WO2012155186A1

WO2012155186A1 - Method and apparatus for controlling a neural stimulus - h

Info

Publication number: WO2012155186A1
Application number: PCT/AU2012/000514
Authority: WO
Inventors: John Louis PARKER; James Hamilton LAIRD; Dean Michael Karantonis; Robert Bruce GORMAN
Original assignee: National Ict Australia Ltd
Priority date: 2011-05-13
Filing date: 2012-05-11
Publication date: 2012-11-22

Abstract

Anodic pulses are used to modify neural sensitivity to a stimulus. Propagation of a neural response from a stimulus site past a distal site can be blocked by applying an anodic pulse just prior to arrival of the travelling neural response at the distal site. The anodic pulse modifies the nerve membrane threshold and prevents one node of Ranvier from activating the next by hyperpolarising its membrane. The modified neural sensitivity can also be used to improve recruitment efficacy of the stimulus, by applying the anodic pulse prior to the stimulus to hyperpolarize the nerve fibre membranes, and then applying the stimulus at a time when the nerve fibre membranes have an inward current due to recovery from the hyperpolarization.

Description

METHOD AND APPARATUS FOR CONTROLLING A NEURAL STIMULUS - H

Cross-Reference to Related Applications

This application claims the benefit of Australian Provisional Patent Application No. 2011901830 filed 13 May 2011, Australian Provisional Patent Application No. 2011901829 filed 13 May 2011, and Australian Provisional Patent Application No. 2011901828 filed 13 May 2011, each of which are incorporated herein by reference.

Technical Field

The present invention relates to application of a neural stimulus, and in particular relates to applying a neural stimulus in a controlled manner by using one or more electrodes implanted proximal to the neural pathway.

Background of the Invention

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'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.

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 Αβ fibres of interest. Αβ 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 Αβ fibres in the DC. The pain relief mechanisms of SCS are thought to include evoked antidromic activity of Αβ fibres having an inhibitory effect, and evoked orthodromic activity of Αβ fibres playing a role in pain suppression. It is also thought that SCS recruits Αβ 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.

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.

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 PI, then a negative peak Nl, 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.

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 Αδ 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 neural recruitment 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.

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. 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

According to a first aspect the present invention provides a method of applying a stimulus to a nerve fibre, the method comprising:

applying a stimulus; and

applying an anodic pulse to modify a nerve membrane threshold, to thereby alter the nerve response to the stimulus.

According to a second aspect, the present invention provides a device for applying a stimulus to a nerve fibre, the device comprising:

at least one electrode configured to be positioned at alongside a neural pathway; and a control unit configured to apply a neural stimulus, the control unit further configured to apply a stimulus; and the control unit further configured to apply an anodic pulse to modify a nerve membrane threshold, to thereby alter the nerve response to the stimulus.

In some embodiments of the invention, the anodic pulse may be applied after the stimulus and a distance away from a site of the stimulus along the neural pathway, in order to effect anodic blocking to selectively obstruct either orthodromic propagation or antidromic propagation of a neural response evoked by the stimulus. In such embodiments, a measurement of the neural response may be obtained after it has passed the site at which the anodic pulse is applied, in order to measure the efficacy of the anodic blocking. Additionally or alternatively, a measurement of the unblocked neural response is preferably also obtained to give a better understanding of the efficacy of the anodic blocking, for example by measuring the neural response at a site closer to the stimulus than the site at which the anodic pulse is applied, or by measuring the neural response at a site on the opposite side of the stimulus site relative to the site at which the anodic pulse is applied. Such neural response measurements may in turn be used to refine future stimuli and/or anodic pulses. For example such neural response measurements may be used as an input to a feedback controller effecting automated control of the anodic pulse.

The anodic pulse may be one phase of a multiphasic pulse, with the stimulus being at least a second phase of the multiphasic pulse.

Additionally or alternatively, the anodic pulse may in some embodiments of the invention be applied prior to a cathodic stimulus pulse, and substantially at the same site as the cathodic stimulus pulse, in order to reduce a membrane threshold for cathodic pulse activation. In such embodiments, a measurement of the evoked neural response may be obtained, in order to measure the improvement of neural recruitment effected by the anodic pulse. Such neural response measurements may in turn be used to refine future stimuli and/or anodic pulses.

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 applying a stimulus to a nerve fibre, the computer program product comprising computer program code means for carrying out the method of the first aspect.

Brief Description of the Drawings

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

Figure 1 illustrates an implantable device suitable for implementing the present invention; Figures 2a and 2b illustrate an anodic-first stimulus and a cathodic-first stimulus, respectively;

Figure 3 illustrates the distinct recruitment threshold of a cathodic-first pulse compared to an anodic-first pulse;

Figures 4a-4d show measured neural responses evoked by the positive first and negative first biphasic pulses of varying inter-phase gap;

Figures 5 a and 5d show the measurements of Figure 4 grouped by phase order; and Figure 6 shows a feedback controller for controlling the anodic pre-pulse in an automated manner.

Description of the Preferred Embodiments

Figure 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. 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 a stimulus electrode. The compound action potential evoked by such a stimulus is the sum of responses from a large number of single fibre action potentials. The single fibre potentials are initiated by the cathodic pulse (depolarisation). In most circumstances, an anodic pulse (hyperpolarisation) can also initiate propagation of action potentials but much larger currents are required. The response of the spinal cord to these two polarities of stimulation are called the "anodic first" (Figure 2a) and "cathodic first" responses (Figure 2b), as referred relative to the electrode closest to the observation point, such as a recording electrode spaced apart from the stimulus electrode(s). That is, anodic first stimulation makes the stimulating electrode closest to the sense electrode anodic in the first phase of stimulus. Usually, cathodic-first stimulation has lower threshold than anodic-first, since the anodic component of the stimulus closer to the sense electrode will somewhat hyperpolarise the membrane around it, and thus reduce the recruitment elicited by the nearby cathode.

In one embodiment the invention is applied to effect anodic blocking of neural propagation in one direction from the stimulus site. In a myelinated nerve fibre, the nerve's membrane is insulated by a myelin sheath, except at discrete, evenly spaced nodes (the nodes of Ranvier). The propagation of an action potential requires that each node which is activated (by an external potential, or by a neighbouring node) then activates the following node (or nodes, in the case of a branching-point). This activation requires that the transmembrane potential at the node be depolarised sufficiently for the membrane's Na+ ion channels to be gated open, leading to a self- sustaining potential rise (the action potential upstroke).

The present invention recognises that it is possible to prevent one nerve fibre node from activating the next by hyperpolarising its membrane, thus preventing the neighbour node from lifting its potential above the threshold required to trigger it. This can be done by delivering an anodic pulse over the nerve fibre. The anodic pulse must begin before the action potential has reached the point in question, and must be long enough to prevent the trailing part of the action potential from propagating after the end of the pulse. As the controller 110 knows the timing of the stimulus, and the fibre conduction velocity of a compound action potential can be known or determined, a suitable time to deliver the anodic pulse to hyperpolarise neurons can in turn be deduced.

Such anodic blocking may be used to selectively induce only one of orthodromic propagation or antidromic propagation in a fibre, bundle or column. This has benefits in spinal cord stimulation (SCS) for delivering antidromic stimulation to the dorsal horn, while attenuating orthodromic stimulation to the sensory centres of the brain, reducing paraesthesia and/or discomfort. In such embodiments, a measurement of the neural response may be obtained using an electrode which is rostral of the electrode used to apply the anodic pulse. This will thus measure the efficacy of the anodic blocking. Such neural response measurements may in turn be used to refine future stimuli and/or anodic pulses.

In another embodiment of the invention, an anodic pre-pulse may be applied at a suitable time prior to a stimulus in order to improve recruitment efficacy of the stimulus. The various ion channels in the nerve fibre membrane act to maintain the membrane potential at a constant, resting potential in the absence of firing, and in recovery after the potential rise of firing. These channels' activation is not instant, but changes slowly; different channels have different time constants. If the membrane is hyperpolarised by an external potential, as during an anodic pulse, the channel activations will adjust to set up an inward current, countering the hyperpolarisation. Due to the activation time constants, when the anodic pulse stops, the inward current will persist for some time. Hence, applying a cathodic pulse immediately after the anodic pulse will activate the fibre, aided by this inward current. This reduces the threshold of the membrane. This effect may be exploited for energy savings; where a biphasic pulse is already required for charge balance, using a minimal interphase gap and providing the anodic pulse first will potentiate firing, and reduce energy required. Figures 4 and 5 illustrate the effect of this technique. To obtain the data shown in Figures 4 and 5 biphasic stimuli were applied to an ovine subject and the evoked responses were measured, for both a positive-first stimulus and a negative-first stimulus. In all cases the pulse width of each phase of the biphasic stimulus was 20 μβ. Figure 4a shows the measured neural responses 402, 404 evoked by the positive first and negative first biphasic pulses, respectively, with inter-phase gap of 10 μβ. Figure 4b shows the measured neural responses 412, 414 evoked by the positive first and negative first biphasic pulses, respectively, with inter-phase gap of 50 μβ. Figure 4c shows the measured neural responses 422, 424 evoked by the positive first and negative first biphasic pulses, respectively, with inter-phase gap of 100 μβ. Figure 4d shows the measured neural responses 432, 434 evoked by the positive first and negative first biphasic pulses, respectively, with inter-phase gap of 200 μβ. It is noted that the scale of the y-axis (voltage) differs between Figures 4a-4d. The x-axis for each of Figures 4a-4d, 5a and 5b denotes time, in milliseconds.

Figure 5 illustrates the data from Figure 4 grouped by stimulus phase ordering, with Figure 5 a showing the measured evoked responses for all negative-first stimuli of varying inter-phase gap, and Figure 5b showing the measured evoked responses for all positive-first stimuli of varying inter-phase gap.

As revealed in Figures 4 and 5, there is a gradient of efficiency improvement effected by the anodic pre-pulse of a positive-first biphasic pulse. If the pre-pulse occurs very shortly before the stimulus pulse (e.g. IPG=10 μβ), then efficiency is reduced (see 402) compared with a cathodic first stimulus (see 404). In this domain it is believed that the positive first pulse is hyperpolarizing the axons, raising their threshold and resistance to recruitment by the negative second phase which is delivered before the axon hyperpolarisation decays. As the interval between the pre-pulse and stimulus pulse is increased, the efficiency becomes comparable (Figure 4c), and then effects improved efficiency (e.g. IPG=200 μβ, 432 being of greater amplitude than 434 in Figure 4d). This embodiment thus recognises that applying an anodic pre- pulse can be used to control the recruitment efficacy of a subsequent cathodic pulse, and moreover that the influence of the anodic pre-pulse can be selected to effect either an increase or decrease in recruitment. This embodiment provides for feedback control of the anodic pre-pulse, whereby measuring the evoked CAP allows the stimulus efficiency to be determined and then optimised by varying suitable parameters of the anodic pre-pulse or biphasic pulse, such as the inter-phase stimulus interval. A similar gradient of efficiency arises, not over time as shown in Figures 4 and 5, but spatially. A spatial gradient of transmembrane potential of an axon (the "activating function") is produced by applying a cathodic or anodic stimuli, and follows a particular curve. For anodic stimuli, the activating function leads to maximal hyperpolarisation of the nerve membrane close to the stimulus electrode, a decreasing hyperpolarisation further from the electrode, and then a smaller (relative the maximal hyperpolarisation) depolarisation at a certain distance from the electrode, such that the spatial gradient of transmembrane potential produced by the anodic pulse approximately takes the shape of a Ricker (Mexican hat) wavelet. The inverse applies for cathodic stimuli. This profile may be exploited in accordance with the present invention, for example by applying an anodic pulse on a first electrode so that the depolarisation portion of the activating function gradient arises proximal to a second electrode used for stimulating by way of a cathodic pulse. By thus spatially delivering a membrane depolarisation effect to the vicinity of the stimulating electrode, recruitment efficiency can be increased. Figure 6 illustrates a suitable feedback controller for controlling the anodic pre -pulse in an automated manner, so as to use the measured evoked responses to determine the anodic pulse parameters required to achieve a particular desired outcome, whether for anodic blocking or for increasing efficiency of stimulation. The present invention may advantageously be used in conjunction with the techniques set out in Australian Provisional Patent Application No. 2011901828 from which the present application claims priority and which has in the preceding been incorporated herein by reference. Together, the present invention and that disclosure may present particularly effective methods for generating a directional or correlated neural response in a desired direction, and blocking the remnant or decorrelated response in an undesired direction. A feedback control technique, such as is disclosed in Australian Provisional Patent Application No. 2011901828 from which the present application claims priority and which has in the preceding been incorporated herein by reference, may advantageously be used to provide ongoing control of the techniques set forth herein.

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 restrictive.

Claims

CLAIMS:

1. A method of applying a stimulus to a nerve fibre, the method comprising:

applying a stimulus; and

2. The method of claim 1 wherein the anodic pulse is applied after the stimulus, at a site which is a distance away from a site of the stimulus along the neural pathway, in order to effect anodic blocking to selectively obstruct either orthodromic propagation or antidromic propagation of a neural response evoked by the stimulus.

3. The method of claim 2 further comprising obtaining a measurement of the neural response after it has passed the site at which the anodic pulse is applied, in order to measure the efficacy of the anodic blocking.

4. The method of claim 3 wherein the neural response measurement is used in feedback control of a subsequent stimulus and/or anodic pulse.

5. The method of claim 1 wherein the anodic pulse is applied prior to a cathodic stimulus pulse, and substantially at the same site as the cathodic stimulus pulse, in order to reduce a membrane threshold for cathodic pulse activation.

6. The method of claim 5 further comprising obtaining a measurement of the evoked neural response, in order to measure the improvement of neural recruitment effected by the anodic pulse.

7. The method of claim 6 wherein the neural response measurement is used in feedback control of a subsequent stimulus and/or anodic pulse.

8. A device for applying a stimulus to a nerve fibre, the device comprising: