50.

[0116] The external system 118 may include an actuator 120 (not shown) which, when pressed by an operator (e.g., a physician or a subject), applies an electrical signal via the controller 101 and a corresponding communication subsystem to trigger the microprocessor 113 of the neural stimulation system 50 to apply an electrical signal to the nerve through the electrode device 15.

[0117] The broader system 100 of the present invention, and in particular the neurostimulation system 50, is preferably made of or coated with a material that is biostable and biocompatible. This means that the system is both protected from damage due to exposure to body tissue and that the risk of the system causing an adverse response to the host (which may ultimately lead to rejection) is minimized. The materials used to make or coat the system should ideally resist the formation of biofilms. Suitable materials include, but are not limited to, poly(p-xylene) polymers (known as parylene) and polytetrafluoroethylene.

[0118] Overview

[0119] The methods described herein can be performed by software in a machine-readable form on a tangible storage medium, such as in the form of a computer program, which includes a computer program code component, which is suitable for performing all steps of any method described herein when the program is run on a computer, and wherein the computer program can be implemented on a computer-readable medium. Examples of tangible (or non-transitory) storage media include disks, thumb drives, memory cards, etc., and do not include propagated signals. The software can be suitable for execution on a parallel processor or a serial processor, so that the method steps can be executed in any suitable order or simultaneously. This confirms that firmware and software can be valuable, separately tradable commodities. It is intended to include software that runs on or controls "non-intelligent" or standard hardware to perform desired functions. It is also intended to include software that "describes" or defines hardware configurations, such as HDL (hardware description language) software, such as for designing silicon chips or for configuring general-purpose programmable chips to perform desired functions.

[0120] Those skilled in the art will recognize that the storage devices used to store program instructions can be distributed across a network. For example, a remote computer can store examples of processes described as software. A local or terminal computer can access the remote computer and download some or all of the software to run the program. Alternatively, the local computer can download pieces of software as needed, or execute some software instructions at the local terminal and some software instructions at the remote computer (or computer network). Those skilled in the art will also recognize that all or part of the software instructions can be executed by dedicated circuits, such as DSPs, programmable logic arrays, etc., by utilizing conventional techniques known to those skilled in the art.

[0121] Unless otherwise stated, each embodiment described herein can be combined with another embodiment described herein. The terms "comprising" include "including" and "consisting of", for example, a composition "comprising" X can consist of only X or can include some additional substances, such as X+Y.

[0122] It should be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments. The embodiments are not limited to those that solve any or all of the problems described, or those that have any or all of the benefits and advantages described.

[0123] It should be understood that the above description of the preferred embodiment is given as an example only, and various modifications may be made by those skilled in the art. Although various embodiments have been described above with a certain degree of particularity or with reference to one or more separate embodiments, those skilled in the art may make many changes to the disclosed embodiments without departing from the scope of the present invention.

Claims

1. A system for stimulating a nerve and measuring impedance, the system comprising: a neural interface device comprising a plurality of electrodes for electrically contacting the nerve; a voltage or current source operably connected to at least a subset of the electrodes, wherein the voltage or current source is configured to generate an electrical signal to be applied to the subset of the electrodes; an impedance measurement module operably connected to at least a subset of the electrodes, wherein the impedance measurement module is configured to measure impedance between the subset of the electrodes; as well as A controller is arranged to determine, via the electrical signal, an amplitude of an action potential induced in the nerve based on the measured impedance, and to adjust the electrical signal so as to induce an action potential having a target amplitude.

2. The system according to claim 1, wherein: The voltage or current source is operably connected to the stimulation electrode pair.

3. The system according to claim 2, wherein: The impedance measurement module is operably connected to the impedance measurement electrode pair.

4. The system according to claim 3, wherein: The stimulation electrode pair is the same electrode pair as the impedance measurement electrode pair.

5. The system according to claim 1, wherein: The voltage or current source is configured to apply an electrical signal to the stimulation electrodes such that the first electrode becomes positively charged and the second electrode becomes negatively charged.

6. The system according to claim 1, wherein: At least one electrical signal comprises a pulse train comprising a plurality of pulses.

7. The system according to claim 1, wherein: The impedance measurement module is configured to measure a relative change in impedance across a plurality of electrodes in response to an applied dose of an electrical signal comprising a stimulation pulse sequence, wherein the relative change in impedance is a change in impedance relative to a baseline impedance prior to application of the electrical signal.

8. The system according to claim 1, wherein: The impedance measurement module is configured to measure impedance between the subset of the electrodes by measuring a differential voltage induced across the stimulation electrodes.

9. The system according to claim 1, wherein: The impedance measurement module is configured to measure a differential voltage across the stimulation electrodes while applying a subthreshold pulse train between two consecutive pulses of the stimulation pulse.

10. The system according to claim 1, wherein: The impedance measurement module is configured to measure a compliance voltage across a plurality of stimulation electrodes during a stimulation pulse.

11. A computer readable medium having stored thereon a computer program including code portions, which, when loaded and run on a computer device, cause the computer device to: generating the electrical signal; measuring the impedance; as well as The amplitude of an action potential induced in the nerve is determined via the electrical signal based on the measured impedance, and the electrical signal is adjusted so as to induce an action potential having a target amplitude.

12. A neural interface device for stimulating a nerve and measuring impedance, the device comprising: a pair of stimulating electrodes for inducing electrical signals in the nerves; as well as Impedance measuring electrode pair, used to measure the impedance between the impedance measuring electrodes, wherein the stimulation electrode pairs are spaced apart from each other in a longitudinal direction with respect to the nerve, and The impedance measuring electrode pairs are spaced apart from each other in a direction perpendicular to a longitudinal direction of the nerve.

13. The neural interface device of claim 12, further comprising at least one cuff portion having an assembly position, wherein the cuff portion forms at least a portion of a channel for receiving the nerve in a longitudinal direction of the nerve.

14. The neural interface device according to claim 12 or 13, wherein: The stimulation electrode pair includes a first conductive ring and a second conductive ring.

15. The neural interface device according to claim 12 or 13, wherein: The impedance measurement electrode pair includes a first conductive element and a second conductive element, wherein the first conductive element is diametrically opposed to the second conductive element.

16. The neural interface device according to claim 12 or 13, wherein: Each of the impedance electrodes is positioned between the pair of stimulation electrodes.

17. A computer readable medium having stored thereon a computer program comprising code portions which, when loaded and run on a computer device, cause the computer device to: generating an electrical signal to be applied to a nerve via a stimulation electrode of a neural interface device according to any one of claims 12 to 16 by at least one voltage or current source operably connected to the stimulation electrode; and The impedance between the impedance measurement electrodes of the neural interface device according to any one of claims 12 to 16 is measured by at least one impedance measurement module operatively connected to the impedance measurement electrodes.

18. A system for stimulating a nerve and measuring impedance, the system comprising: One or more neural interface devices according to any one of the preceding claims 12 to 16; a voltage or current source operably connected to each stimulation electrode pair of each neural interface device, wherein the voltage or current source is configured to generate an electrical signal to be applied to the nerve via the stimulation electrodes; as well as An impedance measurement module is operably connected to each impedance measurement electrode pair, wherein the impedance measurement module is configured to measure the impedance between the impedance measurement electrode pairs.

19. The system of claim 18, further comprising a controller arranged to determine, via the electrical signal, an amplitude of an action potential induced in the nerve based on the measured impedance, and to adjust the electrical signal so as to induce an action potential having a target amplitude.

20. The system of claim 18, wherein: The voltage or current source is configured to apply an electrical signal to the stimulation electrodes such that the first electrode becomes positively charged and the second electrode becomes negatively charged.

21. The system of claim 18, wherein: At least one electrical signal comprises a pulse train comprising a plurality of pulses.

22. The system of claim 21, wherein: The pulse has a waveform that is square, sawtooth, sinusoidal, triangular, trapezoidal, quasi-rhombus, or a composite waveform.

23. The system of claim 18, wherein: The impedance measurement module is configured to measure a relative change in impedance across a plurality of electrodes in response to an applied dose of an electrical signal comprising a stimulation pulse sequence, wherein the relative change in impedance is a change in impedance relative to a baseline impedance prior to application of the electrical signal.

24. The system of claim 18, wherein: The impedance measurement module is configured to measure impedance between a subset of the electrodes by measuring a differential voltage induced across the stimulation electrodes.

25. The system of claim 18, wherein: The impedance measurement module is configured to measure a differential voltage across the stimulation electrodes while applying a subthreshold pulse train between two consecutive pulses of the stimulation pulse.

26. The system of claim 18, wherein: The impedance measurement module is configured to measure a compliance voltage across a plurality of stimulation electrodes during a stimulation pulse.

27. A computer readable medium having stored thereon a computer program comprising code portions which, when loaded and run on a computer device, cause the computer device to: generating the electrical signal; and The impedance is measured.

28. A system for neural stimulation and for impedance-based monitoring of stimulation dose response, the system comprising: a neural interface device comprising a plurality of electrodes for electrically contacting the nerve; a voltage or current source operably connected to at least a subset of the electrodes, wherein the voltage or current source is configured to generate an electrical signal to be applied to the electrodes; an impedance measurement module operably connected to at least a subset of the electrodes, wherein the impedance measurement module is configured to measure impedance between the electrodes; and A controller is arranged to determine a dose response induced by the electrical signal based on the measured impedance and to adjust the electrical signal so as to induce a target dose response.

29. The system of claim 28, wherein: The voltage or current source is operably connected to the stimulation electrode pair.

30. The system of claim 29, wherein: The impedance measurement module is operably connected to the impedance measurement electrode pair.

31. The system of claim 30, wherein: The stimulation electrode pair is the same electrode pair as the impedance measurement electrode pair.

32. The system of claim 30, wherein: The stimulation electrode pairs are spaced apart from each other in a longitudinal direction with respect to the nerve; and The impedance measuring electrode pairs are spaced apart from each other in a direction perpendicular to a longitudinal direction of the nerve.

33. The system of claim 32, wherein: The impedance measurement electrode pair includes a first conductive element and a second conductive element, wherein the first conductive element is diametrically opposed to the second conductive element.

34. The system of claim 28, wherein: The impedance measurement module is configured to measure a relative change in impedance across a plurality of electrodes in response to an applied dose of an electrical signal comprising a stimulation pulse sequence, wherein the relative change in impedance is a change in impedance relative to a baseline impedance prior to application of the electrical signal.

35. The system of claim 28, wherein: The impedance measurement module is configured to measure impedance between the subset of the electrodes by measuring a differential voltage induced across the stimulation electrodes.

36. The system of claim 35, wherein: The impedance measurement module is configured to extract a voltage at a rising edge of a stimulation pulse to determine an indication of access resistance.

37. The system of claim 35, wherein: The impedance measurement module is configured to extract a difference between peak electrode voltages at falling and rising edges of a stimulation pulse to determine an indication of polarization capacitance.

38. The system of claim 28, wherein: The impedance measurement module is configured to measure a differential voltage across the stimulation electrodes while applying a subthreshold pulse train between two consecutive pulses of the stimulation pulse.

39. The system of claim 28, wherein: The impedance measurement module is configured to measure a compliance voltage across a plurality of stimulation electrodes during a stimulation pulse.

40. A computer readable medium having stored thereon a computer program comprising code portions which, when loaded and run on a computer device, cause the computer device to: generating the electrical signal; measuring the impedance; as well as A dose response induced by the electrical signal is determined based on the measured impedance, and the electrical signal is adjusted to induce a target dose response.

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