Bipolar and tripolar confirguration for unidirectional stimulation of A-type nerve fibers

There is provided a neural interface device for unidirectional stimulation of a nerve including at least one A-type nerve fiber or at least one at least partially myelinated nerve fiber. The device includes an electrode arrangement for placing on or around the nerve. The electrode arrangement includes a first electrode configured to be positively charged and a second electrode configured to be negatively charged, where the surface area of the second electrode is larger than the surface area of first electrode.

TECHNICAL FIELD

This disclosure relates to stimulation of neural activity in A-type nerve fibers or at least partially myelinated fibers. More specifically, this disclosure relates to devices and systems that interface A-type nerve fibers or at least partially myelinated fibers and cause unidirectional stimulation of neural activity.

BACKGROUND

A-type nerve fibers are relatively large-size nerve fibers in the body. These fibers are myelinated, which means they carry neural activity around the body at a relatively high conduction velocity. Artificial stimulation of neural activity in A-type nerve fibers is known to be useful for treating and/or preventing various diseases in a subject. For example, artificial stimulation of neural activity in A-type nerve fibers can be used in cases of therapy for epilepsy or organ dysfunction, for instance in immunomodulation and rheumatoid arthritis treatment. Electrical devices of various shapes and sizes including one or more electrodes have been used for artificial stimulation of neural activity for years.

Unidirectional stimulation of neural activity, that is artificially-stimulated neural activity which only propagates along the nerve in one direction, can be advantageous over non-unidirectional stimulation because it may be used for collision blocking of baseline neural activity, or to reduce off-target effects, etc.

Unidirectionality can be achieved by stimulating neural activity in both directions along a nerve, and then impeding the neural activity in one direction. This typically requires an electrical device with either a cathode or an anode (i.e. a bipolar electrode arrangement), or a cathode and two anodes, one anode either side the cathode (i.e. a tripolar electrode arrangement), and a means for causing a charge density differential between the cathode and the anode(s).

For example, in “An asymmetric two electrode cuff for generation of unidirectional propagated action potentials”, IEEE Transactions on Biomedical Engineering, Vol. 33, Pages 541-549, 1986, the authors describe that unidirectional stimulation can be achieved using a bipolar electrode arrangement with one recessed electrode. The cathode is radially recessed away from the nerve to reduce extracellular potential under the cathode in comparison to the extracellular potential under the anode. However, such a design may not be suitable for long-term implantation because movement of the nerve relative to the electrode arrangement may affect the ability of the device to induce unidirectional stimulation of neural activity.

In “Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli”, Science, Vol. 206, No. 4424, Pages 1311-2, the authors report the use of a dual current source with a tripolar electrode arrangement to create a charge density differential between the cathode and anodes. Similarly, U.S. Pat. No. 7,561,922 describes a tripolar electrode configuration for unidirectional stimulation with current differentials being supplied to the cathode and anodes. However, multiple current sources can be difficult to implement in a stimulation device for nerve fibers due to restricted space available for implants.

In “A technique for collision block of peripheral nerve: single stimulus analysis”, IEEE Transactions on Biomedical Engineering, Vol. BME-28, No. 5, May 1981, the authors vary the spacing between identical electrodes in a tripolar electrode configuration to generate unidirectional stimulation of neural activity in myelinated nerve fibers. The tripolar electrode comprises a cathode surrounded by two anodes. If both anodes carry equal current, by symmetry when a block occurs in one direction, it will occur in both directions. This can be mitigated by reducing the amount of current flowing through one of the anodes and spacing it further from the cathode. However, this causes a virtual cathode to arise distal to the insulator, and thus precision is required to ensure that it remains below a threshold, which imposes a limitation on the system.

Therefore, there exists a need for improved devices and systems that can provide unidirectional stimulation of A-type nerve fibers.

SUMMARY

The inventors found that adapting the surface area of the electrodes in a bipolar electrode arrangement, and optionally adapting the distance between said electrodes, leads to preferentially unidirectional stimulation of neural activity in A-type nerve fibers or at least partially myelinated fibers. The inventors also found suitable pulse widths to achieve preferentially unidirectional stimulation for the electrical signal applied to the nerve via the electrode arrangement.

A pulse width refers to a width (or time duration) of a primary phase of the waveform. In some cases where a pulse comprises a first phase that is the primary phase and a second phase which is the recovery phase, for example an anodic and/or a cathodic phase, the pulse width refers to a width (or duration) of the first phase. A pulse duration refers to the time duration during which the pulse is applied or delivered for. This may also be referred to as a stimulation time.

The inventors found that adapting the surface area of the electrodes in a tripolar electrode arrangement, and optionally adapting the distance between said electrodes, leads to preferentially unidirectional stimulation of neural activity in A-type nerve fibers or at least partially myelinated fibers. The inventors also found suitable pulse widths to achieve preferentially unidirectional stimulation for the electrical signal applied to the nerve via the electrode arrangement.

In general, electrically induced compound action potentials are generated if the depolarization under the cathode is sufficient to increase local membrane potentials past the activation threshold for voltage-gated sodium channels from the resting membrane potential. The activation threshold is typically around −40 mV, and the resting membrane potential is typically around −70 mV. Thus, the difference between the activation threshold and the resting membrane potential is around Δ30 mV.

Once the activation threshold is passed and the NaV channels (also known as “voltage-dependent” sodium channels) are opened, positively charged sodium ions flow down their concentration gradient into the cell until reaching their reversal potential (which is typically around +50 mV). This local influx of positively charged sodium ions, which is the first phase of the action potential, initiates a wave of depolarization in both directions along the axon axis, opening adjacent NaV channels, thus propagating an action potential in both directions. This wave of depolarization can locally be greater than ˜Δ100 mV (resting membrane potential to reversal potential), but likely less due to passive diffusion between nodes of Ranvier. In order to arrest this propagation at a second point along the axon axis, electrical hyperpolarization, via a positively charged anode, must be employed to reduce the resting membrane potential (Erest=−70 mV) to a point that the incoming wave of depolarization (˜Δ100 mV) is insufficient to reach the threshold potential (Ethres=−40 mV). Therefore for arrest to occur, the resting membrane potential would need to be hyperpolarized by −70 mV from the previous resting state. This is illustrated in following equation:
Δ100 mV−(Ethres−Erest)=100 mV−(−40 mV−(−70 mV))=−70 mV=Δ70 mV hyperpolarization

Therefore, the electrode charge density required to generate an action potential (i.e. to induce ˜Δ30 mV depolarization to threshold) is always lower than the charge density required to arrest an action potential (induce ˜Δ70 mV hyperpolarization) when the anode and cathode have the same surface area. When using anode or cathode pairs with symmetric surface area, charge density for a given current injection will be equal and opposite on each electrode. This will generate a bell shaped activation/arrest profile as charge density and current increase.

By introducing surface area differences between the electrodes in the pair, one can concentrate or reduce charge on any given electrode. When reducing the anode surface area compared to the cathode, charge density is increased under the anode for any given current injection compared to the cathode. This allows arrest to occur at lower currents than can be achieved in electrodes with equal surface areas. In conjunction, this surface area differential reduces cathodal charge density for a given current injection. This shifts activation to higher currents. The reduction of block current threshold due to anode surface area reduction and increase in activation current threshold due to cathode surface area increases can together result in a convergence of block and activation with the same current.

The disclosure provides a neural interface device for unidirectional stimulation of a nerve comprising at least one A-type nerve fiber or comprising at least one at least partially myelinated fiber. The device comprises an electrode arrangement configured to be placed on or around the nerve. The electrode arrangement comprises at least a first electrode having a first surface area, and configured to be positively charged and a second electrode having a second surface area configured to be negatively charged, and spaced apart from the first electrode so as to define a first gap along the longitudinal axis of the nerve. The second surface area (of the second electrode) is larger than the first surface area (of the first electrode). In some embodiments, the second surface area is three times as large as the first surface area. The first surface area and the second surface area may be arranged to communicate electrically with the nerve, when the device is placed on or around the nerve. The electrical communication between the electrodes' surface areas and the nerve allows an electrical signal to be imparted upon the nerve. This may involve a direct or an indirect physically connection.

The first electrode may have a first width, and the second electrode may have a second width. The width of the second electrode in the direction of the longitudinal axis of the nerve when the neural interface device is placed around the nerve can be at least three times the width of the first electrode. Indeed, the width of the second electrode may be approximately (or exactly) twice the width of the first electrode, approximately (or exactly) three times the width of the first electrode, approximately (or exactly) four times the width of the first electrode, or approximately (or exactly) five times the width of the first electrode. These electrode configurations may be advantageous for alleviating at least some of the issues identified above in respect of known arrangements.

By introducing surface area differences between the electrodes in the (tripolar) electrode configuration, one can concentrate or reduce charge on any given electrode. When reducing the anode surface area compared to the cathode, charge density is increased under the anode for any given current injection compared to the cathode. This allows arrest to occur at lower currents than can be achieved in electrodes with equal surface areas. In conjunction, this surface area differential reduces cathodal charge density for a given current injection. This shifts activation to higher currents. The reduction of block current threshold due to anode surface area reduction and increase in activation current threshold due to cathode surface area increases can together result in a convergence of block and activation with the same current.

The disclosure provides a neural interface device for unidirectional stimulation of a nerve comprising at least one A-type nerve fiber or comprising at least one at least partially myelinated fiber. The device comprises an electrode arrangement configured to be placed on or around the nerve. The electrode arrangement comprises at least a first electrode having a first surface area, and configured to be positively charged and a second electrode having a second surface area configured to be negatively charged, and spaced apart from the first electrode so as to define a first gap along the longitudinal axis of the nerve. The device further comprises a third electrode having a third surface area, and configured to be positively charged and spaced apart from the second electrode so as to define a second gap along the longitudinal axis of the nerve. The first electrode is adjacent the second electrode, and the third electrode is adjacent the second electrode with the second electrode positioned in between the first electrode and the second electrode.

The second surface area (of the second electrode) may be larger than the first surface area (of the first electrode). The second surface area (of the second electrode) may be larger than the third surface area (of the third electrode). The second surface area (of the second electrode) may be larger than both of the surface areas of the first and third electrode respectively.

In some embodiments, the second surface area is two times as large as the first surface area. In some embodiments, the second surface area is two times as large as the third surface area.

The first surface area, the second surface area and the third surface area may be arranged to communicate electrically with the nerve, when the device is placed on or around the nerve. The electrical communication between the electrodes' surface areas and the nerve allows an electrical signal to be imparted upon the nerve. This may involve a direct or an indirect physically connection.

The first electrode may have a first width, the second electrode may have a second width and the third electrode may have a third width. The width of the second electrode in the direction of the longitudinal axis of the nerve when the neural interface device is placed around the nerve can be the sum of the width of the first electrode (i.e. the first width) and the width of the third electrode (i.e. the third width). In another example, the width of the second electrode (i.e. the second width) is two times the first width or the third width. The first and the third widths may be the same. In another example, the widths of each of the first, second and third electrodes are the same.

Indeed, the width of the second electrode may be approximately (or exactly) twice the width of the first electrode, approximately (or exactly) three times the width of the first electrode, approximately (or exactly) four times the width of the first electrode, approximately (or exactly) five times the width of the first electrode, or approximately (or exactly) ten times the width of the first electrode. These electrode configurations may be advantageous for alleviating at least some of the issues identified above in respect of known arrangements.

The width of the second electrode in the direction of the longitudinal axis of the nerve when the neural interface device is placed around the nerve can be three times the width of the third electrode. Indeed, the width of the second electrode may be approximately (or exactly) twice the width of the third electrode, approximately (or exactly) three times the width of the third electrode, approximately (or exactly) four times the width of the third electrode, approximately (or exactly) five times the width of the third electrode, or approximately (or exactly) ten times the width of the third electrode. These electrode configurations may be advantageous for alleviating at least some of the issues identified above in respect of known arrangements.

Specifically, the electrode configurations of the present disclosure allow efficacious treatment to be provided, but with a reduced current to achieve block compared to bipolar electrodes with equal surface area. A reduced current can, for instance, reduce the likelihood of nerve damage and side effects, as well as using energy more efficiently. Energy efficiency may be particularly important in situations in which the implantable device is used in conjunction with a portable energy source, such as a battery.

The configuration in which the second electrode is three times the width of the first electrode and/or third electrode (or, in other words, where the surface area of the second electrode is three times as large as the surface area of the first/third electrode) has been found to be particularly advantageous, specifically for providing a stimulation signal with reduced current. In essence, with a given current coupled between the first electrode (e.g. anode) and the second electrode (e.g. cathode) and coupled between the second electrode and the third electrode, the charge density will be concentrated on the first and/or third electrodes more so than on the second electrode, when the surface area of the second electrode is larger than the first electrode. Thus, the ratio of the second electrode surface area to the first electrode surface area ratio allows a reduced current to be provided to achieve a block. It has been found that an increased second electrode surface area to first electrode surface area ratio can be advantageous. A ratio of 3 was found to be particularly advantageous and ratios up to 5 were found to be particularly advantageous in some embodiments.

The disclosure also provides a system for unidirectional stimulation of a nerve comprising at least one A-type nerve fiber or at least one at least partially myelinated fiber. The nerve may be, for instance, the vagus nerve, somatic nerves, the cervical nerve or any at least partially myelinated peripheral nerve. Thus, the system can allow treatment of disease through autonomic nerves, sensory nerves or nerves for somatic motor control. The device and system described herein can also allow selective stimulation of fibers with a higher activation threshold by creating a bidirectional block of A-fibers.

The system can be used for A-type nerve fibers, as well as for B-type nerve fibers (which have similar conduction velocities and may include Aδ-type nerve fibers). Typically, A-type nerve fibers have a conduction velocity greater than around 8-10 m/s. Typically, B-type and Aδ-type nerve fibers have a conduction velocity less than around 8-10 m/s, but greater than 3 m/s.

The system comprises one or more neural interface devices of the disclosure and a voltage or current source which is electrically connected to the electrode arrangement of the neural interface device, wherein the voltage or current source is configured to generate an electrical signal to be applied to the nerve via the electrode arrangement.

The disclosure also provides a method for unidirectional stimulation of a nerve comprising at least one A-type nerve fiber. The method comprises providing one or more neural interfaces of the disclosure, and generating an electrical signal to be applied to the nerve via the electrode arrangement by least one voltage or current source electrically connected to the electrode arrangement.

The disclosure also provides a computer program comprising code portions which, when loaded and run on a computing device, cause the computing device to generate an electrical signal to be applied to the nerve via the electrode arrangement of a neural interface device of the disclosure and at least one voltage or current source electrically connected to the electrode arrangement. Also provided is a computer-readable medium having stored thereon the computer program.

The disclosure also provides a modified nerve to which the neural interface device or the system of the disclosure is attached. The electrode arrangement of the neural interface device is in signaling contact with the nerve so the nerve can be distinguished from the nerve in its natural state. In some embodiments the nerve comprises a plurality of A-type nerve fibers.

The devices and systems described herein can also allow selective stimulation of fibers with a higher activation threshold by creating a bidirectional block of A-fibers.

DETAILED DESCRIPTION

A nerve fiber is a thread like extension of a neuron, which is formed by an axon and the axon covering. The axons of some nerve fibers, including A-type fibers which are the focus of this disclosure, are typically covered by an insulating layer known as myelin. These nerve fibers are referred to as myelinated or medullated nerve fibers. Nerve fibers including C-type fibers which do not have a myelin sheath are referred to as unmyelinated, non-myelinated or non-medullated nerve fibers.

Myelin prevents action potentials, which are electrical signals that travel along axons, from decaying due to electrical current leaking out through the axonal membrane. Myelinated axons thus conduct action potentials more quickly than unmyelinated axons. For instance, the conduction velocity of action potentials in vagal A-type sensory nerve fibers is typically >10 m/s, whereas the conduction velocity in unmyelinated (i.e. C-type) nerve fibers is typically <2 m/s. As will be discussed below, the higher conduction velocity in myelinated fibers can be exploited in the design of a device for unidirectional stimulation of neural activity.

The myelin covering in a myelinated nerve is arranged on the nerve fiber as a series of individual sheaths positioned along the nerve, each of which circumvents the nerve fiber. Gaps, referred to in the art as nodes of Ranvier, are formed along the nerve between each of the myelin sheaths.

Thus, a myelinated nerve, as referred to herein, may comprise a plurality of individual myelin sheaths along the nerve which circumvent the nerve fiber. A gap between an adjacent pair of myelin sheaths may define a node of Ranvier.

Myelinated nerves include Type I, II, and III sensory fibers (corresponding to Aα-, Aβ- and Aδ-type nerve fibers using Erlandger-Gasser classification) and preganglionic fibers (corresponding to B-type nerve fibers using Erlandger-Gasser classification). Type I sensory fibers typically have a diameter between 13 and 20 μm and a conduction velocity of action potentials in the region of 80 to 120 m/s. Type II sensory fibers typically with a diameter between 6 and 12 μm and a conduction velocity of action potentials in the region of 33 to 75 m/s.

Type III sensory fibers are different from Type I and II sensory fibers in that the myelin covering is far thinner and the diameter of the nerve fiber is much narrower for Type III sensory fibers in comparison to Type I and II sensory fibers. This results in a slower conduction velocity for action potentials in Type III sensory fibers than in Type I and II sensory fibers, but faster than in an unmyelinated nerve. For this reason, Type III sensory fibers are sometimes referred to as mixed fibers. Typically, the diameter of a Type III sensory fiber is 1 to 5 μm and the conduction velocity is greater than 3 m/s but less than around 8-10 m/s.

A-type nerve fibers also have a larger diameter than unmyelinated (i.e. C-type) fibers, typically in the region of 6 to 20 μm.

As discussed above, there exists a need to provide a device which is capable of stimulating A-type nerve fibers (or myelinated fibers) with an efficacious signal for treatment of various ailments, but with a reduced current from paired electrodes.

Unidirectional Stimulation

Stimulation of neural activity, as used herein, is when the neural activity of the nerve is increased from the baseline neural activity. Unidirectional stimulation thus refers to when neural activity of the nerve is increased from the baseline neural activity in one direction along the longitudinal axis of the nerve. It is known that both stimulation and directional stimulation of neural activity can be achieved by applying an electrical signal to the nerve.

Neural activity of a nerve is the signaling activity of the nerve, for example the amplitude and/or frequency of action potentials in the nerve. When the nerve comprises a plurality of A-type nerve fibers, such as in the present disclosure, the signaling activity of each of the nerve fibers is summed to determine a compound action potential at a cross-section of the nerve fiber bundle.

When a functioning nerve fiber is in a normal state, at any point along the axon, the nerve fiber will have a distribution of potassium and sodium ions across the nerve membrane. The distribution at one point along the axon determines the electrical membrane potential of the axon at that point, which in turn influences the distribution of potassium and sodium ions at an adjacent point, which in turn determines the electrical membrane potential of the axon at that point, and so on. This is a nerve fiber operating in its normal state, wherein action potentials propagate from point to adjacent point along the axon, and which can be observed using conventional experimentation.

One way of characterizing stimulation of neural activity is a distribution of ions at one or more points in/around the axon which is created not by virtue of the electrical membrane potential at adjacent points of the nerve as a result of a propagating action potential, but by virtue of the application of a temporary external electrical field. The temporary external electrical field artificially modifies the distribution of ions within/around a point in the nerve fiber, causing depolarization of the nerve membrane that would not otherwise occur. The depolarization of the nerve membrane caused by the temporary external electrical field gives rise to two de novo action potentials which propagate in opposite directions along the nerve fiber from the point of the temporary external electrical field.

This is a nerve fiber operating in a disrupted state, which can be observed by a distribution of potassium and sodium ions at a point in the axon (the point where a temporary external electric field is applied) that has an electrical membrane potential that is not influenced or determined by the electrical membrane potential of an adjacent point.

Stimulation of neural activity in a nerve is thus understood to be increasing neural activity of the nerve fibers from the point of cathodal electrical signal application. Thus, the nerve at the point of signal application is modified in that the nerve membranes are reversibly depolarized by an electric field, such two de novo compound action potentials are generated. Moreover, the nerve past the point of signal application in both direction along the nerve is modified in that the two de novo compound action potentials propagate in opposite directions along the nerve.

In directional stimulation, one of the two de novo compound actions potentials generated by the temporary external electrical field is impeded such that en masse propagation along the nerve is reduced or arrested completely. As a result, a de novo compound action potential propagates in along the nerve more robustly or completely in one direction over the other.

Neural activity can be impeded by applying an electrical signal to the nerve at a second point.

The nerve at the second point of signal application is modified in that the nerve membranes are hyperpolarized by the temporary external electric field of the further electrical signal, such that a compound action potential does not propagate through the modified nerve. Hence, the nerve at the second point of signal application is modified in that it has lost its capacity to propagate compound action potentials, whereas the portions of the nerve before and after the point of signal application have the capacity to propagate compound action potentials.

Disclosed herein are devices, systems and methods that preferentially cause such unidirectional stimulation of neural activity in a nerve comprising at least one or a plurality of A-type nerve fibers (or at least one or a plurality of at least partially myelinated fibers) by applying an electrical signal to the nerve. The nerve may be, for instance, the vagus nerve. Suitable electric signals for use in the devices, systems and methods are also disclosed.

Neural Interface Device (FIGS.1to3)

A neural interface device10according to the disclosure is a device that is in physical contact with a nerve, where the nerve comprises a plurality of A-type nerve fibers. When an electrical signal is applied to the nerve via the neural interface device10, the neural interface device10causes unidirectional stimulation of neural activity in the nerve, such as the vagus nerve in a human or an animal subject.

With reference toFIG.1, the neural interface device10comprises an electrode arrangement15. The electrode arrangement15is configured to be placed on or around the nerve when the neural interface device10is in use. The electrode arrangement15includes a plurality of electrodes which are spaced apart from each other so as to define a gap between each of the electrodes, where the gap is positioned along the longitudinal axis of the nerve (i.e. in the direction of the longitudinal axis of the nerve). In particular, the electrode arrangement10ofFIG.1includes a first electrode11and a second electrode12separated by a first gap21. This electrode arrangement is referred to as a bipolar electrode arrangement.

The first electrode11and the second electrode12can be cuff type electrodes (for example, spiral cuff, helical cuff or flat interface) which at least partially circumvent the nerve. For example, the first electrode11and the second electrode12shown inFIG.1are flat interface cuff electrodes which fully circumvent the nerve. However, other types of electrodes known in the art are also suitable for use in the electrode arrangement15. For instances, one or more of flat interface electrodes, mesh electrodes, linear rod-shaped lead electrodes, paddle-style lead electrodes, disc contact electrodes, hook electrodes, sling electrodes, intrafascicular electrode, glass suction electrodes, paddle electrodes, and percutaneous cylindrical electrodes may be used It will be appreciated that any suitable type of electrode could be used, which may be one of the examples disclosed herein but not limited thereto.

The first electrode11and second electrode12may fabricated from, or be partially or entirely coated with, a high charge capacity material such as platinum black, iridium oxide, titanium nitride, tantalum, poly(elthylene-dioxythiophene) and suitable combinations thereof, such as platinum-iridium alloy.

The surface area of each of the first electrode11and the second electrode12which is in contact with the nerve is specially adapted for unidirectional stimulation. In particular, the first electrode11has a first surface area and the second electrode12has a second surface area, and the second surface area is larger than the first surface area.

In an electrode arrangement15which uses cuff type electrodes that fully circumvent the nerve, the size of this surface area can be calculated by multiplying7C (i.e.3.14159) by the internal diameter and width of the respective electrode (i.e. the first electrode11or the second electrode12). Since the internal diameter of the first electrode11and the second electrode12is fixed by the diameter of the nerve, the surface area of each of the first electrode11and the second electrode12in contact with the nerve is adjusted by changing the width of the electrode. In one example, the internal diameter of the first and second electrodes may be 0.5 mm.

The width of each of the first electrode11and the second electrode12is defined as the distance the electrode spans along the longitudinal axis of the nerve. InFIG.2, the width of the first electrode11is denoted x1, whilst the width of the second electrode is denoted x2.

The width of the first electrode x1is defined by the user. The width of the first electrode x1may be around 0.3 mm.

Similarly, the width of the gap between the first electrode11and the second electrode12is defined as the distance that the gap spans along the longitudinal axis of the nerve. InFIG.2, the width of the first gap is denoted g1.

The width of the first gap g1is also defined by the user. The width of the first electrode x1is around the same size as the first electrode, which in this example is 0.3 mm.

The surface area of the second electrode12is adapted to be larger than the surface area of the first electrode11. When the surface area of the second electrode12is larger than the surface area of the first electrode11this concentrates charge density under the first electrode11for a given current compared to charge under the second electrode12, thus strengthening the hyperpolarization of the nerve without increased energy requirements. Thus, the width of the second electrode x2may be greater than the width of the first electrode x1. For example, the width of the second electrode x2may be at least two, three, four or five times the width of the first electrode x1.

In a bipolar electrode arrangement (e.g. the arrangements ofFIGS.1and2), the width of the second electrode x2may also be less than or equal to five times the width of the first electrode x1. This is to avoid stimulating additional action potentials under the second electrode12.

For example, the width of the second electrode x2may be one of: 2.0x1, 2.5x1, 3.0 x1, 3.5x14.0 x1, 4.5x1or 5.0x1. In other words, the ratio of the surface area of the second electrode to the ratio of the surface area of the first electrode may be 2 (2:1), 2.5 (5:2), 3 (3:1), 3.5 (7:2), 4 (8:2), 4.5 (9:2) or 5 (5:1).

To achieve unidirectional stimulation, the first electrode11is a positively charged electrode, also referred to as the “arrest anode”, and the second electrode12is a negatively charged electrode, also referred to as the “cathode”.

The nerve is stimulated by the second electrode12such that two compound action potentials, which propagate in opposite directions along the nerve, are generated in the nerve under the second electrode12. Once one of the compound action potentials reaches the first electrode11, it is impeded such that it cannot propagate along the nerve any further, leading to unidirectional stimulation from the second electrode12in the direction away from the first electrode11, as shown inFIG.1. Thus, the first electrode11and second electrode12are positioned along the nerve respectively in the direction of the unidirectional stimulation. Put another way, the second electrode12is at the “escape end” of the neural interface device10, from which compound action potentials caused by applying the electrical signal may propagate. The first electrode11, on the other hand, is at the “arrest end” of the neural interface device10, from which compound action potentials cannot propagate.

In particular, a compound action potential is impeded by adapting the pulse width of the electrical signal applied to the nerve based on the size of the gap between the electrodes. More specifically, the width of the first gap g1between the first electrode11and the second electrode12is set so that one of the compound action potential generated in the nerve under the second electrode12arrives at the first electrode11when hyperpolarization of the nerve is present. This stops the compound action potential from propagating along the nerve any further. Suitable electrical signals and pulse widths are discussed in detail below. In one example, the width of the gap g1is 0.3 mm. Thus, the width of the gap g1may be approximately or exactly the same as the width of the first electrode x1.

The width (or surface area) of the first electrode relative to the width (or surface area) of the25second electrode has been found to allow the device to provide an efficacious signal, while reducing the magnitude of the current required to achieve directional propagation. This advantage is explained in greater detail in the summary above.

The neural interface device10may further comprise a flexible non-conductive layer30, as shown inFIG.3. In other words, the flexible non-conductive layer30is an insulator. The electrode arrangement15may be mounted on to or otherwise attached to the flexible non-conductive layer30. When in use, the electrode arrangement15interfaces the nerve and the flexible non-conductive layer interfaces the electrode arrangement15. The flexible non-conductive layer30may conform to the shape of the electrodes such that it resides in the first gap21between the electrodes and additionally interfaces the nerve in that gap. The flexible non-conductive layer30may reside in a second gap23between the first electrode11and a first end17of the device10, and the flexible non-conductive layer30may reside in a third gap24between the second electrode12and a second end18of the device10.

The flexible non-conductive layer30may be made from a polysiloxanes (i.e. silicone) or a similar material to allow the flexible non-conductive layer to conform to the shape of the nerve. In some embodiments, the flexible non-conductive30layer is configured to at least partially circumvent the nerve when in use. The flexible non-conductive layer30may fully circumvent the nerve, as shown inFIG.3.

The flexible non-conductive layer may form a cuff around the nerve. The cuff may be fastened in place on the nerve using any means known in the art. The cuff has two open ends which are perpendicular to the longitudinal axis of the nerve. The first open end17and second open end18of the cuff are shown inFIG.3.

A second gap23is defined as the gap along the longitudinal axis of the nerve between the first open end17and the first electrode11. The second gap23defines a first non-conductive portion.

Similarly, a third gap24is defined as the gap along the longitudinal axis of the nerve between the second open end18and the second electrode12in a bipolar electrode arrangement (shown inFIG.3). The third gap24defines a second non-conductive portion. As shown inFIG.3, the width of the second gap23is denoted as g2, and the width of the third gap24is denoted as g3.

In bipolar electrode arrangement, the width of the second gap g2be (approximately) 3 times the width of the first gap g1.

The width of the third gap g3may be larger than the second gap g2. For instance, the width of the third gap g3may be greater than twice as large at the width of the second electrode. In a specific example, the width of the third gap g3is equal to the sum of the widths of the first gap, the first electrode, the second gap and the second electrode. A larger third gap g3in comparison to the second gap g2(i.e. a smaller insulation portion at the first end17of the cuff relative to a larger insulation portion at the second end18of the cuff) assists in avoiding virtual cathodes.

For example, the width of the third gap g3may be 2.1 mm and the width of the second gap g2may be 0.9 mm. Thus, the width of the third gap g3may be greater than 1.8 mm. In a specific example, the width of the first gap is 0.3 mm, the width of second gap is 0.9 mm, the width of the third gap is 2.1 mm and the width of the first electrode is 0.3 mm, and when the width of the second electrode is 0.9 mm, and the width of the cuff is 4.5 mm.

Neural Interface Device (FIGS.4to6)

A neural interface device10according to the disclosure is a device that is in physical contact with a nerve, where the nerve comprises a plurality of A-type nerve fibers. When an electrical signal is applied to the nerve via the neural interface device10, the neural interface device10causes unidirectional stimulation of neural activity in the nerve, such as the vagus nerve in a human or an animal subject.

With reference toFIG.4, the neural interface device10comprises an electrode arrangement15. The electrode arrangement15is configured to be placed on or around the nerve when the neural interface device10is in use. The electrode arrangement15includes a plurality of electrodes11,12,13which are spaced apart from each other so as to define a gap between each of the electrodes, where each gap is positioned along the longitudinal axis of the nerve (i.e. in the direction of the longitudinal axis of the nerve). In particular, the electrode arrangement15ofFIG.4andFIG.5includes a first electrode11and a second electrode12separated by a first gap (g1)21. The electrode arrangement15further includes a third electrode13that is separated from the second electrode12by a second gap (g2)22. This electrode arrangement is referred to as a tripolar electrode arrangement.

The first electrode11, the second electrode12and the third electrode13can be cuff type electrodes (for example, spiral cuff, helical cuff or flat interface) which at least partially circumvent the nerve. For example, the first electrode11, the second electrode12and the third electrode13shown inFIG.4are flat interface cuff electrodes which fully circumvent the nerve. However, other types of electrodes known in the art are also suitable for use in the electrode arrangement15. For instances, one or more of flat interface electrodes, mesh electrodes, linear rod-shaped lead electrodes, paddle-style lead electrodes, disc contact electrodes, hook electrodes, sling electrodes, intrafascicular electrode, glass suction electrodes, paddle electrodes, and percutaneous cylindrical electrodes may be used.

The first electrode11, the second electrode12, and the third electrode13may fabricated from, or be partially or entirely coated with, a high charge capacity material such as platinum black, iridium oxide, titanium nitride, tantalum, poly(elthylene-dioxythiophene) and suitable combinations thereof, such as platinum-iridium alloy.

The surface area of each of the first electrode11, the second electrode12and the third electrode13which is in contact with the nerve is specially adapted for unidirectional stimulation. In particular, the first electrode11has a first surface area and the second electrode12has a second surface area. The third electrode13has a third surface area.

In examples described herein, the surface area of the second electrode12may be larger than the surface area of the first electrode11and the surface area of the third electrode13respectively. In another example, the first gap (g1)21between the first electrode11and the second electrode12may be different to (i.e. smaller or larger than) the second gap (g2)22between the second electrode12and the third electrode13. However, the first gap (g1)21between the first electrode11and the second electrode12may be the same as the second gap (g2)22between the second electrode12and the third electrode13. In another example, the second surface area may be larger than the first surface area and the third surface area, and also the first gap (g1)21between the first electrode11and the second electrode12may be different to (i.e. smaller or larger than) the second gap (g2)22between the second electrode12and the third electrode13.

In one example the device is operably connected to two stimulation devices. In this example, one stimulation device is connected to the first electrode11and the second electrode12, and the other stimulation device is connected to the third electrode13and the second electrode12. The stimulation devices can be operated to cause a different anodal charge to be injected at the first electrode11compared with the third electrode13. In this example, where there are two stimulators the first gap (g1)21between the first electrode11and the second electrode12may be different to (i.e. smaller or larger than) the second gap (g2)22between the second electrode12and the third electrode13and/or the second surface area may be larger than the first surface area and the third surface area. However, the first gap (g1)21between the first electrode11and the second electrode12may be the same as the second gap (g2)22between the second electrode12and the third electrode13.

In an electrode arrangement15which uses cuff type electrodes that fully circumvent the nerve, the size of this surface area can be calculated by multiplying7C (i.e.3.14159) by the internal diameter and width of the respective electrode (i.e. the first electrode11, the second electrode12or the third electrode13). Since the internal diameter of the first electrode11, the second electrode12and the third electrode13is fixed by the diameter of the nerve, the surface area of each of the first electrode11, the second electrode12and the third electrode13in contact with the nerve is adjusted by changing the width of the electrode. In one example, the internal diameter of the first, second and third electrodes may be 0.5 mm.

The width of each of the first electrode11, the second electrode12and the third electrode13is defined as the distance the electrode spans along the longitudinal axis of the nerve. InFIG.5, the width of the first electrode11is denoted x1, whilst the width of the second electrode is denoted x2and the width of the third electrode is denoted x3.

The width of the first electrode x1is defined by the user. Typically, the width of the first electrode x1is around 0.3 mm. The width of the third electrode x3may also be user defined and typically around 0.3 mm.

Similarly, the width of the first gap between the first electrode11and the second electrode12is defined as the distance that the gap spans along the longitudinal axis of the nerve. InFIG.5, the width of the first gap is denoted g1. The width of the second gap between the second electrode11and the third electrode13is defined as the distance that the gap spans along the longitudinal axis of the nerve. InFIG.5, the width of the second gap is denoted g2.

The width of the first gap g1is also defined by the user. Typically, the width of the first electrode x1is around the same size as the first gap g1, which in this example is 0.3 mm. The width of the second gap g2is also defined by the user. In one example, the width of the second gap g2is at least or greater than the sum of the width of the second electrode and the first gap g1. For instance, the width of the second gap may be 6 mm.

The surface area of the second electrode12is adapted to be larger than the surface area of the first electrode11and the third electrode13. When the surface area of the second electrode12is larger than the surface area of the first electrode11this concentrates charge density under the first electrode11for a given current compared to charge under the second electrode12, thus strengthening the hyperpolarization of the nerve without increased energy requirements. Thus, the width of the second electrode x2may be greater than the width of the first electrode x1and the third electrode x3respectively.

The width of the second electrode x2may be the sum of the width of the first electrode (i.e. the first width) and the width of the third electrode (i.e. the third width). In another example, the width of the second electrode (i.e. the second width) may be two times the first electrode width or the third electrode width.

For example, the width of the second electrode x2may be at least two, three, four or five times the width of the first electrode x1and the third electrode x3respectively.

Where two stimulators are used to provide a different anodal charge density at the first electrode in comparison to the charge at the third electrode, the asymmetry in the charge provided by the first and third electrodes allows directional stimulation to occur, without the need for different surface areas at the electrodes or different spacing between the electrodes to be provided. However, these features may be provided to enhance the directionality of the stimulation.

In the electrode arrangement, the width of the second electrode x2may also be less than or equal to five times the width of the first electrode x1and the third electrode x3respectively. This is to reduce the separation between activation threshold under the second electrode12and blocking threshold under the first electrode11.

To achieve unidirectional stimulation, the first electrode11and the third electrode13are both positively charged electrodes, and the second electrode12is a negatively charged electrode, also referred to as the “cathode”.

The width (or surface area) of the first electrode relative to the width (or surface area) of the second electrode has been found to allow the device to provide an efficacious signal, while reducing the magnitude of the current required. This advantage is explained in greater detail in the summary above.

The neural interface device10may further comprise a flexible non-conductive layer30, as shown inFIG.6. In other words, the flexible non-conductive layer30is an insulator. The electrode arrangement15may be mounted on to or otherwise attached to the flexible non-conductive layer30. When in use, the electrode arrangement15interfaces the nerve and the flexible non-conductive layer interfaces the electrode arrangement15. The flexible non-conductive layer30may conform to the shape of the electrodes such that it resides in the first gap21between the first and second electrodes11,12and additionally interfaces the nerve in that gap. The flexible non-conductive layer30may reside in a second gap22between the second electrode12and the third electrode13. The flexible non-conductive layer30may reside in a third gap (g3)23between the third electrode13and a second end18of the device10. The flexible non-conductive layer30may reside in a fourth gap (g4)24between a first end17of the device10and the first electrode.

The flexible non-conductive layer30may be made from a polysiloxanes (i.e. silicone) or a similar material to allow the flexible non-conductive layer to conform to the shape of the nerve. In some embodiments, the flexible non-conductive30layer is configured to at least partially circumvent the nerve when in use. The flexible non-conductive layer30may fully circumvent the nerve, as shown inFIG.6.

The flexible non-conductive layer may form a cuff around the nerve. The cuff may be fastened in place on the nerve using any means known in the art. The cuff has two open ends which are perpendicular to the longitudinal axis of the nerve. The first open end17and second open end18of the cuff are shown inFIG.6.

A second gap22is defined as the gap along the longitudinal axis of the nerve between the second electrode12and the third electrode. The second gap23defines a first non-conductive portion.

Similarly, a third gap23is defined as the gap along the longitudinal axis of the nerve between the second open end18and the third electrode13in a bipolar electrode arrangement (shown inFIG.6). The third gap23defines another non-conductive portion. As shown inFIG.6, the width of the second gap22is denoted as g2, and the width of the third gap23is denoted as g3.

The width of the third gap23g3may be larger than the second gap22g2. For instance, the width of the third23gap g3may be greater than twice as large at the width of the second electrode12.

In the above-mentioned example, the first gap is different to the second gap, and thus provides an asymmetrical configuration that allows unidirectional stimulation to be achieved. For instance, the first gap may be larger than the second gap, or the second gap may be larger than the first gap. In another example, the first electrode11is arranged to provide a different charge to the charge arranged to be provided by the third electrode13, which provides asymmetric electrode configuration in this example.

Referring toFIGS.4to6, the configuration for the creation of unidirectional action potentials in the nerve is a tripolar ‘passive imbalance’ configuration. The second electrode12is positioned along the nerve axis proximal to the first electrode11and the third electrode13is positioned along the nerve axis proximal to the second electrode12.

The electrode configuration may employ asymmetric spatial variance to provide a passive imbalance such that the first gap21g1between the first electrode11and the second electrode12is shorter than the second gap22g2between the second electrode and the third electrode13. In this configuration, when an electrical signal is applied to the first electrode11and the third electrode13such that they become positively charged (anode) and an electrical signal is applied to the second electrode12such that it becomes negatively charged (cathode), and when the pulse width of the electrical signals applied is tuned with the inter-electrode distance for fiber type conduction velocities, there is an impedance mismatch conveyed by the current path length along the nerve. The first electrode11has a larger current density than the third electrode13. The neural interface devices may comprise a dual current source and tri-polar electrode arrangements with different insulation spacing.

In this example, the second gap g2may be specially adapted for unidirectional stimulation. A compound action potential is impeded under the first electrode11by adapting the pulse width of the electrical signal applied to the nerve based the width of the first gap21g1. This is so that the compound action potential generated under the second electrode12arrives in the nerve under the first electrode11when hyperpolarization of the nerve is present. In order for the compound action potential travelling in the opposite direction along the nerve not to be impeded under the third electrode13, the nerve under the third electrode13should not be hyperpolarized when the compound action potential arrives. In some embodiments, the neural activity of the nerve under the third electrode13has returned to baseline activity upon arrival of the compound action potential, allowing the compound action potential to pass unimpeded. This can be achieved by adapting the width of the second22gap g1based on the width of the first21gap g1.

The width of the second22gap g2may be greater than the sum of the width of the first gap21g1and the width of the second electrode12.

Another exemplary electrode configuration for creation of unidirectional action potentials in a nerve is a tri-polar ‘active, current balance’ configuration comprising a first electrode11, a second electrode12and a third electrode13. The second electrode12is positioned along the nerve axis proximal to the first electrode11and the third electrode13is positioned along the nerve axis proximal to the second electrode12, where the spacing between the first electrode11and the second electrode12is the same distance as the spacing between the second electrode12and the third electrode13. Additionally, the surface area of the first electrode11in contact with the nerve is equal in size to the surface area of the second electrode12in contact with the nerve, and to the surface area of the third electrode13in contact with the nerve. Two independent non-equal current sources in the implantable pulse generator (IPG) provide positive currents to the first electrode and the third electrode respectively and the second electrode shares or sums the negative lead from both current sources. In this configuration, the current source of the first electrode11provides a greater current than the current source of the third electrode13such that the third electrode13becomes more positively charged (anode) than the first electrode11. The second electrode12, which shares both current sources, becomes negatively charged (cathode). The current density mismatch between the first and third electrodes steers action potentials in the direction away from the first electrode11.

Neural interfaces may comprise a dual current source and tri-polar electrode arrangements with different insulation spacing.

The surface area of the second electrode12can be adapted to be larger than the surface area of the first electrode11so that charge density is concentrated under the first electrode11, thus strengthening the hyperpolarization of the nerve without increased energy requirements. Thus, the width of the second electrode12x2(in the longitudinal direction) is greater than the width of the first electrode11x1(in the longitudinal direction). In particular, the width of the second electrode12x2can be at least twice the width of the first electrode11x1. The second electrode12therefore has at least twice the surface area than the first electrode11. In this example, reducing the surface area of the first electrode11relative to the second electrode12reduces the charge density over the second electrode12(i.e. the cathode).

In a tri-polar electrode arrangement, the width of the second electrode12x2may also be less than or equal to ten times the width of the first electrode11x1.

Thus, in a tri-polar electrode arrangement, the width of the second electrode11x2may be set at any value between the upper and lower limits described above. For example, the width of the second electrode12x2may be one of: 2.0x1, 2.5x1, 3.0x1, 3.5x1, 4.0x1, 4.5x1, 5.0x1, 5.5x1, 6.0 x1, 6.5x1, 7.0 x1, 7.5x1, 8.0 x1, 8.5x1, 9.0 x1, 9.5x1or 10.0x1. Typical values for the width of the first electrode x1are described above.

The width of the third electrode13x3may be at least the width of the first electrode11x1.

Experimental Method

Left or right vagi, spanning 40-60 mm from the nodose and jugular ganglia to the subclavian arteries with the carotid artery were removed for processing. Under dissection microscopes, the vagus was separated from the carotid artery, connective tissue, and fat and partially de-sheathed. Tissue was transferred and mounted to a custom3chamber tissue with surgical silk (5.0). All chambers were filled with fresh assay buffer perfused for 30-60 min at 35+/−2° C. prior to recording.

Stimulation was performed in the central chamber on the cervical vagus with custom made 500 μm platinum/iridium silicone cuff electrodes. Stimuli of varying pulse duration (PD) and current were generated with a square-pulse stimulator (Grass model S48; Natus Neurology Inc., Warwick, R.I., U.S.A.) driving an optically isolated constant current source (Model 2200; AM Systems, Seqium, Wash., U.S.A.). Quasitrapezoidal pulses were generated by the addition of a schottky diode to a parallel resistor (770-5770 Ohm)/capacitor (0.1 uF) network prior to isolation. In some cases, the quasitrapezoidal stimulus was generated via a Kiethley 3390 50 MHz arbitrary waveform generator using KI Wave software v1.2 (Tektronix, Beaverton, Oreg., U.S.A) and fed into the constant current stimulus isolator.

Stimulation was applied centrally with compound action potentials recorded on the distal and proximal vagus with a microelectrode AC amplifier (A-M Systems model 1800, Carlsborg, Wash., U.S.A.) using Ag/AgCl hook electrodes in the outside baths. Arrest side of stimulus was always oriented proximally. Differential signals were filtered with a low cut-off frequency of 10 Hz and high cut-off frequency of 1 kHz. Tissue was grounded via a platinum hook electrode in the central bath. After checking viability of tissue, the recording baths were drained and rapidly filled with pre-warmed mineral oil and recording commenced.

Analog signals were digitized at 15 kHz using an analog-to-digital converter (Power1401 625 kHz;

Results are normalized to the maximal area under a curve observed for given fiber type from a square pulse stimulation.

FIG.7illustrates an electrode configuration where electrodes A and C are anodes and electrode B is a cathode. The dimensions of the configuration are as follows (using the same notation as described with reference toFIG.6):

In this configuration the first and the third electrode are equal in width and have the same surface area. The width of second electrode is three times that of the first or the third electrode. The gap between the third and the second electrode is three times that of the gap between the first and the second electrode.

FIG.8illustrates an electrode configuration where electrodes A and C are anodes and electrode B is a cathode. The dimensions of the configuration are as follows (using the same notation as described with reference toFIG.6):

In this configuration the first and the third electrode are equal in width and have the same surface area. The width of second electrode is two times that of the first or the third electrode. The gap between the third and the second electrode is twenty-four times that of the gap between the first and the second electrode.

Experimental Results (FIGS.9A-D)

FIGS.9A-Dillustrate the results of bipolar square pulse stimulation (0.1-0.6 msec, monophasic) of a guinea pig vagus using cuff design #1 where the cathode (electrode B) is three times the geometric surface area of the anode (electrode C). The pulse durations (0.1-0.6 msec) refer to the duration of the pulse where the peak amplitude is provided (i.e. the plateau of the square wave). The stimulation was provided with one current source attached to the cathode and an anode (i.e. ‘passive stimulation’ was provided).

The A fibers (having a conduction velocity of ˜>10 m/s) are donated by the red circles. The Ad fibers (having a conduction velocity of ˜10-3 m/s) are denoted by the blue squares. A pulse width (plateau phase) dependent suppression of compound action potential propagation can be observed in the proximal direction (solid symbols) for both A and Ad fiber types, with a preference for propagation distally (open symbols). A virtual cathode/anode formation occurs close to 1 mA.

Experimental Results (FIGS.10A-D)

FIGS.10A-Dillustrate the results of bipolar quasitrapezoidal stimulation (0.1-0.6 msec plateau phase, >200 us decay) of guinea pig vagus using cuff design #1 where the cathode (electrode B) is 3× the geometric surface area of the anode (electrode C). The pulse durations (0.1-0.6 msec) refer to the duration of the pulse where the peak amplitude is provided (i.e. the plateau of the quasitrapezoidal wave before the amplitude begins to decay). The stimulation was provided with one current source attached to the cathode and an anode (i.e. ‘passive control’ was provided).

The A fibers (having a conduction velocity of ˜>10 m/s) are denoted by the red circles. The Ad fibers (having a conduction velocity of ˜10-3 m/s) are denoted by the blue squares. A pulse width (plateau phase) dependent suppression of compound action potential propagation can be observed in the proximal direction (solid symbols) for both A and Ad fiber types, with a preference for propagation distally (open symbols). Virtual cathode/anode formation occurs close to 1 mA. Quasitrapezoidal stimulation conveys a benefit (lower current requirements to achieve directionality) over square wave stimulation to achieve directionality. The pulse durations (0.1-0.6 msec) refer to the duration of the pulse where the peak amplitude is provided (i.e. the plateau of the quasitrapezoidal wave before the amplitude begins to decay).

Experimental Results (FIGS.11A-D)

FIGS.11A-Dillustrate the results of tripolar quasitrapezoidal stimulation (0.1-0.6 msec plateau phase, >200 us decay) of guinea pig vagus using cuff design #1 where the cathode (electrode B) is 3× the geometric surface area of the anodes (electrode A and C). Positive output of a single stimulator is shorted to the outer two electrodes. A differential charge density on anodes is achieved through design spacings only, using a single current stimulator. The stimulation was provided with one current source attached to central cathode and both anodes (i.e. ‘passive control’ was provided).

The A fibers (having a conduction velocity of ˜>10 m/s) are denoted by the red circles. The Ad fibers (having a conduction velocity of ˜10-3 m/s) are denoted by blue squares. A pulse width (plateau phase) dependent suppression of compound action potential propagation can be observed in both proximal (solid symbols) and distal (open symbols) directions for both A and Ad fiber types. Virtual cathode/anode formation no longer occurs in tripolar configuration. The C-fibers (denoted by green triangles) are shown for reference. This configuration allows a preference for high threshold fiber types with a suppression of lower threshold fiber types in both directions.

Experimental Results (FIGS.12A-D)

FIGS.12A-Dillustrate the results of tripolar quasitrapezoidal stimulation (0.1-0.6 msec plateau phase, >200 us decay) of guinea pig vagus using cuff design #2 where cathode (electrode B) is 2× the geometric surface area of the anodes (electrode A and C). Positive output of a single stimulator is shorted to the outer two electrodes. A differential charge density on the anodes is achieved through design spacings only, using a single current stimulator). The stimulation was provided with one current source attached to the central cathode and both anodes (i.e. ‘passive control’ was provided).

The A fibers (having a conduction velocity of ˜>10 m/s) are denoted by the red circles. The Ad fibers (having a conduction velocity of ˜10-3 m/s) are denoted by the blue squares. A pulse width (plateau phase) dependent suppression of compound action potential propagation can be observed in the proximal direction (solid symbols) for both A and Ad fiber types, with a preference for propagation distally (open symbols). Virtual cathode/anode formation occurs close to 1 mA.

Experimental Results (FIG.15)

The charts illustrated inFIG.15show the results of using tripolar quasitrapezoidal stimulation (0.4 msec plateau phase, >200 us decay) of a guinea pig vagus using cuff design #1 with a dual current stimulator configuration. In this example, two current sources are utilized to differentially control the arresting anode charge density (i.e. ‘active control was applied). The plateau width and decay time constants for both waveforms were matched and only amplitude varied. The reported cathodic amplitude is the sum of both stimulator amplitudes.

The amplitude ratios between the escape and arrest anode varied from 1:1 (50% of total current on arresting electrode) to 1:20 (95% of total current on the arresting anode) and 0:1 (bipolar, 100% of current on arresting anode) served as a comparator. The effect of varying the escape (distal facing) to arresting (proximal facing) anode current ratios are shown for A fibers having a conduction velocity of ˜>10 m/s (red circles).

The percentage of maximal AUC for proximal propagation (solid circles compared to the percentage of maximal AUC for distal propagation (open circles) are shown for varying escape/arrest anode current ratios . . . . A preference for distal compared to proximal Ecap propagation (as illustrated by the blue squares) at 200 uA is shown for all configurations. A preference for directionality was maximized with 85% of current on the arresting anode (1:6.7).

Neural Stimulation System (FIG.13)

The neural interface device10may be part of a neural stimulation system50, as shown inFIG.13. The neural stimulation system comprises a voltage or current source60which is electrically connected to the electrodes of the electrode arrangement15of the neural interface device10, wherein the voltage or current source is configured to generate an electrical signal to be applied to the nerve via the electrode arrangement15. The electrical signal causes unidirectional stimulation of neural activity in the nerve.

The electrical signal applied to the nerve is ideally non-destructive. As used herein, a “non-destructive signal” is a signal that, when applied, does not irreversibly damage the underlying neural signal conduction ability of the nerve. That is, application of a non-destructive signal maintains the ability of the nerve or fibers thereof, or other nerve tissue to which the signal is applied, to conduct action potentials when application of the signal ceases, even if that conduction is in practice artificially stimulated as a result of application of the non-destructive signal.

Stimulation of the neural activity of the nerve can be achieved using electrical signals which serve to replicate the normal neural activity of the nerve (i.e. the action potentials). Accordingly, the electrical signal may be a pulse train, the pulse train comprising a plurality of pulses. The number of pulses per second in the pulse train is set by the frequency, and the duration of the pulses within each phase is determined by the pulse width.

According to the disclosure, compound action potentials are impeded by adapting the pulse width of the electrical signal applied to the nerve based on the width of the gap between the electrodes in the previously described bipolar electrode arrangement of neural interface device10(i.e. the width of first gap g1).

In particular, the pulse width must be set above a lower limit. The lower limit for the pulse width is the width of the first gap g1plus the width of the second electrode12, then divided by the slowest conduction velocity of the fiber types of interest. The pulse width may be any value above the lower limit.

The pulses may have a sawtooth, sinusoidal, triangular, trapezoidal, square, or quasitrapezodial waveform, though a quasitrapezodial waveform can be advantageous. Other complex waveforms which are similar to the waveform of an action potential are also suitable with the disclosure.

The pulses may be biphasic pulses. The term “biphasic” refers to an electrical signal which causes each of the electrodes in the electrode arrangement15to be both positively and negatively charged over time. Biphasic pulses may be charge-balanced. The term “charge-balanced” in relation to a pulse train is taken to mean that the positive charge and negative charge applied by the signal over the pulse duration is equal.

Each pulse may have a duration of between 0.05 ms and 1.0 ms, and the current of the signal provided may be 300 μA. In particular, the pulses may have a duration of at least one of: 0.1 ms, 0.2 ms, 0.4 ms and 0.6 ms.

In addition to the neural interface device10and voltage or current source60, the neural stimulation system50may comprise one or more of the following components: a microprocessor113; an implantable transceiver110; a physiological sensor111; a power source112; a memory114(otherwise referred to as a non-transitory computer-readable storage device); and a physiological data processing module115.

As shown inFIG.14, one or more of the following components may be contained within an implantable device106: the voltage or current source60, the power source112; the memory114; the microprocessor113, and the physiological data processing module115.

The microprocessor113may be responsible for triggering the beginning and/or end of the electrical signals to be applied to the nerve. Optionally, microprocessor113may also be responsible for generating and/or controlling the signal parameters, including the pulse width.

The microprocessor113may be configured to operate in an open-loop fashion, wherein a pre-defined signal (e.g. as described above) is applied to the nerve at a given periodicity (or continuously) and for a given duration (or indefinitely) with or without an external trigger, and without any control or feedback mechanism. Alternatively, the microprocessor113may be configured to operate in a closed-loop fashion, wherein an electrical signal is applied based on a control or feedback mechanism. As described elsewhere herein, the external trigger may be an external controller101operable by the operator to initiate application of an electrical signal.

The microprocessor113may be constructed so as to generate, in use, a preconfigured and/or operator-selectable signal that is independent of any input. Alternatively, the microprocessor113may be responsive to an external signal, for example information (e.g. data) pertaining to one or more physiological parameters of the subject in which the neural stimulation system50is implanted.

The microprocessor113may be triggered upon receipt of a signal generated by an operator, such as a physician or the subject in which the neural stimulation system50is implanted. To that end, the neural stimulation system50may be part of a wider system100which additionally comprises an external system118comprising a controller101. An example of the wider system100is described below.

External system118of wider system100is external the neural stimulation system50and external to the subject, and comprises controller101. Controller101may be used for controlling and/or externally powering neural stimulation system50. To this end, controller101may comprise a powering unit102and/or a programming unit103. The external system118may further comprise a power transmission antenna104and a data transmission antenna105, as further described below.

The controller101and/or microprocessor113may be configured to apply the electrical signal to the nerve periodically or continuously. Periodic application of an electrical signal involves applying the signal in an (on-off)npattern, where n>1. For instance, the electrical signal can be applied continuously for a duration of time, before ceasing for a period, before being again applied continuously for a second duration of time, etc.

The signal may be applied by controller101and/or microprocessor113for a specific amount of times per day. For instance, the signal may be applied in bursts across the day.

Continuous application may continue indefinitely, e.g. permanently. Alternatively, the continuous application may be for a minimum period, for example the signal may be continuously applied for at least 5 days, or at least 7 days.

Whether the signal applied to the nerve is controlled by controller101, or whether the signal is continuously applied directly by microprocessor113, although the signal might be a series of pulses, the gaps between those pulses do not mean the signal is not continuously applied.

The signal may be applied only when the subject is in a specific state e.g. only when the subject is awake, only when the subject is asleep, prior to and/or after the ingestion of food, prior to and/or after the subject undertakes exercise, etc.

Timing for stimulation of neural activity in the nerve may be achieved using controller101.

The power source112may comprise a current source and/or a voltage source for providing power to the current or voltage source50. The power source112may also provide power for the other components of the implantable device106and/or neural stimulation system50, such as the microprocessor113, memory114, and implantable transceiver110. The power source112may comprise a battery, the battery may be rechargeable.

It will be appreciated that the availability of power is limited in implantable devices, and embodiments of the disclosure have been devised with this constraint in mind. The implantable device106and/or neural stimulation system50may be powered by inductive powering or a rechargeable power source.

Memory114may store power data and data pertaining to the one or more physiological parameters from internal neural stimulation system50. For instance, memory114may store data pertaining to one or more signals indicative of the one or more physiological parameters detected by physiological sensor111, and/or the one or more corresponding physiological parameters determined via physiological data processing module115. In addition or alternatively, memory114may store power data and data pertaining to the one or more physiological parameters from external system118via the implantable transceiver110. To this end, the implantable transceiver110may form part of a communication subsystem of the wider system100, as is further discussed below.

The physiological data processing module115is configured to process one or more signals indicative of one or more physiological parameters in a subject detected by the physiological sensor111, to determine one or more corresponding physiological parameters. Physiological data processing module115may be configured for reducing the size of the data pertaining to the one or more physiological parameters for storing in memory114and/or for transmitting to the external system via implantable transceiver110. Implantable transceiver110may comprise an one or more antenna(e). The implantable transceiver100may use any suitable signaling process such as RF, wireless, infrared and so on, for transmitting signals outside of the body, for instance to wider system100of which the neural stimulation system50is one part.

Alternatively or additionally, physiological data processing module115may be configured to process the signals indicative of the one or more physiological parameters and/or process the determined one or more physiological parameters to determine the evolution of the disease in the subject. In such case, the neural stimulation system50, in particular the implantable device106, will include a capability of calibrating and tuning the signal parameters based on the one or more physiological parameters of the subject and the determined evolution of the disease in the subject.

The physiological data processing module115and the at least one physiological sensor111may form a physiological sensor subsystem, also known herein as a detector, either as part of the neural stimulation system50, part of the implantable device106, or external to the system.

Physiological sensor111comprises one or more sensors, each configured to detect a signal indicative of one of the one or more physiological parameters described above. For example, the physiological sensor110is configured for: detecting biomolecule concentration using electrical, RF or optical (visible, infrared) biochemical sensors; detecting blood flow using intra- or perivascular flow tubes in or around an artery; detecting neural activity of a nerve using an electrical sensor; or a combination thereof.

The physiological parameters determined by the physiological data processing module115may be used to trigger the microprocessor113to apply an electrical signal to the nerve via the electrode arrangement15. Upon receipt of the signal indicative of a physiological parameter received from physiological sensor111, the physiological data processor115may determine the physiological parameter of the subject, and the evolution of the disease, by calculating in accordance with techniques known in the art.

The memory114may store physiological data pertaining to normal levels of the one or more physiological parameters. The data may be specific to the subject into which the neural stimulation system50is implanted, and gleaned from various tests known in the art. Upon receipt of the signal indicative of a physiological parameter received from physiological sensor111, or else periodically or upon demand from physiological sensor111, the physiological data processor115may compare the physiological parameter determined from the signal received from physiological sensor111with the data pertaining to a normal level of the physiological parameter stored in the memory114, and determine whether the received signals are indicative of insufficient or excessive of a particular physiological parameter, and thus indicative of the evolution of the disease in the subject.

The neural stimulation system50may be configured such that if and when an insufficient or excessive level of a physiological parameter is determined by physiological data processor115, the physiological data processor115triggers application of the electrical signal to the nerve via the electrode arrangement15, in the manner described elsewhere herein. For instance, if physiological parameter indicative of worsening of any of the physiological parameters and/or of the disease is determined, the physiological data processor115may trigger application of an electrical signal which dampens secretion of the respective biochemical, as described elsewhere herein. Particular physiological parameters relevant to the present disclosure are described above.

When one or more signals indicative of one or more of these physiological parameters are received by the physiological data processor115, an electrical signal may be applied to the nerve via the electrode arrangement15.

Controller101may be configured to make adjustments to the operation of the neural stimulation system50. The data may be specific to the patient into which the device is implanted. The controller101may also be configured to make adjustments to the operation of the power source112, signal generator60and processing elements113,115and/or neural interfacing element10in order to tune the electrical signal applied to the nerve via the electrode arrangement15.

Wider System (FIG.14)

With reference toFIG.14, the neural stimulation device may be part of a wider system100that includes a number of subsystems, for example the external system118. The external system118may be used for powering and programming the neural stimulation system50through human skin and underlying tissues.

The external subsystem118may comprise, in addition to controller101, one or more of: a powering unit102, for wirelessly recharging the battery of power source112used to power the implantable device106; and a programming unit103configured to communicate with the implantable transceiver110. The programming unit103and the implantable transceiver110may form a communication subsystem. The powering unit102may be housed together with programing unit103; alternatively, they can be housed in separate devices.

The external subsystem118may also comprise one or more of: power transmission antenna104; and data transmission antenna105. Power transmission antenna104may be configured for transmitting an electromagnetic field at a low frequency (e.g., from 30 kHz to 10 MHz). Data transmission antenna105may be configured to transmit data for programming or reprogramming the implantable device106, and may be used in addition to the power transmission antenna104for transmitting an electromagnetic field at a high frequency (e.g., from 1 MHz to 10 GHz). The temperature in the skin will not increase by more than 2 degrees Celsius above the surrounding tissue during the operation of the power transmission antenna104. The at least one antennae of the implantable transceiver110may be configured to receive power from the external electromagnetic field generated by power transmission antenna104, which may be used to charge the rechargeable battery of power source112.

The power transmission antenna104, data transmission antenna105, and the at least one antennae of implantable transceiver110have certain characteristics such a resonant frequency and a quality factor (Q). One implementation of the antenna(e) is a coil of wire with or without a ferrite core forming an inductor with a defined inductance. This inductor may be coupled with a resonating capacitor and a resistive loss to form the resonant circuit. The frequency is set to match that of the electromagnetic field generated by the power transmission antenna105. A second antenna of the at least one antennae of implantable transceiver110can be used in neural stimulation system50for data reception and transmission from/to the external system118. If more than one antenna is used in the neural stimulation system50, these antennae are rotated 30 degrees from one another to achieve a better degree of power transfer efficiency during slight misalignment with the with power transmission antenna104.

External system118may comprise one or more external body-worn physiological sensors121(not shown) to detect signals indicative of one or more physiological parameters. The signals may be transmitted to the neural stimulation system50via the at least one antennae of implantable transceiver110. Alternatively or additionally, the signals may be transmitted to the external neural stimulation system50and then to the neural stimulation system50via the at least one antennae of implantable transceiver110. As with signals indicative of one or more physiological parameters detected by the implanted physiological sensor111, the signals indicative of one or more physiological parameters detected by the external sensor121may be processed by the physiological data processing module115to determine the one or more physiological parameters and/or stored in memory114to operate the neural stimulation system50in a closed-loop fashion. The physiological parameters of the subject determined via signals received from the external sensor121may be used in addition to alternatively to the physiological parameters determined via signals received from the implanted physiological sensor111.

The wider system100may include a safety protection feature that discontinues the electrical stimulation of the nerve in the following exemplary events: abnormal operation of the neural stimulation system50(e.g. overvoltage); abnormal readout from an implanted physiological sensor111(e.g. temperature increase of more than 2 degrees Celsius or excessively high or low electrical impedance at the electrode-tissue interface); abnormal readout from an external body-worn physiological sensor121(not shown); or abnormal response to stimulation detected by an operator (e.g. a physician or the subject). The safety precaution feature may be implemented via controller101and communicated to the neural stimulation system50, or internally within the neural stimulation system50.

The external system118may comprise an actuator120(not shown) which, upon being pressed by an operator (e.g. a physician or the subject), will apply the electrical signal, via controller101and the respective communication subsystem, to trigger the microprocessor113of the neural stimulation system50to apply the electrical signal to the nerve by the electrode arrangement15.

Wider system100of the disclosure, in particular neural stimulation system50, can be made from, or coated with, a biostable and biocompatible material. This means that the system is both protected from damage due to exposure to the body's tissues and also minimizes the risk that the system elicits an unfavorable reaction by the host (which could ultimately lead to rejection). The material used to make or coat the system should ideally resist the formation of biofilms. Suitable materials include, but are not limited to, poly(p-xylylene) polymers (known as Parylenes) and polytetrafluoroethylene.

General

The methods described herein may be performed by software in machine readable form on a tangible storage medium e.g. in the form of a computer program comprising computer program code means adapted to perform all the steps of any of the methods described herein when the program is run on a computer and where the computer program may be embodied on a computer readable medium. Examples of tangible (or non-transitory) storage media include disks, thumb drives, memory cards etc. and do not include propagated signals. The software can be suitable for execution on a parallel processor or a serial processor such that the method steps may be carried out in any suitable order, or simultaneously. This acknowledges that firmware and software can be valuable, separately tradable commodities. It is intended to encompass software, which runs on or controls “dumb” or standard hardware, to carry out the desired functions. It is also intended to encompass software which “describes” or defines the configuration of hardware, such as HDL (hardware description language) software, as is used for designing silicon chips, or for configuring universal programmable chips, to carry out desired functions.

Unless otherwise indicated each embodiment as described herein may be combined with another embodiment as described herein. The term “comprising” encompasses “including” as well as “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X+Y.