Improved feedback control of neural stimulation

Abstract

An implantable device for controllably delivering neural stimuli repeatedly delivers a probe stimulus according to a probe stimulus intensity; measures an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjusts, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determines a therapy stimulus intensity based on the adjusted probe stimulus intensity; and controls delivery of a therapy stimulus according to the adjusted therapy stimulus intensity. The target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

Description

IMPROVED FEEDBACK CONTROL OF NEURAL STIMULATION

[0001] The present application claims priority from Australian Provisional Patent Applications Nos. 2024902685 filed on 28 August 2024 and 2024903169 filed on 1 October 2024, the contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The present invention relates to neural stimulation and in particular to feedback control of neural stimulation using measurements of evoked action potentials.BACKGROUND OF THE INVENTION

[0003] There are a range of situations in which it is desirable to apply neural stimuli in order to alter neural function, a process known as neuromodulation. For example, neuromodulation is used to treat a variety of disorders including chronic pain, movement disorders, and voiding disorders. A neuromodulation device applies an electrical pulse (stimulus) to neural tissue (fibres, or neurons) in order to generate a therapeutic effect. In general, the electrical stimulus generated by a neuromodulation device evokes a neural response known as an action potential in a neural fibre which then has either an inhibitory or excitatory effects on neural networks. Inhibitory effects can be used to modulate an undesired process such as the transmission of pain, or excitatory effects may be used to cause a desired effect such as the contraction of a muscle.

[0004] When used to relieve neuropathic pain originating in the trunk and limbs, the electrical pulse is applied to the dorsal column (DC) of the spinal cord, a procedure referred to as spinal cord stimulation (SCS). Such a device typically comprises an implanted electrical pulse generator, and a power source such as a battery that may be transcutaneously rechargeable by wireless means, such as inductive transfer. An electrode array is connected to the pulse generator, and is implanted adjacent the target neural fibre(s) in the spinal cord, typically in the dorsal epidural space above the dorsal column. An electrical pulse of sufficient intensity applied to the target neural fibres by a stimulus electrode causes the depolarisation of neurons in the fibres, which in turn generates an action potential in the fibres. Action potentials propagate along the fibres in an orthodromic direction (in afferent fibres this means towards the head, or rostral) and in an antidromic direction (in afferent fibres this means towards the cauda, or caudal). Action potentials propagating along Ap (A-beta) fibres being stimulated in this way may inhibit the transmission of pain from a region of the body innervated by the target neural fibres (the dermatome) to the brain. To sustain the pain relief effects, stimuli are applied repeatedly, for example at a stimulus frequency in the range of 30 Hz - 100 Hz.

[0005] For effective and comfortable neuromodulation, it is necessary to maintain stimulus intensity above an activation threshold. Stimuli below the activation threshold will fail to recruit sufficientneurons to generate action potentials with a therapeutic effect. In some neuromodulation applications, response from a single class of fibre is desired, but the stimulus waveforms employed can evoke action potentials in other classes of fibres which cause unwanted side effects. In pain relief, it is therefore desirable to apply stimuli with intensity below a discomfort threshold, above which uncomfortable or painful percepts arise due to over-recruitment of Ap fibres or recruitment of undesired fibre classes. When recruitment is too large, Ap fibres produce uncomfortable sensations. Stimulation at high intensity may even recruit AS (A-delta) fibres, which are sensory nerve fibres associated with acute pain, cold and heat sensation. It is therefore desirable to maintain stimulus intensity within a therapeutic range between the activation threshold and the discomfort threshold.

[0006] The task of maintaining appropriate neural activation (or neural recruitment) is made more difficult by electrode migration (change in position over time) or postural changes of the implant recipient (patient), either of which can significantly alter the neural activation arising from a given stimulus, and therefore the therapeutic range. The spinal cord itself moves within the cerebrospinal fluid (CSF) with respect to the dura and the electrode array. During postural changes, the distance between the spinal cord and the electrode can change significantly. This effect is so large that postural changes alone can cause a previously comfortable and effective stimulus regime to become either ineffectual or painful.

[0007] Attempts have been made to address such problems by way of feedback or closed-loop control, such as using the methods set forth in International Patent Publication No. WO2012 / 155188 by the present applicant, the content of which is incorporated herein by reference. Feedback control seeks to compensate for relative nerve / electrode movement by controlling the intensity of the delivered stimuli to maintain neural activation at or near a target value. The intensity of a neural response evoked by a stimulus may be used as a feedback variable representative of the amount of neural activation. A signal representative of the neural response may be sensed by a measurement electrode in electrical communication with the recruited neural fibres, and processed to obtain the feedback variable. Based on the response intensity, the intensity of the applied stimulus may be adjusted to bring the response intensity closer to the target value.

[0008] It is therefore desirable to accurately measure the intensity and other characteristics of a neural response evoked by the stimulus. The action potentials generated by the depolarisation of a large number of fibres by a stimulus sum to form a measurable signal known as an evoked compound action potential (ECAP). Accordingly, an ECAP is the sum of responses from a large number of single fibre action potentials. The ECAP generated from the depolarisation of a group of similar fibres may be sensed by a measurement electrode as a positive peak potential, then a negative peak, followed by a second positive peak. This morphology is caused by the region of activation passing the measurementelectrode as the action potentials propagate along the individual fibres. Approaches proposed for obtaining a neural response measurement are described by the present applicant in International Patent Publication No. WO2012 / 155183, the content of which is incorporated herein by reference.

[0009] However, a feedback control algorithm that simply seeks to maintain the measured response intensity at or near a target value representative of pain relief will not generally maintain constant neural activation as posture changes. This is because a change in distance between the measurement electrode and the site of activation on the dorsal column, such as induced by posture change, affects the measured response intensity even if there is no change to the neural activation. In other words, an ECAP-controlled feedback loop maintains the ECAP amplitude at the measurement site, not at the activation site, which is where the neural activation actually needs to be maintained, and changes in posture cause these two sites to diverge. The result is that an ECAP-controlled feedback loop may adjust stimulus intensity in response to a posture-induced change in measured ECAP amplitude, even if there is no change to the neural activation.

[0010] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present Background is solely for the purpose of providing a context for the present technology. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present technology as it existed before the priority date of each claim of the present disclosure.SUMMARY OF THE INVENTION

[0011] The present invention seeks to provide a method of configuring or programming a sensing- enabled neural stimulation device which will overcome or substantially ameliorate at least some of the deficiencies of the prior art, or at least provide an alternative.

[0012] According to a first aspect of the present technology, there is provided an implantable device for controllably delivering neural stimuli. The device comprises: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit. The control unit is configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulusintensity. The target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

[0013] According to a second aspect of the present technology, there is provided an automated method of controllably delivering neural stimuli to a neural pathway of a patient. The method comprises: delivering a probe stimulus to the neural pathway of the patient, the probe stimulus being configured to evoke a neural response from the neural pathway, the probe stimulus being delivered according to a probe stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the probe stimulus; measuring an intensity of a neural response evoked by the probe stimulus in the signal window; adjusting the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determining a therapy stimulus intensity based on the adjusted probe stimulus intensity; and delivering a therapy stimulus according to the adjusted therapy stimulus intensity. The target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

[0014] According to a third aspect of the present technology, there is provided a neural stimulation system comprising an implantable device for controllably delivering neural stimuli, and a processor. The device comprises: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter. The processor is configured to: instruct the control unit to control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity. The target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

[0015] In some embodiments of the first to third aspects of the present technology, the target response intensity is configured to be close to a noise floor of the measurement circuitry. For example the target response intensity may be configured to be less than 1.5 times a noise floor, less than 1.25 times a noise floor or less than 1.1 times a noise floor of the measurement circuitry.

[0016] In some embodiments of the first to third aspects of the present technology, the control unit is configured to determine the therapy stimulus intensity by multiplying the adjusted probe stimulus intensity by the target dose metric. The control unit may be configured to divide the probe stimulus intensity by a probe dose ratio before determining the therapy stimulus intensity. The control unit may be configured to determine the therapy stimulus intensity by adding the probe stimulus intensity to the product of: the target dose metric minus one, and the probe stimulus intensity raised to the power of a predetermined exponent. The control unit may be configured to subtract a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent. The control unit may be configured to divide the probe stimulus intensity by a probe dose ratio before determining the therapy stimulus intensity. The control unit may be configured to subtract a base current from the ratio of the probe stimulus intensity to the probe dose ratio before the raising to the power of the predetermined exponent.

[0017] In some embodiments of the first to third aspects of the present technology, the control unit is configured to determine the therapy stimulus intensity by: estimating a dose metric from the therapy stimulus intensity; and adjusting, using a therapy feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near the target dose metric. The control unit may be configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the probe stimulus intensity; and the probe stimulus intensity raised to an exponent. The control unit may be configured to estimate the dose metric by determining a ratio of: the therapy stimulus intensity and the probe stimulus intensity. The control unit may be configured to divide the probe stimulus intensity by a probe dose ratio before estimating the dose metric.

[0018] According to a fourth aspect of the present technology, there is provided an implantable device for controllably delivering neural stimuli. The device comprises: a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

[0019] According to a fifth aspect of the present technology, there is provided an automated method of controllably delivering neural stimuli to a neural pathway of a patient. The method comprises: delivering a probe stimulus to the neural pathway of the patient, the probe stimulus being configured to evoke a neural response from the neural pathway, the probe stimulus being delivered according to a probe stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the probe stimulus; measuring an intensity of a neural response evoked by the probe stimulus in the signal window; adjusting the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimating a neural response threshold from the adjusted probe stimulus intensity; adjusting a therapy stimulus intensity based on the estimated neural response threshold; and delivering a therapy stimulus according to the adjusted therapy stimulus intensity.

[0020] According to a sixth aspect of the present technology, there is provided a neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, and a processor. The device comprises: a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; and measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter. The processor is configured to repeatedly: instruct the control unit to control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

[0021] In some embodiments of the fourth to sixth aspects of the present technology, the neural response threshold is the adjusted probe stimulus intensity. The control unit may be configured to estimate the neural response threshold by dividing the adjusted probe stimulus intensity by a probe dose metric. The control unit may be configured to adjust the therapy stimulus intensity by multiplying the estimated neural response threshold by a target dose metric.

[0022] In some embodiments of the fourth to sixth aspects of the present technology, the control unit may be configured to adjust the therapy stimulus intensity by adding the estimated neural responsethreshold to the product of: a target dose metric minus one, and the estimated neural response threshold raised to the power of a predetermined exponent. The control unit may be configured to subtract a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent.

[0023] In some embodiments of the fourth to sixth aspects of the present technology, the control unit is configured to determine the therapy stimulus intensity by: estimating a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjusting, using a therapy feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric. The control unit may be configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the estimated neural response threshold; and the estimated neural response threshold raised to an exponent. The control unit may be configured to estimate the dose metric by determining a ratio of the therapy stimulus intensity and the estimated neural response threshold.

[0024] According to a seventh aspect of the present technology, there is provided a multi-stimset closed-loop neural stimulation device comprising: a control unit configured to control a stimulus source to deliver probe stimuli according to a probe stimset interleaved with therapy stimuli according to a therapy stimset; and adjust, using a feedback controller, a probe stimulus intensity parameter of the probe stimuli so as to maintain a measured neural response intensity at or near a target response intensity. The target response intensity is configured such that the therapy stimuli are delivered at or near a target dose ratio as posture varies.

[0025] According to an eighth aspect of the present technology, there is provided a multi-stimset closed-loop neural stimulation device. The device comprises a control unit configured to: control a stimulus source to deliver probe stimuli according to a probe stimset interleaved with therapy stimuli according to a therapy stimset; adjust, using a feedback controller, a probe stimulus intensity parameter of the probe stimuli so as to maintain a measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity of the therapy stimuli based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

[0026] According to a ninth aspect of the present technology, there is provided a neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, and a processor. The device comprises: a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient in order to evoke neural responses from the neural pathway; measurement circuitry configured to capture signalwindows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity. The processor is configured to: increase the target response intensity; construct a distribution of probe stimulus intensities at each target response intensity; determine a transitional target response intensity at which the distribution achieves a consistently Gaussian form; and program the implantable device using the transitional target response intensity.

[0027] According to a tenth aspect of the present technology, there is provided an automated method of programming a multi-stimset closed-loop neural stimulation device. The method comprising: increasing a target response intensity value; constructing, for each value of target response intensity, a distribution of probe stimulus intensities; determining a transitional target response intensity at which the distribution achieves a consistently Gaussian form; and programming the multi-stimset closed-loop neural stimulation device using the transitional target response intensity.

[0028] According to an eleventh aspect of the present technology, there is provided an implantable device for controllably delivering neural stimuli. The device comprises: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit. The control unit is configured to repeatedly: control the stimulus source to deliver a therapy stimulus according to a therapy stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the therapy stimulus; estimate a neural response threshold of the neural pathway using the measured response intensity; estimate a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjust, using a feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

[0029] According to a twelfth aspect of the present technology, there is provided an automated method of controllably delivering neural stimuli to a neural pathway of a patient. The method comprises: delivering a therapy stimulus to the neural pathway of the patient, the therapy stimulus being configured to evoke a neural response from the neural pathway, the therapy stimulus beingdelivered according to a therapy stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the therapy stimulus; measure an intensity of an evoked neural response in the signal window; estimating a neural response threshold of the neural pathway using the measured response intensity; estimating a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjusting the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

[0030] According to a thirteenth aspect of the present technology, there is provided a neural stimulation system comprising an implantable device and a processor. The implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter. The processor configured to: instruct the control unit to control the stimulus source to deliver a therapy stimulus according to a therapy stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the therapy stimulus; estimate a neural response threshold of the neural pathway using the measured response intensity; estimate a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjust, using a feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

[0031] In some embodiments of the eleventh to thirteenth aspects of the present technology, the control unit is configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the estimated neural response threshold; and the estimated neural response threshold raised to an exponent.

[0032] In some embodiments of the eleventh to thirteenth aspects of the present technology, the control unit is configured to estimate the dose metric by determining a ratio of the therapy stimulus intensity and the estimated neural response threshold.

[0033] In some embodiments of the eleventh to thirteenth aspects of the present technology, the control unit is further configured to: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; and adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity. The control unit may be configured to estimate the neural response threshold as the adjusted probestimulus intensity. The control unit may be configured to estimate the neural response threshold by dividing the adjusted probe stimulus intensity by a probe dose ratio.

[0034] According to a fourteenth aspect of the present technology, there is provided a closed-loop neural stimulation device comprising a control unit configured to: control a stimulus source to deliver therapy stimuli; and adjust, using a feedback controller, a therapy stimulus intensity parameter of the therapy stimuli so as to maintain an estimated dose metric of the therapy stimuli at or near a target dose metric.

[0035] The present technology has been developed primarily for use in or with neurostimulation of the spinal cord and will be described hereinafter mostly with reference to this application. However, it will be appreciated that the present technology is not limited to this particular field of use, and may be applied in other neuromodulation contexts, including but not limited to sacral nerve stimulation, pudendal nerve stimulation, deep brain stimulation, stimulation of other parts of the peripheral and central nervous system. It will further be appreciated that the present technology may be applied for treatment of conditions other than pelvic floor disorders, including but not limited to chronic pain, movement disorders, Crohn’s disease, rheumatoid arthritis, diabetes, Reynaud’s phenomenon, chronic inflammatory conditions, migraine, stroke, or depression.BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Notwithstanding any other implementations which may fall within the scope of the present invention, one or more implementations of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0037] Fig. 1 schematically illustrates an implanted spinal cord stimulator, according to one implementation of the present technology;

[0038] Fig. 2 is a block diagram of the stimulator of Fig. 1;

[0039] Fig. 3 is a schematic illustrating interaction of the implanted stimulator of Fig. 1 with a bundle of target nerve fibres;

[0040] Fig. 4a illustrates an idealised activation plot for one posture of a patient undergoing neural stimulation;

[0041] Fig. 4b illustrates the variation in the activation plots with changing posture of the patient;

[0042] Fig. 5 is a schematic illustrating elements and inputs of a closed-loop neural stimulation (CLNS) system, according to one implementation of the present technology;

[0043] Fig. 6 illustrates the typical form of an electrically evoked compound action potential (ECAP) of a healthy subject;

[0044] Fig. 7 is a block diagram of a neural stimulation therapy system including the implanted stimulator of Fig. 1 according to one implementation of the present technology;

[0045] Fig. 8 is an illustration of the stimulus pulses delivered by a stimulation program with four interleaved stimulation sets (stimsets);

[0046] Fig. 9 is a schematic illustrating elements and inputs of a multi-stimset closed-loop neural stimulation (CLNS) system implementable by the electronics module of Fig. 2 and suitable for use during therapy;

[0047] Fig. 10 is a graph containing activation plots for a patient in a supine posture, a standing posture and a sitting posture, respectively;

[0048] Fig. 11 is a graph showing the ECAP threshold, the probe stimulus intensity, and the therapy stimulus intensity on a current activation plot;

[0049] Fig. 12 is a graph containing a fitted, piecewise linear activation plot in a reference posture, the resulting ECAP threshold, the target ECAP amplitude, and the probe stimulus intensity corresponding to the target ECAP amplitude;

[0050] Fig. 13 is a flow chart illustrating a method 1300 of controllably delivering neural stimuli according to an implementation of the present technology; and

[0051] Fig. 14 illustrates the evolution of the distribution of probe stimulus intensities that the feedback controller determines in order to maintain the response intensity at or near the target ECAP amplitude, as the target ECAP amplitude increases in relation to the measurement noise.DETAILED DESCRIPTION OF THE PRESENT TECHNOLOGY

[0052] Fig. 1 schematically illustrates an implanted spinal cord stimulator 100 in a patient 108, according to one implementation of the present technology. Stimulator 100 comprises an electronics module 110 housed within a conductive case, implanted at a suitable location. In one implementation, stimulator 100 is implanted in the patient’s lower abdominal area or posterior superior gluteal region. In other implementations, the electronics module 110 is implanted in other locations, such as in a flank or sub-clavicularly. The electronics module 110 is configured to electrically connect to an electrode assembly, typically comprising an electrode array 150 implanted within the epidural space and connected to the module 110 by a suitable lead. The electrode array 150 may comprise one or more electrodes such as electrode pads on a paddle lead, circular (e.g., ring) electrodes surrounding the body of a percutaneous lead, conformable electrodes, cuff electrodes, segmented electrodes, or any other type of electrodes capable of forming unipolar, bipolar or multipolar electrode configurations for stimulation and measurement. The electrodes may pierce or affix directly to the tissue itself.

[0053] Numerous aspects of the operation of implanted stimulator 100 may be programmable by an external computing device 192, which may be operable by a user such as a clinician or the patient 108. Moreover, implanted stimulator 100 serves a data gathering role, with gathered data beingcommunicated to external device 192 via a transcutaneous communications channel 190. Communications channel 190 may be active on a substantially continuous basis, at periodic intervals, at non-periodic intervals, or upon request from the external device 192. External device 192 may thus provide a clinical interface configured to program the implanted stimulator 100 and recover data stored on the implanted stimulator 100. This configuration is achieved by program instructions collectively referred to as the Clinical Programming Application (CPA) and stored in an instruction memory of the clinical interface.

[0054] Fig. 2 is a block diagram of the stimulator 100. Electronics module 110 contains a battery 112 and a telemetry module 114. In implementations of the present technology, any suitable type of transcutaneous communications channel 190, such as infrared (IR), radiofrequency (RF), capacitive or inductive transfer, may be used by telemetry module 114 to transfer power or data to and from the electronics module 110 via communications channel 190. Module controller 116 has an associated memory 118 storing one or more of clinical data 120, clinical settings 121, control programs 122, and the like. Controller 116 is configured by control programs 122, sometimes referred to as firmware, to control a pulse generator 124 to generate stimuli, such as in the form of electrical pulses, in accordance with the clinical settings 121. Electrode selection module 126 switches the generated pulses to the selected electrode(s) of electrode array 150, for delivery of the pulses to the tissue surrounding the selected electrode(s). Measurement circuitry 128, which may comprise an amplifier or an analog-to-digital converter (ADC), is configured to process signals comprising neural responses sensed by measurement electrode(s) of the electrode array 150 as selected by electrode selection module 126.

[0055] Fig. 3 is a schematic illustrating interaction of the implanted stimulator 100 with a bundle of target nerve fibres 180 in the patient 108. In the implementation illustrated in Fig. 3 the target fibres 180 may be located in the spinal cord, however in alternative implementations the stimulator 100 may be positioned adjacent any target neural tissue including a peripheral nerve, visceral nerve, sacral nerve, parasympathetic nerve, or a brain structure. Electrode selection module 126 selects a stimulus electrode 2 of electrode array 150 through which to deliver a pulse from the pulse generator 124 to surrounding neural tissue including target fibres 180. A pulse may comprise one or more phases, e.g. a monophasic pulse comprises one phase, and a biphasic stimulus pulse 160 comprises two phases. Electrode selection module 126 also selects a return electrode 4 of the electrode array 150 for stimulus current return in each phase, to maintain a zero net charge transfer. An electrode may act as both a stimulus electrode and a return electrode over a complete multiphasic stimulus pulse. The use of two electrodes in this manner for delivering and returning current in each stimulus phase is referred to as bipolar stimulation. Alternative implementations may apply other forms of bipolar stimulation, ormay use a greater number of stimulus or return electrodes. By contrast, in monopolar stimulation, current is returned through the conductive case of the stimulator 100, which may therefore be configured and function as an electrode though it is not physically part of the electrode array 150. The set of stimulus electrodes and return electrodes is referred to as the stimulus electrode configuration. Electrode selection module 126 is illustrated as connecting to a ground 130 of the pulse generator 124 to enable stimulus current return via the return electrode 4. However, other connections for current return may be used in other implementations.

[0056] Delivery of an appropriate stimulus via electrodes 2 and 4 to the target fibres 180 evokes a neural response 170 comprising an evoked compound action potential (ECAP) which will propagate along the target fibres 180 as illustrated at a rate known as the conduction velocity. The ECAP may be evoked for therapeutic purposes, which in the case of a spinal cord stimulator for chronic pain may be associated with paresthesia at a desired location. To this end, the electrodes 2 and 4 are used to deliver stimuli periodically at any therapeutically suitable stimulus frequency, for example 30 Hz, although other frequencies may be used including frequencies as high as the kHz range. In alternative implementations, stimuli may be delivered in a non-periodic manner such as in bursts, or sporadically, as appropriate for the patient 108. To program the stimulator 100 to the patient 108, a clinician may cause the stimulator 100 to deliver stimuli of various configurations which seek to produce a sensation that may be experienced by the patient as paresthesia. When a stimulus electrode configuration is found which evokes paresthesia in a location and of a size which is congruent with the area of the patient’s body affected by pain and of a quality that is comfortable for the patient, the clinician or the patient nominates that configuration for ongoing use. The therapy parameters may be loaded into the memory 118 of the stimulator 100 as the clinical settings 121.

[0057] Fig. 6 illustrates the typical form of an ECAP 600 of a healthy subject, as sensed by a single measurement electrode referenced to the system ground 130 or referenced to an indifferent electrode. Such configurations are referred to as single-ended ECAP measurement. The shape and duration of the single-ended ECAP 600 shown in Fig. 6 is predictable because it is a result of the ion currents produced by the ensemble of fibres depolarising and generating action potentials (APs) in response to stimulation. The evoked action potentials (EAPs) generated synchronously among a large number of fibres sum to form the ECAP 600. The ECAP 600 generated from the synchronous depolarisation of a group of similar fibres comprises a positive peak Pl, then a negative peak Nl, followed by a second positive peak P2. This shape is caused by the region of activation passing the measurement electrode as the action potentials propagate along the individual fibres.

[0058] The ECAP may be recorded differentially using two measurement electrodes, as illustrated in Fig. 3. Differential ECAP measurements are less subject to common-mode noise on the surroundingtissue than single-ended ECAP measurements. Depending on the polarity of recording, a differential ECAP may take an inverse form to that shown in Fig. 6, i.e. a form having two negative peaks N1 and N2, and one positive peak Pl. Alternatively, depending on the distance between the two measurement electrodes, a differential ECAP may resemble the time derivative of the ECAP 600, or more generally the difference between the ECAP 600 and a time-delayed copy thereof.

[0059] The ECAP 600 may be characterised by any suitable character! stic(s) of which some are indicated in Fig. 6. The amplitude of the positive peak Pl is Api and occurs at time Tpi. The amplitude of the positive peak P2 is Api and occurs at time Tpi. The amplitude of the negative peak Pl is Am and occurs at time Tm. The peak-to-peak amplitude is Api + Am. A recorded ECAP will typically have a maximum peak-to-peak amplitude in the range of microvolts and a duration of 2 to 3 milliseconds.

[0060] The stimulator 100 is further configured to measure the intensity of ECAPs 170 propagating along target fibres 180, whether such ECAPs are evoked by the stimulus from electrodes 2 and 4, or otherwise evoked. To this end, any electrodes of the array 150 may be selected by the electrode selection module 126 to serve as recording electrode 6 and reference electrode 8, whereby the electrode selection module 126 selectively connects the chosen electrodes to the inputs of the measurement circuitry 128. Thus, signals sensed by the measurement electrodes 6 and 8 subsequent to the respective stimuli are passed to the measurement circuitry 128, which may comprise a differential amplifier and an analog-to-digital converter (ADC), as illustrated in Fig. 3. The recording electrode and the reference electrode are referred to as the measurement electrode configuration. The measurement circuitry 128 for example may operate in accordance with the teachings of the above- mentioned International Patent Publication No. WO2012 / 155183.

[0061] Signals sensed by the measurement electrodes 6, 8 and processed by measurement circuitry 128 are further processed by an ECAP detector implemented within controller 116, configured by control programs 122, to obtain information regarding the effect of the applied stimulus upon the target fibres 180. In some implementations, the sensed signals are processed by the ECAP detector in a manner which measures and stores one or more characteristics from each evoked neural response or group of evoked neural responses contained in the sensed signal. In one such implementation, the characteristics comprise a peak-to-peak ECAP amplitude in microvolts (pV). For example, the sensed signals may be processed by the ECAP detector to determine the peak-to-peak ECAP amplitude in accordance with the teachings of International Patent Publication No. W02015 / 074121, the contents of which are incorporated herein by reference. Alternative implementations of the ECAP detector may measure and store an alternative characteristic from the neural response, or may measure and store two or more characteristics from the neural response.

[0062] Stimulator 100 applies stimuli over a potentially long period such as days, weeks, or months and during this time may store characteristics of neural responses, clinical settings, target response intensity, and other operational parameters in memory 118. To effect suitable SCS therapy, stimulator 100 may deliver tens, hundreds or even thousands of stimuli per second, for many hours each day. Each neural response or group of responses generates one or more characteristics such as a measure of the intensity of the neural response. Stimulator 100 thus may produce such data at a rate of tens or hundreds of Hz, or even kHz, and over the course of hours or days this process results in large amounts of clinical data 120 which may be stored in the memory 118. Memory 118 is however necessarily of limited capacity and care is thus required to select compact data forms for storage into the memory 118, to ensure that the memory 118 is not exhausted before such time that the data is expected to be retrieved wirelessly by external device 192, which may occur only once or twice a day, or less.

[0063] An activation plot, or growth curve, is an approximation to the relationship between stimulus intensity (e.g. an amplitude of the current pulse 160) and intensity of neural response 170 evoked by the stimulus (e.g. an ECAP amplitude). Fig. 4a illustrates an idealised activation plot 402 for one posture of the patient 108. The activation plot 402 shows a linearly increasing ECAP amplitude for stimulus intensity values above a threshold 404 referred to as the ECAP threshold. The ECAP threshold exists because of the binary nature of fibre recruitment; if the field strength is too low, no fibres will be recruited. However, once the field strength exceeds a threshold, fibres begin to be recruited, and their individual evoked action potentials are independent of the strength of the field. The ECAP threshold 404 therefore reflects the field strength at which significant numbers of fibres begin to be recruited, and the increase in response intensity with stimulus intensity above the ECAP threshold reflects increasing numbers of fibres being recruited. Below the ECAP threshold 404, the ECAP amplitude may be taken to be zero. Above the ECAP threshold 404, the activation plot 402 has a positive, approximately constant slope indicating a linear relationship between stimulus intensity and the ECAP amplitude. Such a relationship may be modelled in piecewise linear form as:

[0064] where 5 is the stimulus intensity, y is the ECAP amplitude, IT is the ECAP threshold and S is the slope of the activation plot (referred to herein as the patient sensitivity) above the ECAP threshold IT. The sensitivity S and the ECAP threshold IT are the key parameters of the activation plot 402.

[0065] Fig. 4a also illustrates a discomfort threshold 408, which is a stimulus intensity above which the patient 108 experiences uncomfortable or painful stimulation. Fig. 4a also illustrates a perception threshold 410. The perception threshold 410 corresponds to an ECAP amplitude that is barely perceptible by the patient. There are a number of factors which can influence the position of theperception threshold 410, including the posture of the patient. Perception threshold 410 may correspond to a stimulus intensity that is greater than the ECAP threshold 404, as illustrated in Fig. 4a, if patient 108 does not perceive low levels of neural activation. Conversely, the perception threshold 410 may correspond to a stimulus intensity that is less than the ECAP threshold 404, if the patient has a high perception sensitivity to lower levels of neural activation than can be detected in an ECAP, or if the signal-to-noise ratio of the ECAP is low.

[0066] For effective and comfortable operation of an implantable neuromodulation device such as the stimulator 100, it is desirable to maintain stimulus intensity within a therapeutic range. A stimulus intensity within a therapeutic range 412 is above the ECAP threshold 404 and below the discomfort threshold 408. In principle, it would be straightforward to measure these limits and ensure that stimulus intensity, which may be closely controlled, always falls within the therapeutic range 412. However, the activation plot, and therefore the therapeutic range 412, varies with the posture of the patient 108.

[0067] Fig. 4b illustrates the variation in the activation plots with changing posture of the patient. A change in posture of the patient may cause a change in impedance of the electrode-tissue interface or a change in the distance between electrodes and the spinal cord. While the activation plots for only three postures, 502, 504 and 506, are shown in Fig. 4b, the activation plot for any given posture can lie between or outside the activation plots shown, on a continuously varying basis depending on posture. Consequently, as the patient’s posture changes, the ECAP threshold changes, as indicated by the ECAP thresholds 508, 510, and 512 for the respective activation plots 502, 504, and 506. Additionally, as the patient’s posture changes, the patient sensitivity also changes, as indicated by the varying slopes of activation plots 502, 504, and 506. In general, as the distance between the stimulus electrodes and the spinal cord increases, the ECAP threshold increases and the sensitivity decreases. The activation plots 502, 504, and 506 therefore correspond to increasing distance between stimulus electrodes and spinal cord, and decreasing patient sensitivity.

[0068] To keep the applied stimulus intensity within the therapeutic range as patient posture varies, in some implementations an implantable neuromodulation device such as the stimulator 100 may adjust the applied stimulus intensity based on a feedback variable that is determined from one or more measured ECAP characteristics. In one implementation, the device may adjust the stimulus intensity to maintain the measured ECAP amplitude at or near a target response intensity. For example, the device may calculate an error between a target ECAP amplitude and a measured ECAP amplitude, and adjust the applied stimulus intensity to bring the measured ECAP amplitude closer to the target ECAP amplitude, such as by adding the scaled error to the current stimulus intensity. A neuromodulation device that operates by adjusting the applied stimulus intensity to maintain afeedback variable at or near a target value is said to be operating in closed-loop mode and will also be referred to as a closed-loop neural stimulation (CLNS) device. By adjusting the applied stimulus intensity to maintain the measured ECAP amplitude at or near an appropriate target response intensity, such as a target ECAP amplitude 520 illustrated in Fig. 4b, a CLNS device will generally keep the stimulus intensity within the therapeutic range as patient posture varies.

[0069] A CLNS device comprises a pulse generator that takes a stimulus intensity value and converts it into a neural stimulus comprising a sequence of electrical pulses according to a predefined stimulation pattern. The stimulation pattern is parametrised by multiple stimulus parameters including stimulus amplitude, pulse width, number of phases, order of phases, number of stimulus electrode poles (two for bipolar, three for tripolar etc.), and stimulus rate or frequency. At least one of the stimulus parameters, for example the stimulus amplitude, is controlled by the pulse generator to implement the received stimulus intensity value. For example, all stimulus parameters may be held constant except stimulus amplitude which is determined in proportion to the received stimulus intensity value. Alternatively, all stimulus parameters may be held constant except pulse width which is varied in proportion to the desired stimulus intensity.

[0070] In an example CLNS system, the user (e.g. the patient or a clinician) sets a target response intensity, and the CLNS device performs proportional-integral-differential (PID) control. In some implementations, the differential and proportional contributions are disregarded and the CLNS device uses a first order integrating feedback loop. The pulse generator generates a stimulus in accordance with a stimulus intensity parameter, which evokes a neural response in the patient. The intensity of an evoked neural response (e.g. an ECAP) is measured by the CLNS device and compared to the target response intensity.

[0071] The measured neural response intensity, and its deviation from the target response intensity, is used by the feedback loop to determine possible adjustments to the stimulus intensity parameter to maintain the neural response at or near the target response intensity. If the target response intensity is properly chosen, the patient receives consistently comfortable and therapeutic stimulation through posture changes and other perturbations to the stimulus / response behaviour.

[0072] Fig. 5 is a schematic illustrating elements and inputs of a closed-loop neural stimulation (CLNS) system 300, according to one implementation of the present technology. The system 300 comprises a pulse generator 312 which converts a stimulus intensity parameter (for example a stimulus current amplitude) s, in concert with a set of predefined stimulus parameters, into neural stimuli comprising a sequence of electrical pulses delivered via the stimulus electrodes (not shown in Fig. 5). According to one implementation, the predefined stimulus parameters comprise the number and order of phases, the number of stimulus electrode poles, the pulse width, and the stimulus rate orfrequency, and the pulse generator 312 determines the stimulus amplitude in proportion to the stimulus intensity parameter 5.

[0073] The generated stimulus crosses from the electrodes to the spinal cord, which is represented in Fig. 5 by the dashed box 308. The box 309 represents the evocation of a neural response y by the stimulus as described above. The box 311 represents the evocation of an artefact signal a, which is dependent on stimulus intensity and other stimulus parameters, as well as the electrical environment of the measurement electrodes. Various sources of measurement noise «, as well as the artefact a, may add to the evoked response y at the summing element 313 to form the sensed signal r, including: electrical noise from external sources such as 50 Hz mains power; electrical disturbances produced by the body such as neural responses evoked not by the device but by other causes such as peripheral sensory input; EEG; EMG; and electrical noise from measurement circuitry 318.

[0074] The neural activation arising from the stimulus is affected by mechanical changes, including posture changes, walking, breathing, heartbeat and so on. Mechanical changes may cause impedance changes, or changes in the location and orientation of the nerve fibres relative to the electrode array(s). As described above, the intensity of the evoked response provides a measure of the activation of the fibres being stimulated. In general, the more intense the stimulus, the more activation and the more intense the evoked response. An evoked response typically has a maximum amplitude in the range of microvolts, whereas the voltage resulting from the stimulus applied to evoke the response is typically several volts.

[0075] Measurement circuitry 318, which may be identified with measurement circuitry 128, amplifies the sensed signal r (potentially including evoked neural response, artefact, and measurement noise), and samples the amplified sensed signal r to capture a “signal window” 319 comprising a predetermined number of samples of the amplified sensed signal r. The ECAP detector 320 processes the signal window 319 and outputs a measured neural response intensity d. In one implementation, the neural response intensity comprises a peak-to-peak ECAP amplitude. The measured response intensity d (an example of a feedback variable) is input into the feedback controller 310. The feedback controller 310 comprises a comparator 324 that compares the measured response intensity d to a target ECAP amplitude as set by the target ECAP controller 304 and provides an indication of the difference between the measured response intensity d and the target ECAP amplitude. This difference is the error value, e.

[0076] The feedback controller 310 calculates an adjusted stimulus intensity parameter, 5, with the aim of maintaining a measured response intensity d equal to the target ECAP amplitude. Accordingly, the feedback controller 310 adjusts the stimulus intensity parameter 5 to minimise the error value, e. In one implementation, the controller 310 utilises a first order integrating function, using a gainelement 336 and an integrator 338, in order to provide suitable adjustment to the stimulus intensity parameter 5. According to such an implementation, the current stimulus intensity parameter 5 may be determined by the feedback controller 310 as s = f Kedt (2)

[0077] where K is the gain of the gain element 336 (the controller gain). This relation may also be represented as6s = Ke (3)

[0078] where 85 is an adjustment to the current stimulus intensity parameter ,v.

[0079] A target ECAP amplitude is input to the feedback controller 310 via the target ECAP controller 304. In one implementation, the target ECAP controller 304 provides an indication of a specific target ECAP amplitude. In another implementation, the target ECAP controller 304 provides an indication to increase or to decrease the present target ECAP amplitude. The target ECAP controller 304 may comprise an input into the CLNS system 300, via which the patient or clinician can input a target ECAP amplitude, or indication thereof. The target ECAP controller 304 may comprise memory in which the target ECAP amplitude is stored, and from which the target ECAP amplitude is provided to the feedback controller 310.

[0080] A clinical settings controller 302 provides clinical settings to the system 300, including the feedback controller 310 and the stimulus parameters for the pulse generator 312 that are not under the control of the feedback controller 310. In one example, the clinical settings controller 302 may be configured to adjust the controller gain K of the feedback controller 310 to adapt the feedback loop to patient sensitivity. The clinical settings controller 302 may comprise an input into the CLNS system 300, via which the patient or clinician can adjust the clinical settings. The clinical settings controller 302 may comprise memory in which the clinical settings are stored, and are provided to components of the system 300.

[0081] In some implementations, two clocks (not shown) are used, being a stimulus clock operating at the stimulus frequency (e.g. 60 Hz) and a sample clock for sampling the sensed signal r (for example, operating at a sampling frequency of 16 kHz). As the ECAP detector 320 is linear, only the stimulus clock affects the dynamics of the CLNS system 300. On the next stimulus clock cycle, the pulse generator 312 generates a stimulus in accordance with the adjusted stimulus intensity 5. Accordingly, there is a delay of one stimulus clock cycle before the stimulus intensity is updated in light of the error value e.

[0082] Fig. 7 is a block diagram of a neural stimulation system 700. The neural stimulation system 700 is centred on a neuromodulation device 710. In one example, the neuromodulation device 710 may be implemented as the stimulator 100 of Fig. 1, implanted within a patient (not shown). Theneuromodulation device 710 is connected wirelessly to a remote controller (RC) 720. The remote controller 720 is a portable computing device that provides the patient with control of their stimulation in the home environment by allowing control of the functionality of the neuromodulation device 710, including one or more of the following functions: enabling or disabling stimulation; adjustment of stimulus intensity or target response intensity; and selection of a stimulation control program from the control programs stored on the neuromodulation device 710.

[0083] The charger 750 is configured to recharge a rechargeable power source of the neuromodulation device 710. The recharging is illustrated as wireless in Fig. 7 but may be wired in alternative implementations.

[0084] The neuromodulation device 710 is wirelessly connected to a Clinical System Transceiver (CST) 730. The wireless connection may be implemented as the transcutaneous communications channel 190 of Fig. 1. The CST 730 acts as an intermediary between the neuromodulation device 710 and the Clinical Interface (CI) 740, to which the CST 730 is connected. A wired connection is shown in Fig. 7, but in other implementations, the connection between the CST 730 and the CI 740 is wireless.

[0085] The CI 740 may be implemented as the external computing device 192 of Fig. 1. The CI 740 is configured to program the neuromodulation device 710 and recover data stored on the neuromodulation device 710. This configuration is achieved by program instructions collectively referred to as the Clinical Programming Application (CPA) and stored in an instruction memory of the CI 740.Multi-stimset neural stimulation

[0086] For some patients, it is beneficial for a neural stimulation therapy program to comprise multiple stimulation sets. A stimulation set (“stimset”) is a set of stimulus and return electrodes, or more precisely a stimulus electrode configuration (SEC), along with the stimulus parameters that govern the stimulation pulses delivered via that SEC.

[0087] Fig. 8 is an illustration 800 of the stimulus pulses delivered by a stimulation program with four interleaved stimsets. The stimulus pulse train delivered according to each stimset is illustrated on a separate, but vertically aligned, horizontal axis representing time. All the stimulus pulse trains are delivered at the same stimulus frequency. (It is not a requirement that all the stimulus pulse trains for the respective stimsets are delivered at the same stimulus frequency; however it is so represented in Fig. 8 for ease of illustration.) The first stimulus pulse 810, delivered according to the first stimset, is illustrated as a biphasic, anodic-first stimulus pulse, though many other stimulus pulse types are contemplated. The second, third, and fourth stimulus pulses 820, 830, and 840, delivered according to the second, third, and fourth stimsets in the program respectively, are also biphasic, anodic-firststimulus pulses with different pulse widths and different amplitudes. Each stimulus pulse is illustrated as delayed in time by a constant amount (the inter-stimulus interval, or ISI, 815) from the stimulus pulse delivered according to the preceding stimset. However, this is not to be interpreted as limiting, since the intervals between the pulses in the various stimsets may be different. Because all the stimulus pulse trains in Fig. 8 are delivered at the same stimulus frequency, the four stimulus pulses 810, 820, 830, 840 form a cycle that repeats indefinitely without any change to the relative timing of the pulses from the different stimsets. The fifth stimulus pulse 850 is a subsequent pulse in the pulse train delivered according to the first stimset and is therefore illustrated on the same time axis as the first stimulus pulse 810, and the cycle repeats thereafter. The stimulus period 890 is the period of repetition of the full cycle and is equal to the reciprocal of the stimulus frequency. In one implementation, the ISI 815 is the stimulus period divided by the number of stimsets, so that the stimuli are evenly spaced throughout the stimulus period 890.

[0088] Also illustrated is an evoked neural response in the form of an evoked compound action potential (ECAP) 860 as sensed by a predetermined measurement electrode configuration (MEC) on a common time axis with the stimulus pulses. The illustrated ECAP 860 is evoked by the fourth stimulus pulse 840. A closed-loop neural stimulation (CLNS) system programmed with multiple interleaved stimsets, as illustrated in Fig. 8, may be based on measurements of the ECAP 860. That is to say, closed-loop adjustments to the stimulus parameters of all stimsets may all be based on measurements of the ECAP 860 evoked by a single stimset, referred to as the applied stimset. In Fig. 8, the final stimset in the cycle is the applied stimset.

[0089] If the ISI 815 is short, ECAPs evoked by the first three stimulus pulses 810, 820, and 830 are potentially obscured by stimulus crosstalk or artefact from the stimulus pulses 820, 830, and 840. Therefore, if the ISI 815 is short, only the final stimset in the cycle may evoke a measurable ECAP. If the ISI 815 is greater than the refractory period of the neural tissue and sufficiently long that ECAPs evoked by the earlier stimsets are not obscured by stimulus crosstalk and artefact from the other stimulus pulses in the cycle, any of the stimsets in the cycle may evoke a measurable ECAP. In such implementations, an ECAP may be measured from each stimset in the cycle.

[0090] Fig. 9 is a schematic illustrating elements and inputs of a multi-stimset CLNS system 900 with multiple stimsets. The multi-stimset CLNS system 900 is the same as the CLNS system 300 of Fig. 5, with like numbers indicating like elements, with the addition of three further stimsets. The noise addition and artefact generation in Fig. 5 have been omitted from Fig. 9 for clarity. The four stimsets are labelled A, B, C, and D and are delivered by pulse generators 312A, 312B, 312C, and 312D (the latter of which corresponds to the pulse generator 312 in the CLNS system 300) according to respective stimulus intensity parameters SA, SB, SC, and SD, and via respective SECs. The pulsesdelivered by the pulse generators 312A, 312B, 312C, and 312D correspond to the stimulus pulses 810, 820, 830, and 840 of Fig. 8. The neural response y may be measured from any of stimsets A, B, C, and D, which is why the neural response box 309 is joined by dashed lines to all four pulse generators 312A, 312B, 312C, and 312D in Fig. 9.

[0091] Stimset D, delivered by the stimulator 312D, is delivered last in the cycle and is the applied stimset, from which the ECAP is measured. In the implementation of Fig. 9, the stimulus intensity parameter SD for stimset D is scaled by stimset ratios RA, RB, and Rc to obtain the stimulus intensity parameters SA, SB, and sc for stimsets A, B, and C respectively at the end of each cycle. The stimset ratios RA, RB, and Rc are fixed at the ratios of the respective stimulus intensities SA, SB, and sc at which the respective stimsets were originally programmed, to the originally programmed stimulus intensity SD of the applied stimset D and form part of the clinical settings 121 of the multi-stimset program. In such an implementation, the stimulus intensity parameters SA, SB, and sc always remain in fixed ratio with the applied stimulus intensity parameter SD and with each other. This is referred to as ratiometric adjustment. So for example, if the originally programmed stimulus intensities were 1 mA, 2 mA, 4 mA, and 6 mA for the four stimsets A, B, C, and D respectively, the stimset ratios RA, RB, and Rc are fixed at programming time at 1 / 6, 1 / 3, and 2 / 3 respectively. If during therapy the feedback controller 310 adjusts the applied stimset intensity parameter SD to 6.6 mA, the stimulus intensity parameters SA, SB, and sc of the non-applied stimsets are automatically adjusted to 1.1 mA, 2.2 mA, and 4.4 mA respectively. The clinical settings controller 302 provides the respective stimulus parameters to the pulse generators 312A, 312B, 312C, and 312D.

[0092] It may be seen from Fig. 9 that the adjustments to the stimulus intensity parameters after each stimulus cycle are all in fixed proportion. A ratiometric multi-stimset CLNS system therefore emulates a CLNS system with four separate feedback loops driven by the four stimsets, wherein each loop has the same controller gain. A ratiometric multi-stimset CLNS system is effective to maintain the responses evoked by each stimset at a constant neural response intensity on the condition that when the patient moves to a new posture, the threshold and slope of all activation plots, both for applied and non-applied stimsets, move in a proportional manner. (See Fig. 4b for examples of activation plots for a given stimset in different postures.)A measure of neural activation

[0093] Neural activation refers to the number of fibres recruited by a stimulus provided by a neural stimulator. The stimulus current flowing through the one or more stimulus electrodes to the one or more return electrodes generates a field at the neural tissue (e.g. the spinal cord). It will be appreciated that for a given stimulus intensity, as the stimulus electrode changes distance with respect to the cord, the field intensity at the neural tissue changes. The stimulus intensity at which the field generated bythe stimulus begins to recruit fibres, for a given stimulus electrode configuration (SEC) and a specific posture of a patient, is the activation threshold (or ECAP threshold) for that SEC and posture of the patient.

[0094] The recruitment of fibres begins at approximately the same field intensity at the spinal cord regardless of the patient’s posture. Therefore, the ECAP threshold for a patient’s current posture provides a calibration point for estimating the neural activation resulting from stimuli at a given stimulus intensity. At stimulus intensities above the ECAP threshold, the neural activation of the field generated by the stimulus increases with the ratio by which the stimulus intensity exceeds the ECAP threshold. A measure R of neural activation resulting from stimuli at a stimulus intensity I may therefore be written as follows:« = r - i (4)‘T where ITis the ECAP threshold for the patient’s current posture.

[0095] In other words, neural activation may be estimated as the excess of the stimulus intensity over the ECAP threshold, normalised by the ECAP threshold.

[0096] A simpler, though equivalently indicative, measure of neural activation than that given by equation (4) is the dose ratio D, which is the ratio of stimulus intensity to the ECAP threshold:D =lT (5)

[0097] If the patient moves into a less sensitive posture at a fixed stimulus intensity, the neural activation decreases, and the measured ECAP amplitude decreases. If the patient moves into a more sensitive posture, the neural activation increases, and the measured ECAP amplitude increases. Although there may be alignment between the variation in ECAP amplitude and the variation in neural activation due to posture changes, the relationship between these two quantities is not proportional in all situations.

[0098] Fig. 10 is a graph 1000 containing activation plots 1002, 1004 and 1006, fitted to real data for a patient in a supine posture, a standing posture and a sitting posture, respectively. Dashed line 1014 indicates a measured response intensity (ECAP amplitude) of 240pV.

[0099] The activation plot 1002 for the supine (most sensitive) posture has an ECAP threshold 1016 at 3.5mA, and has a measured ECAP amplitude of 240pV when the stimulus intensity (implemented in this example as stimulus current) is 5.4mA, as indicated by dashed line 1008. Applying Equation (5), the dose ratio at a measured ECAP amplitude of 240pV, when the patient is in the supine posture, is equal to 1.54.

[0100] The activation plot 1004 for the standing posture has an ECAP threshold 1018 at 4.2mA, and has a measured ECAP amplitude of 240pV when the stimulus current is 6.9mA, as indicated bydashed line 1010. Applying Equation (5), the dose ratio at a measured ECAP amplitude of 240pV, when the patient is in the standing posture, is equal to 1.64.

[0101] The activation plot 1006 for the sitting (least sensitive) posture has an ECAP threshold 1020 at 5.2mA, and has a measured ECAP amplitude of 240pV when the stimulus current is 8.8mA, as indicated by dashed line 1012. Applying Equation (5), the dose ratio at a measured ECAP amplitude of 240pV, when the patient is in the sitting posture, is equal to 1.69.

[0102] Accordingly, for the same ECAP amplitude (e.g. 240pV in the example of Fig. 10) the dose ratio varies from 1.54 to 1.64 to 1.69 as the patient moves from one, most sensitive, posture to a second and a third, least sensitive, posture. In the example of Fig. 10, the neural activation increases as the patient moves from the supine (most sensitive) posture, to the standing posture, and then to the sitting (least sensitive) posture.

[0103] Accordingly, a CLNS system 300 that is configured to maintain a target ECAP amplitude (a constant-ECAP CLNS system) may result in the patient perceiving more intense stimulation, as indicated by a higher dose ratio, for the same ECAP amplitude, as the patient moves from a more sensitive posture to a less sensitive posture. A more intense level of stimulation may be undesirable as it may exceed the patient’s discomfort threshold.

[0104] Methods and devices according to a first aspect of the present technology are configured to maintain an approximately constant dose ratio as defined by Equation (5), as patient posture varies. Methods and systems according to a second aspect of the present technology are configured to program devices to maintain an approximately constant dose ratio, as defined by Equation (5), as patient posture varies. Maintaining an approximately constant dose ratio, i.e. maintaining neural activation at or near a target neural activation, may lead to a constant level of neural stimulation, as perceived by the patient, and therefore a more consistent therapy as posture varies.Constant dose ratio CLNS devices

[0105] According to a first feedforward implementation of the present technology, a CLNS device that does a better job of maintaining constant dose ratio as posture varies may be implemented using a ratiometric multi-stimset CLNS system, as illustrated in Fig. 8, comprising two stimsets of equal frequency, with the ISI 815 greater than the refractory period of the target neural tissue. The applied stimset, referred to as the probe stimset, is delivered second in the cycle as described above in relation to Fig. 8. The probe stimset is configured with a target response intensity (target ECAP amplitude) dtgt that is close to the noise floor of the ECAP detector 320. (Choice of an appropriate target ECAP amplitude dtgt will be described in more detail below.) The non-applied stimset, referred to as the therapy stimset, is delivered first in the cycle. The therapy stimset is configured with the same SEC as the probe stimset (and therefore the same target neural tissue) and a stimset ratio RA equal to atarget dose ratio Dtgt for the patient divided by a dose ratio Dpr<>be for the probe stimset. The probe dose ratio DProbe may be predetermined from the target ECAP amplitude dtgt as described below. That is, for all cycles, j _Dtgt j‘therapyD‘probe 0-

[0106] where ItheraPyis the therapy stimulus intensity and IProbe is the probe stimulus intensity. It may be seen that equation (6) is equivalent to determining the therapy stimulus intensity by multiplying the target dose ratio Dtgt by the ECAP threshold Zr, i.e. maintaining the dose ratio DtheraPyfor the therapy stimset from equation (5) at or near the target dose ratio Dtgt.

[0107] Alternatively for the first feedforward implementation, the stimset ratio RA may be set equal to the target dose ratio Dtgt, which is a good approximation to equation (6) to the extent that the probe stimulus intensity Ipmbe is a good approximation to the ECAP threshold IT.

[0108] Assuming a piecewise linear activation plot (AP) model, as illustrated in Fig. 4a, and typical variation of AP with posture, as illustrated in Fig. 10, it may be shown that the error (deviation from target dose ratio Dtgt) in dose ratio DtheraPydelivered by the therapy stimset as posture changes is smaller than in a fixed-ECAP single-stimset CLNS system 300 as illustrated in Fig. 3. In a fixed- ECAP single-stimset CLNS system 300, the single stimset is configured with a target ECAP amplitude that emulates the target dose ratio Dtgt in an intermediate, reference posture. (Fig. 10 illustrates the variation in dose ratio between 1.54 and 1.69 with posture delivered by such a system with a target ECAP amplitude of 240pV, equivalent to a dose ratio of 1.64 in the standing posture.) Furthermore, the error in dose ratio delivered by the therapy stimset as posture changes decreases as the target ECAP amplitude of the probe stimset decreases towards the noise floor. For this reason, the above-described dual stimset CLNS system is referred to herein as a constant dose ratio CLNS device, though the delivered dose ratio is only approximately constant.

[0109] To explain this reduction in error, there are two variables (ECAP threshold and patient sensitivity) that impact what the dose ratio is for a CLNS system at any given target ECAP amplitude. By operating the probe stimset near the ECAP threshold, the probe dose ratio (which will be close to unity) is less sensitive to changes in patient sensitivity with posture (though it remains sensitive to changes in ECAP threshold). Delivering therapy pulses with stimulus intensity at a fixed multiple of the stimulus intensity of the probe pulses simply scales up the dose ratio delivered by the probe pulses to a value that is truly therapeutic, and therefore preserves this reduced sensitivity of dose ratio to changes in patient sensitivity. As a result, there is less variation in dose ratio with posture.

[0110] To look at it another way, in the theoretical limit (an ideal, noise-free system) where the target ECAP amplitude is zero, the probe stimset is effectively measuring the ECAP threshold at all times, so the therapy stimset is by definition always at the target dose ratio and the variation of dose ratiowith posture is zero. In practice, the target ECAP amplitude must be above zero, which detracts from this perfect invariance, but the disclosed constant dose ratio CLNS device still achieves a reduction in variation of dose ratio compared to a fixed-ECAP single-stimset CLNS device.

[0111] As the first feedforward implementation is described above, the probe pulses of the disclosed constant dose ratio CLNS device are delivered last in each cycle. This means that the adjustment of the probe stimset stimulus intensity determined by the feedback controller 310 for the next cycle immediately flows through to the first pulse in the next cycle, which is the therapy pulse.

[0112] However, in a variant of the first feedforward implementation, the constant dose ratio CLNS device may be configured such that the probe pulses are delivered first in each cycle, provided that the ISI 815 is sufficiently long that ECAPs evoked by the probe pulses are not obscured by stimulus crosstalk and artefact arising from the subsequent, therapy pulses in each cycle. This means that, if implemented as described above, the adjustment of the probe stimset stimulus intensity determined by the feedback controller 310 for the next cycle would not immediately flow through to the next pulse in the current cycle, which is the therapy pulse. This may detract from the responsivity (loop speed) of such an implementation. Therefore, according to the variant of the first feedforward implementation, the adjustment may be applied immediately to the therapy pulse without waiting for the start of the next cycle. Such an ordering of operations would bring the variant of the first feedforward implementation back to the responsivity of the of the first feedforward implementation of a constant dose ratio CLNS device.

[0113] In the first feedforward implementation, the target neural tissue will effectively be stimulated twice per cycle, once by the probe pulse and once by the therapy pulse. This means the effective stimulation frequency for the portion of the target tissue activated by the probe pulse is twice the stimulation frequency. Because of frequency effects on patient characteristics such as ECAP threshold, this makes the probe pulse more likely to be perceived, which is undesirable. To mitigate this effect, the ISI 815 for the variant of the first feedforward implementation may be configured to be less than the refractory period, though still long enough that ECAPs evoked by the probe pulses are not obscured by stimulus crosstalk and artefact arising from the subsequent, therapy pulses. This means that the portion of the target neural tissue activated by the probe pulse will mostly be in refraction when the subsequent therapy pulse within the cycle is delivered. The effective frequency for that portion of the target neural tissue is equal to the stimulation frequency.

[0114] According to a first feedback implementation of the present technology, an estimate ITof the ECAP threshold is obtained as either the probe stimulus intensity Ipmbe or, more accurately, the probe stimulus intensity Ipmbe divided by the predetermined probe dose ratio DProbe. The dose ratio Ddelivered by the previous therapy pulse may be estimated as the ratio of the therapy stimulus intensity Itherapy to the ECAP threshold estimate lT'.

[0115] Then the estimated delivered dose ratio D may be subtracted from the target dose ratio Dtgt to obtain an error e, which may be fed to a feedback controller such as the feedback controller 310 of Fig. 5. The feedback controller 310 then determines the therapy stimulus intensity Itherapy for the next cycle.

[0116] A second feedforward implementation makes use of the ECAP evoked by each therapy pulse to refine the current estimate of ECAP threshold IT. Under this second feedforward implementation, the probe stimulus intensity Iprobe is set to a predetermined “probe multiple” k of ECAP threshold IT, where k is small but greater than one. The therapy stimulus intensity Itherapy is a predetermined “therapy multiple” I of the probe stimulus intensity Iprobe, where I is greater than one. Fig. 11 is a graph 1100 showing the ECAP threshold IT, the probe stimulus intensity Iprobe, and the therapy stimulus intensity Itherapy on a current activation plot 1110.

[0117] Since according to the second feedforward implementation the probe stimulus intensity Iprobe is by design not an accurate estimate of the ECAP threshold IT, the intensity dthempy of the neural response to the therapy pulse may be used, together with the intensity dprobe of the neural response to the probe pulse (both illustrated on the graph 1100), to estimate the ECAP threshold IT. This may be done, for example, by extrapolation of a straight line fit between the two points (Iprobe, dprobe) and Itherapy, dthempy to the stimulus intensity axis. There are then two options for choosing the next values of probe stimulus intensity Iprobe and therapy stimulus intensity Itherapy for the next cycle.(Second Feedforward implementation) Set the probe stimulus intensity Iprobe to the ECAP threshold estimate ITmultiplied by the probe multiple k, and the therapy stimulus intensity Itherapy to the ECAP threshold estimate ITmultiplied by the probe multiple k and then by the therapy multiple I. The delivered dose ratio D is some function of the probe multiple k and the product k*l of the probe multiple k and the therapy multiple ID = f (k, k * l) (8)For example, the function / may be a sum. The probe multiple k and the therapy multiple I may be predetermined from equation (8) such that the delivered dose ratio D is equal to the target dose ratio Dtgt.(Second feedback implementation) Estimate the dose ratio D delivered by the previous probe pulse and therapy pulse as the function / of the ratios of the probe stimulus intensity Iprobe and the therapy stimulus intensity Itherapy to the ECAP threshold estimate lT'.Then subtract the estimated delivered dose ratio D from the target dose ratio Dtgt to obtain an error e, which may be fed to a feedback controller such as the feedback controller 310 of Fig. 5, which determines the probe stimulus intensity Ipmbe for the next cycle. The probe stimulus intensity Ipmbe may then be multiplied by the therapy multiple I to determine the therapy stimulus intensity Itherapy for the next cycle.

[0118] The estimation of the ECAP threshold IT, and hence the updating of the probe and therapy stimulus intensities, may be carried out once per cycle using each pair of neural response intensity measurements independently. This may be referred to as pairwise calculation. Alternatively, the estimation of the ECAP threshold IT may be updated after each neural response intensity measurement. This may be referred to as alternate calculation. Alternate calculation does not impose as much delay in the loop, which is advantageous as delay causes phase lag which affects stability.

[0119] In variants of the implementations so far described, the therapy pulses (which are at the same frequency as the probe pulses, i.e. the stimulus frequency) are replaced by bursts of therapy pulses of constant intensity within each burst, with an intra-burst frequency that is substantially higher than the inter-burst frequency, which remains the same as the frequency of the probe pulses (the stimulus frequency). For example, the intra-burst frequency may be 1 kHz at a stimulus (inter-burst) frequency of 50 Hz. The overall intensity of each therapy burst remains in fixed ratio RA with the probe stimset, but in general the therapy bursts need not have a constant intra-burst intensity profile. Instead, the burst pulses may follow a non-constant intensity profile that is configured to provide approximately constant activation throughout the burst. Depending on the profile chosen, the therapy pulses may not generate paresthesia and may therefore not be perceivable by the patient. One such example of an intra-burst intensity profile is a profile that ramps down from a maximum value to a plateau as disclosed in Patent Cooperation Treaty Application no. PCT / AU2025 / 050633, the contents of which are herein incorporated by reference in their entirety. However, the stimset ratio RA of the therapy pulse bursts is no longer equal, or approximately equal, to the target dose ratio Dtgt, since the ECAP threshold iT(thempy) of the therapy pulses, which are delivered at the higher, intra-burst frequency, is different from the ECAP threshold of the probe stimset. Based on the assumption that the ratio C between the ECAP threshold iT(thempy) of the therapy pulses and the ECAP threshold IT of the probe stimset remains approximately constant with posture, such variants may still deliver a dose ratio that is approximately constant across postures.

[0120] In other variants of the implementations so far described, the SEC of the therapy stimset is not configured to be identical with that of the probe stimset. Instead, the therapy stimset may be configured to have a different SEC to that of the probe stimset, on condition that the probe stimsetSEC and the therapy stimset SEC have the same electrode to tissue transfer function across all postures. For example, the therapy stimset SEC could be a wide tripole and the probe stimset SEC could be a narrow tripole, but with the same centre of field in relation to the neural tissue.

[0121] A generalisation of the dose ratio relies on distance-dependent modelling of the ECAP threshold and rate of change of neural activation with stimulus intensity. One model of the variation of ECAP threshold IT with electrode-to-cord distance x may be written as follows: / T(x) = / 0+axP(10)

[0122] where Io and a are parameters that depend on the target neural tissue, and the exponent p is a (positive) constant. The model of equation (10) may be simplified if Io is negligible to / T(x) = axp(11)

[0123] The variation of the rate of changeof neural activation R with respect to stimulus intensity I with electrode-to-cord distance x may be modelled as follows:

[0124] where K is a parameter that depends on the target neural tissue, and the exponent q is a (positive) constant.

[0125] Combining equations (10) and (12) yields the following expression for neural activation R as a function of stimulus intensity I and distance x:R(x, r) = KX~q(J — / 0— axp) (13)

[0126] for I > Io+ axp.

[0127] It may be shown using equation (13) that to ensure constant neural activation R as electrode- to-cord distance x varies, it is sufficient to set the therapy stimulus intensity Ithempy to the following function of the ECAP threshold IT.

[0128] where the exponent y is the ratio p / q, and the quantity X has been introduced as a dose metric linearly related to the neural activation R. In other words, as long as the therapy stimulus intensity Itherapy is related to the ECAP threshold IT in accordance with Equation (14) for some constant dose metric X as electrode-to-cord distance varies, the neural activation R will remain constant as electrode- to-cord distance varies.

[0129] The dose metric X, which is related to neural activation R as follows: qR = K<ZP(TI — 1) (15)

[0130] is a generalisation of the dose ratio defined in equation (5). This may be seen by rewriting equation (14):

[0131] In the special case in which y equals one (y is equal to y>), and the base current Zo is negligible, equation (16) degenerates to

[0132] which may be compared to equation (5) defining dose ratio D as the ratio of stimulus intensity to ECAP threshold.

[0133] Equation (14) may be implemented using the constant dose ratio CLNS devices described above. In one such implementation, based on the assumption that the feedback-adjusted probe stimulus intensity Iprobe is a good estimate of the ECAP threshold IT, the therapy stimulus intensity Itherapy may be adjusted in feedforward fashion from the feedback-adjusted probe stimulus intensity Iprobe as follows:

[0134] where tgt is a target dose metric. The first feedforward implementation of a constant dose ratio CLNS device, in which Itherapy is determined via equation (6), may be regarded as a special case of equation (18) in which the exponent y is equal to one and the base current 7o is negligible. In such a special case the target dose metric tgt is equal to the target dose ratio Dtgt divided by the probe dose ratlO Dprobe.

[0135] In another such implementation, the ECAP threshold IT may first be estimated from the feedback-adjusted probe stimulus intensity Iprobe by dividing Iprobe by the reference posture probe dose ratio Dprobe. The reference posture probe dose ratio Dprobe may be predetermined during programming as described below. The estimate ITof the ECAP threshold IT may then be plugged into equation (14) with set to the target dose metric tgt to adjust the therapy stimulus intensity Itherapy in feedforward fashion. As mentioned above, the actual (unknown) dose ratio delivered by the probe stimset will not depart far from the predetermined probe dose ratio Dprobe as posture differs from the reference posture, so the ratio Iprobe I Dprobe will remain a good estimate of the ECAP threshold IT as posture varies.

[0136] According to a generalisation of the first feedback implementation of the present technology, a feedback controller may adjust the therapy stimulus intensity Itherapy in feedback fashion using the dose metric of equation (16) as a feedback variable. In such implementations, the feedback controller adjusts the therapy stimulus intensity Itherapy so as to maintain the dose metric at or near a target dose metric k ' tgt.

[0137] Fig. 13 contains a flow chart illustrating a method 1300 of controllably delivering neural stimuli according to feedback implementations of the present technology. The method 1300 may becarried out by the controller 116, having been configured by control programs 122, of a closed-loop neural stimulation device such as the stimulator 100.

[0138] The method 1300 starts at step 1310, at which a therapy stimulus is delivered according to the therapy stimset and the therapy stimulus intensity Ithempy. An optional step 1320 follows, at which the method 1300 measures the response intensity dthempy of the ECAP evoked by the therapy stimulus.

[0139] At step 1330, an estimate lTof the ECAP threshold IT is obtained. The ECAP threshold estimate ITmay be obtained by any convenient means, including (but not limited to):• As a probe stimulus intensity Iprobe of a probe stimset as described above;• By dividing the probe stimulus intensity Iprobe of a probe stimset by the probe dose ratio Dprobe as described above;• By extrapolation of a straight line fit between the two points (Iprobe, dprobe and (Ithempy, dthempy) to the stimulus intensity axis as described above;• By interpolation at the point (Ithempy, dthempy) between two activation plots in extreme positions, as described in International Patent Publication no. WO2024243634, the content of which is herein incorporated by reference;• Using the point (Ithempy, dthempy) based on the assumption that all activation plots intersect at a known point (7o, do) as described in International Patent Publication no. WO2023272343, the content of which is herein incorporated by reference.

[0140] The first three of the above options for estimating the ECAP threshold require a probe stimset to be delivered interleaved with the therapy stimset as described above, while the latter two do not. If a probe stimset is required, it may be adjusted in its own feedback loop to maintain its neural response intensity dprobe at or near a target ECAP amplitude dtgt as described above, independently of the feedback loop that adjusts the therapy stimulus intensity Ithempy. The latter three options require step 1320 to have been carried out to obtain the response intensity dthempy of the ECAP evoked by the therapy stimulus.

[0141] Once the ECAP threshold estimate IThas been obtained, at step 1340 the feedback controller determines an estimated dose metric A by applying equation (16) to the ECAP threshold estimate ITand the therapy stimulus intensity Ithempy. In the special case in which the dose metric is equal to the dose ratio, step 1340 may instead use equation (7) to estimate the dose metric from the ECAP threshold estimate ITand the therapy stimulus intensity Ithempy.

[0142] The feedback controller then at step 1350 subtracts the estimated dose metric from the target dose metric tgt to obtain the error signal e. The feedback controller then uses the error signal e to adjust the therapy stimulus intensity Ithempy as described above in relation to Fig. 5.

[0143] The method 1300 then returns to step 1310 to recommence the stimulate / measure / adjust cycle.Programming constant dose ratio CLNS devices

[0144] Programming the above-described implementations of constant dose ratio CLNS devices comprises selecting various loop parameters such as:(First feedforward implementation) The target ECAP amplitude dtgt for the probe stimset, the probe dose ratio Dpmbe for the probe stimset in a reference posture, and the target dose ratio Dtgt for the therapy stimset.(Second feedforward implementation) Probe and therapy multiples k and I.(Second feedback implementation) Target dose ratio Dtgt, and therapy multiple I.(Burst variants) The target ECAP amplitude dtgt for the probe stimset, the probe dose ratio Dprobe in a reference posture, the target dose ratio Dtgt for the therapy stimset, and the stimset ratio for RA for the therapy stimset.(Generalisation of the first feedforward implementation) The target ECAP amplitude dtgt for the probe stimset, the probe dose ratio Dprobe for the probe stimset in a reference posture, the target dose metric tgt for the therapy stimset, the exponent y, and the base current h.(Generalisation of the first feedback implementation) The target dose metric tgt for the therapy stimset, the exponent y, and the base current h.

[0145] To determine a target ECAP amplitude dtgt for the probe stimset, start dtgt at 0 and increase it gradually, while monitoring the distribution of probe stimulus intensities Iprobe that the feedback controller determines in order to maintain the response intensity dpmbe at or near dtgt. The distribution will start out very skewed, then gradually become more Gaussian in form as dtgt increases above the noise floor. The Gaussianity of the distribution may be measured by conventional statistical tests of normality. At some transitional target value, the distribution will achieve and maintain a consistently Gaussian form, regardless of any further increases in dtgt. The transitional target value is the value at which to set the target ECAP amplitude dtgt.

[0146] Fig. 14 illustrates the evolution of the distribution of probe stimulus intensities Iprobe that the feedback controller determines in order to maintain the response intensity dp be at or near the target ECAP amplitude dtgt, as dtgt increases in relation to the measurement noise. Fig. 14 contains a series 1400 of histograms 1410, 1420, 1430, 1440, 1450, and 1460 representing distributions of probe stimulus intensities, captured at increasing values of dtgt, namely 5 pV, 10 pV, 15 pV, 20 pV, and 100 pV respectively. The measurement noise standard deviation is 20 pV. It may be seen that the distribution 1410, when dtgt is well below the measurement noise standard deviation, is distinctly non-symmetrical and therefore non-Gaussian. As the value of dtgt increases in relation to the measurement noise standard deviation, the distributions 1420, 1430, 1440, and 1450 become more symmetrical and more Gaussian in shape. There is very little difference in shape between the distributions 1450 (20 pV) and 1460 (100 pV), indicating that the transitional target value has been reached by the time dtgt reaches the measurement noise standard deviation (20 pV).

[0147] The probe and therapy multiples k and / , as mentioned above, should both be greater than one. The probe multiple k may be set to a value that is close to, but greater than, one, such as 1.05. The therapy multiple / may be determined from the probe multiple k and a target dose ratio Dtgt by inverting equation (8). For example, if the function f is a sum, the therapy multiple / may be determined by subtracting the probe multiple k from the target dose ratio Dtgt.

[0148] The probe dose ratio Dprobe in a reference posture may be determined by dividing the probe stimulus intensity Ipmbe corresponding to the target ECAP intensity dtgt in the reference posture by the ECAP threshold IT in that same reference posture. The activation plot in the reference posture may be determined by conventional activation plot fitting. Fig. 12 is a graph 1200 containing a fitted, piecewise linear activation plot 1210 in the reference posture, the resulting ECAP threshold Zr, the target ECAP amplitude dtgt, and the corresponding probe stimulus intensity Ip be as obtained from the activation plot 1210. The ratio of Ipmbe to IT is the reference posture probe dose ratio Dprobe.

[0149] A target dose ratio Dtgt or a target dose metric tgt for the therapy stimset may be obtained by varying that quantity and running the corresponding constant dose ratio CLNS implementation until the patient is satisfied with their pain relief in a reference posture.

[0150] In some implementations, the target dose ratio Dtgt or the target dose metric tgt or the therapy multiple / may be adjusted by the patient via the patient remote controller 720, rather than the target ECAP amplitude as in conventional CLNS systems.

[0151] The stimset ratio for RA for the therapy stimset for the burst variants may be obtained from the target dose ratio Dtgt, the probe dose ratio Dprobe, and the ratio C between the ECAP threshold iT(therapy) of the therapy pulses and the ECAP threshold IT of the probe stimset, as follows:

[0152] The exponent y may be determined by running the generalised implementation with the patient in two static extreme postures (such as supine and sitting) and various values of y, and asking the patient to indicate for what value of y the perceived difference of paresthesia sensation between the two postures goes to zero or at least to a minimum. Alternatively, a population mean value for y may be used for every patient.

[0153] The base current Io may be determined by measuring the ECAP threshold IT across many postures and fitting the model to the resulting values. According to the model of ECAP threshold IT vs distance in equation (10), the base current Io will be the lower bound for the ECAP threshold IT in the most sensitive postures.INTERPRETATION

[0154] The technology disclosed herein may be implemented in hardware (e.g., using digital signal processors, application specific integrated circuits (ASICs) or field programmable gate arrays (FPGAs)), or in software (e.g., using instructions tangibly stored on non-transitory computer-readable media for causing a data processing system to perform the steps described herein), or in a combination of hardware and software. The disclosed technology can also be implemented as computer-readable code on a computer-readable medium. The computer-readable medium can include any data storage device that can store data which can thereafter be read by a computer system. Examples of the computer-readable medium include read-only memory ("ROM"), random-access memory ("RAM"), magnetic tape, optical data storage devices, flash storage devices, or any other suitable storage devices. The computer-readable medium can also be distributed over network-coupled computer systems so that the computer-readable code is stored or executed in a distributed fashion. The present technology is not limited to any particular programming language or operating system.Wireless

[0155] In the context of the present disclosure, the term “wireless” and its derivatives may be used to describe circuits, devices, systems, methods, techniques, communications channels, etc., that may communicate data through the use of modulated electromagnetic radiation through a non-solid medium. The term does not imply that the associated devices do not contain any wires, although in some embodiments they might not. In the context of the present disclosure, the term “wired” and its derivatives may be used to describe circuits, devices, systems, methods, techniques, communications channels, etc., that may communicate data through the use of modulated signals propagating through a conductive medium. The term does not imply that the associated devices are coupled by electrically conductive wires.

[0156] Wireless communication standards that can be accommodated include IEEE 802.11 wireless LANs and links, Bluetooth, and wireless Ethernet. The technology disclosed herein may be implemented using devices conforming to other network standards and for other applications, including, for example other WLAN standards and other wireless standards such as MICS.Processes

[0157] Unless specifically stated otherwise, as apparent from the following discussions, it is appreciated that throughout the specification discussions utilizing terms such as “processing”, “computing”, “comparing”, “estimating”, “calculating”, “determining”, “analysing” or the like, refer to the action or processes of a computer or computing system, or similar electronic computing device, that manipulate or transform data represented as physical, such as electronic, quantities into other data similarly represented as physical quantities, or to otherwise execute a predefined procedure suitable to effect the described actions.Processor

[0158] In a similar manner, the term “processor” may refer to any device or portion of a device that processes electronic data, e.g., from registers or memory, to transform that electronic data into other electronic data that, e.g., may be stored in registers or memory. A “computer” or a “computing device” or a “computing machine” or a “computing platform” may include one or more processors.

[0159] The methods described herein are, in one embodiment, performable by one or more processors that accept computer-readable (also called machine-readable) code containing a set of instructions that when executed by one or more of the processors cause the one or more processors to carry out at least one of the methods described herein. Any processor capable of executing a set of instructions (sequential or otherwise) that specify actions to be taken are included within the meaning of the term “processor”. Thus, one example is a typical processing system that includes one or more processors. The processing system further may include a memory subsystem including main RAM or a static RAM, or ROM.Networked or Multiple Processors

[0160] In alternative embodiments, the one or more processors operate as respective standalone device(s) or may be connected, e.g., networked to other processor(s), in a networked deployment. The one or more processors may operate in the capacity of a server or a client machine in serverclient network environment, or as a peer machine in a peer-to-peer or distributed network environment. The one or more processors may form a web appliance, a network router, switch or bridge, or any machine capable of executing a set of instructions (sequential or otherwise) that specify actions to be taken by that machine.

[0161] Note that while some diagram(s) only show(s) a single processor and a single memory that carries the computer-readable code, those in the art will understand that many of the components described above are included, but not explicitly shown or described in order not to obscure the inventive aspect. For example, while only a single machine may be illustrated, the term “machine”shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methods discussed herein.Additional Implementations

[0162] Thus, one implementation of each of the methods described herein is in the form of a computer-readable medium carrying a set of instructions, e.g., a computer program that are for execution on one or more processors. Thus, as will be appreciated by those skilled in the art, aspects of the present technology may be implemented as a method, an apparatus such as a special purpose apparatus, an apparatus such as a data processing system, or a computer-readable medium. The computer-readable medium carries computer-readable code including a set of instructions that when executed on one or more processors cause the processor or processors to implement a method. Accordingly, aspects of the present technology may take the form of a method, an entirely hardware implementation, an entirely software implementation or an implementation combining software and hardware aspects. Furthermore, the present technology may take the form of a carrier medium (e.g., a computer program product) carrying computer-readable program code embodied in the medium.Carrier Medium

[0163] The software may further be transmitted or received over a network via a network interface device. While the carrier medium is shown in an example embodiment to be a single medium, the term “carrier medium” should be taken to include a single medium or multiple media (e.g., a centralized or distributed database, or associated caches and servers) that store the one or more sets of instructions. A carrier medium may take many forms, including but not limited to, non-volatile media, volatile media, and transmission media.Means For Carrying out a Method or Function

[0164] Furthermore, some of the implementations are described herein as a method or combination of elements of a method that can be implemented by a processor of a processor device, computer system, or by other means of carrying out the function. Thus, a processor with the necessary instructions for carrying out such a method or element of a method forms a means for carrying out the method or element of a method. Furthermore, an element described herein of an apparatus is an example of a means for carrying out the function performed by the element.

[0165] Those of skill would further appreciate that the various illustrative logical blocks, modules, and algorithm steps described in connection with the implementations disclosed herein may be implemented as electronic hardware, computer software running on a special purpose machine that is programmed to carry out the operations described in the present disclosure, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrativecomponents, blocks, modules, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the exemplary implementations.Implementations

[0166] Reference throughout the present disclosure to “one implementation” or “an implementation” means that a particular feature, structure or characteristic described in connection with the implementation is included in at least one implementation of the present technology. Thus, appearances of the phrases “in one implementation” or “in an implementation” in various places throughout the present disclosure are not necessarily all referring to the same implementation, but may refer to different implementations. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more implementations.

[0167] Similarly, it should be appreciated that in the above description of example implementations of the present technology, various features are sometimes grouped together in a single implementation, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects may lie in less than all features of a single foregoing disclosed implementation. Thus, the claims following the Detailed Description of the Present Technology are hereby expressly incorporated into this Detailed Description of the Present Technology, with each claim standing on its own as a separate implementation of the present technology.

[0168] Furthermore, while some implementations described herein include some, but not other features included in other implementations, combinations of features of different implementations are meant to be within the scope of the present technology, and form different implementations of the present technology, as would be understood by those in the art. For example, in the following claims, any of the claimed implementations can generally be used in any combination.

[0169] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word "about" or "approximately," even if the term does not expressly appear. The phrase "about" or "approximately" may be used when describing magnitude or position to indicate that the value or position describedis within a reasonable expected range of values or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value "10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that each value between two particular values is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.Different Instances of Objects

[0170] As used herein, unless otherwise specified the use of the ordinal adjectives “first”, “second”, “third”, etc., to describe a common object, merely indicates that different instances of like objects are being referred to, and is not intended to imply that the objects so described must be in a given sequence, either temporally, spatially, in ranking, or in any other manner.Specific Details

[0171] In the description provided herein, numerous specific details are set forth. However, it is understood that implementations of the present technology may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of the present technology.Terminology

[0172] Throughout the present disclosure, the terms "a" and "an" mean "one or more", unless expressly specified otherwise.

[0173] Throughout the present disclosure, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer, or step, or group of elements, integers, or steps, but not the exclusion of any other element, integer, or step, or group of elements, integers, or steps.

[0174] Throughout the present disclosure, a statement that an element may be “at least one of’ or “one or more of’ a list of options is to be understood to mean that the element may be any one of the listed options, or may be any combination of two or more of the listed options.

[0175] Throughout the present disclosure, the word “or” is to be read inclusively rather than exclusively, except where otherwise indicated.

[0176] Neither the title nor any abstract of the present disclosure should be taken as limiting in any way the scope of the claimed invention.

[0177] Where the preamble of a claim recites a purpose, benefit or possible use of the claimed invention, it does not necessarily limit the claimed invention to having only that purpose, benefit or possible use.

[0178] In the present specification, terms such as "part", "component", "means", "section", or "segment" may refer to singular or plural items and are terms intended to refer to a set of properties, functions, or characteristics performed by one or more items having one or more parts. It is envisaged that where a "part", "component", "means", "section", "segment", or similar term is described as consisting of a single item, then a functionally equivalent object consisting of multiple items is considered to fall within the scope of the term; and similarly, where a "part", "component", "means", "section", "segment", or similar term is described as consisting of multiple items, a functionally equivalent object consisting of a single item is considered to fall within the scope of the term. The intended interpretation of such terms described in this paragraph should apply unless the contrary is expressly stated or the context requires otherwise.

[0179] The term "connected" or a similar term, should not be interpreted as being limited to direct connections only. Thus, the scope of the expression “an item A connected to an item B” should not be limited to items or systems wherein an output of item A is directly connected to an input of item B. It means that there exists a path between an output of A and an input of B which may be a path including other items or means. "Connected", or a similar term, may mean either that two or more elements are in direct physical or causal contact, or that two or more elements are not in direct contact with each other yet still co-operate or interact with each other.

[0180] It will be appreciated by persons skilled in the art that numerous variations or modifications may be made to the present technology as shown in the specific implementations without departing from the spirit or scope of the invention as broadly described. For example, any formulas given above are merely representative of procedures that may be used. Functionality may be added or deleted from the block diagrams and operations may be interchanged among functional blocks. Steps may be added or deleted to methods described within the scope of the present technology. The disclosed implementations are, therefore, to be considered in all respects as illustrative and not limiting or restrictive.

[0181] The features described in relation to one or more aspects of the present technology are to be understood as applicable to other aspects of the present technology. More generally, combinations of the steps in the method(s) of the present technology or the features of the system(s) or device(s) of the present technology described elsewhere in the present disclosure, including in the claims, are to be understood as falling within the scope of the disclosure of the present disclosure.INDUSTRIAL APPLICABILITY

[0182] It is apparent from the above that the arrangements described are applicable to the health care industries.LABEL LIST stimulator 100 perception threshold 410 patient 108 therapeutic range 412 electronics module 110 activation plot 502 battery 112 activation plot 504 telemetry module 114 activation plot 506 controller 116 ECAP threshold 508 memory 118 ECAP threshold 510 clinical data 120 ECAP threshold 512 clinical settings 121 target ECAP amplitude 520 control programs 122 ECAP 600 pulse generator 124 neural stimulation system 700 electrode selection module 126 neuromodul ati on devi ce 710 measurement circuitry 128 patient remote controller 720 ground 130 CST 730 array 150 CI 740 biphasic stimulus pulse 160 charger 750ECAP 170 illustration 800 target fibres 180 stimulus pulse 810 communications channel 190 ISI 815 external computing device 192 stimulus pulse 820CLNS system 300 stimulus pulse 830 clinical settings controller 302 stimulus pulse 840 target ECAP controller 304 stimulus pulse 850 box 308 ECAP 860 box 309 stimulus period 890 controller 310 multi - stimset CLNS system 900 box 311 graph 1000 stimulator 312 activation plot 1002 stimulator 312A activation plot 1004 stimulator 312B activation plot 1006 stimulator 312C dashed line 1008 stimulator 312D dashed line 1010 element 313 dashed line 1012 measurement circuitry 318 dashed line 1014 signal window 319 ECAP threshold 1016ECAP detector 320 ECAP threshold 1018 comparator 324 ECAP threshold 1020 gain element 336 graph 1100 integrator 338 activation plot 1110 activation plot 402 graph 1200ECAP threshold 404 activation plot 1210 discomfort threshold 408 method 1300step 1310 histogram 1410 step 1320 histogram 1420 step 1330 histogram 1430 step 1340 histogram 1440 step 1350 histogram 1450 series 1400 histogram 1460

Claims

CLAIMS:

1. An implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity, wherein the target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

2. The device of claim 1, wherein the target response intensity is configured to be close to a noise floor of the measurement circuitry.

3. The device of any one of claims 1 to 2, wherein the control unit is configured to determine the therapy stimulus intensity by multiplying the adjusted probe stimulus intensity by the target dose metric.

4. The device of claim 3, wherein the control unit is configured to divide the probe stimulus intensity by a probe dose ratio before determining the therapy stimulus intensity.

5. The device of any one of claims 1 to 2, wherein the control unit is configured to determine the therapy stimulus intensity by adding the probe stimulus intensity to the product of: the target dose metric minus one, and the probe stimulus intensity raised to the power of a predetermined exponent.

6. The device of claim 5, wherein the control unit is configured to subtract a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent.

7. The device of claim 5, wherein the control unit is configured to divide the probe stimulus intensity by a probe dose ratio before determining the therapy stimulus intensity.

8. The device of claim 7, wherein the control unit is configured to subtract a base current from the ratio of the probe stimulus intensity to the probe dose ratio before the raising to the power of the predetermined exponent.

9. The device of any one of claims 1 to 2, wherein the control unit is configured to determine the therapy stimulus intensity by: estimating a dose metric from the therapy stimulus intensity; and adjusting, using a therapy feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near the target dose metric.

10. The device of claim 9, wherein the control unit is configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the probe stimulus intensity; and the probe stimulus intensity raised to an exponent.

11. The device of claim 10, wherein the control unit is configured to estimate the dose metric by determining a ratio of: the therapy stimulus intensity and the probe stimulus intensity.

12. The device of any one of claims 10 to 11, wherein the control unit is configured to divide the probe stimulus intensity by a probe dose ratio before estimating the dose metric.

13. An automated method of controllab ly delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a probe stimulus to the neural pathway of the patient, the probe stimulus being configured to evoke a neural response from the neural pathway, the probe stimulus being delivered according to a probe stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the probe stimulus; measuring an intensity of a neural response evoked by the probe stimulus in the signal window; adjusting the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determining a therapy stimulus intensity based on the adjusted probe stimulus intensity; and delivering a therapy stimulus according to the adjusted therapy stimulus intensity, wherein the target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

14. The method of claim 13, wherein the target response intensity is configured to be close to a noise floor of measurement circuitry.

15. The method of any one of claims 13 to 14, wherein determining the therapy stimulus intensity comprises multiplying the adjusted probe stimulus intensity by the target dose metric.

16. The method of any one of claims 13 to 14, wherein determining the therapy stimulus intensity comprises adding the probe stimulus intensity to the product of: the target dose metric minus one, and the probe stimulus intensity raised to the power of a predetermined exponent.

17. The method of claim 16, further comprising subtracting a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent.

18. The method of claim 16, wherein further comprising dividing the probe stimulus intensity by a probe dose ratio before determining the therapy stimulus intensity.

19. The method of claim 18, further comprising subtracting a base current from the ratio of the probe stimulus intensity to the probe dose ratio before the raising to the power of the predetermined exponent.

20. A neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter; a processor configured to: instruct the control unit to control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity;determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity, wherein the target response intensity is configured such that the therapy stimuli are delivered at or near a target dose metric as posture varies.

21. An implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

22. The device of claim 21, wherein the neural response threshold is the adjusted probe stimulus intensity.

23. The device of claim 21, wherein the control unit is configured to estimate the neural response threshold by dividing the adjusted probe stimulus intensity by a probe dose metric.

24. The device of any one of claims 21 to 23, wherein the control unit is configured to adjust the therapy stimulus intensity by multiplying the estimated neural response threshold by a target dose metric.

25. The device of any one of claims 21 to 23, wherein the control unit is configured to adjust the therapy stimulus intensity by adding the estimated neural response threshold to the product of: a target dose metric minus one, andthe estimated neural response threshold raised to the power of a predetermined exponent.

26. The device of claim 25, wherein the control unit is configured to subtract a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent.

27. The device of any one of claims 21 to 23, wherein the control unit is configured to determine the therapy stimulus intensity by: estimating a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjusting, using a therapy feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

28. The device of claim 27, wherein the control unit is configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the estimated neural response threshold; and the estimated neural response threshold raised to an exponent.

29. The device of claim 27, wherein the control unit is configured to estimate the dose metric by determining a ratio of the therapy stimulus intensity and the estimated neural response threshold.

30. An automated method of controllably delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a probe stimulus to the neural pathway of the patient, the probe stimulus being configured to evoke a neural response from the neural pathway, the probe stimulus being delivered according to a probe stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the probe stimulus; measuring an intensity of a neural response evoked by the probe stimulus in the signal window; adjusting the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimating a neural response threshold from the adjusted probe stimulus intensity; adjusting a therapy stimulus intensity based on the estimated neural response threshold; and delivering a therapy stimulus according to the adjusted therapy stimulus intensity.

31. The method of claim 30, wherein the neural response threshold is the adjusted probe stimulus intensity.

32. The method of claim 30, wherein estimating the neural response threshold comprises dividing the adjusted probe stimulus intensity by a probe dose metric.

33. The method of any one of claims 30 to 32, wherein adjusting the therapy stimulus intensity comprises multiplying the estimated neural response threshold by a target dose metric.

34. The method of any one of claims 30 to 32, wherein adjusting the therapy stimulus intensity comprises adding the estimated neural response threshold to the product of: a target dose metric minus one, and the estimated neural response threshold raised to the power of a predetermined exponent.

35. The method of claim 34, further comprising subtracting a base current from the probe stimulus intensity before raising the probe stimulus intensity to the power of the predetermined exponent.

36. The method of any one of claims 30 to 32, further comprising determining the therapy stimulus intensity by: estimating a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjusting, using a therapy feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

37. The method of claim 36, further comprising estimating the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the estimated neural response threshold; and the estimated neural response threshold raised to an exponent.

38. The method of claim 36, further comprising estimating the dose metric by determining a ratio of the therapy stimulus intensity and the estimated neural response threshold.

39. A neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; and measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter; and a processor configured to repeatedly: instruct the control unit to control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity;measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

40. A multi-stimset closed-loop neural stimulation device comprising: a control unit configured to: control a stimulus source to deliver probe stimuli according to a probe stimset interleaved with therapy stimuli according to a therapy stimset; and adjust, using a feedback controller, a probe stimulus intensity parameter of the probe stimuli so as to maintain a measured neural response intensity at or near a target response intensity, wherein the target response intensity is configured such that the therapy stimuli are delivered at or near a target dose ratio as posture varies.

41. A multi-stimset closed-loop neural stimulation device comprising: a control unit configured to: control a stimulus source to deliver probe stimuli according to a probe stimset interleaved with therapy stimuli according to a therapy stimset; adjust, using a feedback controller, a probe stimulus intensity parameter of the probe stimuli so as to maintain a measured neural response intensity at or near a target response intensity; estimate a neural response threshold from the adjusted probe stimulus intensity; adjust a therapy stimulus intensity of the therapy stimuli based on the estimated neural response threshold; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity.

42. A neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, the device comprising:a stimulus source configured to deliver neural stimuli to be delivered via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient in order to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity; determine a therapy stimulus intensity based on the adjusted probe stimulus intensity; and control the stimulus source to deliver a therapy stimulus according to the adjusted therapy stimulus intensity; and a processor configured to: increase the target response intensity; construct a distribution of probe stimulus intensities at each target response intensity; determine a transitional target response intensity at which the distribution achieves a consistently Gaussian form; and program the implantable device using the transitional target response intensity.

43. An automated method of programming a multi-stimset closed-loop neural stimulation device, the method comprising: increasing a target response intensity value; constructing, for each value of target response intensity, a distribution of probe stimulus intensities; determining a transitional target response intensity at which the distribution achieves a consistently Gaussian form; and programming the multi-stimset closed-loop neural stimulation device using the transitional target response intensity.

44. An implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to repeatedly: control the stimulus source to deliver a therapy stimulus according to a therapy stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the therapy stimulus; estimate a neural response threshold of the neural pathway using the measured response intensity; estimate a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjust, using a feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

45. The device of claim 44, wherein the control unit is configured to estimate the dose metric by determining a ratio of: the difference between the therapy stimulus intensity and the estimated neural response threshold; and the estimated neural response threshold raised to an exponent.

46. The device of claim 44, wherein the control unit is configured to estimate the dose metric by determining a ratio of the therapy stimulus intensity and the estimated neural response threshold.

47. The device of any one of claims 44 to 46, wherein the control unit is further configured to: control the stimulus source to deliver a probe stimulus according to a probe stimulus intensity; measure an intensity of an evoked neural response in a signal window captured subsequent to the probe stimulus; and adjust, using a feedback controller, the probe stimulus intensity so as to maintain the measured neural response intensity at or near a target response intensity.

48. The device of claim 47, wherein the control unit is configured to estimate the neural response threshold as the adjusted probe stimulus intensity.

49. The device of claim 47, wherein the control unit is configured to estimate the neural response threshold by dividing the adjusted probe stimulus intensity by a probe dose ratio.

50. An automated method of controllably delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a therapy stimulus to the neural pathway of the patient, the therapy stimulus being configured to evoke a neural response from the neural pathway, the therapy stimulus being delivered according to a therapy stimulus intensity; capturing a signal window from a signal sensed on the neural pathway subsequent to the therapy stimulus; measure an intensity of an evoked neural response in the signal window; estimating a neural response threshold of the neural pathway using the measured response intensity; estimating a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjusting the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

51. A neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to deliver neural stimuli via one or more stimulus electrodes of an electrode assembly to a neural pathway of a patient, the neural stimuli being configured to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes of the electrode assembly; and a control unit configured to control the stimulus source to deliver each neural stimulus according to a stimulus intensity parameter; a processor configured to: instruct the control unit to control the stimulus source to deliver a therapy stimulus according to a therapy stimulus intensity;measure an intensity of an evoked neural response in a signal window captured subsequent to the therapy stimulus; estimate a neural response threshold of the neural pathway using the measured response intensity; estimate a dose metric from the therapy stimulus intensity and the estimated neural response threshold; and adjust, using a feedback controller, the therapy stimulus intensity so as to maintain the estimated dose metric at or near a target dose metric.

52. A closed-loop neural stimulation device comprising: a control unit configured to: control a stimulus source to deliver therapy stimuli; and adjust, using a feedback controller, a therapy stimulus intensity parameter of the therapy stimuli so as to maintain an estimated dose metric of the therapy stimuli at or near a target dose metric.

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