Patent Document

CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of Australian Provisional Patent Application No. 2011901827 filed 13 May 2011 and Australian Provisional Patent Application No. 2011901817 filed 13 May 2011, both of which are incorporated herein by reference. 
       TECHNICAL FIELD 
       [0002]    The present invention relates to measuring a neural response to a stimulus, and in particular relates to measurement of a compound action potential by using one or more electrodes implanted proximal to the neural pathway, in order to estimate neural recruitment resulting from an applied stimuli. 
       BACKGROUND OF THE INVENTION 
       [0003]    There are a range of situations in which it is desirable to apply neural stimuli in order to give rise to a compound action potential (CAP). For example, neuromodulation is used to treat a variety of disorders including chronic pain, Parkinson&#39;s disease, and migraine. A neuromodulation system applies an electrical pulse to tissue in order to generate a therapeutic effect. When used to relieve chronic pain, the electrical pulse is applied to the dorsal column (DC) of the spinal cord. Such a system typically comprises an implanted electrical pulse generator, and a power source such as a battery that may be rechargeable by transcutaneous inductive transfer. An electrode array is connected to the pulse generator, and is positioned in the dorsal epidural space above the dorsal column. An electrical pulse applied to the dorsal column by an electrode causes the depolarisation of neurons, and generation of propagating action potentials. The fibres being stimulated in this way inhibit the transmission of pain from that segment in the spinal cord to the brain. To sustain the pain relief effects, stimuli are applied substantially continuously, for example at 100 Hz. 
         [0004]    While the clinical effect of spinal cord stimulation (SCS) is well established, the precise mechanisms involved are poorly understood. The DC is the target of the electrical stimulation, as it contains the afferent Aβ fibres of interest. Aβ fibres mediate sensations of touch, vibration and pressure from the skin, and are thickly myelinated mechanoreceptors that respond to non-noxious stimuli. The prevailing view is that SCS stimulates only a small number of Aβ fibres in the DC. The pain relief mechanisms of SCS are thought to include evoked antidromic activity of Aβ fibres having an inhibitory effect, and evoked orthodromic activity of Aβ fibres playing a role in pain suppression. It is also thought that SCS recruits Aβ nerve fibres primarily in the DC, with antidromic propagation of the evoked response from the DC into the dorsal horn thought to synapse to wide dynamic range neurons in an inhibitory manner. 
         [0005]    Neuromodulation may also be used to stimulate efferent fibres, for example to induce motor functions. In general, the electrical stimulus generated in a neuromodulation system triggers a neural action potential which then has either an inhibitory or excitatory effect. Inhibitory effects can be used to modulate an undesired process such as the transmission of pain, or to cause a desired effect such as the contraction of a muscle. 
         [0006]    The action potentials generated among a large number of fibres sum to form a compound action potential (CAP). The CAP is the sum of responses from a large number of single fibre action potentials. The CAP recorded is the result of a large number of different fibres depolarising. The propagation velocity is determined largely by the fibre diameter and for large myelinated fibres as found in the dorsal root entry zone (DREZ) and nearby dorsal column the velocity can be over 60 ms −1 . The CAP generated from the firing of a group of similar fibres is measured as a positive peak potential P1, then a negative peak N1, followed by a second positive peak P2. This is caused by the region of activation passing the recording electrode as the action potentials propagate along the individual fibres. An observed CAP signal will typically have a maximum amplitude in the range of microvolts, whereas a stimulus applied to evoke the CAP is typically several volts. 
         [0007]    To resolve a 10 μV SCP with 1 μV resolution in the presence of an input 5V stimulus, for example, requires an amplifier with a dynamic range of 134 dB, which is impractical in implant systems. As the neural response can be contemporaneous with the stimulus and/or the stimulus artefact, CAP measurements are difficult to obtain. This is particularly so for pain relief where patients typically obtain best effects with a pulse width in the range of 100-500 μs which ensures much of the neural response occurs while the stimulus is still ongoing, making measurement of the neural response effectively impossible. 
         [0008]    For effective and comfortable operation, it is necessary to maintain stimuli amplitude or delivered charge above a recruitment threshold, below which a stimulus will fail to recruit any neural response. It is also necessary to apply stimuli which are below a comfort threshold, above which uncomfortable or painful percepts arise due to increasing recruitment of M fibres which are thinly myelinated sensory nerve fibres associated with acute pain, cold and pressure sensation. In almost all neuromodulation applications, a single class of fibre response is desired, but the stimulus waveforms employed can recruit other classes of fibres which cause unwanted side effects, such as muscle contraction if motor fibres are recruited. The task of maintaining appropriate stimulus amplitude is made more difficult by electrode migration and/or postural changes of the implant recipient, either of which can significantly alter the neural recruitment arising from a given stimulus, depending on whether the stimulus is applied before or after the change in electrode position or user posture. Postural changes alone can cause a comfortable and effective stimulus regime to become either ineffectual or painful. 
         [0009]    Another control problem, faced by neuromodulation systems of all types, is achieving neural recruitment at a sufficient level required for therapeutic effect, but at minimal expenditure of energy. The power consumption of the stimulation paradigm has a direct effect on battery requirements which in turn affects the device&#39;s physical size and lifetime. For rechargeable systems, increased power consumption results in more frequent charging and, given that batteries only permit a limited number of charging cycles, ultimately this reduces the lifetime of the device. 
         [0010]    Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. 
         [0011]    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. 
       SUMMARY OF THE INVENTION 
       [0012]    According to a first aspect the present invention provides a method of estimating neural recruitment arising from a selected neural stimulus, the method comprising:
       applying the selected neural stimulus;   after the selected neural stimulus, applying a probe stimulus having a short pulse width;   measuring a remnant neural response evoked by the probe stimulus; and   from the remnant neural response, estimating neural recruitment caused by the selected neural stimulus.       
 
         [0017]    According to a second aspect the present invention provides an implantable device for estimating neural recruitment arising from a selected neural stimulus, the device comprising:
       a plurality of electrodes including one or more nominal stimulus electrodes and one or more nominal sense electrodes;   a stimulus source for providing stimuli to be delivered from the one or more stimulus electrodes to neural tissue;   measurement circuitry for obtaining a measurement of a neural signal sensed at the one or more sense electrodes; and   a control unit configured to control application of a selected stimulus to neural tissue using the stimulus electrodes; the control unit further configured to, after the selected neural stimulus, apply a probe stimulus having a short pulse width; the control unit further configured to measure a remnant neural response evoked by the probe stimulus; and the control unit further configured to estimate from the remnant neural response a neural recruitment caused by the selected neural stimulus.       
 
         [0022]    The present invention thus provides for probing of an un-recruited fibre population which was not recruited by the selected stimulus, by reference to which an understanding of the population recruited by the selected stimulus can be obtained. 
         [0023]    Embodiments of the invention may be particularly beneficial in providing for estimation of neural recruitment effected by a selected stimulus having a long pulse width, for example in the range of 100-500 μs, in relation to which it is not possible to directly measure a neural response due to temporal overlap of the stimulus and response. 
         [0024]    In preferred embodiments, the probe stimulus is applied quickly after the selected stimulus, within the refractory period of the fibres recruited by the selected stimulus. 
         [0025]    In some embodiments, a second probe stimulus is applied after the refractory period of fibres recruited by either the selected stimulus or the probe stimulus, and a second measure of evoked neural response is obtained as caused by the second probe stimulus. In such embodiments, the neural recruitment arising from the selected neural stimulus may be estimated by comparing the remnant neural response to the second measure. 
         [0026]    Additionally or alternatively, some embodiments may comprise:
       a) applying the probe stimulus at a time t after conclusion of the selected stimulus;   b) obtaining a measure of a remnant neural response arising from the probe stimulus;   c) changing t; and   d) repeating (a), (b) and (c) to determine variations in the remnant neural response measure, with varying t.       
 
         [0031]    For example, with increasing t an increase in the remnant neural response may indicate the refractory period of the fibre population recruited by the selected stimulus. 
         [0032]    In embodiments of the invention in which an estimate of refractory period is obtained, the refractory period may be monitored over time in order to diagnose onset or progression of a disease. 
         [0033]    According to another aspect the present invention provides a computer program product comprising computer program code means to make a computer execute a procedure for estimating neural recruitment arising from a selected neural stimulus, the computer program product comprising computer program code means for carrying out the method of the first aspect. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0034]    An example of the invention will now be described with reference to the accompanying drawings, in which: 
           [0035]      FIG. 1  illustrates an implantable device suitable for implementing the present invention; 
           [0036]      FIG. 2  is a schematic of a feedback controller which refines future stimuli based on estimated recruitment of neurons by past stimuli; 
           [0037]      FIG. 3  illustrates the masked to unmasked stimulation paradigm provided by the present embodiment of the invention; 
           [0038]      FIG. 4  illustrates recordings of actual evoked responses in accordance with the method of one embodiment of the present invention; and 
           [0039]      FIG. 5  is a plot of the (P1-N1) amplitude of measurements of responses evoked by two pulses, for varying inter-stimulus interval. 
       
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0040]      FIG. 1  illustrates an implantable device  100  suitable for implementing the present invention. Device  100  comprises an implanted control unit  110 , which controls application of neural stimuli, and controls a measurement process for obtaining a measurement of a neural response evoked by the stimuli from each of a plurality of electrodes. Device  100  further comprises an electrode array  120  consisting of a three by eight array of electrodes  122 , each of which may be selectively used as either the stimulus electrode or sense electrode, or both. 
         [0041]      FIG. 2  is a schematic of a feedback controller which refines future stimuli based on estimated recruitment of neurons by past stimuli. The present embodiment provides for the recruitment estimator in  FIG. 2  to obtain a measurement of a masked neural response arising in response to a probe stimuli applied during a refractory period of a therapeutic stimulus, and also provides for measurement of an unmasked neural response arising in response to a probe stimuli applied after a refractory period of the same or equivalent subsequent therapeutic stimulus. Comparing the ratio or difference between the masked and unmasked neural responses indicates a level of recruitment achieved by the therapeutic stimulus. 
         [0042]    In this embodiment the evoked CAP measurements are made by use of the neural response measurement techniques set out in the Australian provisional patent application No. 2011901817 in the name of National ICT Australia Ltd entitled “Method and apparatus for measurement of neural response” from which the present application claims priority. 
         [0043]    Long pulse widths on the order of 400 μs, as used in many commercially available stimulators, cause problems for the measurement of evoked response, as much of the neural response passes the recording electrodes during the stimulus period. That is, in such a biphasic pulse, at least 0.8 ms passes from stimulus onset before measurement is possible. As shown in  FIG. 3   a , the therapeutic stimulus  302  continues for a sufficiently long period of time that it substantially temporally overlaps the evoked neural response  304 . The signal amplitudes in  FIG. 3  are not to scale, and the therapeutic stimulus is of the order of volts while the neural response measurement is of the order of tens of microvolts, so that in the case shown in  FIG. 3   a  the evoked response is practically impossible to measure directly. Nevertheless, for many reasons it is desirable to measure or estimate the amplitude of the response R t  induced by stimulus  302 . 
         [0044]      FIGS. 3   b  and  3   c  illustrate the masked to unmasked stimulation paradigm provided by the present embodiment of the invention. In order to estimate how many fibres are recruited in the neural response  304  arising from the long therapeutic pulse  302 , a shorter probe pulse  306  is delivered shortly after the therapeutic stimulus  302 . The neural response  308  caused by probe pulse  306  is not contemporaneous with any stimulus, and is therefore able to be measured without being swamped by large stimulus voltages. Notably, by delivering the probe pulse  306  during the refractory period of the fibres triggered in response  304 , the response  308  has an amplitude R I  which is proportional to the number of fibres which were not triggered by the long pulse  302 . 
         [0045]    After a time delay of sufficient length to allow all fibres triggered as part of either response  304  or response  308  to exit their refractory states, another short probe pulse  310  is delivered as shown in  FIG. 3   c . Probe pulse  310  preferably has the same parameters as probe pulse  306 . Obtaining a measure of response  312  provides an unmasked response amplitude measurement R S , with R S &gt;R I , against which the first, masked response  308  can be compared. This masked/unmasked ratio (R I :R S ) can be used to estimate what proportion of the accessible fibre population was stimulated in response  304  by therapeutic stimulus  302 , thereby allowing R t  to be estimated. Notably, when performed sufficiently quickly that a fibre-to-electrode distance will remain substantially constant, this technique is not susceptible to the problem of unknown fibre-to-electrode distance as the ratios cancel the effect of variable electrode-to-fibre distance. 
         [0046]    In addition to determining recruitment of long pulse width stimuli, it can be useful to measure physiological parameters such as refractory periods in order to give a diagnosis of various conditions or diseases. Thus, in another embodiment of the invention the refractory period is estimated by first obtaining a measure R S  of the unmasked neural response to a given probe stimulus. Then, two stimuli are applied close together separated by a variable delay t d  ( FIG. 3   b ). With increasing t d , the amplitude R I  can be expected to markedly increase when the onset of pulse  306  is delayed sufficiently to allow the average refractory period of the neural population recruited in response  304  to conclude, so that observing such an increase in R I  allows that population&#39;s refractory period to be estimated. There are a number of neurological conditions and non-neurological conditions which can affect the refractory period. This measurement technique may thus serve as a useful diagnostic indicator. 
         [0047]      FIG. 4  illustrates recordings of actual evoked responses in accordance with the embodiment of  FIG. 3 . The recordings of a response pair were made on 8 spaced apart electrodes along the spinal column as the evoked responses  404 ,  408  travelled along the spinal column adjacent to the array. As can be seen, an initial response  404  is evoked by a first stimulus, and then a second response  408  is evoked immediately afterwards in the refractory period of the neural population recruited as part of response  404 . Response  408  is of reduced, but non-zero, amplitude. The relative ratios of the amplitudes of the measurements of the two responses thus permit the above-described information to be elicited. 
         [0048]      FIG. 5  is a plot of the (P1-N1) amplitude of measurements of responses  502 ,  506  respectively evoked by a first pulse  302  and a second pulse  306  of equal amplitude and pulse width, for varying inter-stimulus interval t d . As can be seen at  502 , the first pulse  302  produces the same recruitment and response amplitudes irrespective of t d . However, the recruitment effected by the second pulse  306  varies considerably with t d , as shown by  506 . Two fibre population characteristics are evident in this plot, either or both of which may be investigated in accordance with the present invention in order to determine suitable stimulus parameters and/or physiological state or change. First, pulse  302  will depolarise some fibres close to threshold, but without activating them. This partial depolarisation means that for small t d , in the range ( 512 ) of about 0 to 200 μs, where pulse  306  is sufficiently close in time to pulse  302 , some fibres that had not been activated by  302  may be activated by  306  more easily than is the case for the remainder of the refractory period for t d &gt;200 μs. This depolarisation will decay with time, usually to resting levels before the end of the absolute refractory period for the fibres that were activated by  302 . This means for short inter-stimulus intervals (e.g. &lt;200 us), there will be a response  308  from fibres which had residual depolarisation from  302 . Second, for t d  greater than about 400 μs, a relative refractory period  514  commences, during which fibres activated by  302  gradually become able to be activated again. Between the remnant depolarisation period  512  and the relative refractory period  514 , the absolute refractory period dominates and the second pulse  306  is almost entirely unable to recruit any response (it is noted that curve  506  is at levels around 5 μV in this period which may be noise and does not necessarily indicate any response has been evoked). Thus assessing curve  506  instantaneously permits a current state of both (a) the residual depolarisation decay  512 , and (b) onset of the relative refractory period  514  to be assessed. Monitoring curve  506  over time permits changes in these characteristics to be determined, for example to be used for feedback to optimise therapeutic stimuli or in order to diagnose or monitor an underlying disease. 
         [0049]    While  FIG. 3   b  shows the probe pulse  306  as having the same amplitude as therapeutic pulse  302 , alternative embodiments may advantageously use probe pulses  306  and/or  310  which are of a different amplitude to therapeutic pulse  302 . For example, therapeutic pulse  302  is usually set to a comfortable level for the patient, and at such a level not all fibres are usually recruited by pulse  302 . Pulse  306  may therefore be set to have a greater amplitude and/or a greater total charge than therapeutic stimulus  302  in order to ensure that the probe pulse  306  will recruit at least some fibres even when applied during the refractory period of fibres recruited as part of response  304 . 
         [0050]    In another embodiment the probe stimulus  306  may be configured to have reduced recruitment capability as compared to pulse  302 , so that if pulse  306  is applied during the absolute refractory period of fibres recruited as part of response  304  then pulse  306  will recruit no additional response. In such embodiments, when the relative delay t d  is such that probe stimulus  306  occurs in the relative refractory period of response  304 , being the period in which some fibres recruited as part of response  304  have concluded their refractory period but some have not, then the probe stimulus response  308  will begin to recruit fibres. Determining the value of t d  at which a threshold exists for response  308  starting to arise provides useful information regarding the refractory period of response  304 . 
         [0051]    Routinely, during assessment of patients for spinal cord stimulation therapy, the patient will undergo a trial stimulation procedure. This is where the patient is implanted with a percutaneous lead with an externalised set of contacts. The lead is attached to an external pulse generator and the patient has use of the device for several days. At the end of the trial period the clinician and patient assess the performance of the system with regard to pain relief and a choice is made whether or not to proceed with a full implantation. The take-home device for trial purposes may consist of both a stimulus generator but also an evoked response measurement system. The ERT responses recorded during the trial period could be used to adjust the stimulus parameters as described above. 
         [0052]    The ERT system measures amplitude growth functions etc., collected at time of surgery and during the trial stimulation period, and together with subjective performance measures could be used to develop a correlation between the response parameters and the patient outcomes. For instance, there is considerable variation in threshold response and there may exist a correlation between threshold and outcome where lower thresholds generate better outcomes. There are a large number of neurological parameters that can be collected in performing ERT measures, including refractory periods. Systematic collection of this data across a number of patients will allow analysis for correlation with outcome. 
         [0053]    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. For example the neural response measurement may be conducted in accordance with any suitable CAP measurement technique. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Technology Category: 1