Therapy delivery devices and methods for non-damaging neural tissue conduction block
Patent Information
- Application Number
- JP2024114183
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2013-05-10
- Filing Date
- 2024-07-17
- Publication Date
- 2025-01-14
Smart Images
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Abstract
Description
[Technical field]
[0001] ==CROSS REFERENCE TO RELATED APPLICATIONS== This application claims the benefit of priority to U.S. Provisional Patent Application No. 61 / 660,383, filed June 15, 2012, and U.S. Provisional Patent Application No. 61 / 821,862, filed May 10, 2013, the entire contents of each of the above-referenced applications being incorporated herein by reference for all purposes.
[0002] The present invention relates generally to systems, devices and methods for blocking signal transmission through neural tissue, such as nerve fibers, and more particularly to therapeutic systems, devices and methods for blocking neural signal transmission without damaging neural tissue, using direct current. [Background technology]
[0003] Many neurological disorders are characterized by unwanted neural activity that leads to severe symptoms, such as seizures, movement disorders, and chronic pain of peripheral origin. Localized and reversible electrical nerve conduction blockade would be an attractive approach to address these symptoms. Summary of the Invention [Problem to be solved by the invention]
[0004] High frequency alternating current (HFAC) waveforms have been shown to provide highly localized, immediate, and complete reversible conduction block of motor and sensory nerve fibers in acute animal studies without nerve fiber damage. However, HFAC produces a transient neural activity upon application. This effect has been termed the "onset response." The onset response may take many seconds to subside and cease. When HFAC nerve blocks are applied to mixed nerves, the onset response may produce a pain sensation accompanied by muscle contraction. This onset response has hindered the practical use of HFAC blocks for applications such as spasticity control. HFAC typically lasts less than 2 seconds, and efforts have been made to shorten it. These methods include the use of larger HFAC amplitudes, higher frequencies (>20 kHz), and various electrode configurations. However, the initial onset response, which lasts 1-2 seconds, is a component of HFAC block that has not been eliminated by changes in waveform or electrode design alone.
[0005] An alternative electrical nerve block can be achieved with direct current (DC). In addition to other maneuvers, DC amplitude can be slowly increased or decreased over a few seconds to produce DC block without inducing action potentials. This allows DC block without onset reactions. However, application of DC waveforms leads to nerve fiber damage. This is probably due to the generation of free radicals at the electrode-electrolyte interface after the charge injection capacity of the interface is exhausted and the voltage applied to the interface leaves a water window. The water window is a specific voltage range at each electrode-electrolyte interface that is limited by the activation energy required to generate molecular oxygen and molecular hydrogen or the externally applied voltage. The advantage of DC block is that it can be achieved without onset reactions by gradually ramping the current amplitude, an effect not achieved with HFAC block waveforms.
[0006] Thus, there is a need for better ways to block nerve conduction. [Means for solving the problem]
[0007] Generally, the present invention relates to devices and methods for blocking signaling through neural tissue.
[0008] In one embodiment, the present invention provides a therapeutic device comprising electrode contacts comprising a material with high charge capacity, the electrode contacts having a geometric surface area of at least about 1 mm 2 It is.
[0009] In another embodiment, the present invention provides a method of blocking signaling through neural tissue by placing a therapy delivery device in electrical communication with the neural tissue, the therapy delivery device including electrode contacts that include a material with high charge capacity, the method further including applying an electrical current to the neural tissue to block signaling through the tissue without damaging the tissue.
[0010] In certain embodiments, the neural tissue is subjected to a multi-phase DC current, the multi-phase DC current including a first polarity phase configured to block signaling through the neural tissue and a second opposite polarity phase configured to reduce the net charge delivered by the therapy delivery device. Preferably, subsequent energizing currents have an equal but opposite polarity counter charge to the first energizing current, resulting in a net zero charge being delivered. In certain embodiments, the multi-phase DC current includes a cathodic phase configured to block signaling through the neural tissue and an anodic phase configured to reduce the net charge delivered by the therapy delivery device. In other embodiments, the anodic phase is configured to block signaling and the cathodic phase is configured to reduce the net charge. In certain embodiments, applying the cathodal DC phase includes applying DC with a first DC amplitude, increasing the first DC amplitude to a second DC amplitude over a first time period that is insufficient to block neural signaling, maintaining the second DC amplitude for a second time period that is sufficient to block neural signaling, and decreasing the second DC amplitude to a third DC amplitude to reduce the net charge delivered to the neural tissue. The net charge may be reduced to substantially zero. In certain embodiments, applying the first and second DC amplitudes over the first and second time periods prevents firing in the axon. The duration of the recharge phase may be approximately equal to or longer than the duration of the block phase. When multiple electrode contacts are used, the multi-phase DC may be continuously repeated at each electrode contact to achieve a continuous block of neural signaling.
[0011] In another embodiment, multiphasic DC is applied to the neural tissue, the application including cathodal and anodal DC phases configured to collectively block neural signaling and reduce the charge delivered by the therapy delivery device. The method further includes applying HFAC to the neural tissue before, during, or after the application of the multiphasic DC. The HFAC has an HFAC amplitude, an HFAC frequency, and an HFAC current. The HFAC is configured to block neural signaling. The combination of multiphasic DC and HFAC, and the order in which the multiphasic DC and HFAC are applied, reduces onset activity in the neural tissue associated with blocking signaling through the neural tissue while preventing damage to the nervous system. [Brief description of the drawings]
[0012] These and other features of the present disclosure will become apparent to those skilled in the art to which the present disclosure pertains upon reading the following description and upon reference to the accompanying drawings. [Figure 1A] 1 is an exemplary therapy delivery device according to one embodiment of the present invention. [Figure 1B] 1 is another exemplary therapy delivery device according to an embodiment of the present invention. [Diagram 2] FIG. 1 is a schematic diagram of an example waveform and its application to four electrode contacts according to an embodiment of the present invention. The graph shows the current flowing by each electrode contact over time. The total time is approximately 60 seconds. Each plateau is approximately 5 seconds long. The dotted current indicates zero current for each electrode contact. A typical current for each plateau is 1-2 mA. The bars above the plateaus indicate the time the nerve is blocked by each electrode contact. At any one time, at least one electrode contact is blocking the nerve, so the nerve is continuously blocked. The signal from each electrode contact repeats with the same waveform (as indicated by the dotted line for electrode contact number 1). [Diagram 3]Figure 3 is a schematic of an onset-free block system using DC and HFAC. Figure 3A is a schematic of the electrode contacts placed on the nerve. The gastrocnemius tendon is attached to a force transducer to measure force. Figure 3B is a graph showing onset-free block. The top line shows the tension in the tendon during the test in Newtons. The proximal stimulation (PS) line shows the time when the proximal stimulation was applied (once per second). A proximal stimulation (PS) of 2 Hertz (Hz) is applied throughout the test, and the muscle twitches every time a PS is applied at the beginning of the test. The DC ramps down (cathodal block) and plateaus at 4.5 seconds, producing a complete block. At that point, the PS is still applied, but no muscle force is produced. The DC block allows the HFAC to be applied at 7.5 seconds without producing an onset response. The DC is de-energized and the block is maintained by the HFAC. The HFAC was de-energized at 17.5 seconds and normal conduction was restored. Figure 3C is a graph showing normal HFAC onset (when no DC block was used). [Figure 4] Graphs showing the effect of electrical nerve block waveforms on evoked gastrocnemius muscle force. FIG. 4A shows that application of HFAC alone evoked a large onset response before muscle activity was suppressed. FIG. 4B shows that a ramped DC waveform reduced PS-induced twitches and minimized the onset response evoked by the HFAC waveform. The bar under "HFAC" indicates the time it was applied. The bar under "DC" indicates the ramp down of DC from zero to the block level and back to zero again (zero DC not shown). [Diagram 5]Graph showing DC energization with precharge pulse, reverse polarity block phase, and final recharge phase. The precharge phase lasts from 2 to 26 seconds, the reverse polarity block phase lasts from 26 to 36 seconds, and the final recharge phase lasts from 36 to 42 seconds. The top line shows that this waveform can be achieved without significant unwanted activity of the nerve fiber (nerve fiber stimulated at 1 Hz). Results are obtained from a rat sciatic nerve. "A" in Figure 5 is the area under the curve of the spike and Fmax is the maximum force. [Figure 6] 6A and 6B are graphs showing that different amplitudes of DC block block different percentages of the HFAC onset response. The onset response compared in Figures 6A and 6B is a single spike occurring at approximately 12 seconds in Figure 6A and approximately 16 seconds in Figure 6B. [Figure 7A] 1 is a graph showing the use of different slopes and multiple transitions in a DC waveform to avoid muscle activation as current levels change. A steeper slope between transitions induces significant activity in the nerve. This activity can be reduced or eliminated by decreasing the slope of the DC waveform transitions. The bottom two lines show the delivery of HFAC and DC. HFAC and DC are zero at the start of the test (0 seconds). [Figure 7B] 1 is a graph showing the use of different slopes and multiple transitions in a DC waveform to avoid muscle activation as current levels change. A steeper slope between transitions induces significant activity in the nerve. This activity can be reduced or eliminated by decreasing the slope of the DC waveform transitions. The bottom two lines show the delivery of HFAC and DC. HFAC and DC are zero at the start of the test (0 seconds). [Figure 8] This graph shows a DC block that is too brief to block the entire onset response by HFAC. The bottom two lines show the time of HFAC and DC application. HFAC and DC are zero at the beginning of the test (0 seconds). [Figure 9]FIG. 1 shows an example of a system for blocking nerve signaling without nerve damage using DCs, according to one embodiment of the present invention. [Figure 10] 13 is an example DC block test showing that twitch contractions caused by proximal stimulation are blocked during the block phase of the trapezoidal waveform, according to an embodiment of the present invention. [Figure 11] 1 shows cyclic voltammograms of several electrode contacts with different Q values. [Figure 12] Graph showing whether sciatic nerve conduction occurs after nerve block with DC (PS / DS is the muscle force ratio, which is used as a measure of power to determine acute nerve fiber damage). [Figure 13] Schematic diagram of potential clinical applications of HFAC nerve conduction blocks. For blocking dystonic muscle spasms such as torticollis, one or more HFAC block electrode contacts can be placed on the motor branch to the target muscle to relax that muscle. For blocking neuroma pain, HFAC block electrode contacts can be placed on the nerve close to the neuroma. In this application, the block is continuous. Recorded signal triggered motor nerve blocks include blocking intractable hiccups. Impending hiccups are recorded as a large signal in the phrenic nerve, triggering an HFAC block of the phrenic nerve to briefly prevent diaphragm contraction. Control of muscle spasms in stroke, multiple sclerosis, and cerebral palsy is achieved by recording muscle signals from spasmodic and non-spastic muscles to determine the user's intended movement. The spasmodic muscle may be partially blocked to allow voluntary control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0013] In the context of the present invention, the term "patient" refers to a mammal, such as a human. Also, as used herein, the term "high frequency" in reference to alternating current (e.g., HFAC) refers to frequencies greater than about 1 kilohertz (kHz), such as, for example, about 5 to about 50 kHz. The term "electrical communication" refers to the ability to move an electric field within and / or on at least one neural tissue, including nerve fibers, neurons or other types of neural tissue of a patient, i.e., to have a neuromodulatory effect (e.g., block neural signaling). The therapeutic delivery devices described in more detail herein can be placed directly on the neural tissue or in close proximity to, but not in direct contact with, the neural tissue. The phrase "electrode contacts having a material with high charge capacity" refers to electrode contacts that can carry charge without damaging the neural tissue or have a "Q value" greater than about 100 microcoulombs (μC). As known in the art, the Q value of an electrode contact is the charge capacity of the electrode contact, which is effectively the total amount of charge that can be carried through the electrode contact before the electrode contact begins to undergo an irreversible chemical reaction. The irreversible primary reaction that occurs is the evolution of oxygen or hydrogen depending on the polarity of the charge being carried. Other irreversible reactions may also occur, such as dissolution of the electrode material. The disclosure herein refers to the term "geometric surface area" of the electrode contact. This refers to the two-dimensional surface area of the electrode contact, such as a smooth surface on one side of the electrode contact, as calculated by multiplying the width and length of the two-dimensional outer surface of the electrode contact. The "effective or true surface area" of the electrode contact is estimated from the area within the curve of the cyclic voltammogram of the electrode contact. Furthermore, as used herein with respect to the components described herein, "a," "an," and "the" include at least one or more of the components, unless otherwise specified. Furthermore, the term "or" includes "and / or" unless otherwise specified.
[0014] In general, the present invention relates to methods and therapy delivery devices for blocking signaling through neural tissue. The therapy delivery device includes electrode contacts that include a high charge capacity material. As described above, the electrode contacts have a Q value greater than about 100 μC. In certain embodiments, the electrode contacts have a Q value between about 1 and about 100 milliCoulombs (mC). In a preferred embodiment, the Q value is about 10 mC. In certain embodiments, the high charge capacity material has a charge injection capability (charge density that can be safely carried through the material) of about 1 to about 5 mC / cm. 2 In contrast, polished platinum, a non-high charge capacity material, has a charge injection capability of about 0.05 mC / cm 2 With electrode contacts comprising high charge capacity materials, the effective surface area of the electrode contacts is several orders of magnitude larger than the geometric surface area. More charge can be safely delivered to the nerve tissue for a longer period of time compared to conventional stimulating electrodes, such as those made of platinum or stainless steel. Thus, DC can be safely delivered through the monopolar nerve cuff electrode contacts for periods as long as 10 seconds without damaging the nerve fibers. Thus, the present invention provides systems, devices, and methods for providing effective and reversible "onset-free" nerve blocks.
[0015] 1A and 1B, in one embodiment, the present invention provides a therapy delivery device 10 that includes an electrode contact 12. The electrode contact 12 includes a material with high charge capacity. The electrode contact 12 has a geometric surface area of at least about 1 mm2. 2 In a particular embodiment, the geometric surface area of the electrode contacts 12 is about 3 mm 2 From about 9 mm 2 The electrode contact itself can be made of a high charge capacity material. Alternatively, the electrode contact may include a base body at least partially covered, and preferably completely covered, with a high charge capacity material. Non-limiting examples of high charge capacity materials are platinum black, indium oxide, titanium nitride, tantalum, poly(ethylenedioxythiophene), and suitable combinations thereof.
[0016] As shown in FIG. 1A, the therapy delivery device 10A is a nerve spiral cuff electrode. As shown in FIG. 1B, the therapy delivery device 10B is a flat interface nerve electrode. The nerve cuff electrode may take the form of a spiral cuff, a helical wound cuff, a flat interface nerve electrode, or other nerve cuff electrode that places electrode contacts around the nerve or nerve tissue. However, the therapy delivery device may have other configurations, such as mesh, straight rod leads, paddle leads, or disk contact electrodes, including multi-disk contact electrodes. The therapy delivery device may also be placed directly on the nerve or in the nerve tissue, such as a protruding intraneural electrode. As shown in FIG. 1A and FIG. 1B, the therapy delivery devices 10A and 10B each include a plurality of electrode contacts 12A and 12B. However, the therapy delivery device may include less than a certain number of electrode contacts. Additionally, the therapy delivery device may include electrode contacts that do not include a high charge capacity material. The electrode contacts may be unipolar or bipolar. In certain embodiments, the therapy delivery device includes a plurality of adjacent electrode contacts. In one example, the number of adjacent electrode contacts is four.
[0017] Generally, the present invention also provides methods for blocking neural signaling. Such methods are distinct from applying short pulses (lasting a few microseconds) to neural tissue to activate neural signaling. One method includes placing a therapeutic delivery device in electrical communication with the neural tissue. In certain embodiments, the therapeutic delivery device is applied directly to or within the neural tissue. In other embodiments, the therapeutic delivery device is placed near the neural tissue but is not in direct contact with the neural tissue. The therapeutic delivery device has electrode contacts that include a material with a high charge capacity. The method further includes applying a current to the neural tissue to block neural signaling without damaging the neural tissue. In certain embodiments, the current is direct current (DC). In other embodiments, the current is DC and HFAC. Preferably, HFAC is applied after DC. Due to the use of a material with a high charge capacity, DC can be applied for a longer period of time than previous blocking DC waveforms without damaging the neural tissue or the electrode contacts. For example, DC can be applied for at least about 10 seconds. In certain embodiments, DC can be applied for about 1 second to about 10 seconds. DC can be applied for about 10 seconds to about 600 seconds.
[0018] In certain embodiments, multi-phase DC is applied to the neural tissue without causing damage to the neural tissue. The multi-phase DC may include a cathodal DC phase and a reciprocal anodal DC phase. The cathodal DC need not be applied first. That is, multi-phase DC can be applied to the neural tissue including applying an anodal DC current followed by a reciprocal cathodal DC current. One phase of DC is configured to produce a complete, substantially complete, or even partial nerve block, and the other phase is configured to reduce or balance the charge returned to the therapy delivery device (e.g., by reversing the current). An exemplary multi-phase DC includes a relatively slow ramp of current that is unable to produce an onset response in the neural tissue. For example, referring to FIG. 2, a slow ramp of cathodal current can be applied to the neural tissue followed by a plateau, followed by a slow ramp in the anodal direction. The net total charge carried by either electrode contact can be equal to or close to zero. Advantageously, zero net charge delivered is fairly safe for neural tissue. FIG. 2 shows a substantially trapezoidal waveform delivered by the four electrode contacts ("1", "2", "3", "4") of the therapy delivery device. The cathodal DC phase and the anodal DC phase each begin and end with a ramp. This prevents or substantially prevents axonal firing. At the plateau of the cathodal DC phase, for example, complete nerve block is achieved. As mentioned above, the cathodal DC phase can induce nerve block, after which the current is reversed (anodal DC phase) to balance the charge delivered by the therapy delivery device. The anodal recharge time may be approximately equal to the cathodal block time or moderately longer. Moreover, cathodal block and anodal recharge cycles can be applied to neural tissue continuously for extended periods of time without any nervous system damage. As mentioned above, the sequence of DC phases may be reversed, with an anodal DC phase inducing nerve block and a cathodal DC phase balancing the charge delivered by the therapy delivery device.
[0019] In some cases, the cathodal DC phase is performed as follows: DC having a first DC amplitude can be applied to the nerve tissue; the first DC is then increased to a second DC amplitude over a first period of time; the DC having the first amplitude is insufficient to produce a partial or complete nerve block; the second DC amplitude is then substantially maintained for a second period of time sufficient to produce a complete nerve block; after the second period of time, the second DC amplitude is decreased to a third DC amplitude equal or approximately equal to the first DC amplitude.
[0020] In one embodiment of the method, multiple adjacent electrode contacts can be in electrical communication with the nerve tissue. Such a configuration can be useful when nerve conduction is not entirely blocked during the anodal or cathodal DC phases. In this case, cathodal and anodal DC phases can be sequentially repeated between the electrode contacts to provide a continuous nerve block without nerve system damage. In one example, as shown in FIG. 2, cathodal and anodal DC phases can be sequentially repeated between four adjacent monopolar electrode contacts to provide a continuous nerve block without nerve system damage.
[0021] As already mentioned, another aspect of the present invention may include a method (as described above) that can be combined with the administration of HFAC to reduce or eliminate the "onset response" in a subject. HFAC has been shown to provide a safe, localized, and reversible electrical nerve conduction block. However, HFAC causes an onset response at its onset, a brief but intense burst of firing. Using DC for a short period to block nerve conduction during this HFAC onset phase can eliminate the onset problem. DC can produce a nerve block, but can cause nerve tissue damage within a short period of time.
[0022] Advantageously, the above-described method can be combined with HFAC to eliminate onset responses without damaging the nervous system. For example, multiphasic DC may be applied to the nervous tissue. As described above, the cathodal DC phase can be configured to produce a nerve block, and the anodal DC phase can be configured to balance the charge carried by the treatment delivery device, or vice versa. HFAC may be applied to the nervous tissue before, during, or after the application of multiphasic DC. The HFAC may have an HFAC amplitude, HFAC frequency, and HFAC current. The HFAC may be configured to produce a nerve conduction block in the nervous tissue. This combination of multiphasic DC and HFAC, and the application sequence of multiphasic DC and HFAC, reduces onset activity in the nervous tissue associated with producing a conduction nerve block, again while preventing nerve damage.
[0023] In certain embodiments, a "pre-charge" pulse is applied to the neural tissue. In particular, DC with a first polarity is applied to the neural tissue, followed by DC with a second polarity that is opposite to the first polarity. DC with a third polarity that is the same as the first polarity can also be applied to the neural tissue to reduce the net charge passed by the therapy delivery device. In this configuration, the total charge that can be safely passed during the second phase can be double that of a typical pulse.
[0024] The electric current in any of the above embodiments can be applied to any suitable nerve tissue for which blocking of signaling is desired. For example, the nerve tissue can be a component of the peripheral or central nervous system. With respect to the peripheral nervous system, the nerve tissue can be a peripheral nerve, including cranial nerves, spinal nerves, efferent motor nerves, afferent sensory nerves, autonomic nerves, or any suitable combination thereof. The electric current can also be applied to a collection of neurons, such as the brain, spinal cord, or ganglia. The electric current can also be applied to the axon, cell body, or dendrites of the nerve, so long as signaling is blocked and the nerve tissue is not damaged.
[0025] These methods can be used to affect abnormal functions in patients. In particular, the methods of the present invention can be used for motor, sensory or autonomic nerve blocks. Furthermore, the methods of the present invention can be applied in an open loop manner, where the block is controlled by a switch, or in a closed loop manner, where the block is automatically controlled by one or more physiological sensors. An exemplary clinical system is shown in FIG. 13.
[0026] Applications in motor block include blocking muscle spasms in stroke, cerebral palsy, and multiple sclerosis. Such applications take advantage of the gradual nature and rapid reversibility of HFAC blocks. Partial block of motor activity similar to that achieved by injection of Botox or phenol can be used to restore function. In other instances, HFAC blocks can be combined with intelligent control systems that vary the block based on sensed activity to provide additional functionality. For example, powerful spasms of the flexor muscles often prevent stroke patients from voluntarily opening their hand. By monitoring the electromyographic signals of the flexor and extensor muscles, the patient's intent can be identified, and if hand opening is desired, electrical stimulation can be used to partially block the finger flexors while activating the finger extensors.
[0027] In another embodiment, the method of the invention is used to induce relaxation of the urinary sphincter "on command." One example of an application where this is important is electrical stimulation systems designed to induce bladder emptying in individuals with spinal cord injury. In these systems, stimulation of the sacral roots induces bladder contraction for urination, but also produces unwanted sphincter contraction. The method of the invention can be applied to both pudendal nerves to prevent sphincter activity upon bladder activation. Once the bladder is emptied, the block can be terminated to restore continence. Blocking of electrode contacts may be used as a stimulus to activate weak sphincters and improve continence. Nerve conduction blocks at the sacral sensory roots can also be used to prevent natural bladder contractions, thus improving continence. The method of the invention can also be used to control bladder sphincter dyssynergia in spinal cord injury.
[0028] The method of the present invention can also be used as an alternative to neurolysis to relieve contractures caused by muscle spasms. For example, spasms of the ankle plantar flexors and hip adductor muscles in cerebral palsy lead to characteristic patterns of contractures that limit function, make hygiene difficult, and can be painful. Relief of gastrocnemius tone by tendon lengthening or neurolysis is usually only performed as a last resort due to the irreversibility of these procedures. HFAC block according to the method of the present invention is reversible and therefore applicable as a fairly early treatment method. HFAC block can be applied throughout the night or at specific times during the day, creating a period of complete relaxation of the gastrocnemius / soleus hip adductor muscles. Blocks can also be stopped during walking movements to allow the patient to utilize the voluntary function of these muscles for walking. Early intervention can prevent the progression of contractures of these muscles, eliminating the need for irreversible procedures.
[0029] Voluntary movements and spasms resulting from conditions such as dystonia, chorea, and tics can also be controlled by HFAC nerve blocks in accordance with the methods of the present invention. In many of these conditions, injections of botulinum toxin are a common treatment option. However, the need for repeated injections every few months is a major drawback and can be quite costly. Some cases may be resistant to treatment with botulinum toxin or may become resistant as a result of repeated treatment. Currently, surgical alternatives remain a last resort in these cases. In the latter cases, HFAC blocks according to the present invention may provide a better treatment than irreversible surgical management and may be preferable to repeated botulinum toxin injections for some patients. An example of this type of application, torticollis, is shown in FIG. 13 and involves a block of the sternocleidomastoid muscle and, in some cases, a block of the posterior cervical muscles.
[0030] The methods of the invention can also be used to alleviate intractable hiccups by blocking phrenic nerve conduction. Impending hiccups can be detected by recording nerve signals at the proximal phrenic nerve. A large volley of activity indicative of impending hiccups can be used to trigger an HFAC block more distal to the phrenic nerve. In certain embodiments, the block is applied for a very short period of time to interrupt the hiccup, so that it does not interfere with normal breathing.
[0031] For use in sensory nerve blocks, the method of the present invention can be used to block painful neuromas that lead to traumatic injuries such as limb amputations. Neuromas can be extremely painful and the resulting disability can be significant and difficult to treat. Because the nerve fiber ends have been ablated (by amputation), the nerve fibers do not carry any useful information. Thus, it is desirable to completely block nerve activity.
[0032] HFAC block according to the present invention may be useful for any painful nerve conduction that is currently treated by neurolysis or chemical block, such as cancer pain, post-herpetic neuralgia, and some cases of low back pain and headache. Some of these conditions are currently treated with peripheral nerve stimulation, which is not always effective and may cause intermittent sensation with stimulation. With HFAC block, a screening time with a short-acting local anesthetic applied to the nerve may be a prognostic factor for the success of HFAC.
[0033] Use in autonomic nerve blocks is described. Destruction of certain elements of the autonomic nervous system is used to treat certain conditions that do not have good alternative treatments. For example, destruction of the thoracic sympathetic ganglion is used to treat hyperhidrosis. This procedure can be successful, but possible side effects include Horner's syndrome. Using HFAC nerve blocks in these locations according to the methods of the present invention allows the procedure to be performed reversibly. Side effects can be alleviated or reduced by activating the autonomic nerve block only when needed. In other embodiments, HFAC blocks are used in autonomic disorders, including the treatment of excessive salivation and the treatment of pancreatic cancer pain (currently treated in extreme cases by destruction of the celiac plexus).
[0034] Thus, the methods of the present invention can be used to reduce spasticity in patients with cerebral palsy, stroke, or multiple sclerosis, for example, by blocking signaling through nerve fibers associated with spasticity. The methods of the present invention can be used to block muscle spasms in spinal cord injuries, or postoperatively after orthopedic surgery to prevent voluntary muscle contraction. These methods can be used to block sensory signals, such as acute and chronic pain signals, to relieve pain. The methods of the present invention can be used to block neural pain circuits in the spinal cord or brain to relieve chronic pain. The methods of the present invention can be used to block tremors in Parkinson's disease and related disorders, either by blocking peripheral nerves to muscles or by blocking neural circuits in the brain. The methods of the present invention can also be used to regulate the autonomic nervous system. Other applications include improving asthma symptoms in asthma patients, including blocking signaling through nerves that cause airway constriction in asthma.
[0035] The present invention includes data using electrode contacts fabricated from high charge capacity ("Hi-Q") materials to achieve DC nerve block without nerve fiber damage. In particular, in one example, platinum-coated Pt electrode contacts were used to achieve DC nerve block without nerve fiber damage even after multiple (>100) repeated applications. High charge capacity materials lead to a significant increase in the charge injection capability of the electrode contacts, quantified by the Q value. To avoid nerve fiber damage, the accumulated charge was recovered after the block time by reversing the current drive and allowing the Helmholtz double layer (HDL) charge to balance.
[0036] Using a combination of Hi-Q DC and HFAC electrode contacts, we have demonstrated successful onset-free block, as shown in Figure 3. In experiments using this method, over 50 consecutive block sessions were achieved without deterioration of nerve conduction. DC blocks (2.4 mA) were applied repeatedly over a period of approximately 2 hours with a cumulative 1500 seconds of DC current without deterioration of nerve conduction. Figure 4 shows additional data demonstrating successful elimination of onset responses using a combination of HFAC and Hi-Q DC nerve block.
[0037] To combine HFAC with Hi-Q DC nerve block, it is necessary to be able to deliver DC for a sufficient time to block the entire onset response of HFAC. This typically lasts 1-10 seconds, so DC should be delivered for the entire time. A method to further extend the total plateau time that DC can be delivered safely is to use a "precharge" pulse as shown in Figure 5. The use of a precharge pulse involves delivering a DC wave of opposite polarity to the desired block effect for a period of time until the maximum charge capacity of the electrode contacts is reached. The DC polarity is then reversed to produce the block effect. However, the block can now be delivered for a much longer period, potentially twice as long, because the electrode contacts have been "precharged" to the opposite polarity. At the end of the extended block phase, the polarity is reversed again to the same polarity as the precharge phase, reducing the total charge by the delivery of this final phase. In most cases, the net total charge of this waveform will be zero, but beneficial effects can be obtained even when the net total charge is not completely balanced.
[0038] As shown in Figure 6, varying levels of DC can partially or completely block the onset response from HFAC. This can be useful to assess the health of nerve fibers by verifying small responses even in the middle of a significant nerve block. The depth of DC block can be assessed in this manner.
[0039] Multi-slope transitions can also help avoid onset responses, especially in real-world devices with discrete changes (gradients) in DC current amplitude over time. This is shown in Figure 7, which shows results obtained in rat sciatic nerves. In these examples, DC is initiated with a low gradient to prevent nerve fibers from firing at low amplitudes. The gradient can then be increased to quickly reach the blocking amplitude. Once the DC block amplitude is achieved, the block is maintained for the time required to block the HFAC onset response. HFAC is delivered once DC has reached the plateau for blocking. HFAC is delivered at the amplitude required for blocking. Once the onset response is complete, DC is ramped down, quickly at first and then more slowly, to prevent nerve activation. DC is then slowly transitioned to a recharge phase where the total charge injection is reduced. In this example, the recharge phase is at low amplitude and lasts for over 100 seconds. The HFAC block can be maintained throughout this period and then beyond the end of the DC current if continuation of the nerve block is desired. Once the full desired period of block (which may be several hours) is completed, the HFAC can be de-energized to allow the nerve fibers to return to their normal conduction state. This process can be repeated as many times as necessary to produce the desired on command nerve block to treat a disease.
[0040] Figure 8 shows that DC is maintained throughout the time of the onset response from HFAC to block the entire onset response. In this example (rat sciatic nerve), the onset response lasts for approximately 30 seconds. The DC waveform (blue line) initially blocks the onset response, but as DC ramps back to zero, the onset response becomes prominent (at approximately 50 seconds). This shows an extremely long DC block waveform that combines HFAC and DC block to achieve an onset-free block.
[0041] In another example, monopolar nerve cuff electrode contacts were fabricated using platinum foil. These electrode contacts were then coated with platinum in chloroplatinic acid solution to form platinum black coatings with various roughness factors ranging from 50 to over 600. Cyclic voltammograms were generated for each electrode contact to determine the water window. The amount of charge that could be safely carried by these electrode contacts ("Q value") was estimated by calculating the charge associated with hydrogen adsorption from -0.25V to +0.1V versus a standard Ag / AgCl electrode contact.
[0042] Acute experiments were performed in Sprague-Dawley rats to test the efficacy of DC nerve block with these electrode contacts. Under anesthesia, the sciatic nerve and gastrocnemius muscle were dissected on one side. Bipolar stimulating electrode contacts were placed proximal and distal to the sciatic nerve. Proximal stimulation (PS) induced muscle twitches, allowing quantification of motor nerve block. Distal stimulation (DS) also induced muscle twitches, and these twitches were compared to PS as a measure of nerve fiber damage under the DC electrode contacts. A monopolar electrode contact was placed between the two stimulating electrode contacts as shown diagrammatically in Figure 9. Both platinum and platinum black electrode contacts were tested in this position.
[0043] DC experiments were performed in rats to determine the effects of DC pulses of various current levels and durations. A current-controlled waveform generator (Keithley Instruments, Solon, Ohio) was used to generate the DC waveform. As shown in the bottom graph of FIG. 10, the waveform had a trapezoidal block phase followed by a rectangular recharge phase. Ramp-up and ramp-down ensured no onset firing from the DC. DC parameters were selected such that the total charge delivered was less than the Q value of a given electrode contact. Each cathodic (block) pulse was then followed by a recharge phase in which 100% of the charge was transferred back to the electrode contact by an anodic pulse maintained at 100 μA.
[0044] Cyclic voltammograms for some of these electrode contacts in 0.1 M H2SO4 are shown in Figure 11. Typically, the Q values of these electrode contacts ranged from 2.9 mC to 5.6 mC. In contrast, a standard Pt foil electrode contact has a Q value of 0.035 mC.
[0045] Utilizing platinum black electrode contacts, conduction block could be achieved while keeping the total charge below the maximum Q value of each electrode contact. Figure 10 shows a study in which complete motor nerve block was obtained using DC with a peak amplitude of 0.55 mA. PS-evoked muscle twitch contractions were completely blocked during the plateau phase of DC current application.
[0046] FIG. 12 compares the effect of cumulative doses of DC for five of the platinum black electrode contacts with one standard platinum electrode contact. DC was delivered as shown in FIG. 10 (lower subplot). Each cycle of DC was followed by PS and DS to produce some twitching (not shown in FIG. 10). The PS / DS ratio is a measure of acute nerve fiber damage. If the nerve fiber conducts normally through the area under the block electrode contact, this ratio should be close to 1. The platinum electrode contacts showed nerve fiber damage in less than 1 minute after less than 50 mC of current, and the nerve fiber did not recover for 30 minutes afterwards. The platinum black electrode contacts showed no sign of significant neurological damage during each experiment, up to a cumulative charge of 350 mC. Repeated experiments with other platinum black electrode contacts of various Q values gave similar results.
[0047] The above description and examples are merely provided to illustrate the present invention and are not intended to be limiting. Each aspect and embodiment of the present invention disclosed herein may be considered individually or in combination with other aspects, embodiments, and variations of the present invention. In addition, certain features of embodiments of the present invention may be shown only in certain figures, but such features may be incorporated into other embodiments shown in other figures while remaining within the scope of the present invention. In addition, unless otherwise specified, none of the steps of the method of the present invention are intended to be performed in a particular order. Modifications of the disclosed embodiments that incorporate the spirit and substance of the present invention may occur to those skilled in the art, and such modifications are within the scope of the present invention. In addition, all references cited herein are incorporated herein in their entirety.
Claims
1. a therapy delivery device including four electrode contacts in electrical communication with a nerve and configured to apply the direct current waveform to the nerve; a waveform generator connected to the four electrode contacts, The waveform generator includes: a first one of the DC waveforms to be transmitted to a first one of the four electrode contacts at a first time; a second one of the DC waveforms to be transmitted to a second one of the four electrode contacts at a second time; a third one of the DC waveforms to be transmitted to a third one of the four electrode contacts at a third time; a fourth one of the DC waveforms to be transmitted to a fourth electrode contact of the four electrode contacts at a fourth time; the first, second, third, and fourth ones of the DC waveforms are shifted in time with respect to one another; The application of the first, second, third, and fourth waveforms establishes a predetermined pattern that continuously at least partially blocks conduction in the nerve.
2. 10. The system of claim 1, wherein the DC waveform is a multi-phase DC waveform including at least one cathodic phase and at least one anodic phase.
3. 3. The system of claim 2, wherein at least one of the at least one cathodic phase or the at least one anodic phase begins and ends with a current gradient to prevent at least a portion of the axonal firing of the nerve.
4. 3. The system of claim 2, wherein one of the at least one cathodic phase or the at least one anodic phase establishes a conduction block of the nerve, and the other of the at least one cathodic phase or the at least one anodic phase is a recharge phase.
5. 3. The system of claim 2, wherein the multi-phase DC waveform is charge balanced or charge unbalanced.
6. The system sequentially repeats the predetermined pattern to continuously block conduction of the nerve; 3. The system of claim 2, wherein the time shifting enables the first electrode contact, the second electrode contact, the third electrode contact, and the fourth electrode contact to apply cathodic phases of the first, second, third, and fourth waveforms, respectively, of the direct current waveform, and the fourth electrode contact, the first electrode contact, the second electrode contact, and the third electrode contact to apply anodic phases of the fourth, first, second, and third waveforms, respectively, of the direct current waveform.
7. The system sequentially repeats the predetermined pattern to discontinuously block conduction of the nerve; 3. The system of claim 2, wherein the time shifting allows the block to be paused and then resumed by application of the cathodic phases of the second, third, and / or fourth waveforms of the direct current waveform.
8. 3. The system of claim 2, wherein the multi-phase DC waveform is asymmetric, such that a plateau of the at least one cathodic phase and a plateau of the at least one anodic phase have different absolute amplitudes and / or durations.
9. The system of claim 1 , wherein one or more of the four electrode contacts comprises a high charge capacity material.
10. The system of claim 9 , wherein each of the four electrode contacts includes a base body at least partially covered with the high charge capacity material.