Characterisation of Neurostimulation Therapeutic Efficacy

Abstract

Assessing therapeutic efficacy of electrical neurostimulation therapy. A neuromodulation device delivers the electrical neurostimulation therapy. Measurement circuitry captures recordings of neural responses evoked by the electrical neurostimulation therapy. A processor processes the recordings of the neural responses in order to obtain a plurality of measures of neural activation in response to a plurality of stimuli delivered over time, and calculates from the plurality of measures of neural activation at least one statistical measure of neural activation. From the at least one statistical measure the processor produces and outputs an indication of therapeutic efficacy.

Claims

1. A system for assessing therapeutic efficacy of electrical neurostimulation therapy, the system comprising: a neuromodulation device configured to deliver the electrical neurostimulation therapy; measurement circuitry configured to capture recordings of neural responses evoked by the electrical neurostimulation therapy; and a processor configured to process the recordings of the neural responses in order to obtain a plurality of measures of neural activation in response to a plurality of stimuli delivered over time, the processor further configured to calculate from the plurality of measures of neural activation at least one statistical measure of neural activation, the processor further configured to produce from the at least one statistical measure an indication of therapeutic efficacy, the processor further configured to output the indication of therapeutic efficacy.

2. The system of claim 1 wherein the recordings of neural responses each comprise a recording of at least a portion of an evoked compound action potential (ECAP), and wherein the measures of neural activation each comprise a measure of ECAP amplitude.

3. The system of claim 1 or claim 2 wherein the processor is configured to assemble the measures of neural activation into a neural activation histogram, and to determine the at least one statistical measure of neural activation from the neural activation histogram.

4. The system of claim 1 wherein the at least one statistical measure calculated from the plurality of measures comprises a mode of the plurality of measures.

5. The system of claim 1 wherein the at least one statistical measure calculated from the plurality of measures comprises a mode/comfort+ ratio of the plurality of measures, where comfort+ is a clinician prescribed level of desirable neural activation.

6. The system of claim 1 wherein the at least one statistical measure calculated from the plurality of measures comprises a normalised interdecile range of the plurality of measures.

7. The system of claim 6 wherein the interdecile range is normalised by dividing each of the plurality of measures by at least one of a median, mean or mode of the plurality of measures.

8. The system of claim 1 wherein the at least one statistical measure calculated from the plurality of measures comprises a measure of distribution asymmetry.

9. The system of claim 8 wherein the measure of distribution asymmetry comprises at least one of: a mean/median ratio of the plurality of measures, a measure of dispersion of the plurality of measures, a coefficient of variation of the plurality of measures, a kurtosis of the plurality of measures, and a skew of the plurality of measures.

10. The system of claim 1 wherein the plurality of measures are measures of evoked compound action potential (ECAP) amplitude at a comfort+ level, in a pre-determined posture, and wherein the processor is configured to calculate the at least one statistical measure as being a coefficient of variation of the plurality of measures.

11. The system of claim 10 wherein the processor is configured to produce a greater indication of therapeutic efficacy when the coefficient of variation is small, and to produce a lesser indication of therapeutic efficacy when the coefficient of variation is large.

12. The system of claim 1 wherein the processor is configured to derive two or more statistical measures from the plurality of measures of neural activation, and is further configured to produce a combinatorial indication of therapeutic efficacy from the two or more statistical measures.

13. The system of claim 1 wherein the processor is further configured to compensate the at least one statistical measure for a distance-dependent transfer function of stimulation.

14. The system of claim 1 wherein the processor is further configured to compensate the at least one statistical measure for a distance-dependent transfer function of measurement.

15. The system of claim 1 wherein the processor is further configured to produce the indication of therapeutic efficacy from the at least one statistical measure by comparing the at least one statistical measure to a predefined reference.

16. The system of claim 1 wherein the neuromodulation device is a trial device for use during a neurostimulation trial.

17. The system of claim 1 wherein the neuromodulation device is a permanent implant.

18. The system of claim 17 wherein the measurement circuitry is within the permanent implant.

19. The system of claim 1 wherein the processor is part of an external device which receives the recordings from the neuromodulation device.

20. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to selection of stimulating electrode(s) to improve therapy.

21. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to selection of recording electrode(s) to improve therapy.

22. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to at least one of: selection of a stimulus intensity, selection of a stimulus current, and selection of a stimulus pulse width(s).

23. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to selection of measurement amplifier settings.

24. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to selection of a target level of neural activation.

25. The system of claim 1 configured to use the indication of therapeutic efficacy to guide changes to at least one of: selection of feedback loop implementation, selection of feedback loop parameters, selection of feedback loop gain, selection of feedback loop noise bandwidth, and selection of feedback loop instant backoff threshold.

26. The system of claim 1 wherein the processor is configured to perform an automated procedure for improving therapeutic efficacy, by iteratively revising the therapy to seek an improvement in the indication of therapeutic efficacy.

27. The system of claim 26 wherein the processor is configured to iteratively revise the therapy by: (i) measuring a first indication of therapeutic efficacy with a feedback loop gain set at a first value, (ii) adjusting feedback loop gain from the first value to a second value, (iii) measuring a second indication of therapeutic efficacy and (iv) if the second indication indicates higher therapeutic efficacy than the first indication, retaining the second value of loop gain for ongoing use.

28. The system of claim 1 wherein the indication of therapeutic efficacy is normalised to compensate for variations caused by at least one of: postural changes, and physiological events.

29. A method for assessing therapeutic efficacy of electrical neurostimulation therapy, the method comprising: delivering electrical neurostimulation therapy; capturing recordings of neural responses to the electrical neurostimulation therapy; processing the recordings of the neural responses in order to obtain a plurality of measures of neural activation in response to a plurality of stimuli delivered over time, calculating from the plurality of measures of neural activation at least one statistical measure of neural activation, producing from the at least one statistical measure an indication of therapeutic efficacy; and outputting the indication of therapeutic efficacy.

30. A non-transitory computer readable medium for assessing therapeutic efficacy of electrical neurostimulation therapy, comprising instructions which, when executed by one or more processors, causes performance of the following: delivering electrical neurostimulation therapy; capturing recordings of neural responses to the electrical neurostimulation therapy; processing the recordings of the neural responses in order to obtain a plurality of measures of neural activation in response to a plurality of stimuli delivered over time, calculating from the plurality of measures of neural activation at least one statistical measure of neural activation, producing from the at least one statistical measure an indication of therapeutic efficacy; and outputting the indication of therapeutic efficacy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] An example of the invention will now be described with reference to the accompanying drawings, in which:

[0046] FIG. 1 schematically illustrates an implanted spinal cord stimulator;

[0047] FIG. 2 is a block diagram of the implanted neurostimulator;

[0048] FIG. 3 is a schematic illustrating interaction of the implanted stimulator with a nerve;

[0049] FIGS. 4A and 4B are plots of a series of recordings of ECAP amplitude obtained in closed loop mode, and open loop mode, respectively;

[0050] FIG. 5 illustrates an alternative presentation of clinical data FIG. 6 illustrates a histogram of neural activation data FIG. 7 illustrates the respective VAS reduction observed in two groups of SCS trial participants.

[0051] FIG. 8 illustrates the average mode of ECAP amplitude for each SCS trial group.

[0052] FIG. 9 illustrates the average of the mode/comfort+ ratio for each SCS trial group.

[0053] FIG. 10 illustrates the average of the (90th−10th)/median ratio for each SCS trial group.

[0054] FIG. 11 illustrates the average of the mean/median ratio for each SCS trial group.

[0055] FIG. 12 illustrates an intraoperative procedure in accordance with a further embodiment of the invention

[0056] FIG. 13 illustrates an SCS trial procedure in accordance with another embodiment of the invention;

[0057] FIG. 14 illustrates an SCS implant procedure in accordance with yet another embodiment of the invention;

[0058] FIG. 15 is a dose response plot for both neurostimulation benefit and detriment;

[0059] FIG. 16 is a dose response plot also showing a first example of a broad histogram of neural measures and the resulting net benefit and net detriment;

[0060] FIG. 17 is a dose response plot also showing a second example of a broad histogram of neural measures and the resulting net benefit and net detriment;

[0061] FIG. 18 is a dose response plot also showing a third example of a broad histogram of neural measures and the resulting net benefit and net detriment;

[0062] FIG. 19 is a dose response plot also showing an example of a narrow histogram of neural measures and the resulting net benefit and net detriment; and

[0063] FIG. 20 is a plot of summed net benefit and detriment for open loop neurostimulation, for closed loop stimulation achieving a broad histogram, and for closed loop stimulation achieving a narrow histogram.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0064] FIG. 1 schematically illustrates an implanted spinal cord stimulator 100. Stimulator 100 comprises an electronics module 110 implanted at a suitable location in the patient's lower abdominal area or posterior superior gluteal region, and an electrode assembly 150 implanted within the epidural space and connected to the module 110 by a suitable lead. Numerous aspects of operation of implanted neural device 100 are reconfigurable by an external control device 192. Moreover, implanted neural device 100 serves a data gathering role, with gathered data being communicated to external device 192 via any suitable transcutaneous communications channel 190.

[0065] FIG. 2 is a block diagram of the implanted neurostimulator 100. Module 110 contains a battery 112 and a telemetry module 114. In embodiments of the present invention, any suitable type of transcutaneous communication 190, such as infrared (IR), electromagnetic, capacitive and inductive transfer, may be used by telemetry module 114 to transfer power and/or data between an external device 192 and the electronics module 110. Module controller 116 has an associated memory 118 storing patient settings 120, control programs 122 and the like. Controller 116 controls a pulse generator 124 to generate stimuli in the form of current pulses in accordance with the patient settings and control programs 122. Electrode selection module 126 switches the generated pulses to the appropriate electrode(s) of electrode array 150, for delivery of the current pulse to the tissue surrounding the selected electrode(s). Measurement circuitry 128 is configured to capture measurements of neural responses sensed at sense electrode(s) of the electrode array as selected by electrode selection module 126.

[0066] It is to be noted that in alternative embodiments of the invention, the electronics module 110 may be outside the body, for example in the form of a trial SCS controller, or an intraoperative control device. In such alternative embodiments the power source 112 may be substituted with mains power, and telemetry module 114 may be simplified or substituted by other forms of data connection modules.

[0067] FIG. 3 is a schematic illustrating interaction of the implanted stimulator 100 with a nerve 180, in this case the spinal cord however alternative embodiments may be positioned adjacent any desired neural tissue including a peripheral nerve, visceral nerve, parasympathetic nerve or a brain structure. Electrode selection module 126 selects a stimulation electrode 2 of electrode array 150 to deliver a biphasic tripolar electrical current pulse to surrounding tissue including nerve 180. Electrode selection module 126 also selects two return electrodes 1 and 3 of the array 150 for stimulus current recovery to maintain a zero net charge transfer. Alternative embodiments may employ alternative stimulus configuration(s), such as tripolar triphasic stimulation, for the reasons set out in the present Applicant's International Patent Publication No. WO 2017219096 A1, the content of which is incorporated herein by reference.

[0068] Delivery of an appropriate stimulus to the nerve 180 evokes a neural response comprising a compound action potential which will propagate along the nerve 180 as illustrated, for therapeutic purposes which in the case of a spinal cord stimulator for chronic pain might be to create paraesthesia at a desired location. To this end the stimulus electrodes are used to deliver stimuli at any therapeutically suitable frequency, for example 30 Hz, although other frequencies may be used including as high as the kHz range, and/or stimuli may be delivered in a non-periodic manner such as in bursts, or sporadically, as appropriate for the patient. To fit the device, a clinician applies stimuli of various configurations which seek to produce a sensation that is experienced by the user as a paraesthesia. When a stimulus configuration is found which evokes paraesthesia, which is in a location and of a size which is congruent with the area of the user's body affected by pain, the clinician nominates that configuration for ongoing use.

[0069] The device 100 is further configured to sense the existence and intensity of compound action potentials (CAPs) propagating along nerve 180, whether such CAPs are evoked by the stimulus from electrodes 1-3, or otherwise evoked. To this end, any electrodes of the array 150 may be selected by the electrode selection module 126 to serve as measurement electrode 6 and measurement reference electrode 8. Signals sensed by the measurement electrodes 6 and 8 are passed to measurement circuitry 128, which for example may operate in accordance with the teachings of International Patent Application Publication No. WO2012155183 by the present applicant, the content of which is incorporated herein by reference. The output of circuitry 128 is used by controller 116 in a feedback arrangement to control the application of subsequent stimuli, and the controller 116 also stores the recording of the neural response, or one or more parameters thereof such as ECAP amplitude, to the Clinical Data storage 120.

[0070] Stimulator 100 applies stimuli over a potentially long period such as days or weeks, and records neural responses, stimulation settings, paraesthesia target level, and other operational parameters, discussed further below. The stimulator 100 comprises a closed loop stimulator (CLS), in that the recorded neural responses are used in a feedback arrangement to control stimulation settings on a continuous or ongoing basis. To effect suitable SCS therapy stimulator 100 may deliver tens, hundreds or even thousands of stimuli per second, for many hours each day. The feedback loop may operate for most or all of this time, by obtaining neural response recordings following every stimulus, or at least obtaining such recordings sufficiently regularly that the feedback loop can respond in a timely manner, for example to respond to postural changes of the user. Each recording generates a feedback variable such as a measure of the amplitude of the evoked neural response, which in turn results in the feedback loop changing the stimulation parameters for a following stimulus if required. Stimulator 100 thus produces 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. This is unlike past neuromodulation devices such as SCS devices which lack any ability to record any neural response.

[0071] When brought in range with a receiver, or when operating during a programming session under control of an external device of a clinician, stimulator 100 transmits data via telemetry module 114 to a clinical programming application, which compiles a clinical data log file which can be manipulated and optimised and presented by a clinical data viewer for field diagnosis by the clinician or field clinical engineer (FCE). The software application used to analyse the data generated by the stimulator 100 is installed on a Clinical Interface (CI) tablet computer, or on another computer 192 running any suitable operating system such as Microsoft Windows. The data can be grouped into two main sources: 1. Data collected in real-time during a programming session, and 2. Data downloaded from a stimulator after a period of non-clinical use by a patient.

[0072] The present invention recognises that the mechanisms of action (MoA) for SCS propose an inhibitory effect of spinal cord stimulation on neuropathic pain, with activated axons likely responsible for the paresthesia of conventional SCS. The present invention further recognises that the evoked compound action potential (ECAP) recordings obtained by the implant 100, or by a trial device with transcutaneous leads, can be assessed and serve to elucidate that SCS activates Aβ fibres in the dorsal column. This enables a patient's electrophysiological response to SCS stimulation, such as ECAP amplitude, to be correlated with pain relief. This in turn facilitates closed loop SCS, whereby ECAP amplitude can be maintained within a narrow therapeutically effective range, referred to herein as the therapeutic window (TW). FIG. 4A is a plot of a series of recordings of ECAP amplitude obtained over approximately 6 minutes, obtained by device 100 when operating in closed loop mode. As can be seen, despite the patient undertaking a range of physical and physiological tasks including standing, lying supine, sitting, coughing and walking in place, the closed loop mode is highly effective at maintaining the ECAP amplitude within the therapeutic window 410. The therapeutic window 410 is defined herein as residing between a perception threshold 412 and a maximum level 414. The perception threshold 412 is the minimum ECAP amplitude which is subjectively perceived by the patient, which as can be seen in FIG. 4A is a non-zero ECAP amplitude level. The maximum level 414 is the largest ECAP amplitude which the patient can comfortably tolerate. The closed loop mode feedback is configured to produce ECAPs at a target level 416 within the therapeutic range, the target level 416 being the ECAP level at which the patient reports comfortable paresthesia.

[0073] The therapeutic window 410 can also be defined as residing between an ECAP threshold 412 and a maximum level 414. The ECAP threshold 412 is the minimum current amplitude at which an ECAP can be detected.

[0074] This is in contrast to conventional SCS which operates without feedback control, in what is referred to as an open loop mode. FIG. 4B is a plot of a series of recordings of ECAP amplitude over an approximately 2 minutes period of time, obtained by device 100 when operating in open loop mode. In open loop mode, at any given setting of stimulus intensity, significant ECAP amplitude variation can result from normal physical and physiological activity, as shown in FIG. 4B. As can be seen, as the patient undertakes a range of physical and physiological tasks including standing, walking in place, lying supine, sitting and coughing, the open loop mode is ineffective at maintaining the ECAP amplitude within the therapeutic window 410. Open loop mode SCS thus often causes overstimulation, whereby the evoked ECAP amplitude exceeds the therapeutic window. The overstimulation range is indicated at 420. The present invention recognises that such overstimulation can result in repeated Aβ nociceptor activation which in turn may cause spinal cord sensitisation. And, spinal cord sensitisation reduces or negates the pain inhibition afforded by SCS, leading to a loss of therapeutic benefit.

[0075] FIG. 5 illustrates an alternative presentation of clinical data from device 100, for a non-clinical usage period of about two hours, effected by the Clinical Data Viewer software. Therapy Logs 510 are displayed, in the form of a heat-map. Each heat map is a representation of the proportion of stimuli (intensity) which had a particular magnitude (y-axis) at each time point (x-axis), as derived from a histogram of the data retrieved from the device 100 over a short period of time. For example, each such histogram may be compiled over a respective 2 minutes time period. The more intense the heat map, the greater the proportion of stimuli with that magnitude at that time. Three heat maps are displayed, Feedback Variable 512, Feedback Target 514, and Stimulus Current 516. The feedback variable for example could be observed ECAP amplitude as measured as being the peak to peak value from N1 to P2 of each measured ECAP. The Feedback Variable 512 heat map is thus an alternative display method for ECAP amplitude data of the type shown in FIGS. 4A and 4B, being conducive to the display of larger such data sets obtained over a longer period of time.

[0076] Within tab 520, slider bar 530 is a graphical user interface which allows the reviewer to select a temporal subset of the data 510. For that selected subset of data, the clinical data viewer extracts histogram data for the feedback variable as shown in plot 532, and extracts histogram data for the feedback target as shown in plot 534, and extracts histogram data for the stimulus current as shown in plot 536, for closer assessment. The histogram extracted from each short period of data is also presented as Therapy Logs 510, which show the individual histograms in heat map form over the entire 2 hours period, using a heat-map to efficiently represent the column heights of each histogram 532, 534, 536, for each segment of time.

[0077] Of particular interest to the present invention, each individual histogram of ECAP amplitude in the Therapy Log 512 can be displayed and analysed as shown in FIG. 6, whether the device 100 is operating in open loop mode (no feedback) or closed loop mode (feedback control of stimulation based on observed ECAP amplitude). The present invention recognises that obtaining a sufficient number of individual neural activation measurements provides a sufficient sample size of such data to permit one or more statistical measures of the neural activation to be determined. For example, statistical measures of the ECAP amplitude histogram data which can be extracted include the minimum value, maximum value, mean, median, mode, and standard deviation. In more detail, particularly preferred statistical measures in accordance with some embodiments of the invention include (1) the mode, (2) the ratio of the mode to the comfort+ level (mode/comfort+), and the difference between the 90.sup.th percentile and 10.sup.th percentile, divided by the median ((90.sup.th−10.sup.th)/median).

[0078] Table I below describes how some such statistics are calculated on individual histograms in accordance with some embodiments of the invention. Note that the units (except for the Total Number of Stimulations) are the same units as used by the x-axis, i.e. μV for the FBV.

TABLE-US-00001 TABLE I Histogram definitions and parameter information Bin Width Specifies the range of the unit for each bin (b). The bin width is calculated from a numerator (n) and a denominator in bit shifts (d) field using the formula: [00001]$b=\frac{2^d}{n}$ Number of Bins The number of elements in the ″Bins″ array. Bins An array of stimulations for a given range. The range is calculated using the formula: [ib, (i + 1)b) where i is the index of the element in the array and b is the bin width. Total Number of Stimulations [00002]$C=\underset{i=0}{\overset{N-1}{.Math.}}{c}_i$ Minimum (left-hand-edge of ib for min i where c.sub.i > 0 the smallest bin with a count greater than 0) Maximum (right-hand-edge of the largest bin with a (i + 1)b for max i where c.sub.i > 0 count greater than 0) Mean (μ) [00003]$\mu =\frac{1}{C}\underset{i=0}{\overset{N-1}{.Math.}}{c}_i\left(\frac{ib+\left(i+1\right)b}{2}\right)$ Median (M.sub.d) [00004]$\underset{i=0}{\overset{M_d/b}{.Math.}}{c}_i=\frac{C+1}{2}$ Mode (M.sub.0) [00005]$M_0=\left(\frac{ib+\left(i+1\right)b}{2}\right)$ for i where [00006]$c_i=\underset{i\mathrm{.Math.}\left[0,N-1\right]}{\max }{c}_i$ Standard Deviation (σ) [00007]$\sigma =\sqrt{\frac{1}{N}\underset{i=0}{\overset{N-1}{.Math.}}{c_i\left(\left(\frac{ib+\left(i+1\right)b}{2}\right)-\mu \right)}^2}$

[0079] Example 1: A closed-loop SCS system measured human spinal cord evoked compound action potentials (ECAPs) in real time, allowing correlation of dorsal column activation (ECAP amplitude) with patient-reported outcomes, thus providing objective measures of SCS effectiveness in pain management. Subjects were implanted with a new SCS system in a clinical trial study. Histograms of the distribution of ECAP amplitudes were extracted from each subject's device at the 12-month visit and are representative of everyday use. An example histogram is shown in FIG. 6. Statistical measures of these histograms were performed to form a neural response profile (NRP). The NRP is a quantitative summary of dorsal column response to electrical stimulus over a defined period (Table 2). Pain reduction using the Visual Analog Scale (VAS) and NRPs were summarized, for two groups of participants: Group 1, patients with minimally important pain relief, being those with VAS reduction <30% at the 12-month visit (N=5, Table 3(A)); and Group 2, patients with substantial pain relief, being those with VAS reduction ≥50% at the 12-month visit (N=18, Table 3(A)). FIG. 7 illustrates the respective VAS reduction observed in these two groups.

TABLE-US-00002 TABLE 2 Neural Response Profile Variables Variable Statistical Description Mode Most frequent ECAP amplitude Mode/Comfort+ Subject's in-clinic comfort level normalized to the mode: values close to 1 indicate a close match. Comfort+ may be replaced with any suitable clinician prescribed activation level (90.sup.th-10.sup.th)/Median The interdecile spread of the NRP normalized to the median indicating the NRP width and ECAP amplitude variability Mean/Median Measures the symmetry of the NRP: 1 indicates symmetry

[0080] Initial observations indicate notable differences between cohorts in NRP values (Table 3; FIGS. 7-11). When considered subjectively, FIG. 7 shows that this division gives an average VAS reduction of 14% in Group 1, and a much improved VAS reduction in Group 2 of 95%.

[0081] FIG. 8 illustrates the average mode of ECAP amplitude for each SCS trial group. As shown, the average of the mode ECAP amplitude was twice as high in Group 2 as in Group 1. Thus, a relatively higher mode may be associated with greater efficacy of SCS.

[0082] FIG. 9 illustrates the average of the mode/comfort+ ratio for each SCS trial group. As shown, the mode/comfort+ ratio was twice as high in Group 2 as in Group 1. Thus, a relatively higher mode/comfort+ ratio may be associated with greater efficacy of SCS.

[0083] FIG. 10 illustrates the average of the (90th−10th)/median ratio for each SCS trial group. As shown, in FIG. 10, the average of the (90th−10th)/median ratio was 1.4 for Group 1 and 1.0 for Group 2. Thus, a relatively narrower normalised interdecile range may be associated with increased SCS efficacy.

[0084] FIG. 11 illustrates the average of the mean/median ratio for each SCS trial group. As shown, the mean/median ratio was 1.03 in Group 2 and 1.08 in Group 2. Thus, patients with substantial pain relief had more consistent spinal cord activation, so that greater asymmetry may be associated with reduced SCS efficacy. This may manifest as a mean/median ratio which deviates away from 1.0 in either direction, whether higher or lower.

TABLE-US-00003 TABLE 3 12-Month VAS and NRP Variables Compared Between Group 1 (VAS reduction <30%) and Group 2 (VAS reduction ≥50%) VAS Mode Mode/ (90.sup.th-10.sup.th)/ Mean/ Reduction (%) (μV) Comfort+ Median Median (A) (B) (C) (D) (E) VAS Reduction <30% (Group 1) N 5 5 5 5 5 Mean 13.93 21.60 0.48 1.36 1.08 Median 15.46 16.50 0.38 1.31 1.04 STD 11.12 19.62 0.44 0.75 0.09 VAS Reduction ≥50% (Group 2) N 19 18 17 18 18 Mean 95.11 41.97 0.99 1.00 1.03 Median 97.47 27.75 0.70 0.99 1.01 STD 5.18 41.28 1.09 0.58 0.05

[0085] Example 1 thus provides human neurophysiological data suggesting that the magnitude of pain relief in SCS correlates with the magnitude of dorsal column activation, and is inversely related to the variability of activation. The NRP, comprising such statistical measures of neural activation, thus provides the first objective neurophysiological tool in SCS in contrast to past subjective measures. The NRP in turn may provide diagnostic support for predicting response to SCS, whether intraoperatively (FIG. 12), during SCS trials (FIG. 13) or during permanent implant stage (FIG. 14), and may thus in some embodiments assist in improving long-term success rates.

[0086] FIG. 12 illustrates a procedure as may be executed in part by a software application in accordance with an embodiment of the invention. The application is configured to assess a statistically significant sample size of intraoperatively obtained ECAP recordings, in order to give a rapid and intraoperative output indication to clinicians as to whether the patient undergoing surgery is likely to benefit from an SCS trial. In cases where the patient's neural response profile is indicative that the patient will be a non-responder, the trial can be cancelled and the trial electrode lead can be removed, avoiding the costs and risks of a transcutaneous lead during a SCS trial.

[0087] FIG. 13 illustrates a procedure as may be executed in part by a software application in accordance with an embodiment of the invention. The application is configured to assess a statistically significant sample size of ECAP recordings obtained during an SCS trial, in order to give an indication to clinicians as to whether the patient undergoing the trial is likely to benefit from permanent SCS implantation. In cases where the patient's neural response profile is indicative that the patient will be a non-responder, the trial can be concluded and the trial electrode lead can be removed, avoiding the costs and risks of a permanent SCS implant.

[0088] FIG. 14 illustrates a procedure as may be executed in part by a software application in accordance with an embodiment of the invention. The application is configured to assess a statistically significant sample size of ECAP recordings obtained during normal day to day operation of a permanent SCS implant, in order to give an indication to clinicians or to the user as to whether the implant recipient is continuing to benefit from permanent SCS implantation. In cases where the patient's neural response profile is indicative that the patient has been a non-responder for that time period, the device operation can be revised or optimised, or the patient may be referred for consideration for explantation of the permanent SCS implant.

[0089] Without intending to be limited by theory, it is noted that one hypothesis for optimal therapeutic efficacy involves considering a dose response plot, as illustrated in FIG. 15. A dose response benefit curve 1510 reflects the increasing beneficial pain relief effected by increasing neural recruitment, while a dose-response detriment curve 1520 reflects the harm caused by excessive stimulation. Such harm may comprise worsening of the disease state and/or immediate pain. Each individual stimulus can produce a beneficial part and a detrimental part, which sum to provide a net benefit as indicated by curve 1530. The x-axis units are arbitrary for illustrative purposes, but can be tens of microvolts of ECAP in a typical situation and will vary from one patient to the next.

[0090] The onset of therapeutic benefit is measured as the patient's threshold. A stimulus that does not recruit any ECAP does not provide benefit. The onset of harm might coincide with the patient's comfort+ value or their maximum value or may fall at a value in between. This diagram matches clinical experience, where for low values of stimulation (say, ECAP Amplitude <2 in FIG. 15) there is no benefit, but if the stimulation is too high (ECAP Amplitude >9) then the patient would prefer no stimulation at all, so the detrimental side effects exceed the beneficial pain relief above this point and the net benefit falls below zero, i.e. there is a net detriment. The black line 1530 is referred to herein as a “biphasic dose response curve”.

[0091] The present invention can be considered as recognising that when repeated stimuli are presented, they add to produce a net benefit and harm over time. These are found by multiplying the probability density function of the ECAP amplitude (i.e. the histogram) by the benefit and detriment curves, and summing the total area produced (where detriment takes negative values).

[0092] In FIG. 16, the green line 1610 represents the benefit dose/response curve and the red line 1620 represents the harm dose response curve. The blue line 1640 illustrates the ECAP probability density function (PDF), which in preferred embodiments is captured as a histogram by the implanted device. The green area 1650 represents net benefit as a probability density function and the red area 1660 represents net harm in a similar manner.

[0093] By varying the stimulation amplitude, the proportion of benefit and harm areas (1650: 1660) varies. In FIG. 16 it can be seen that some benefit is derived and little harm. However, a significant portion of the recruited ECAPs fall below or near the onset of the benefit curve 1610 and are thus ineffectual and this portion of the therapy might thus be considered to be wasted.

[0094] In FIG. 17, the stimulation level has been increased causing ECAP pdf 1740 to be positioned further to the right than 1640. This causes the benefit 1750 to increase to close to an optimum value, significantly larger than benefit 1650. However, the net detriment 1760 has also increased and is significantly larger than detriment 1660.

[0095] In FIG. 18, the stimulation has been further increased causing ECAP pdf 1840 to shift further to the right again. The benefit 1850 has reached a plateau and is not significantly greater than benefit 1750, whereas the harm 1860 has increased significantly beyond detriment 1760, to the point that detriment 1860 outweighs the benefit 1850.

[0096] FIGS. 16-18 thus illustrate that knowledge of the benefit and detriment dose-response curves permits the optimum stimulation amplitude to be determined.

[0097] Embodiments of the present invention can further be considered to recognise that a narrower ECAP pdf 1640/1740/1840, i.e. a narrower histogram, is a desirable goal of stimulation as this improves the system's ability to increase the proportion of beneficial stimuli as compared to detrimental stimuli. This is illustrated in FIGS. 19 and 20.

[0098] In FIG. 19, ECAP pdf 1940 is centred around a value of about 8.5, greater than the centre value of ECAP pdfs 1640 and 1740. However, as the dispersion or variance of the histogram 1940 is reduced compared to ECAP pdfs 1640/1740/1840, fewer low amplitude ECAPs occur and thus fewer stimuli result in wasted or ineffectual therapy. Consequently, the benefit curve 1950 maximises the benefit of the applied stimuli and nearly conforms to curve 1940. Moreover, the narrow profile also results in fewer large amplitude ECAPs and thus a reduced amount of highly detrimental stimuli, and a small overall amount of detriment as reflected by curve 1960.

[0099] FIG. 20 compares open loop (green), closed loop with a variance of 5 and closed loop with a variance of 1. For each histogram, the net benefit and detriment were summed and added. This shows that, when the therapeutic efficacy of neurostimulation is evaluated by way of such a theoretical dose response curve, the narrower histogram produces the greatest benefit as it fits the greatest proportion of stimuli between the peak benefit curve and the onset of detriment. Open loop operation delivers the poorest net benefit.

[0100] It will be appreciated by persons skilled in the art that numerous variations and/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.