Improved measurement of evoked responses to neural stimulation

Abstract

An implantable device that deliver neural stimuli to a neural pathway of a patient 108 in order to evoke neural responses 130 using implanted stimulation electrodes. A control unit configured to control the stimulus source to provide a first neural stimulus according to a first stimulation set. Then using one or more shorting pulse parameters of a first stimulation set, connect the stimulation electrodes. Measure an intensity of an evoked neural response in a captured signal window subsequent to a second neural stimulus. The captured signal window includes an artefact resulting from the first neural stimulus. The one or more shorting pulse parameters are configured to minimise a magnitude of the artefact in the captured signal window.

Description

IMPROVED MEASUREMENT OF EVOKED RESPONSES TO NEURAL STIMULATION

[0001] The present application claims priority from Australian Provisional Patent Application No 2023902643 filed on 21 August 2023, 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 methods and devices for measurement of evoked responses to neural stimulation in the presence of artefact.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 neuropathic pain, Parkinson’s disease, and migraine. 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 effect. 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 A0 (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 frequency in the range of 30 Hz - 100 Hz.

[0005] For effective and comfortable neuromodulation, it is necessary to maintain stimulus intensity above a recruitment threshold. Stimuli below the recruitment threshold will fail to recruit sufficient neurons 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 A0 fibres or recruitment of undesired fibre classes. When recruitment is too large, A0 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 recruitment threshold and the discomfort threshold.

[0006] The task of maintaining appropriate 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 recruitment arising from a given stimulus, and therefore the therapeutic range. There is room in the epidural space for the electrode array to move, and such array movement from migration or posture change alters the electrode-to-cord distance and thus the recruitment efficacy of a given stimulus. Moreover, the spinal cord itself can move within the cerebrospinal fluid (CSF) with respect to the dura. During postural changes, the amount of CSF or 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. Feedback control seeks to compensate for relative nerve / electrode movement by controlling the intensity of the delivered stimuli so as to maintain neural recruitment 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 recruitment. 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 largenumber 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 measured at 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 measurement electrode as the action potentials propagate along the individual fibres.

[0009] 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.

[0010] However, neural response measurement can be a difficult task as a neural response component in the sensed signal will typically have a maximum amplitude in the range of microvolts. In contrast, a stimulus applied to evoke the response is typically several volts, and manifests in the sensed signal as crosstalk of that magnitude. Moreover, stimulus generally results in electrode artefact, which may manifest in the sensed signal as a decaying output of the order of several millivolts after the end of the stimulus. As the neural response can be contemporaneous with the stimulus crosstalk or the stimulus artefact, neural response measurements present a difficult challenge of measurement amplifier design. For example, to resolve a 10 pV ECAP with 1 pV resolution in the presence of stimulus crosstalk of 5 V requires an amplifier with a dynamic range of 134 dB, which is impractical in implantable devices. In practice, many non-ideal aspects of a circuit lead to artefact, and as these aspects mostly result in a time-decaying artefact waveform of positive or negative polarity, their identification and elimination can be laborious.

[0011] Evoked neural responses are less difficult to measure when they appear later in time than the artefact, or when the signal-to-noise ratio is sufficiently high. The artefact is often restricted to a time of 1 - 2 ms after the stimulus and so, provided the neural response is measured after this time window, a neural response measurement can be more easily obtained. This is the case in surgical monitoring where there are large distances (e.g. more than 12 cm for nerves conducting at 60 ms'1) between the stimulus and measurement electrodes so that the propagation time from the stimulus site to the measurement electrodes exceeds 2 ms, which is longer than the typical duration of stimulus artefact.

[0012] However, to characterize the responses from the dorsal column, high stimulation currents are required. Similarly, any implanted neuromodulation device will necessarily be of compact size, so that for such devices to monitor the effect of applied stimuli, the stimulus electrode(s) and measurement electrode(s) will necessarily be in close proximity. In such situations the measurement process must overcome artefact directly.

[0013] In a feedback-controlled implantable neuromodulation device, it is beneficial to have a wide choice of measurement electrodes among the electrodes in the implanted array. Ideally any electrode should be available to be selected as a measurement electrode, so that the best quality signal may be sensed regardless of which electrodes are used to stimulate the neural tissue. For example, a measurement electrode at the opposite end of the array to the stimulation electrode may yield the highest quality sensed signals on account of the delay between the stimulus and the time of arrival of the evoked response. Such a delay increases the separation in time between artefact and evoke response.

[0014] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. 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 invention as it existed before the priority date of each claim of this application.

[0015] Throughout this specification 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.

[0016] In this specification, a statement that an element may be “at least one 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.SUMMARY OF THE INVENTION

[0017] As mentioned above, a measurement electrode at the opposite end of the array to the stimulation electrode may yield the highest quality sensed signals on account of the delay between the stimulus and the time of arrival of the evoked response. In a multi-stimset neural stimulation system, this may mean that the optimally-located measurement electrode for a given stimset has recently been used as a stimulation electrode for a previous stimset. While this configuration, in which the measurement electrode is referred to as being subject to role overlap, may be optimal in principle, artefact may occur at the measurement electrode as a result of the stimuli delivered according to the previous stimset. Such artefact is referred to herein as overlap artefact. It is therefore important that overlap artefact is mitigated to enable role-overlapped electrodes to be used as measurement electrodes.

[0018] Disclosed herein are methods and devices configured to mitigate overlap artefact that occurs at a measurement electrode that has recently been used as a stimulation electrode. The disclosedmethods and devices are configured to apply a shorting pulse involving the role-overlapped measurement electrode before the measurement phase in such a way as to mitigate the artefact. Such a shorting pulse may, if properly configured, give rise to artefact that counteracts the stimulus artefact resulting from the recent use of that measurement electrode as a stimulation electrode. Also disclosed are methods and systems for configuring the shorting pulse so as to maximally mitigate the stimulus artefact.

[0019] 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 provide neural stimuli to be delivered according to a stimulation set to a neural pathway of a patient in order to evoke neural responses from the neural pathway, wherein the stimulation set comprises a plurality of implanted stimulation electrodes; measurement circuitry configured to capture signal windows sensed on the neural pathway via one or more implanted measurement electrodes; and a control unit configured to: control the stimulus source to provide a first neural stimulus according to a first stimulation set; connect together, using one or more shorting pulse parameters of the first stimulation set, the stimulation electrodes of the first stimulation set; control the stimulus source to provide a second neural stimulus according to a second stimulation set; and measure an intensity of an evoked neural response in a captured signal window subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus, wherein the one or more shorting pulse parameters are configured to minimise a magnitude of the artefact in the captured signal window.

[0020] 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 first neural stimulus to the neural pathway of the patient according to a first stimulation set, wherein the first stimulation set comprises a plurality of implanted stimulation electrodes; connecting together, using one or more shorting pulse parameters, the stimulation electrodes of the first stimulation set; delivering a second neural stimulus to the neural pathway of the patient in order to evoke a neural response from the neural pathway, the second neural stimulus being delivered according to a second stimulation set; capturing, via one or more implanted measurement electrodes, a signal window sensed on the neural pathway subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus; and measuring an intensity of the neural response evoked by the second neural stimulus in the captured signal window, wherein the one or more shorting pulse parameters are configured to minimise a magnitude of the artefact in the captured signal window.

[0021] According to a third aspect of the present technology, there is provided a neural stimulation system comprising: an implantable neuromodulation device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to provide neural stimuli to be delivered to a neural pathway of a patient in order to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows sensed on the neural pathway via one or more implanted measurement electrodes, subsequent to respective neural stimuli; and a control unit configured to control the stimulus source to provide neural stimuli according to a stimulation set, wherein the stimulation set comprises a plurality of implanted stimulation electrodes; and a processor configured to repeatedly, for each candidate shorting pulse parameter value of a set of candidate shorting pulse parameter values: instruct the control unit to control the stimulus source to provide a first neural stimulus according to a first stimulation set; instruct the control unit to connect together, using a candidate shorting pulse parameter value, the stimulation electrodes of the first stimulation set; instruct the control unit to control the stimulus source to provide a second neural stimulus according to a second stimulation set; and measure a magnitude of an artefact in a captured signal window subsequent to the second neural stimulus, the artefact resulting from the first neural stimulus; thereby obtaining a plurality of measured artefact magnitudes at respective candidate shorting pulse parameter values; and choose a shorting pulse parameter value for the first stimulation set based on the plurality of measured artefact magnitudes.

[0022] According to a fourth 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 first neural stimulus to the neural pathway of the patient according to a first stimulation set, wherein the first stimulation set comprises a plurality of implanted stimulation electrodes; connecting together, using a candidate shorting pulse parameter value, the stimulation electrodes of the first stimulation set; delivering a second neural stimulus to the neural pathway of the patient in order to evoke a neural response from the neural pathway, the second neural stimulus being delivered according to a second stimulation set; capturing, via one or more implanted measurement electrodes, a signal window sensed on the neural pathway subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus; measuring a magnitude of an artefact in a captured signal window subsequent to the second neural stimulus, the artefact resulting from the first neural stimulus; repeating the delivering, connecting, delivering, capturing, and measuring for a plurality of candidate shorting pulse parameter values to obtain a plurality of measured artefact magnitudes at respective candidate shorting pulse parameter values; and choosing a shorting pulse parameter value for the first stimulation set based on the plurality of measured artefact magnitudes.

[0023] References herein to estimation, determination, comparison and the like are to be understood as referring to an automated process carried out on data by a processor operating to execute a predefined procedure suitable to effect the described estimation, determination or comparison step(s). 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 embodied 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Notwithstanding any other implementations which may fall within the scope of the present invention, implementations of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0025] Fig. 1 schematically illustrates an implanted spinal cord stimulator, according to one implementation of the present technology;

[0026] Fig. 2 is a block diagram of the stimulator of Fig. 1;

[0027] Fig. 3 is a schematic illustrating interaction of the implanted stimulator of Fig. 1 with a nerve;

[0028] Fig. 4a illustrates an idealised activation plot for one posture of a patient undergoing neural stimulation;

[0029] Fig. 4b illustrates the variation in the activation plots with changing posture of the patient;

[0030] 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;

[0031] Fig. 6 illustrates the typical form of an electrically evoked compound action potential (ECAP) of a healthy subject;

[0032] 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;

[0033] Fig. 8 is an illustration of the stimulus pulses delivered by a stimulation program with four interleaved stimulation sets (stimsets);

[0034] Fig. 9 is a schematic illustrating elements and inputs of a closed-loop neural stimulation (CLNS) system with multiple stimsets;

[0035] Figs. 10a and 10b are an illustrations of situations of role overlap;

[0036] Fig. 11 illustrates a multi-stimset program comprising two stimsets and a shorting pulse for each stimset;

[0037] Fig. 12 contains a graph showing two traces of measured peak-to-peak artefact amplitude;

[0038] Fig. 13 illustrates a multi-stimset program comprising two stimsets and a shorting pulse for each stimset, according to one aspect of the present technology;

[0039] Fig. 14 contains a graph showing two traces of measured peak-to-peak artefact amplitude;

[0040] Fig. 15 is a flow chart illustrating a method of mitigating inter-stimset overlap artefact according to one implementation of the present technology; and

[0041] Fig. 16 is a flow chart illustrating a method of controllably delivering neural stimuli according to one implementation of the present technology.DETAILED DESCRIPTION OF THE PRESENT TECHNOLOGY

[0042] 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 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.

[0043] 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.

[0044] 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 at measurement electrode(s) of the electrode array 150 as selected by electrode selection module 126.

[0045] 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 to tissue. 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,or may 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, and the stimulus electrodes and return electrodes are referred to generally as the stimulation electrodes.. 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.

[0046] 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 to create paraesthesia at a desired location. To this end, the electrodes 2 and 4 are used to deliver stimuli periodically at any therapeutically suitable 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 is experienced by the user as paraesthesia. When a stimulus electrode configuration is found which evokes paraesthesia 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.

[0047] Fig. 6 illustrates the typical form of an ECAP 600 of a healthy subject, as recorded at a single measurement electrode referenced to the system ground 130. 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.

[0048] 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 surrounding tissue 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.

[0049] The ECAP 600 may be characterised by any suitable characteristic(s) of which some are indicated in Fig. 6. The amplitude of the positive peak Pl isApi and occurs at time Tpi. The amplitude of the positive peak P2 is A pi 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 Ap\ + 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 ms.

[0050] 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.

[0051] 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 ECAPdetector may measure and store an alternative characteristic from the neural response, or may measure and store two or more characteristics from the neural response.

[0052] 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.

[0053] 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:

[0054] where 5 is the stimulus intensity, y is the ECAP amplitude, T is the ECAP threshold and S is the slope of the activation plot (referred to herein as the patient sensitivity) above the ECAP threshold T. The sensitivity S and the ECAP threshold T are the key parameters of the activation plot 402.

[0055] 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 the perception 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.

[0056] 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.

[0057] 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.

[0058] 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 intensityto maintain the measured ECAP amplitude at 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 reduce the error as much as possible, such as by adding the scaled error to the current stimulus intensity. A neuromodulation device that operates by adjusting the applied stimulus intensity based on a measured ECAP characteristic 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 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.

[0059] A CLNS device comprises a stimulator 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 feedback loop.

[0060] In an example CLNS system, a 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 contribution is disregarded and the CLNS device uses a first order integrating feedback loop. The stimulator produces 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.

[0061] 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 the target intensity. If the target intensity is properly chosen, the patient receives consistently comfortable and therapeutic stimulation through posture changes and other perturbations to the stimulus / response behaviour.

[0062] 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 stimulator 312 which converts a stimulus intensity parameter (for example a stimulus current amplitude) s, in concert with a set of predefined stimulus parameters, to a neural stimulus comprising a sequence of electrical pulses on 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 or frequency.

[0063] 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.

[0064] The neural recruitment 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 recruitment of the fibres being stimulated. In general, the more intense the stimulus, the more recruitment 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.

[0065] Measurement circuitry 318, which may be identified with measurement circuitry 128, amplifies the sensed signal r (including evoked neural response, artefact, and measurement noise), and samples the amplified sensed signal r to capture a “signal window” 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.

[0066] 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 gain element 336 and an integrator 338, in order to provide suitable adjustment to the stimulus intensityparameter 5. According to such an implementation, the current stimulus intensity parameter .s may be determined by the feedback controller 310 as s = f Kedt (2)

[0067] where K is the gain of the gain element 336 (the controller gain). This relation may also be represented as8s = Ke (3)

[0068] where 6 is an adjustment to the current stimulus intensity parameter .s.

[0069] 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.

[0070] A clinical settings controller 302 provides clinical settings to the system 300, including the feedback controller 310 and the stimulus parameters for the stimulator 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.

[0071] 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 stimulator 312 outputs 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.

[0072] 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 710may be implemented as the stimulator 100 of Fig. 1, implanted within a patient (not shown). The neuromodulation 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.

[0073] 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.

[0074] 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.

[0075] 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

[0076] 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.

[0077] 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 arecontemplated. 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-first stimulus 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.

[0078] Also illustrated is an evoked neural response in the form of an evoked compound action potential (ECAP) 860 as sensed via 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 from a single stimset, referred to as the applied stimset. In Fig. 8, the final stimset in the cycle is the applied stimset.

[0079] 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 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.

[0080] 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 four stimsets are labelled A, B, C, and D and are delivered by stimulators 312A, 312B, 312C, and 312D (the latter of which corresponds to the stimulator 312 in the CLNS system 300) according to respective stimulus intensity parameters SA, SB, SC, and SD, and via respective SECs. The pulses delivered by the stimulators 312A, 312B, 312C, and 312D correspond to the stimulus pulses 810,820, 830, and 840 of Fig. 8. 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. 8, the stimulus intensity parameter SD for stimset D is scaled by ratios RA, RB, and Rc to obtain the stimulus intensity parameters SA, SB, and sc for stimsets A, B, and C respectively. The ratios RA, RB, and Rc are fixed at the ratios of the respective stimulus intensities at which the respective stimsets were originally programmed, to the originally programmed stimulus intensity of the applied stimset D. 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 ratios RA, RB, and Rc are fixed at programming time at 1 / 6, 1 / 3, and 2 / 3 respectively and form part of the clinical settings 121 of the multi-stimset program. 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 to the stimulators 312 A, 312B, 312C, and 312D the stimulus parameters that are not under the control of the feedback controller 310.

[0081] 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.Inter-stimset overlap

[0082] Figs. 10a and 10b illustrate two situations of role overlap in a multi-stimset CLNS system. Both situations are examples of a species of role overlap referred to herein as inter-stimset overlap. In Fig. 10a, the electrode array 1000 is depicted twice. In the left depiction, a first stimulus is being delivered in tripolar fashion in accordance with a first stimset, comprising stimulus electrode 1020 and return electrodes 1010a and 1010b. In the right depiction, a second stimulus is being delivered in tripolar fashion in accordance with a second stimset, comprising stimulus electrode 1045 and return electrodes 1040a and 1040b. Since the second stimset is the applied stimset, a signal is to be sensed subsequent to the stimulus via measurement electrodes 1020 and 1030. Box 1035 indicates that electrode 1020 is subject to inter-stimset overlap, since electrode 1020 acts as a stimulus electrode for the first stimset and a measurement electrode for the second stimset.

[0083] In Fig. 10b, the electrode array 1050 is depicted twice. In the left depiction, a first stimulus is being delivered in tripolar fashion in accordance with a first stimset, comprising stimulus electrode1070 and return electrodes 1060a and 1060b. In the right depiction, a second stimulus is being delivered in tripolar fashion in accordance with a second stimset, comprising stimulus electrode 1095 and return electrodes 1090a and 1090b. Since the second stimset is the applied stimset, a signal is to be sensed subsequent to the stimulus via measurement electrodes 1080 and 1060a. Box 1085 indicates that electrode 1060a is subject to inter-stimset overlap, since electrode 1060a acts as a return electrode for the first stimset and a measurement electrode for the second stimset.

[0084] The interface between a metallic electrode and human tissue may be modelled as a constantphase element (CPE), distinct from a capacitor (which is a special case of CPE in which the phase shift is 90 degrees). The bidirectional flow of current during the stimulus pulse through the CPE of an electrode subject to inter-stimset overlap causes subsequent artefact at the input to the measurement circuitry 128 connected to such an electrode. In general (as in Figs. 10a and 10b), the other measurement electrode is not so overlapped, so different charge dynamics apply at the other input to the measurement circuitry 128, meaning that the artefact is not “common mode” and will be amplified by the differential amplifier in the measurement circuitry 128. This is referred to as inter- stimset overlap artefact.Passive charge recovery (electrode shorting)

[0085] A biphasic stimulus pulse, such as the pulse 810 illustrated in Fig. 8, comprises a first phase in which a volume of charge is sourced from a first electrode, passes through the adjacent neural tissue, and is sunk into a second electrode. Then in a second phase, a volume of charge is sourced from the second electrode, passes through the same neural tissue, and is sunk into the first electrode. Because the electrode-tissue interface may be modelled as a CPE, which is quasi-capacitive in character, charge flowing through it tends to build up charge across the interface. In addition, in some stimulators, there is a capacitor referred to as the electrode capacitor between the electrode selection module 126 (Fig. 3) and each electrode. The flow of charge through electrodes during a stimulus phase also builds up a charge across the corresponding electrode capacitors, if present. In principle, as long as the charge delivered during each phase matches precisely, no net charge will be added to the CPE or the electrode capacitor (if present) as a result of a biphasic pulse. If, however, there is a mismatch, however slight, between the charges delivered in each phase, for example due to tolerances of the current sources in the pulse generator 124, a net charge will accumulate across both elements. The resulting polarisation will eventually render the pulse generator 124 unable to deliver the stimulus pulses instructed by the controller 116. To prevent this occurring, after each stimulus pulse, any residual charge on the electrode-tissue interface (and the electrode capacitors, if present) resulting from charge mismatch between the phases may be passively recovered by connecting (shorting) thestimulation electrodes together for a duration referred to as the shorting interval (e.g. 100 microseconds). Optionally, while connected, the stimulation electrodes may also be connected to one of the voltage supply rails (VDDHV or ground) of the pulse generator 124. This is referred to as a shorting pulse or shorting event.

[0086] However, the present inventor has ascertained that such a shorting event also causes significant artefact at an overlapped electrode, since a shorting event in general involves current flow through the CPEs of the stimulation electrodes. The subsequent redistribution of charge within and between the CPEs results in results in artefact if any of the stimulation electrodes is subsequently used as a measurement electrode, as occurs in inter-stimset overlap. This artefact is referred to herein as shorting artefact.

[0087] Fig. 11 illustrates a multi-stimset program 1100 comprising two stimsets and a shorting pulse for each stimset. The stimulus pulses 1110 and 1150 are delivered according to the first stimset. The stimulus pulse 1120 is delivered according to the second stimset, which is the applied stimset. There is an inter-stimset interval 1115 between the pulses of the first stimset and those of the second stimset. The stimulus pulse 1120 evokes the neural response 1130 which may be used to adjust the parameters of both stimsets, as in a multi-stimset CLNS system as described above. The stimulation electrodes of the first stimset are shorted together during the shorting pulse 1140. The stimulation electrodes of the second stimset are shorted together during the shorting pulse 1160. The shorting pulse 1140 occurs a fixed interval 1145 before the stimulus pulse 1120 of the second stimset and causes artefact while capturing the neural response.Inter-stimset overlap artefact mitigation

[0088] In methods and devices according to the present technology, shorting artefact may be used to mitigate inter-stimset overlap artefact. This is possible because the shorting artefact may be of opposite sign to the inter-stimset overlap artefact. Therefore, if any or all of the shorting pulse parameters such as the delay (in relation to the start of the stimulus pulse) and the duration of the shorting event is properly configured, the magnitude of the shorting current may be such that the shorting artefact may substantially cancel the inter-stimset overlap artefact at the electrode subject to inter-stimset overlap.

[0089] This mitigation is illustrated in Fig. 12, which contains a graph 1200 showing two traces 1210 and 1220. Trace 1210 plots the measured peak-to-peak artefact amplitude against inter-stimset interval (ISI) in a configuration similar to that of Fig. 10a, except that neither measurement electrode is subject to inter-stimset overlap. Trace 1210 therefore shows a baseline level of artefact, and is generally independent of ISI since the artefact is a result of the stimuli delivered according to theapplied stimset (via electrodes 1040a, 1040b, and 1045 in Fig. 10a), rather than the first stimset (via electrodes 1010a, 1010b, and 1020).

[0090] Trace 1220 plots the measured peak-to-peak artefact in the configuration of Fig. 10a, in which one measurement electrode is subject to inter-stimset overlap, against inter-stimset interval (ISI). The artefact is much higher than the baseline 1210 for small values of ISI, since the artefact is dominated by the inter-stimset overlap artefact at the overlapped electrode 1020. As the ISI increases, the inter- stimset overlap artefact decreases, as expected, since the delay between the stimulus pulses of the first stimset (which give rise to the artefact) and the measurement after the second stimset increases with ISI. For large values of ISI, the shorting artefact resulting from the shorting pulse 1140 involving the overlapped electrode 1020 comes to dominate the measured artefact trace 1220. This is evident from the convergence of the measured artefact to a constant value above the baseline 1210, which comes about because the shorting pulse 1140 is delivered at a fixed interval 1145 before the stimulus pulse 1120 of the second stimset. The shorting artefact is therefore independent of ISI. At the ISI value 1230, the measured artefact reaches a minimum close to the baseline due to the substantial cancellation of the inter-stimset overlap artefact at this ISI value 1230 by the shorting artefact, which is independent of ISI.

[0091] Fig. 13 illustrates a multi-stimset program 1300 comprising two stimsets and a shorting pulse for each stimset, according to one aspect of the present technology. The stimulus pulses 1310 and 1350 are delivered according to the first stimset. The stimulus pulse 1320 is delivered according to the second stimset, which is the applied stimset. There is an inter-stimset interval 1315 between the pulses of the first stimset and those of the second stimset. The stimulus pulse 1320 evokes the neural response 1330 which may be used to adjust the parameters of both stimsets, as in a multi-stimset CLNS system as described above. The stimulation electrodes of the first stimset are shorted together during the shorting pulse 1340. The stimulation electrodes of the second stimset are shorted together during the shorting pulse 1360. In contrast with the shorting pulse 1140 in Fig. 11, the shorting pulse 1340 occurs a fixed interval 1345 after the stimulus pulse 1310 of the first stimset.

[0092] Fig. 14 contains a graph 1400 showing two traces 1410 and 1420. Trace 1410 is a reproduction of the baseline artefact trace 1210 of Fig. 12 in which no inter-stimset overlap artefact is present. Trace 1420 plots the measured peak-to-peak artefact in the configuration of Fig. 10a, in which one measurement electrode is subject to inter-stimset overlap, against ISI for the multi-stimset program 1300 of Fig. 13, in which the shorting pulse 1340 of the first stimset occurs a fixed interval 1345 after the stimulus pulse 1310 of the first stimset. Since the parameters of the shorting pulse 1340 are fixed in relation to the stimulus pulse 1310, the amount of cancellation does not change with ISI. The trace1420 therefore does not go through a minimum value as in the trace 1220, but simply declines towards baseline 1410 as the ISI increases and the combined effect of the inter-stimset overlap artefact and the shorting artefact fade into the background compared to the artefact resulting from the stimulus pulse 1320.

[0093] According to one implementation of the present technology, during programming of a multi - stimset program containing a stimset comprising a stimulation electrode that will be subject to inter- stimset overlap (the overlapped stimset), a parameter of the shorting pulse for the overlapped stimset may be configured such that the measured artefact is at a minimum. The artefact may be measured subsequent to delivery of sub-threshold stimulus pulses that evoke no neural responses, to avoid such evoked responses contaminating the artefact measurements. The resulting artefact-minimising shorting pulse parameter may be stored as part of the clinical settings of the overlapped stimset of the multi-stimset program.

[0094] Fig. 15 is a flow chart illustrating a method 1500 of mitigating inter-stimset overlap artefact according to one such implementation of the present technology. The method 1500 may be carried out by a processor of the clinical interface 740 during programming of the neuromodulation device 710 with a multi-stimset program comprising at least one electrode that is subject to inter-stimset overlap. The clinical interface 740 may be configured to carry out the method 1500 by program instructions forming part of the CPA and stored in an instruction memory of the clinical interface 740. Alternatively, the method 1500 may be carried out by a controller of the device 710, configured by control program 122 stored in memory 118 of the device 710, after programming of the device 710 with a multi-stimset program comprising at least one electrode that is subject to inter-stimset overlap.

[0095] The method 1500 starts at step 1510, which delivers a stimulus pulse according to the first stimset (the overlapped stimset containing the stimulation electrode that is subject to inter-stimset overlap, e.g. the electrode 1020 in Fig. 10a). Step 1510 may optionally have been preceded by delivery of other pulses in accordance with other, non-overlapped stimsets such as the first and second stimsets of Fig. 8. Step 1520 follows, which shorts the stimulation electrodes of the first stimset in accordance with the shorting pulse parameter being configured, in order to recover any residual charge on those electrodes as described above. In one implementation, the shorting pulse parameter is delay in relation to the first stimulus pulse; in another implementation, the shorting pulse parameter is duration. The shorting pulse parameter used at step 1520 may be chosen from a set of candidate shorting pulse parameter values. Step 1530 then delivers a stimulus pulse according to the second (applied) stimset (e.g. the electrodes 1040a, 1040b, and 1045 in Fig. 10b). The stimulus pulsedelivered at step 1530 may be of an intensity that is less than the ECAP threshold for the second stimset, to avoid evoking a neural response that may contaminate the artefact measurement. Step 1540 measures the magnitude of the artefact (e.g. a peak-to-peak value) subsequent to the stimulus pulse delivered at step 1530 using the measurement electrodes of the second stimset, and records the measured artefact magnitude in association with the shorting pulse parameter value used at step 1520.

[0096] Step 1550 then tests whether there are any remaining candidate shorting pulse parameter values. If so (“Y”), the method 1500 returns to step 1510 to deliver another stimulus pulse according to the first stimset. The method 1500 thus iterates over all candidate shorting pulse parameter values and records the measured artefact magnitude at each candidate shorting pulse parameter value. The intensity of the stimulus pulses delivered at steps 1510 and 1530 should remain constant at each iteration so that the only varying stimulus parameter between iterations is the shorting pulse parameter.

[0097] If there are no remaining candidate shorting pulse parameter values (“N” at step 1550), the method 1500 proceeds to step 1560 which chooses the parameter value of the shorting pulse of the first stimset based on the measured artefact magnitudes. In one implementation, step 1560 chooses the shorting pulse parameter value that resulted in the lowest measured artefact magnitude. The chosen shorting pulse parameter value may be saved with the therapy parameters of the multi-stimset program and ultimately form part of the clinical settings 121 of the multi-stimset program.

[0098] In other implementations, candidate values for multiple parameters of the shorting pulse may be iterated over jointly, and the artefact-minimising shorting pulse parameter values may be saved with the therapy parameters of the multi-stimset program.

[0099] In yet other implementations, instead of performing an exhaustive search over a set of candidate shorting pulse parameter values, as in the method 1500, an inter-stimset overlap artefact mitigation method may traverse a search space of shorting pulse parameter values in an efficient manner, such as using a binary search. Additionally, prior knowledge of device, electrode, or patient characteristics, either measured at an individual level or derived from population statistics, could be used to reduce this search space or produce a single set of shorting pulse parameters that is suitable to mitigate inter-stimset overlap artefact for a large percentage of the patient population. Such knowledge may include: stimulation current leakage, therapy parameters, electrode CPE model parameters, and tissue impedances.

[0100] Fig. 16 is a flow chart illustrating a method 1600 of controllably delivering neural stimuli according to one implementation of the present technology. The method 1600 may be carried out by a controller of the device 710, configured by control program 122 stored in memory 118 of the device710, after programming of the device 710 with a multi-stimset program comprising at least one electrode that is subject to inter-stimset overlap.

[0101] The method 1600 starts at step 1610, which delivers a stimulus pulse according to the first stimset (the overlapped stimset containing the stimulation electrode that is subject to inter-stimset overlap, e.g. the electrode 1020 in Fig. 10a). Step 1610 may optionally have been preceded by delivery of other pulses in accordance with other, non-overlapped stimsets such as the first and second stimsets of Fig. 8. Step 1620 follows, which shorts the stimulation electrodes of the first stimset in accordance with a shorting pulse parameter, in order to recover any residual charge on those electrodes as described above.. In one implementation, the shorting pulse parameter is delay in relation to the first stimulus pulse; in another implementation, the shorting pulse parameter is duration. Step 1630 then delivers a stimulus pulse according to the second (applied) stimset (e.g. the electrodes 1040a, 1040b, and 1045 in Fig. 10b). Step 1640 measures the intensity of a neural response evoked by the stimulus pulse delivered at step 1630 using the measurement electrodes of the second stimset. The shorting pulse parameter used at step 1620 is configured to minimise a magnitude of the artefact in the signal window captured subsequent to the stimulus pulse delivered at step 1630, from which the evoked neural response intensity is measured at step 1640.

[0102] Step 1650 then adjusts a stimulus parameter of the second stimset based on the measured intensity of the evoked neural response from step 1640. The method 1600 then returns to step 1610.

[0103] It will be appreciated by persons skilled in the art that numerous variations or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not limiting or restrictive.LABEL LIST stimulator 100 ground 130 patient 108 array 150 module 110 current pulse 160 battery 112 neural response 170 telemetry module 114 nerve 180 controller 116 communications channel 190 memory 118 external computing device 192 clinical data 120 neural stimulation system 300 clinical settings 121 clinical settings controller 302 control programs 122 target ECAP controller 304 pulse generator 124 box 308 electrode selection module 126 box 309 measurement circuitry 128 feedback controller 310box 311 return electrode 1040a stimulator 312 return electrode 1040b stimulator 312A electrode 1045 stimulator 312B electrode array 1050 stimulator 312C measurement electrode 1060a stimulator 312D return electrode 1060b element 313 stimulus electrode 1070 measurement circuitry 318 measurement electrode 1080 signal window 319 box 1085ECAP detector 320 return electrode 1090a comparator 324 return electrode 1090b gain element 336 stimulus electrode 1095 integrator 338 multi - stimset program 1100 activation plot 402 stimulus pulse 1110ECAP threshold 404 inter - stimset interval 1115 discomfort threshold 408 stimulus pulse 1120 perception threshold 410 neural response 1130 therapeutic range 412 pulse 1140 activation plot 502 interval 1145 activation plot 504 stimulus pulse 1150 activation plot 506 pulse 1160ECAP threshold 508 graph 1200ECAP threshold 510 trace 1210ECAP threshold 512 trace 1220 target ECAP amplitude 520 ISI value 1230ECAP 600 multi - stimset program 1300 neural stimulation system 700 stimulus pulse 1310 device 710 inter - stimset interval 1315 remote controller 720 stimulus pulse 1320CST 730 neural response 1330 clinical interface 740 pulse 1340 charger 750 interval 1345 illustration 800 stimulus pulse 1350 stimulus pulse 810 pulse 1360 inter - stimulus interval 815 graph 1400 stimulus pulse 820 trace 1410 stimulus pulse 830 trace 1420 stimulus pulse 840 method 1500 stimulus pulse 850 step 1510ECAP 860 step 1520 multi - stimset CLNS system 900 step 1530 electrode array 1000 step 1540 return electrode 1010a step 1550 return electrode 1010b step 1560 electrode 1020 method 1600 electrode 1030 step 1610 box 1035 step 1620step 1630 step 1650 step 1640

Claims

CLAIMS:

1. An implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to provide neural stimuli to be delivered according to a stimulation set to a neural pathway of a patient in order to evoke neural responses from the neural pathway, wherein the stimulation set comprises a plurality of implanted stimulation electrodes; measurement circuitry configured to capture signal windows sensed on the neural pathway via one or more implanted measurement electrodes; and a control unit configured to: control the stimulus source to provide a first neural stimulus according to a first stimulation set; connect together, using one or more shorting pulse parameters of the first stimulation set, the stimulation electrodes of the first stimulation set; control the stimulus source to provide a second neural stimulus according to a second stimulation set; and measure an intensity of an evoked neural response in a captured signal window subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus, wherein the one or more shorting pulse parameters are configured to minimise a magnitude of the artefact in the captured signal window.

2. The implantable device of claim 1, wherein the one or more shorting pulse parameters comprise delay in relation to the first neural stimulus.

3. The implantable device of any one of claims 1 to 2, wherein the one or more shorting pulse parameters comprise duration.

4. The implantable device of any one of claims 1 to 3, wherein the control unit is further configured to adjust a stimulus parameter of the second stimulation set based on the measured intensity of the evoked neural response.

5. The implantable device of claim 4, wherein the control unit is further configured to adjust a stimulus parameter of the first stimulation set based on the adjustment to the stimulus parameter of the second stimulation set.

6. The implantable device of any one of claims 1 to 5, wherein a stimulation electrode of the first stimulation set is also a measurement electrode of the one or more implanted measurement electrodes.

7. An automated method of controllably delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a first neural stimulus to the neural pathway of the patient according to a first stimulation set, wherein the first stimulation set comprises a plurality of implanted stimulation electrodes; connecting together, using one or more shorting pulse parameters, the stimulation electrodes of the first stimulation set; delivering a second neural stimulus to the neural pathway of the patient in order to evoke a neural response from the neural pathway, the second neural stimulus being delivered according to a second stimulation set; capturing, via one or more implanted measurement electrodes, a signal window sensed on the neural pathway subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus; and measuring an intensity of the neural response evoked by the second neural stimulus in the captured signal window, wherein the one or more shorting pulse parameters are configured to minimise a magnitude of the artefact in the captured signal window.

8. The method of claim 7, wherein the one or more shorting pulse parameters comprise delay in relation to the first neural stimulus.

9. The method of any one of claims 7 to 8, wherein the one or more shorting pulse parameters comprise duration.

10. The method of any one of claims 7 to 9, further comprising adjusting a stimulus parameter of the second stimulation set based on the measured intensity of the evoked neural response.

11. The method of claim 10, further comprising adjusting a stimulus parameter of the first stimulation set based on the adjustment to the stimulus parameter of the second stimulation set.

12. The method of any one of claims 7 to 11, wherein a stimulation electrode of the first stimulation set is also a measurement electrode of the one or more implanted measurement electrodes.

13. A neural stimulation system comprising: an implantable neuromodulation device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to provide neural stimuli to be delivered to a neural pathway of a patient in order to evoke neural responses from the neural pathway; measurement circuitry configured to capture signal windows sensed on the neural pathway via one or more implanted measurement electrodes, subsequent to respective neural stimuli; and a control unit configured to control the stimulus source to provide neural stimuli according to a stimulation set, wherein the stimulation set comprises a plurality of implanted stimulation electrodes; and a processor configured to repeatedly, for each candidate shorting pulse parameter value of a set of candidate shorting pulse parameter values: instruct the control unit to control the stimulus source to provide a first neural stimulus according to a first stimulation set; instruct the control unit to connect together, using a candidate shorting pulse parameter value, the stimulation electrodes of the first stimulation set; instruct the control unit to control the stimulus source to provide a second neural stimulus according to a second stimulation set; and measure a magnitude of an artefact in a captured signal window subsequent to the second neural stimulus, the artefact resulting from the first neural stimulus; thereby obtaining a plurality of measured artefact magnitudes at respective candidate shorting pulse parameter values; and choose a shorting pulse parameter value for the first stimulation set based on the plurality of measured artefact magnitudes.

14. The neural stimulation system of claim 13, wherein the candidate shorting pulse parameter value comprises delay in relation to the first neural stimulus.

15. The neural stimulation system of claim 13, wherein the candidate shorting pulse parameter value comprises duration.

16. The neural stimulation system of any one of claims 13 to 15, wherein the processor is configured to choose the shorting pulse parameter value to be the candidate shorting pulse parameter value that resulted in the lowest artefact magnitude of the plurality of measured artefact magnitudes.

17. The neural stimulation system of any one of claims 13 to 16, wherein the control unit is further configured to repeatedly: control the stimulus source to provide a first neural stimulus according to the first stimulation set; connect together, using the chosen shorting pulse parameter value, the stimulation electrodes of the first stimulation set; control the stimulus source to provide a second neural stimulus according to the second stimulation set; and measure an intensity of an evoked neural response in a captured signal window subsequent to the second neural stimulus.

18. The neural stimulation system of claim 17, wherein the control unit is further configured to adjust a stimulus parameter of the second stimulation set based on the measured intensity of the evoked neural response.

19. The neural stimulation system of claim 18, wherein the control unit is further configured to adjust a stimulus parameter of the first stimulation set based on the adjustment to the stimulus parameter of the second stimulation set.

20. The neural stimulation system of any one of claims 13 to 19, wherein a stimulation electrode of the first stimulation set is also a measurement electrode of the one or more measurement electrodes.

21. An automated method of controllably delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a first neural stimulus to the neural pathway of the patient according to a first stimulation set, wherein the first stimulation set comprises a plurality of implanted stimulation electrodes;connecting together, using a candidate shorting pulse parameter value, the stimulation electrodes of the first stimulation set; delivering a second neural stimulus to the neural pathway of the patient in order to evoke a neural response from the neural pathway, the second neural stimulus being delivered according to a second stimulation set; capturing, via one or more implanted measurement electrodes, a signal window sensed on the neural pathway subsequent to the second neural stimulus, the captured signal window comprising an artefact resulting from the first neural stimulus; measuring a magnitude of an artefact in a captured signal window subsequent to the second neural stimulus, the artefact resulting from the first neural stimulus; repeating the delivering, connecting, delivering, capturing, and measuring for a plurality of candidate shorting pulse parameter values to obtain a plurality of measured artefact magnitudes at respective candidate shorting pulse parameter values; and choosing a shorting pulse parameter value for the first stimulation set based on the plurality of measured artefact magnitudes.

22. The method of claim 21, wherein the candidate shorting pulse parameter value comprises delay in relation to the first neural stimulus.

23. The method of claim 21, wherein the candidate shorting pulse parameter value comprises duration.

24. The method of any one of claims 21 to 23, wherein the choosing comprises choosing the shorting pulse parameter value to be the candidate shorting pulse parameter value that resulted in the lowest artefact magnitude of the plurality of measured artefact magnitudes.

25. The method of any one of claims 21 to 24, further comprising: delivering a first neural stimulus according to the first stimulation set; connecting together, using the chosen shorting pulse parameter value, the stimulation electrodes of the first stimulation set; delivering a second neural stimulus according to the second stimulation set in order to evoke a neural response from the neural pathway; andmeasuring an intensity of an evoked neural response in a captured signal window subsequent to the second neural stimulus.

26. The method of claim 25, further comprising adjusting a stimulus parameter of the second stimulation set based on the measured intensity of the evoked neural response.

27. The method of claim 26, further comprising adjusting a stimulus parameter of the first stimulation set based on the adjustment to the stimulus parameter of the second stimulation set.

28. The method of any one of claims 21 to 27, wherein a stimulation electrode of the first stimulation set is also a measurement electrode of the one or more measurement electrodes.

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