Neuromodulation systems and methods for pain management

Abstract

An implantable device for controllably delivering neural stimuli, comprising a stimulus source configured to provide neural stimuli to be delivered via one or more stimulus electrodes to a neural pathway of a patient; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes subsequent to respective neural stimuli; and a control unit. The control unit is configured to: control the stimulus source to provide a direct current (DC) pulse according to a stimulus intensity parameter; control the stimulus source to provide a titration pulse in order to evoke a neural response from the neural pathway; measure an intensity of an evoked neural response in a captured signal window subsequent to the titration pulse; and adjust, using a feedback controller, the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

Description

NEUROMODULATION SYSTEMS AND METHODS FOR PAIN MANAGEMENT

[0001] The present application claims priority from Australian Provisional Patent Application No 2023903982 filed on 8 December 2023, the contents of which are incorporated herein by reference in their entirety.TECHNICAL FIELD

[0002] The present invention relates to neuromodulation and in particular to neuromodulation systems for pain management by blocking nerve conduction.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 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 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) directions. 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 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 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 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 moves 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, 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 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 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 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] The above-described conventional neuromodulation therapy has been shown to be effective in treating neuropathic pain, which is caused by damage to the nervous system or abnormal nerve function. However, it has not been as effective in treating nociceptive pain, which is pain resulting from physical damage to the tissues of the body, such as skin, muscles, bones, or organs.

[0011] One neuromodulation therapy that has been proposed as effective for nociceptive pain is direct current (DC) neuromodulation, referred to herein as “DC stimulation”. By contrast with conventional neuromodulation therapy, which involves repeated (often periodic) delivery of brief pulses of stimulation energy, DC stimulation involves holding the neural tissue at a constant potential for extended periods. It is hypothesised that if the potential is correctly chosen, a portion of any adjacent neurons is placed in a state of hyperpolarisation. In this hyperpolarised state, the ability of the neurons to conduct action potentials is impaired, perhaps even to the point where the neurons that would otherwise conduct action potentials conveying the sensation of pain are blocked. As a result, the sensation of pain is muted or even nullified, regardless of whether the pain is neuropathic or nociceptive in origin. The effect of DC stimulation is therefore sometimes referred to as “conduction block”. The blocking effect may remain for a period after the externally imposed potential is withdrawn. Therefore, DC stimulation is usually delivered in constant-current or constant-voltage “DC pulses” of extended length compared to conventional stimulus pulses, separated by inter-pulse intervals during which the adjacent nerves gradually recover their conduction properties.

[0012] However, it is not straightforward to determine the ideal intensity for DC pulses, nor the ideal duration of the inter-pulse interval to maintain the efficacy of the therapy. If the intensity is too low, or the inter-pulse interval is too long, the blocking effect weakens or disappears; if the intensity is toohigh, or the inter-pulse interval is too short, there may be unwanted side effects, as well as an unnecessary increase in power consumption.

[0013] Postural change, as described above, further complicates the titration problem, rendering it unlikely that a single intensity and inter-pulse interval, however well-chosen, will remain effective for all postures once the patient leaves the clinic.

[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 technology as it existed before the priority date of each claim of the present disclosure.

[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] Disclosed herein are devices and methods for direct current (DC) stimulation in which the intensity of the DC pulses, and the interval between those pulses, are dynamically titrated, even pulse- by-pulse, by delivering titration stimuli during the inter-pulse intervals, and measuring the ECAPs evoked by the titration stimuli. The measured intensities, or other characteristics, of the ECAPs may be used to adjust the intensity and inter-pulse interval of the DC pulses so that both parameters are just sufficient to maintain the blocking effect on the pain fibres. In this manner, the risk of unwanted side effects and over-consumption of power are minimised while delivering effective pain relief.

[0018] 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 pulses to be delivered via one or more stimulus electrodes to a neural pathway of a patient; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes subsequent to respective neural stimuli; and a control unit. The control unit is configured to: control the stimulus source to provide a direct current(DC) pulse according to a stimulus intensity parameter; control the stimulus source to provide a titration pulse in order to evoke a neural response from the neural pathway; measure an intensity of an evoked neural response in a captured signal window subsequent to the titration pulse; and adjust, using a feedback controller, the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

[0019] 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 direct current (DC) pulse to the neural pathway of the patient, the DC pulse being delivered according to a stimulus intensity parameter; delivering a titration pulse to the neural pathway of the patient in order to evoke a neural response from the neural pathway; capturing a signal window from a signal sensed on the neural pathway subsequent to the titration pulse; measuring an intensity of a neural response evoked by the titration pulse in the signal window; and adjusting the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

[0020] 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 plurality of electrodes including one or more stimulus electrodes and one or more measurement electrodes; a stimulus source configured to provide neural stimuli to be delivered via the one or more stimulus electrodes to a neural pathway of a patient; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway via the one or more measurement electrodes subsequent to respective neural stimuli; and a control unit configured to control the stimulus source to provide each neural stimulus according to a stimulus intensity parameter. The processor is configured to: instruct the control unit to control the stimulus source to provide a direct current (DC) pulse according to the stimulus intensity parameter; instruct the control unit to control the stimulus source to provide a titration pulse in order to evoke a neural response from the neural pathway; measure an intensity of an evoked neural response in a captured signal window subsequent to the titration pulse; and adjust, using a feedback controller, the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

[0021] Some embodiments of the invention may provide the titration pulse simultaneously with the DC pulse. Alternatively or additionally, some embodiments may provide the or a titration pulse during a titration phase that commences after the end of the DC pulse.

[0022] Some embodiments of the invention may comprise providing a further titration pulse in order to evoke a further neural response from the neural pathway; and measuring a further intensity of afurther evoked neural response in a captured signal window subsequent to the further titration pulse. Such embodiments may further comprise fitting an intensity curve to the measured intensity and the further measured intensity. In turn, some embodiments may further comprise determining the evoked neural response intensity value when the neural pathway is in an unblocked state from the intensity curve.

[0023] In some embodiments, the target value may be an evoked neural response intensity value when the neural pathway is in a blocked state.

[0024] Some embodiments may further comprise ending the titration phase and repeat the controlling, controlling, measuring, and adjusting upon the intensity curve exceeding a recovery threshold. Some embodiments may comprise determining the recovery threshold from the evoked neural response intensity value when the neural pathway is in an unblocked state.

[0025] In some embodiments of the invention, the titration pulse is charge-unbalanced. Some embodiments may further comprise determining an imbalance fraction of the charge-unbalanced titration pulse so as to recover any imbalance of delivered charge remaining after the end of the DC pulse. The imbalance fraction may in some embodiments be determined by dividing the imbalance of delivered charge by an expected number of titration pulses to be delivered before the next DC pulse. The expected number of titration pulses may be the number of titration pulses delivered during the previous titration phase.

[0026] In some embodiments of the invention a DC stimulus electrode configuration (SEC) used to provide the direct current pulse may be interposed between a titration stimulus electrode configuration (SEC) used to provide the titration pulse and a titration measurement electrode configuration (MEC) used to measure the intensity of the evoked neural response, whereby the evoked neural response evoked by the titration pulse at the titration SEC must pass the DC SEC before reaching the titration MEC.

[0027] In some embodiments of the invention a titration pulse intensity parameter may be adjusted based on a measured intensity of at least one evoked neural response, to maintain titration recruitment efficacy during changes in electrode-to-nerve distance.

[0028] 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 signalprocessors, 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

[0029] 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:

[0030] Fig. 1 schematically illustrates an implanted spinal cord stimulator, according to one implementation of the present technology;

[0031] Fig. 2 is a block diagram of the stimulator of Fig. 1;

[0032] Fig. 3 is a schematic illustrating interaction of the implanted stimulator of Fig. 1 with a nerve;

[0033] Fig. 4a illustrates an idealised activation plot for one posture of a patient undergoing neural stimulation;

[0034] Fig. 4b illustrates the variation in the activation plots with changing posture of the patient;

[0035] 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;

[0036] Fig. 6 illustrates the typical form of an electrically evoked compound action potential (ECAP) of a healthy subject;

[0037] 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;

[0038] Fig. 8 is an illustration of the stimulus pulses delivered by a DC stimulation program according to one implementation of the present technology;

[0039] Fig. 9 is a schematic illustrating elements and inputs of an ECAP-titrated DC stimulation system according to one aspect of the present technology;

[0040] Fig. 10 is a flowchart illustrating a method of operation of the ECAP-titrated DC stimulation system of Fig. 9 according to one implementation of the present technology; and

[0041] Fig. 11 is a flowchart illustrating a method of operation of the ECAP-titrated DC stimulation system of Fig. 9 according to another 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 being communicated 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 and 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.

[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. 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. 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 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 user 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 user 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 by 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 Nl 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 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 amplitudeof 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 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 selected 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 (MEC). 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 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.

[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 largeamounts 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:(S(s - T), s > T y=l 0, s < T (1)

[0054] where s 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 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 thepatient 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 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 intensity to 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 or near an appropriate target response intensity, such as a target ECAP amplitude 520 illustrated in Fig. 4b, aCLNS 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 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 or near the target response 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 n, 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 (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.

[0066] The feedback controller 310 calculates an adjusted stimulus intensity parameter, s, 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 intensity parameter 5. According to such an implementation, the current stimulus intensity parameter 5 may be determined by the feedback controller 310 as(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 5s 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 user 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 user 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 .v. 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.ECAP -titrated direct current (DC) stimulation

[0076] A DC stimulation program according to the present technology may be thought of as a stimulation program comprising two interleaved 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 stimulus pulses delivered via that SEC.

[0077] Fig. 8 is an illustration of the pulses delivered by a DC stimulation program 800 according to one implementation of the present technology. The pulse train delivered according to each stimset is illustrated on a separate, but vertically aligned, horizontal axis representing time.

[0078] In some implementations, the DC stimulation program 800 comprises two alternating phases, a DC or blocking phase 810-1 and 810-2, and a titration phase 820. Such implementations are particularly suitable for the situation where there are some shared electrodes between the SEC of the DC stimset (the DC SEC) and the SEC of the titration stimset (the titration SEC), because the DC pulses and the titration pulses do not overlap in time.

[0079] The DC pulses 830-1 and 830-2, delivered during respective blocking phases 810-1 and 810- 2, according to the DC stimset in the program 800, are illustrated as monophasic, anodic pulses, though cathodic pulses are also contemplated for the DC stimset. The DC pulses may be monopolar, in which case their polarity (anodic or cathodic) is significant, or the DC pulses may be bipolar, in which case their polarity is insignificant because for each DC pulse, a DC pulse of the opposite polarity is effectively being delivered simultaneously via the adjacent return electrode. Both cathodic and anodic monopolar DC pulses have demonstrated the ability to block neural activity, albeit through different mechanisms. Anodic monopolar DC pulses hyperpolarise the membrane as described above. Cathodic monopolar DC pulses, by contrast, depolarise the membrane, but hold the voltage-gated sodium channels in an inactivated state and prevent them from recovering from inactivation. Cathodic DC pulses have been shown to require substantially lower intensity than anodic DC pulses to achieve a blocked state [1],

[0080] The pulse width of the DC pulses in implementations with alternating blocking and titration phases, such as the program 800, should be chosen short enough that posture may be regarded as constant over the DC pulse. DC pulse widths of up to several milliseconds generally meet this criterion.

[0081] The intensity of the DC pulse 830-1 may be adjusted to a different intensity for the subsequent DC pulse 830-2, as illustrated, based on the interleaved titration phase 820 as described below.

[0082] The titration pulses 850-1, 850-2, and 850-3, delivered at a fixed frequency during the titration phase 820 according to the titration stimset in the program 800, are illustrated as charge-balanced triphasic, anodic-first stimulus pulses with the same phase durations and intensities for each pulse. Triphasic pulses, if correctly configured, are advantageous for minimising stimulus artefact in the subsequent sensed signals. However, different polarities and numbers of phases for the titration pulses 850-1 etc. are contemplated. In particular, the titration pulses may be charge-unbalanced, as described below.

[0083] Also illustrated are evoked neural responses in the form of evoked compound action potentials (ECAPs) 860-1, 860-2, and 860-3 as sensed by a predetermined measurement electrode configuration (MEC) subsequent to, and evoked by, the respective titration pulses 850-1, 850-2, and 850-3. Adjustments to the intensity of the subsequent DC pulse 830-2, and the duration of the titration phase 820, may be based on measurements of the ECAPs 860-1, 860-2, and 860-3. In other words, closed- loop adjustments to the DC stimulation program parameters may be based on measurements of the ECAPs 860-1, 860-2, and 860-3.

[0084] If the inter-stimulus interval (ISI) 815 of the titration stimset is short, ECAPs 860-1 and 860- 2 evoked by the first two titration pulses 850-1 and 850-2 respectively are potentially obscured by stimulus crosstalk or artefact from the titration pulses 850-2 and 850-3 respectively. Therefore, if the ISI 815 is short, only the final titration pulse 850-3 may evoke a measurable ECAP 860-3, which is contrary to the needs of the titration phase 820, as further described below. The ISI 815 (which is the reciprocal of the titration frequency) should therefore be chosen to be greater than the refractory period of the neural tissue adjacent the SEC of the titration stimset and sufficiently long that ECAPs evoked by the earlier titration pulses are not obscured by stimulus crosstalk and artefact from the subsequent titration pulses in the titration phase 820, so that all of the titration pulses in the titration phase 820, at least potentially, evoke a measurable ECAP.

[0085] The titration SEC is configured to evoke neural responses in the same nerves as those to which the DC pulses are applied. The MEC of the titration stimset (the titration MEC) is configured to optimally sense those evoked responses. In one example, the DC SEC is configured to be in the middle of the electrode array 150. The titration SEC is configured to be at one end of the electrode array 150, while the titration MEC is configured to be at the other end of the electrode array 150. ECAPs evoked by the titration pulses at the titration SEC therefore need to propagate past the DC SEC before reaching the titration MEC and are therefore potentially affected by the conduction block imposed by the DC pulses. Alternatively, the titration SEC and titration MEC may both be positioned to one side of the DC SEC on the electrode array, provided that at least one of the titration SEC and the titration MEC is positioned proximal to the DC SEC in a manner such that the stimulation and / or recording of titration ECAPs (860) is potentially affected by the conduction block imposed by the DC pulses.

[0086] The ECAPs 860-1, 860-2, and 860-3 in Fig. 8 are illustrated to represent a configuration of SECs and titration MEC that reflects such an impact of the DC pulses on the titration ECAPs. As illustrated in Fig. 8, the intensity, such as the peak-to-peak or root-mean-square amplitude, of the ECAPs 860-1, 860-2, and 860-3 starts out small and increases with time. This is because the blockingeffect of the DC pulse 830-1 gradually decreases with time following the end of the blocking phase 810-1 and the start of the titration phase 820.

[0087] A useful property of DC stimulation is that smaller-diameter fibres (i.e. AS- or C-fibres, those responsible for pain sensation) tend to be blocked at lower potentials than larger-diameter fibres (e.g. Ap fibres) due to the relative robustness of larger fibres to action potential propagation failure. This contrasts with conventional SCS, in which larger-diameter fibres are preferentially activated compared to smaller-diameter fibres. This property means that when applying DC stimulation, if the Ap fibres can be shown to have been blocked by a given DC pulse, it is likely that any adjacent AS fibres are also in a blocked state, and therefore pain is potentially relieved. The neural responses evoked by titration pulses delivered to the dorsal column and measurable on the dorsal column are preferentially those of the larger-diameter fibres. Therefore, in some implementations of the present technology, the intensity of the first neural response after the end of the blocking phase (e.g. the ECAP 860-1 after the blocking phase 810-1), in comparison with the intensity of responses evoked when the fibres are known to be wholly unblocked, is indicative of the depth of the conduction block of the larger-diameter fibres and therefore of the smaller-diameter, pain-conveying fibres as well. Furthermore, the profile of the increase in evoked response intensity with time elapsed since the conclusion of the last DC pulse is indicative of the recovery of the larger-diameter fibres from a blocked state, and therefore the need to end the current titration phase and commence the next blocking phase in order to preserve the efficacy of the DC stimulation.

[0088] Fig. 9 is a schematic illustrating elements and inputs of an ECAP-titrated DC stimulation system 900 according to one aspect of the present technology. The ECAP-titrated DC stimulation system 900 is similar to the CLNS system 300 of Fig. 5, with like numbers indicating like elements, but with some differences as follows.

[0089] The DC pulses are delivered by the DC stimulator 912-1 (which corresponds to the stimulator 312 in the CLNS system 300) via the DC SEC according to a variable DC stimulus intensity parameter s, and other stimulus parameters provided by the clinical settings controller 302. The pulses delivered by the DC stimulator 912-1 correspond to the DC pulses 830-1 and 830-2 of Fig. 8.

[0090] The titration pulses, from which ECAPs are measured, are delivered by the titration stimulator 912-2 (which also corresponds to the stimulator 312 in the CLNS system 300) via the titration SEC according to a set of stimulus parameters provided by the clinical settings controller 302, including a titration stimulus intensity parameter z. The pulses delivered by the titration stimulator 912-2 correspond to the titration pulses 850-1, 850-2, and 850-3 of Fig. 8.

[0091] Titration pulses delivered by the titration stimulator 912-2 evoke neural responses that are sensed by the titration MEC and measured by the ECAP detector 320 as described above in relation to Fig. 5. The measured intensity d of the first neural response in each titration phase is compared with a target ECAP amplitude dtgt by the feedback controller 310. The feedback controller 310 determines the adjusted DC stimulus intensity parameter 5 for the subsequent DC pulse to be delivered by the DC stimulator 912-1 during the subsequent blocking phase. The feedback controller 310 is configured such that when the error is negative (i.e. the measured response intensity d exceeds the target ECAP amplitude dtgt), the DC stimulation intensity is increased, in order to increase the blocking effect of the subsequent DC pulse and reduce the measured response intensity d after the subsequent DC pulse towards the target ECAP amplitude dtgt. This may be accomplished in one implementation by setting the gain K of the gain element 336 to be negative.

[0092] The target ECAP amplitude dtgt may be determined during programming of the ECAP -titrated DC stimulation system 900 and provided by the target controller 904. In one implementation, the target ECAP amplitude dtgt may be set to the amplitude dbiocked of ECAPs that are measured when the smaller-diameter fibres are in an effectively blocked state due to DC stimulation, as indicated by patient sensation of satisfactory pain relief. Alternatively, the target ECAP amplitude dtgt may be dynamically determined by the target controller 904 during therapy. In one implementation, the target ECAP amplitude dtgt may be set to some fraction / of the “unblocked” ECAP amplitude do, i.e. the ECAP amplitude that would be measured if the smaller-diameter fibres were in an unblocked state, in the total absence of DC stimulation. The fraction / may be determined during programming as the ratio of the “blocked” ECAP amplitude dbiocked when pain relief is satisfactory, to the unblocked ECAP amplitude do.

[0093] Alternatively, or additionally, the target ECAP amplitude dtgt may be dynamically adjustable from its programmed or dynamically determined value via the remote controller 720 so that the patient may control the amount of pain relief according to their needs of the moment.

[0094] As in conventional closed-loop neural stimulation, by adjusting the DC stimulus intensity so as to maintain measured neural responses, which are dependent on the electrode-cord distance, at or near a target amplitude, the effect of variation in that distance, e.g. due to posture change, may be compensated to some extent, so that the efficacy of the DC stimulation may be preserved as posture changes.

[0095] As mentioned above, the titration phase may continue, with the titration stimulator 912-2 delivering titration pulses at times ti (counted since the start of the titration phase) and the intensitiesd(ti) of the subsequent neural responses being measured, until the time profile of the sequence {d(ti)} of measured response intensities indicates the recovery of the larger-diameter fibres from a blocked state, and therefore the need to end the current titration phase and commence the next blocking phase. In one implementation, an intensity curve d (t) may be fitted to the sequence {d(ti)} after each measurement, and the titration phase ended at the time / v after the Mh titration pulse, when the intensity curve d(t) reaches a predetermined threshold indicative of recovery.

[0096] Like the target ECAP amplitude, the recovery threshold drecovery may be determined during programming of the ECAP -titrated DC stimulation system 900. In one such implementation, the recovery threshold drecovery may be set to a predetermined multiple of the amplitude dbiocked of ECAPs that are measured when the smaller-diameter fibres are in an effectively blocked state due to DC stimulation, as indicated by patient sensation of satisfactory pain relief. Alternatively, the recovery threshold drecovery may be dynamically determined during therapy. In one such implementation, the recovery threshold drecovery may be set to the unblocked ECAP amplitude o, or some predetermined near-unity multiple (such as 90%) thereof. In another such implementation, the recovery threshold drecovery may be set, and maintained, at a predetermined multiple of the current target ECAP amplitude dtgt provided by the target controller 904, being updated if and when the target ECAP amplitude dtgt is dynamically varied via the remote controller 720.

[0097] The intensity curve d(t) may be of a predetermined form, such as exponentially increasing asymptotically to a final value. In such an implementation, the final value corresponds to the unblocked ECAP amplitude do in the current posture. In implementations in which the unblocked ECAP amplitude do is used to obtain the target ECAP amplitude dtgt or the recovery threshold drecovery, the fitting of the intensity curve d(t) may yield the unblocked ECAP amplitude do as one of its parameters. Alternatively, the intensity curve d(t), once fitted, may be extrapolated to infinity to obtain the unblocked ECAP amplitude do.

[0098] Fig. 10 is a flowchart illustrating a method 1000 of operation of the ECAP -titrated DC stimulation system 900 according to one implementation of the present technology. The method 1000 may be carried out by the controller 116 of the stimulator 100, as configured by control programs 122 stored in memory 118.

[0099] The method 1000 starts at step 1005 with the system 900 entering the blocking phase, e.g. the blocking phase 810-1, upon which the DC stimulator 912-1 is instructed to deliver a DC pulse, e.g. the DC pulse 830-1. At the conclusion of the DC pulse, the system 900 enters the titration phase, e.g. the titration phase 820, and the next step 1010 instructs the titration stimulator 912-2 to deliver atitration pulse, e.g. the titration pulse 850-1, at intensity z. The ECAP detector 320 and the measurement circuitry 318 of the system 900 are then, at step 1020, instructed to measure the intensity d(tN) of the neural response evoked by the titration pulse. The subscript N indicates that the present iteration of step 1020 is the A-th iteration, and / is the time of the A-th iteration. The measured response intensity d(tN) is added to the sequence {d(ti), i = 1, ..., A} of response intensity measurements.

[0100] At step 1030, the intensity curve d (t) is fitted to the sequence {d(ti)} of response intensity measurements during the current titration phase, including the intensity measured most recently at step 1020. The intensity curve d(t) may be fitted to the sequence {d(ti)} of intensity measurements according to a predetermined form using conventional statistical methods such as least squares. Step 1030 may be an update to an existing intensity curve fit d(t) using only the most recent intensity measurement d(t ), or a completely new curve fit to the complete intensity sequence {d( )} . Step 1030 is shown dashed as it may not be executed until the sequence {d(ti)} of response intensity measurements contains sufficient measurements for a reasonable curve fit.

[0101] The feedback controller 310 of the system 900 then, at step 1040, adjusts the intensity of the subsequent DC pulse to be delivered in the next blocking phase based on the measured intensity d(t ). As described above, the adjustment at step 1040 is configured to maintain the measured response intensity d(tv) at or near the target ECAP amplitude dtgt. Step 1040 is shown dashed as it is only executed once, e.g. at the first iteration (A = 1), during the current titration phase, not at every iteration of the steps 1010 to 1050. As mentioned above, the target ECAP amplitude dtgt may be predetermined during programming, or dynamically determined from the intensity curve d(t). In the latter case, step 1040 may not be executed until an iteration in which the curve fitting step 1030 has been executed.

[0102] Step 1050 then tests whether, at the current time tv, the current value d(tN) of the intensity curve d(t) exceeds the recovery threshold drecovery. As mentioned above, the recovery threshold drecovery may be programmed or dynamically determined from the intensity curve d(t). In the latter case, step 1050 may not be executed (in which case the method 1000 returns directly to step 1010) until an iteration in which the curve fitting step 1030 has been executed. If not (“N”), the system 900 remains in the titration phase and the method 1000 returns to step 1010 for another iteration through steps 1010 to 1050. If so (“Y”), step 1060 ends the titration phase and returns to step 1005 to commence the next blocking phase. The current time tv is recorded as the recovery time trecovery.

[0103] In an alternative implementation of the method 1000, the adjustment step 1040 is not carried out until the current value d(tN) of the intensity curve d(t) exceeds the recovery threshold drecovery,which occurs (with a “Y” at step 1050) at the recovery time trecovery. In such an implementation, instead of the adjustment being based on the measured intensity d(tN), the adjustment is based on the recovery time trecovery. In one such implementation, if the recovery time trecovery exceeds a predetermined upper limit Tmax, step 1040 decreases the intensity of the subsequent DC pulse to be delivered in the next blocking phase. This occurs because the inference is that the target tissue took too long to recover, so the previous DC pulse was excessively intense. Conversely, if the recovery time trecovery is less than a predetermined lower limit Tmtn, step 1040 increases the intensity of the subsequent DC pulse. This occurs because the inference is that the target tissue recovered too quickly, so the previous DC pulse was insufficiently intense. If the recovery time trecovery is within the range [Tmtn, Tmax], step 1040 leaves the intensity of the subsequent DC pulse unchanged. In another such implementation, step 1040 compares the recovery time trecovery with a target recovery time and adjusts the intensity of the subsequent DC pulse based on the error between the two times in similar fashion to the feedback controller 310.

[0104] In an alternative implementation of the ECAP -titrated DC stimulation system 900, there are no alternating phases. Rather, DC pulses and titration pulses may be delivered simultaneously. Such an implementation is suitable for the situation where the DC SEC and the titration SEC and MEC involve different electrodes with no overlap between them. In such an implementation, a method of operation that is a modification of the method 1000 may be utilised. Fig. 11 is a flowchart illustrating a method 1100 of operation of the ECAP -titrated DC stimulation system 900 according to another implementation of the present technology. The method 1100 may be carried out by the controller 116 of the stimulator 100, as configured by control programs 122 stored in memory 118.

[0105] The method 1100 is similar to the method 1000, with like numbers indicating the same steps (e.g. step 1005 and step 1105). However, in the method 1100, delivery of the titration pulse (step 1110) need not wait until the end of the DC pulse (step 1105), but may take place during the delivery of the DC pulse, possibly at some predetermined delay after the start of the DC pulse to give the DC pulse time to take full blocking effect. Steps 1120 and 1140 are the same as steps 1020 and 1040 respectively. The target ECAP intensity dtgt used at the adjusting step 1140 may be predetermined during programming as described above. There is no need for intensity curve fitting as at step 1030 or checking for recovery as at step 1050; instead, the method 1100 returns to step 1105 for the next DC pulse after the adjustment at step 1140.

[0106] In an alternative implementation of an ECAP -titrated DC stimulation system, the feedback variable provided to the feedback controller 310 may be a ratio R between the measured response intensity d(ti) and the unblocked ECAP amplitude do in the current posture. In such animplementation, the adjustment at step 1040 is configured to maintain the measured response intensity ratio R at or near a target ECAP amplitude ratio Rtgt provided by the target controller 904. The target ECAP amplitude ratio Rtgt may be determined during programming of the ECAP-titrated DC stimulation system 900. In one implementation, the target ECAP amplitude ratio Rtgt may be set to the fraction / (the amplitude ratio dbiocked I do) described above.Mitigating charge accumulation

[0107] The un-charge-balanced nature of DC stimulation when delivered from conventional neuromodulation devices such as the stimulator 100 may cause charge accumulation at the electrodetissue interface, which may in turn cause electrochemical reactions, resulting in toxic byproducts or electrode corrosion.

[0108] International Patent Publication no. WO2011 / 088130 discloses methods of implementing “ionic direct current” stimulation of neural tissue with charge-balanced alternating current stimulus pulses and fluid-mechanical valves. This mode of stimulation avoids the problem of charge accumulation at electrode-tissue interfaces. Therefore in some implementations, the DC stimulator 912-1 is configured to deliver ionic direct current. The intensity of the ionic direct current pulses is directly proportional to the intensity of the charge-balanced alternating current stimulus pulses delivered by the ionic direct current stimulator. An ionic current stimulator implementation is particularly suitable for the implementation described above in which there are no alternating blocking and titration phases.

[0109] In implementations of the ECAP-titrated DC stimulation system 900 that use alternating blocking and titration phases as described above, and in particular those implementations in which some or all of the electrodes in the DC SEC are shared with the electrodes in the titration SEC, charge delivered during DC pulses may be balanced during the subsequent titration phases. Such implementations may use a conventional stimulator such as the stimulator 100 as the DC stimulator 912-1. In such implementations, the titration stimulator 912-2 may deliver charge-unbalanced titration pulses that are configured to recover, over the duration of the titration phase, any imbalance of charge remaining at the end of the preceding blocking phase. A charge-unbalanced titration pulse is a pulse in which the combined charge delivered during the anodic phase(s) does not equal the combined charge delivered during the cathodic phase(s). An imbalance fraction u, which may be positive or negative, parametrises the imbalance of charge in a titration pulse. For a rectangular pulse with the same amplitude in each phase, the imbalance fraction u may be determined as the combined pulse width of the anodic phases minus the combined pulse width of the cathodic phases, as aproportion of the combined pulse width of the cathodic phases. For example, a biphasic pulse in which the anodic phase is half the pulse width of the cathodic phase has an imbalance fraction of -0.5. The amount of charge recovered by a single titration pulse may be determined by multiplying the imbalance fraction u by the intensity (amplitude) of the titration pulse and the combined width of the cathodic phases.

[0110] In one implementation, the controller 116 carries out a “charge-accounting” process to determine imbalance fractions for the titration pulses that aim to recover any imbalance of charge at the start of the titration phase by the expected end of the titration phase. In one implementation, if the imbalance of charge at the end of a DC pulse is AQ, and there are expected to be N titration pulses during the titration phase (N may be set to the number of titration pulses during the previous titration phase), the imbalance fraction for the titration phase may be determined using the following equation:

[0111] where wcis the cathodic pulse width and z is the intensity of the titration pulses. N titration pulses with an imbalance fraction u determined according to Equation (4) will reduce the charge imbalance AQ to zero by the end of the titration phase. The charge-accounting process may adjust the imbalance of charge AQ by the amount of charge imbalance of each delivered titration pulse, and by the delivered charge of the DC pulse, which may be determined as its pulse width multiplied by its amplitude (positive for anodic, negative for cathodic). If the titration phase contains more or fewer than the expected N titration pulses, the charge imbalance AQ will be non-zero at the end of the titration phase.

[0112] Variations in the titration pulse shape resulting from adjustments to the imbalance fraction at the start of each titration phase should maintain the cathodic pulse width constant, since this parameter affects ECAP amplitude.

[0113] In some implementations, the delivered charge of the DC pulses may not be fully recovered as, depending on the electrode materials, a non-zero amount of residual charge on the DC SEC electrodes may be desirable to protect against unwanted reactions at the electrode-tissue interface.

[0114] As the DC pulse intensity increases, the DC pulses will start to affect neural properties such as ECAP threshold, chronaxie / rheobase, and adaptation, before reaching the point of blockade. Tracking any of these properties may provide an indication of the degree of blockade and maytherefore be used in some implementations as an alternative to, or in collaboration with, ECAP amplitude as a feedback variable to control the DC stimulus intensity.

[0115] 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.REFERENCES1. Yang et al., Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current . Science Advances 4(4), eeaql438, April 2018. DOI:10.1126 / sciadv.aaql438LABEL LIST stimulator 100 measurement circuitry 318 patient 108 signal window 319 electronics module 110 ECAP detector 320 battery 112 comparator 324 telemetry module 114 gain element 336 controller 116 integrator 338 memory 118 activation plot 402 clinical data 120 ECAP threshold 404 clinical settings 121 discomfort threshold 408 control programs 122 perception threshold 410 pulse generator 124 therapeutic range 412 electrode selection module 126 activation plot 502 measurement circuitry 128 activation plot 504 ground 130 activation plot 506 array 150 ECAP threshold 508 biphasic stimulus pulse 160 ECAP threshold 510ECAPs 170 ECAP threshold 512 nerve 180 target ECAP amplitude 520 communications channel 190 ECAP 600 external computing device 192 neural stimulation system 700CLNS system 300 neuromodul ati on devi ce 710 clinical settings controller 302 remote controller 720 target ECAP controller 304 CST 730 box 308 clinical Interface CI 740 box 309 charger 750 controller 310 DC stimulation program 800 box 311 phase 810 - 1 stimulator 312 phase 810 - 2 element 313 ISI 815titration phase 820 method 1000DC pulse 830 - 1 step 1005DC pulse 830 -2 step 1010 titration pulse 850 - 1 step 1020 titration pulse 850 -2 step 1030 titration pulse 850 -3 step 1040 ECAP 860- 1 step 1050ECAP 860-2 step 1060ECAP 860-3 method 1100ECAP - titrated DC step 1105 stimulation system 900 step 1110 target controller 904 step 1120 DC stimulator 912- 1 step 1140 titration stimulator 912-2

Claims

CLAIMS:

1. An implantable device for controllably delivering neural stimuli, the device comprising: a stimulus source configured to provide pulses to be delivered via one or more stimulus electrodes to a neural pathway of a patient; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway by one or more measurement electrodes subsequent to respective neural stimuli; and a control unit configured to: control the stimulus source to provide a direct current (DC) pulse according to a stimulus intensity parameter; control the stimulus source to provide a titration pulse in order to evoke a neural response from the neural pathway; measure an intensity of an evoked neural response in a captured signal window subsequent to the titration pulse; and adjust, using a feedback controller, the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

2. The device of claim 1, wherein the control unit is configured to control the stimulus source to provide the titration pulse simultaneously with the DC pulse.

3. The device of claim 2, wherein the target value is an evoked neural response intensity value when the neural pathway is in a blocked state.

4. The device of claim 1, wherein the control unit is configured to control the stimulus source to provide the titration pulse during a titration phase that commenced after the end of the DC pulse.

5. The device of claim 4, wherein the target value is an evoked neural response intensity value when the neural pathway is in a blocked state.

6. The device of claim 4, wherein the control unit is further configured to: control the stimulus source to provide a further titration pulse in order to evoke a further neural response from the neural pathway; and measure a further intensity of a further evoked neural response in a captured signal window subsequent to the further titration pulse.

7. The device of claim 6, wherein the control unit is further configured to fit an intensity curve to the measured intensity and the further measured intensity.

8. The device of claim 7, wherein the target value is based on an evoked neural response intensity value when the neural pathway is in an unblocked state.

9. The device of claim 8, wherein the control unit is further configured to determine the evoked neural response intensity value when the neural pathway is in an unblocked state from the intensity curve.

10. The device of any one of claims 7 to 9, wherein the control unit is configured to end the titration phase and repeat the controlling, controlling, measuring, and adjusting upon the intensity curve exceeding a recovery threshold.

11. The device of claim 10, wherein the control unit is further configured to determine the recovery threshold from the evoked neural response intensity value when the neural pathway is in an unblocked state.

12. The device of claim 10, wherein the control unit is further configured to determine the recovery threshold from the target value.

13. The device of any one of claims 4 to 12, wherein the titration pulse is charge-unbalanced.

14. The device of claim 13, where the control unit is further configured to determine an imbalance fraction of the charge-unbalanced titration pulse so as to recover any imbalance of delivered charge remaining after the end of the DC pulse.

15. The device of claim 14, wherein the control unit is configured to determine the imbalance fraction by dividing the imbalance of delivered charge by an expected number of titration pulses to be delivered before the next DC pulse.

16. The device of claim 15, wherein the expected number of titration pulses is the number of titration pulses delivered during the previous titration phase.

17. The device of any one of claims 1 to 16, configured such that a DC stimulus electrode configuration (SEC) configured to provide the direct current pulse is interposed between a titration stimulus electrode configuration (SEC) configured to provide the titration pulse and a titration measurement electrode configuration (MEC) configured to measure the intensity of the evoked neural response, whereby the evoked neural response evoked by the titration pulse at the titration SEC must pass the DC SEC before reaching the titration MEC.

18. An automated method of controllab ly delivering neural stimuli to a neural pathway of a patient, the method comprising: delivering a direct current (DC) pulse to the neural pathway of the patient, the DC pulse being delivered according to a stimulus intensity parameter; delivering a titration pulse to the neural pathway of the patient in order to evoke a neural response from the neural pathway; capturing a signal window from a signal sensed on the neural pathway subsequent to the titration pulse;measuring an intensity of a neural response evoked by the titration pulse in the signal window; and adjusting the stimulus intensity parameter so as to maintain the measured intensity at or near a target value.

19. The automated method of claim 18 further comprising providing the titration pulse simultaneously with the DC pulse.

20. The automated method of claim 19, wherein the target value is an evoked neural response intensity value when the neural pathway is in a blocked state.

21. The automated method of claim 20 further comprising providing the titration pulse during a titration phase that commenced after the end of the DC pulse.

22. The automated method of claim 21, wherein the target value is an evoked neural response intensity value when the neural pathway is in a blocked state.

23. The automated method of claim 21 further comprising: providing a further titration pulse in order to evoke a further neural response from the neural pathway; and measuring a further intensity of a further evoked neural response in a captured signal window subsequent to the further titration pulse.

24. The automated method of claim 23 further comprising fitting an intensity curve to the measured intensity and the further measured intensity.

25. The automated method of claim 24, wherein the target value is based on an evoked neural response intensity value when the neural pathway is in an unblocked state.

26. The automated method of claim 25 further comprising determining the evoked neural response intensity value when the neural pathway is in an unblocked state from the intensity curve.

27. The automated method of any one of claims 24 to 26 further comprising ending the titration phase and repeat the controlling, controlling, measuring, and adjusting upon the intensity curve exceeding a recovery threshold.

28. The automated method of claim 27 further comprising determining the recovery threshold from the evoked neural response intensity value when the neural pathway is in an unblocked state.

29. The automated method of claim 27 further comprising determining the recovery threshold from the target value.

30. The automated method of any one of claims 21 to 29, wherein the titration pulse is charge- unbalanced.

31. The automated method of claim 30 further comprising determining an imbalance fraction of the charge-unbalanced titration pulse so as to recover any imbalance of delivered charge remaining after the end of the DC pulse.

32. The automated method of claim 31 further comprising determining the imbalance fraction by dividing the imbalance of delivered charge by an expected number of titration pulses to be delivered before the next DC pulse.

33. The automated method of claim 32, wherein the expected number of titration pulses is the number of titration pulses delivered during the previous titration phase.

34. The automated method of any one of claims 18 to 33 wherein a DC stimulus electrode configuration (SEC) used to provide the direct current pulse is interposed between a titration stimulus electrode configuration (SEC) used to provide the titration pulse and a titration measurement electrode configuration (MEC) used to measure the intensity of the evoked neural response, whereby the evoked neural response evoked by the titration pulse at the titration SEC must pass the DC SEC before reaching the titration MEC.

35. A neural stimulation system comprising: an implantable device for controllably delivering neural stimuli, the device comprising: a plurality of electrodes including one or more stimulus electrodes and one or more measurement electrodes; a stimulus source configured to provide neural stimuli to be delivered via the one or more stimulus electrodes to a neural pathway of a patient; measurement circuitry configured to capture signal windows from signals sensed on the neural pathway via the one or more measurement electrodes subsequent to respective neural stimuli; and a control unit configured to control the stimulus source to provide each neural stimulus according to a stimulus intensity parameter; a processor configured to: instruct the control unit to control the stimulus source to provide a direct current (DC) pulse according to the stimulus intensity parameter; instruct the control unit to control the stimulus source to provide a titration pulse in order to evoke a neural response from the neural pathway; measure an intensity of an evoked neural response in a captured signal window subsequent to the titration pulse; and adjust, using a feedback controller, the stimulus intensity parameter so as to maintain the measured intensity at a target value.

36. The system of claim 35, wherein the processor is part of the implantable device.

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