Patent Publication Number: US-2022212001-A1

Title: Systems and methods for establishing a nerve block

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This patent application is a continuation of U.S. patent application Ser. No. 16/785,400, filed Feb. 7, 2020, titled “SYSTEMS AND METHODS FOR ESTABLISHING A NERVE BLOCK,” now U.S. Pat. No. 11,278,718, which is a continuation of U.S. patent application Ser. No. 15/406,619, filed Jan. 13, 2017, titled “SYSTEMS AND METHODS FOR ESTABLISHING A NERVE BLOCK,” now U.S. Pat. No. 10,596,367, which claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 62/278,337, filed Jan. 13, 2016, titled “SYSTEMS AND METHODS FOR ESTABLISHING A NERVE BLOCK” and U.S. Provisional Patent Application No. 62/286,952, filed Jan. 25, 2016, titled “CALIBRATION OF CLOCK SIGNAL WITHIN AN IMPLANTABLE MICROSTIMULATOR,” each of which is herein incorporated by reference in its entirety. 
     This patent application may be related to U.S. patent application Ser. No. 14/931,711, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR,” filed on Nov. 3, 2015, Publication No. US-2016-0051813-A1, which claims priority as a continuation of U.S. patent application Ser. No. 14/536,461, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR,” filed on Nov. 7, 2014, now U.S. Pat. No. 9,174,041, which is a divisional of U.S. patent application Ser. No. 12/797,452, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR”, filed on Jun. 9, 2010, now U.S. Pat. No. 8,886,339, which claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 61/185,494, titled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR”, filed on Jun. 9, 2009, each of which is herein incorporated by reference in its entirety. 
    
    
     INCORPORATION BY REFERENCE 
     All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. 
     FIELD 
     Embodiments of the invention relate generally to systems, devices, and methods of establishing a nerve block, and more specifically to systems, devices, and method of delivering a drug to establish a nerve block. 
     BACKGROUND 
     A nerve block can be used to treat a variety of pain, such as chronic pain, acute pain, or the pain resulting from a surgical procedure. The nerve block can be established by delivering a local anesthetic to a nerve or ganglia to block a specific nerve distribution to reduce or eliminate pain in a specific portion of the anatomy. The anesthetic is typically delivered to the nerve by needle injection or catheter infusion. One drawback with this delivery method is that the anesthetic may diffuse rapidly into the surrounding tissue and into the vasculature, which can reduce the effectiveness of the anesthetic at the target site and cause adverse side effects. 
     An alternative technique for establishing a nerve block is via electrical stimulation of the nerve or ganglia. However, such electrical stimulation typically requires a relatively high level of power in order to block the nerve, which results in a rapid discharge of a battery powered device. 
     Accordingly, it would be desirable to provide a system and method for establishing a nerve block in an efficient and effective manner. 
     Furthermore, in any implanted device including circuitry it may be useful or necessary to include some form of time keeping or clocking function. A common example of such an implantable device is a pacemaker which must keep time for each beat of the patient&#39;s heart. Other examples include an implantable neuro stimulation device that periodically outputs some form of stimuli to address some underlying disorder (e.g. chronic pain). Nerve blocking implants are an example of such an implantable neurostimulation device. A clocking function may be necessary or helpful in these implantable devices because stimulating output from these devices may occur periodically and/or regularly over some period of time. Thus, these devices may utilize a clocking function to keep track of when a simulating session has occurred or will occur, and particularly clocks that are able to determine the time of day and/or date. 
     In designing the clocking function within implantable devices, certain considerations should be addressed. While a high level of accuracy is always desirable, there may be certain drawbacks associated with having a clocking assembly with high accuracy. While highly accurate main clocking systems are able to synchronize and coordinate various circuit and component operations, a major drawback is that they operate on a relatively large current and thus consume a lot of power. In addition, high accuracy clocking mechanism such as piezoelectric crystals are more expensive and more prone to damage. Because implantable devices are powered by batteries with a finite life and more recently through wireless charging, it is desirable to have a clocking mechanism for an implantable device that is able to maintain accuracy but does not draw a lot of power and is fairly inexpensive. Thus, it would be advantageous to have a clocking system that incorporated the low power consumption characteristics of a less accurate clocking module but still maintain a certain level of clocking accuracy. 
     SUMMARY OF THE DISCLOSURE 
     The present invention may relate generally to systems, devices, and methods of establishing a nerve block, and more specifically to systems, devices, and method of delivering a drug to establish a nerve block. 
     In some embodiments, the apparatus for establishing a nerve block may include a nerve cuff. A nerve cuff can include a cuff body having a channel extending within the length of the cuff body for passage of a nerve; a reservoir within the cuff body, the reservoir configured to hold a drug, the reservoir in fluid communication with the channel; and an elongate opening slit extending the length of the cuff body configured to be opened to provide access to the channel, and configured to be closed around the channel and thereby enclose the cuff body around the nerve. 
     In some embodiments, the nerve cuff further includes a controller disposed within the cuff body; and an electrode in electrical communication with the controller, the electrode configured to be in electrical communication with the nerve when the nerve is enclosed in the channel. 
     In some embodiments, the controller and electrode are configured to sense electrical activity in the nerve enclosed in the channel. 
     In some embodiments, the nerve cuff further includes a pump, wherein the controller is configured to activate the pump to transfer drug from the reservoir to the channel based in part on the sensed electrical activity of the nerve. 
     In some embodiments, the pump is a screw pump. 
     In some embodiments, the electrode is in electrical communication with an electrical pulse generator and is configured to deliver electrical stimulation to the nerve enclosed in the channel. 
     In some embodiments, the electrode comprises a lumen in fluid communication with the reservoir and the channel, the lumen of the electrode configured to deliver drug from the reservoir to the channel. 
     In some embodiments, the controller is programmable. 
     In some embodiments, the controller is programmed to drive the pump at a constant rate. 
     In some embodiments, the controller is programmed to drive the pump at an intermittent rate. 
     In some embodiments, the nerve cuff further includes a drug disposed within the reservoir. 
     In some embodiments, the drug is disposed in a passive diffusion matrix and both the drug and passive diffusion matrix are disposed within the reservoir. 
     In some embodiments, the drug is an anesthetic or analgesic. 
     In some embodiments, the nerve cuff further includes a needle in fluid communication with the reservoir, the needle configured to deliver drug from the reservoir to the nerve. 
     In some embodiments, a system for establishing a nerve block on a nerve is provided. The system includes an implantable drug delivery device that includes a housing; a reservoir disposed within the housing, the reservoir configured to hold a drug; a pump disposed within the housing, the pump configured to meter the drug out of the reservoir; and a controller in communication with the pump, the controller configured to control the pump. The system further includes a sensor in communication with the controller, wherein the controller is configured to activate the pump when the sensor detects electrical activity from a nerve that meets or exceeds a predetermined threshold. 
     In some embodiments, the sensor comprises a wireless transmitter configured to communicate wirelessly with the controller. 
     In some embodiments, the sensor is configured to be remotely placed away from the implantable drug delivery device. 
     In some embodiments, the housing includes a channel extending within the length of the housing for passage of a nerve; and an elongate opening slit extending the length of the housing, the elongate slit configured to be opened to provide access to the channel, the elongate slit configured to be closed around the channel and thereby enclose the housing around the nerve. 
     In some embodiments, the system further includes a microstimulator that is removably disposed in a pocket within the housing, wherein the elongate opening slit is configured to be opened to provide access to the pocket, and configured to be closed around the pocket to secure the microstimulator within the pocket. 
     In some embodiments, a method of establishing a nerve block on a nerve is provided. The method includes implanting a drug delivery device proximate the nerve, the drug delivery device configured to deliver a drug to the nerve; sensing an electrical signal transmitted to or by the nerve; and delivering a drug from the drug delivery device to the nerve based at least in part on the step of sensing an electrical signal transmitted to or by the nerve. 
     In some embodiments, the drug delivery device includes an electrode configured to sense the electrical signal. 
     In some embodiments, the method further includes delivering an electrical stimulus to the nerve through the electrode. 
     In some embodiments, the method further includes implanting a remote sensor configured to sense the electrical signal. 
     In some embodiments, the remote sensor and the drug delivery device are in wireless communication. 
     In some embodiments, the method further includes placing the nerve within a channel that extends through the drug delivery device, wherein the drug is delivered to the channel. 
     In some embodiments, the method further includes opening a slit on the drug delivery device to provide access to the channel; and closing the slit to secure the nerve within the channel. 
     In any of the apparatuses described herein, the apparatuses described herein may be configured to include a nerve cuff and to apply electrical stimulation to induce a nerve block. 
     Also described herein are apparatuses (systems and devices) having a dual clocking system in which a generally less accurate, but lower power, clock may run continuously and be updated periodically with a more accurate secondary clock. Although these apparatuses are described in the context of an apparatus configured for use in deploying a nerve block, this principle may be implemented in any implantable system. For example, generally described herein are apparatuses and methods for calibrating a first clock within an implantable device with a more accurate secondary clock. The first (e.g., central) clock may be the primary time keeping mechanism within the implantable device. While not all implantable devices require a time-keeping unit, those that provide periodic outputs to the patient often require a method for keeping time that contribute to controlling when an output is given. 
     For example, described herein are implantable neuro stimulator device having a low-power clock calibration system. Such a device may include: a first clock configured to keep time within the implantable neurostimulator; a second clock having more accurate time-keeping capabilities than the first clock, wherein the second clock is in an off or idle mode while the first clocking is running; and control circuitry configured to be triggered by an event such that upon triggering, the control circuitry turns on the second clock, and uses the second clock to calibrate the the first clock, then turns the second clock back off. 
     The first clock may count time based upon a reference voltage generated within a circuitry of the implantable device. The second clock may comprises a piezoelectric crystal oscillator. The control circuitry may be configured to be triggered by an event comprising a preset signal programmed into the control circuitry. 
     In some variations, the event or trigger is thermal, e.g., temperature change. 
     In some variations, the preset signal may be based on a set length of time, such as a few hours, a day, a few days, a week, a couple of weeks, a month, or a few months. The preset signal may be a voltage value above a certain threshold. 
     Also described herein are methods of calibrating a neurostimulator. For example, a method of calibrating a clock within an implantable neurostimulator device may include: keeping time using a first clock of the implantable neurostimulator device, wherein the first clock runs continuously and is operating based upon a reference voltage generated within a circuitry of the implantable neurostimulator device; triggering a calibration protocol; turning on a reference clock within the implantable neurostimulator device; and calibrating the first clock based on the reference clock to correct for thermally-dependent time drift; and turning off the reference clock. 
     The first clock may comprise a reference voltage associated with an RC circuit to produce a time reference. 
     As mentioned above, the event that triggers the calibration may be thermal or temporal. For example, the event that triggers the calibration protocol may be a period of time (e.g., as determined by the first clock). The length of time may be a few hours, a day, a few days, a week, a couple of weeks, a month, a few months, and a year. 
     In some variations, the event that triggers the calibration protocol may be a change in the reference voltage above a threshold value. 
     As mentioned, the second clock may comprise a piezoelectric clock. 
     Also described herein are neurostimulator devices including these self-calibrating clocks. For example, described herein are leadless, implantable microstimulator devices for treating chronic inflammation. Such a device may include: a housing; at least two electrically conductive contacts disposed on the housing; a resonator within the sealed capsule body, the resonator comprising a coil and a capacitor configured to resonate at a predetermined frequency range; a battery within the housing; and an electronic assembly within the housing; wherein the electronic assembly comprises power management circuitry configured to receive power from the resonator to charge the battery, a microcontroller configured to control stimulation of the vagus nerve from the electrically conductive contacts, a first clock configured to keep time, a second clock having more accurate time-keeping capabilities than the first clock, wherein the second clocking is configured to periodically calibrate the first clock. 
     While having a central clocking module that is able to keep highly accurate time would be ideal, higher accuracy time-keeping modules are not only more expensive, but also require more power. Thus, it would be advantageous to have an internal clocking arrangement that is able to provide sufficient clocking accuracy for the lifetime of the implanted device but does not drain the power from the implanted device in an inordinately quick fashion. 
     Described herein are clock calibration systems contained within an implantable device. The system includes a first clocking module configured to keep time within the implantable device for the majority of the time. The system also includes a second clocking module that possesses more accurate time-keeping capabilities that only turns on when a calibration routine is triggered. For the remainder of the time, the second clocking module is either in an OFF or idle mode. The triggering event may be the passage of a certain amount of time, or by a threshold parameter being met. In some instances, the triggering event may be a preset signal programmed into the control circuitry. the preset signal is based on a set length of time, such as a few hours, a day, a few days, a week, a couple of weeks, a month, or a few months. The preset signal may also be a voltage or current value above a certain threshold value. 
     The system also includes control circuitry that is able to coordinate signals triggered by the event and signals sent to the central clocking module and the secondary clocking module. The system also may include a calibration module that corrects any time drifts within the first or central clocking module after the clocking calibration has been performed. In some examples, the first clocking module are able to measure and count time based upon a reference voltage generated within general circuitry of the implantable device. In some instances, the more accurate secondary time keeping module is a piezoelectric crystal oscillator. 
     Also disclosed herein, is a method of calibrating a central clocking module within an implantable device. The method includes obtaining a clocking value associated with the central clocking module, where the clocking value is associated with how the central clocking module keeps time, establishing an event that will trigger a calibration protocol of the clocking module using a reference clocking module, activating the reference clocking module from an OFF mode to an active mode, calibrating the central clocking module based on the reference voltage, correcting any time drifts within the central clocking module, and turning off the reference clocking module. The clocking value is associated with a reference voltage associated with a reference voltage associated with the clocking module charges an RC circuit to produce a time reference. The events that trigger the calibration step may be the running of a set amount of time where at the end of such a period of time, a calibration routine is run. The length of time may be a few hours, a day, a few days, a week, a couple of weeks, a month, a few months, and a year. The event that triggers the calibration protocol may also be a change in the reference voltage above a threshold value. 
     Also disclosed herein are implantable microstimulation devices for treating chronic inflammation. The implantable device may include a housing, at least two electrically conductive contacts disposed on the housing, a resonator within the sealed capsule body, where the resonator comprising a coil and a capacitor configured to resonate at a predetermined frequency range, a battery within the housing, and an electronic assembly within the housing. The electronic assembly may include a power management circuitry configured to receive power from the resonator to charge the battery, a microcontroller configured to control stimulation of the vagus nerve from the electrically conductive contacts, a first clocking module configured to keep time, a second clocking module having more accurate time-keeping capabilities than the first clocking module, and where the second clocking module is configured to periodically calibrate the first clocking module. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a perspective view depicting a nerve cuff with an electrical (e.g., neurostimulation device) implanted proximate a nerve, according to an embodiment of the invention. This implant may also be configured to include a reservoir for delivery of a drug; alternatively or additionally, this implant may be configured to apply high-frequency nerve-block stimulation to the nerve from one or more electrodes (e.g., electrode pairs). 
         FIG. 1B  is a top view depicting an implanted nerve cuff with stimulation device of  FIG. 1A . 
         FIG. 1C  is a top view of another variation of an implanted nerve cuff including a reservoir for delivery of a nerve blocking agent. 
         FIG. 1D  is a top view of another variation of an implanted nerve cuff including a reservoir for delivery of a nerve blocking agent, including a reservoir and one or more (one is shown) cannula for delivery of the active agent, which may be metered. 
         FIG. 1E  is another example of a nerve cuff apparatus adapted for delivery of a nerve blocking agent (such as a drug) including a connection to a remote depot for holding (and/or loading or reloading) agent into the apparatus. Either or both the nerve cuff and/or the implanted and tethered depot may include control circuitry for controlling delivery of the blocking agent. 
         FIG. 2  is a front view depicting an implanted nerve cuff with strain relief according to an embodiment of the invention. 
         FIG. 3  is a front view depicting an implanted nerve cuff with suture holes according to an embodiment of the invention. 
         FIG. 4  is an open view depicting the nerve cuff with suture holes of  FIG. 3 . 
         FIG. 5  is a top view depicting a closing device for the implanted nerve cuff. 
         FIG. 6  is a perspective view depicting marsupializaton of components such as electronic circuitry and/or a drug depot within a pocket of the nerve cuff of  FIG. 1A ; 
         FIG. 7A  is a top view depicting a nerve cuff having a conforming shield according to an embodiment of the invention. 
         FIG. 7B  is a front view of the nerve cuff of  FIG. 7A . 
         FIG. 8A  is a top view depicting another example of an open nerve cuff. 
         FIG. 8B  is a front view of the nerve cuff of  FIG. 8A . 
         FIG. 8C  is a top view depicting the nerve cuff of  FIG. 8A  in a closed configuration. 
         FIGS. 9A and 9B  show side views through a section of the cuff body wall, indicating uniform and varying thicknesses, respectively. 
         FIGS. 10A-10C  illustrate one variation of a nerve cuff as described herein.  FIG. 10A  shows an end view,  FIG. 10B  is a side perspective view,  FIG. 10C  is a side view. 
         FIGS. 11A-11H  illustrate steps for inserting a nerve cuff such as the nerve cuffs described herein. 
         FIG. 12A  shows an embodiment of a nerve cuff having a drug reservoir for releasing drug to a nerve. 
         FIG. 12B  shows another embodiment of a nerve cuff having a drug reservoir. 
         FIG. 12C  shows yet another embodiment of a nerve cuff having a drug reservoir. 
         FIG. 13  is a flowchart showing the steps of calibrating a first clocking module (“first clock”) with a second clocking module (“second clock”). 
         FIG. 14  is a diagram showing calibration of a first clocking module by a second clocking module based on a change in voltage. 
         FIG. 15  is a diagram showing calibration of a first clocking module by a second clocking module based on a pre-determined period of time. 
     
    
    
     DETAILED DESCRIPTION 
     Described herein are apparatuses (devices, systems, including implants) configured to apply a nerve block. These devices may be part of or used in conjunction with a nerve stimulator that delivers electrical stimulation to a nerve. In some variations, the nerve block may be part of a nerve sensing and/or stimulation apparatus that provides electrical stimulation to modulate the activity of the nerve and cause a wide variety of effects. For example, electrical stimulation of the vagus nerve can result in a reduction of inflammation through activation of the cholinergic anti-inflammatory pathway. 
     Nerve blocking drugs and/or electrical stimulation can be delivered to a nerve. For example, an anesthetic or analgesic can be delivered to the nerve to establish a nerve block or otherwise modulate the activity of the nerve, with or without electrical nerve stimulation. In some embodiments, the nerve securing device described herein can also be used to deliver drugs to the nerve. 
     Referring to  FIG. 1A , one example of a nerve cuff  100  adapted for holding a device coupled to a nerve  102  is shown. Nerve  102  can comprise any nerve in the human body targeted for therapeutic treatment, such as, for example, the vagus nerve. Nerve cuff adapter  100  generally comprises an outer carrier or cuff  104  body that can comprise any of a variety of medical grade materials, such as, for example, Silastic™ brand silicone elastomers, or Tecothane™ polymer. 
     In general, a nerve cuff including a cuff  104  body having (or forming) one or more pouches or pockets  106  for removably receiving an active, implantable stimulation device  108  (e.g., including a stimulation device configured to apply a nerve block electrical signal) having one or more integrated, leadless electrodes  110  on a surface of stimulation device  108  proximate nerve  102 . Alternatively or additionally, the one or more pouches may include a depot holding an active agent and/or a controller (including circuitry and/or a valve for regulating flow of active agent from the depot). As illustrated in  FIGS. 1A and 1B , a nerve cuff  100  may wrap around nerve  102  such that electrodes  110  and/or one or more outputs  133  for an active agent from the drug depot are positioned proximate nerve  102 . These outputs  133  may be regulated by including a valve, pump, or other fluid control to regulate when an active agent is delivered from the apparatus onto the nerve. 
     The depot (which may be referred to as a reservoir) may be of any appropriate size. For example, the depot may include between 0.1 and 10 mL of liquid drug solution (e.g., between 0.1 and 5 mL, etc.). In some variations, the depot includes a solid drug formulation that is configured to be applied (and may include being mixed with fluid already present or surrounding the nerve). As mentioned, the depot may be refillable, as from an external port and/or from a second internal depot. 
     Contacts or electrodes  110  can be positioned directly against nerve  102 , as illustrated in  FIG. 1B , or in close proximity to nerve. 
     Referring specifically to  FIG. 1C , in some variations the nerve cuff may include a pocket holding a depot  142  that includes a drug or other active agent (such as an anesthetic or any other compound for topically inhibiting nerve activity). Drug may be delivered from the depot onto the nerve and kept at a locally precise concentration for a a sustained period by holding it within the nerve cuff surrounding the nerve  102 , allowing lower amounts of active agent to be applied more precisely over all or just a portion of the nerve. In some variations additional depots or reservoirs may be included for adding additional agents to the nerve or other regions of the nerve within the cuff. In some variations a second reservoir may include a wash-out material (e.g., saline) for diluting or removing the drug or active agent. In any of these variations, a controller (e.g., electronics board) for releasing or delivering the active agent/drug may be included. In  FIG. 1A , the controller may be included instead of or along with (e.g., integrated into) the electronics  108  of the stimulator. In  FIG. 1D , for example, the depot holding the active agent/drug  142 ′ may be connected to the output  133  onto the nerve in the cuff by a channel  145 ; this channel may be regulated (opened/closed) by a drug delivery controller  147  that may include hardware, software and/or firmware for actively controlling the application of drug onto the nerve. The drug delivery controller may also include a valve for opening/closing the channel, such as a piezo valve, or a pump. The depot  142  may be pressurized so that drug is emitted when the channel  145  is opened by the drug delivery controller  147 . The controller may also regulate pressurizing of the depot. 
     In some variations, the depot may be located remotely from the nerve cuff, as illustrated in  FIG. 1E . In this example, the nerve cuff  100  is configured to include one or more outputs for active agent/drug (not visible in  FIG. 1E ), and may also include a drug delivery controller for regulating the delivery of drug onto the nerve. A second depot may be included within the cuff, which may be filled by the primary depot  142 ′. The remote depot  142 ′ may be connected by tubing  148   
     In general, a drug delivery controller may include control logic for controlling delivery of the active agent onto the nerve. The drug delivery controller may therefore include a timer (e.g., for delivering doses at a prescribed time) and/or may include wireless communication circuitry and/or antenna for transmitting and/or receiving control information from a remote source. The drug delivery controller may also include a power source/supply (e.g., battery and/or inductive loop(s), capacitive power source, etc.), and one or more pumps and/or valves. In particular, a micro pump for delivering small (e.g., less than a 1 ml, less than 0.5 ml, less than 0.1 ml, etc.) of drug per time period (e.g., min, second, etc.). Any of the apparatuses described herein may be configured to apply drug based on activity on the nerve. For example the drug delivery controller may include input from one or more electrodes (or may be integrated with an electrical activity detector) receiving input from the electrodes on the nerve within the cuff or separate from the cuff. Electrical activity above a particular threshold may trigger release of drug. 
     In one embodiment, a pocket  106  for containing a drug delivery controller, stimulation device, and/or drug depot. One or more pockets may be defined by the open space between the nerve  102  and the inner surface of the cuff body  104 . The sensing and/or stimulation device, drug depot and/or drug delivery controller (including any pump and/or valve components) can be passively retained within pocket by the cuff body, or can be actively retained on cuff body with fastening means, such as, for example, sutures. In other embodiments, a pocket can comprise a pouch-like structure attached to cuff body into which sensing and/or stimulation device, drug depot and/or drug delivery controller can be inserted. The sensing and/or stimulation device, drug depot and/or drug delivery controller can be passively retained within a pouch-like pocket by simply inserting into the pocket or can be actively retained with fastening means. A pouch-like pocket can be positioned either in the interior or on the exterior of cuff body  104 . Pouch-like pocket and/or cuff body can include access openings to allow electrodes and/or drug outputs (including needles or cannula) to be positioned directly proximate or adjacent to nerve  102 . 
     Cuff body  104  can have a constant thickness or a varying thickness as depicted in  FIGS. 9A and 9B . The thickness of cuff body  104  can be determined to reduce the palpable profile of the device once the stimulation device is inserted. In one embodiment, the thickness of cuff body can range from about 1 to about 30 mils, or from about 5 to about 20 mils. In one embodiment shown in  FIG. 9B , cuff  104  can have a greater thickness at a top and bottom portion of the cuff and a smaller thickness in a middle portion where the stimulation device is contained. 
     A key obstacle to overcome with implanting stimulation devices proximate nerves or nerve bundles is attaching a rigid structure that makes up the stimulation device along a fragile nerve in soft tissue. In one embodiment of the invention, this issue is resolved by encasing nerve  102  and device  108  in a cuff body  104  that comprises a low durometer material (e.g., Silastic™ or Tecothane™) as described above, that conforms around nerve  102 . Further, as illustrated in  FIG. 2 , cuff body  104  can comprise strain reliefs  114  on its ends that reduce or prevent extreme torsional rotation and keep nerve  102  from kinking. Strain reliefs  114  can coil around nerve  102 , and are trimmable to a desired size, such as the size of nerve  102 . Further, strain relief  114  can be tapered. In some variations, the lateral ends of the nerve cuff, forming the channel into which the nerve may be place, are tapered and have a tapering thickness, providing some amount of support for the nerve. In some variations, the channel through the nerve cuff in which the nerve may sit, is reinforced to prevent or limit axial loading (e.g., crushing) of the nerve or associated vascular structures when the nerve is within the cuff. 
     Given the design or architecture of cuff body  104 , any vertical movement of cuff body  104  on nerve  102  is not critical to electrical performance, but can result in friction between device  108  and nerve  102  that could potentially damage nerve  102 . For that reason, device  108  should readily move up and down nerve  102  without significant friction while being sufficiently fixated to nerve  102  so that eventually connective tissue can form and aid in holding device  108  in place. The challenge is stabilizing device  108  so that it can be further biologically stabilized by connective tissue within several weeks. 
     Nerve cuff  100  should not be stabilized to surrounding muscle or fascia that will shift relative to the nerve. Therefore, referring to  FIGS. 3 and 4 , nerve cuff  100  can further comprise connection devices, such as suture holes or suture tabs, for coupling and stabilizing cuff body  104  with device  108  to at least one of the nerve bundle or nerve  102 , and the surrounding sheath that contains nerve  102 . In one embodiment of the invention, for example, as shown in  FIG. 3 , cuff body  104  can comprise suture holes  116  that can be used with sutures to couple cuff  104  body with device  108  to the surrounding nerve sheath. In an alternative embodiment of the invention, shown in  FIG. 4 , suture tabs  118  with suture holes  116  extend from one or both sides of cuff body  104 . 
     Several stabilizing mechanisms can be used, including suture tabs and holes, staples, ties, surgical adhesives, bands, hook and loop fasteners, and any of a variety of coupling mechanisms.  FIGS. 3 and 4 , for example, illustrates suture tabs and holes that can be fixed to the surrounding sheath with either absorbable sutures for soft tissue or sutures demanding rigid fixation. 
       FIG. 5  illustrates sutures  120  that clamp or secure cuff body  104  with device  108  to a surgeon-elected tension. Sutures  120  can be tightened or loosened depending on the level of desired stability and anatomical concerns. As shown in  FIG. 5 , a gap  122  can be present so long as cuff adapter  100  is sufficiently secured to nerve  102 , with a limit set to a nerve diameter to prevent compression of the vasculature within nerve  102 . Surgical adhesives (not shown) can be used in combination with sutures  120  on surrounding tissues that move in unison with the neural tissue. 
     Muscle movement against cuff adapter  100  can also transfer undesired stresses on nerve  102 . Therefore, in an embodiment of the invention, low friction surfaces and/or hydrophilic coatings can be incorporated on one or more surfaces of cuff body  104  to provide further mechanisms reducing or preventing adjacent tissues from upsetting the stability of nerve cuff  100 . 
       FIG. 6  illustrates a nerve cuff  100  with a sensing and/or stimulation device, drug depot and/or drug delivery controller device removably or marsupially secured within pocket or pouch  106  of cuff body  104 . By the use of recloseable pouch  106 , active stimulator device  108  can be removed or replaced from cuff body  104  without threatening or endangering the surrounding anatomical structures and tissues. Device  108  can be secured within cuff body  104  by any of a variety of securing devices  124 , such as, for example, sutures, staples, ties, zippers, hook and loop fasteners, snaps, buttons, and combinations thereof. Sutures  124  are shown in  FIG. 6 . Releasing sutures  124  allows access to pouch  106  for removal or replacement of device  108 . Not unlike typical cuff style leads, a capsule of connective tissue can naturally encapsulate nerve cuff  100  over time. Therefore, it will most likely be necessary to palpate device  108  to locate device  108  and cut through the connective tissue capsule to access sutures  124  and device. The removable/replaceable feature of nerve cuff  100  is advantageous over other cuff style leads because such leads cannot be removed due to entanglement with the target nerve and critical vasculature. 
     As discussed above, compression of nerve  102  must be carefully controlled. Excess compression on nerve  102  can lead to devascularization and resulting death of the neural tissue. Compression can be controlled by over-sizing or rightsizing nerve cuff  100 , so that when pocket sutures  124  are maximally tightened, the nerve diameter is not reduced less that the measured diameter. Cuffs formed from Silastic™ or Tecothane™ materials are relatively low cost, and therefore several sizes can be provided to the surgeon performing the implantation of nerve cuff  100  to better avoid nerve compression. 
     Sensing and/or stimulation devices, drug depots and/or drug delivery controllers, may be large enough to be felt and palpated by patients. Referring to  FIG. 7A , to avoid such palpation, nerve cuff  100  can further comprise a protecting shield  126  conforming to the shape of the anatomical structures, such as in the carotid sheath. In this embodiment, nerve cuff  100  is secured around the vagus nerve, while isolating device  108  from contact with both the internal jugular vein (IJV)  132 , and common carotid artery  134 . Shield  126  then further isolates device  108  from other surrounding tissues. The profile of the entire cuff adapter  100  may be minimized while maintaining the compliance of such materials as Silastic™ or Tecothane™. In one embodiment of the invention, protective shield  126  is formed from a PET material, such as Dacron®, optionally coated with Silastic™ or Tecothane™ forming a thin and compliant structure that will allow for tissue separation when required. 
     When a nerve does not provide sufficient structural strength to support nerve cuff adapter  100 , collateral structures can be included in or on cuff body  104 . Because of a high degree of anatomical variance such a scheme must demand the skill of the surgeon to utilize a highly customizable solution.  FIG. 8A  illustrates a variable size nerve cuff  100  with a wrappable retainer portion  128  extending from cuff body  104 . As shown in  FIG. 8C , cuff body  104  is secured around nerve  102 , while retainer portion  128  is secured around the sheath or other surrounding anatomical structures, such as the IJV  132  and/or carotid artery  134 . As shown in  FIG. 8B , wrappable retainer portion  128  can include securing devices  130 , such as suture holes, for securing the entire nerve cuff  100  around the desired anatomical structures. This configuration allows for access to sensing and/or stimulation device, drug depot and/or drug delivery controller devices  108  through pocket  106  as in previous embodiments, while adapting to a multitude of anatomical variations to obtain the desired stability of nerve cuff  100  on nerve  102 . 
       FIGS. 10A-10C  illustrate a variation of a nerve cuff that includes a cuff body forming a channel (into which a nerve may be fitted) and an slit formed along the length of the nerve cuff body. In this example, the nerve cuff body also includes one or more pocket regions (not visible in  FIGS. 10A-10C ) within the cuff body positioned above the nerve channel. The top of the body (opposite from the nerve channel) includes a long slit  1003  along its length forming on opening. The cuff body may be along the slit by pulling apart the edges, which may form one or more flaps. In the example shown in  FIG. 10A , the slit may be split open to expose the inside of the nerve cuff and allow the nerve to be positioned within the internal channel, so that the cuff is positioned around the nerve. The same split may be used to insert the sensing and/or stimulation device, drug depot and/or drug delivery controller device as well. In some variations a separate opening (slit or flap) may be used to access the pocket or pouch for the sensing and/or stimulation device, drug depot and/or drug delivery controller. 
       FIG. 10B  shows a perspective view of the nerve cuff holding a sensing and/or stimulation device, drug depot and/or drug delivery controller after it has been inserted onto a nerve (e.g., the vagus nerve).  FIG. 10C  shows a side view of the same. 
     The exemplary cuff shown in  FIGS. 10A-10C  has a conformal configuration, in which the wall thickness is relatively constant; in some variations of a nerve cuff, the wall thickness may vary along the perimeter. This non-uniform thickness may effectively cushion the device relative to the surrounding tissue, even as the patient moves or palpitates the region. This may have the added benefit of preventing impingement of the nerve. Similarly, the variable thickness may enable smooth transitions and help conform the cuff to the surrounding anatomy. 
     The nerve cuff may be substantially rounded or conforming, and have non-traumatic (or atraumatic) outer surfaces. As mentioned, this relatively smooth outer surface may enhance comfort and limit encapsulation of the nerve cuff within the tissue. 
     A nerve may sit within a supported channel through the nerve cuff. The channel may be formed having generally smooth sides, so as to prevent damage to the nerve and associated tissues. In some variations the nerve channel though the cuff is reinforced to prevent the cuff from pinching the device or from over-tightening the device when closed over the nerve. Supports may be formed of a different material forming the nerve cuff body, or from thickened regions of the same material. Although multiple sizes of nerve cuff may be used (e.g., small, medium, large), in some variations, an oversized nerve cuff may be used, because the insulated cuff body will prevent leak of current from the sensing and/or stimulation device, drug depot and/or drug delivery controller to surrounding tissues. 
     In operation, any of the devices described herein may be positioned around the nerve, and the sensing and/or stimulation device, drug depot and/or drug delivery controller inserted into the nerve cuff, in any appropriate manner.  FIGS. 11A-11H  illustrate one variation of a method for applying the nerve cuff around the nerve and inserting a sensing and/or stimulation device, drug depot and/or drug delivery controller. In this example, the patient is prepared for application of the nerve cuff around the nerve to hold a sensing and/or stimulation device, drug depot and/or drug delivery controller device securely relative to the nerve ( FIG. 11A ). An incision is then made in the skin (≈3 cm), e.g., when inserting onto the vagus nerve, along Lange&#39;s crease between the Facial Vein and the Omohyoid muscle ( FIG. 11B ), and the Sternocleidomastoid is retracted away to gain access to the carotid sheath ( FIG. 11C ). The IJV is then reflected and ≤2 cm of the vagus is dissected from the carotid wall. 
     In some variations, a sizing tool may be used to measure the vagus (e.g., diameter) to select an appropriate sensing and/or stimulation device, drug depot and/or drug delivery controller and cuff (e.g., small, medium, large). In some variations of the method, as described above, an oversized cuff may be used. The nerve cuff is then placed under the nerve with the opening into the nerve cuff facing the surgeon ( FIG. 11D ), allowing access to the nerve and the pocket for holding the sensing and/or stimulation device, drug depot and/or drug delivery controller. The sensing and/or stimulation device, drug depot and/or drug delivery controller can then be inserted inside cuff ( FIG. 11E ) while assuring that the sensing and/or stimulation device, drug depot and/or drug delivery controller contacts capture the nerve, or communicate with any internal contacts/leads. The nerve cuff may then be sutured shut ( FIG. 11F ). In some variations, the sensing and/or stimulation device, drug depot and/or drug delivery controller may then be tested ( FIG. 11G ) to confirm that the device is working and coupled to the nerve. For example, a surgical tester device, covered in a sterile plastic cover, may be used to activate the sensing and/or stimulation device, drug depot and/or drug delivery controller and perform system integrity and impedance checks, and shut the sensing and/or stimulation device, drug depot and/or drug delivery controller off. If necessary the procedure may be repeated to correctly position and connect the sensing and/or stimulation device, drug depot and/or drug delivery controller. Once this is completed and verified, the incision may be closed ( FIG. 11H ). 
     Systems for electrically stimulating one or more nerves to treat chronic inflammation may include an implantable, wireless sensing and/or stimulation device, drug depot and/or drug delivery controller such as those described herein and an external charging device (which may be referred to as a charging wand, charger, or energizer). In some variations the system also includes a controller such as a “prescription pad” that helps control and regulate the dose delivered by the system. The sensing and/or stimulation device, drug depot and/or drug delivery controller may be secured in position using a securing device (which may be referred to as a “POD”) to hold the sensing and/or stimulation device, drug depot and/or drug delivery controller in position around or adjacent to a nerve. 
     In any of the apparatuses described herein, doses of active agent (e.g., nerve block agent) may be applied continuously, periodically or may the apparatus may be configured to apply a dose or additional dose upon triggering of an event such as an electrical activity on the never. For example, a microliter and even picoliter doses of active agent may be delivered either continuously or periodically (e.g., at a frequency of x uL or pL per second, where x is between 0.001 and 10) or for a single dose (e.g. of x uL or pL, where x is between 0.001 and 10). A single dose may be delivered within the cuff, or multiple doses maybe delivered within the cuff. Doses may be separated by a dosage interval that may be predefined, regular, scheduled (based on time of day) and/or triggered (e.g., by nerve activity). Doses may be delivered on demand. For example, a doctor or patient may communicate wirelessly or via an input in the drug delivery control to trigger release of a dose. 
     As described above, and as shown in  FIG. 12A , the nerve cuff  2800  can be modified to include a reservoir  2802  to hold an active agent/drug, such as an anesthetic like lidocaine. The nerve cuff  2800  can have one or more outputs/channels (ports  2804 ) for releasing the drug into the region surrounding the nerve  2806  within the cuff. Because the nerve cuff  2800  surrounds the portion of the nerve  2806  where the drug is being delivered, the diffusion of the drug away from the nerve is greatly reduced as compared to injection or infusion of the drug using a needle or catheter. Consequently, a low volume, low diffusion system for delivering the drug to the nerve can be sufficient to establish an effective nerve block over a long period of time, such as days, weeks, or months. In some embodiments, the modified nerve cuff  2800  can be used with a microstimulator  2808  as described herein. In other embodiments, the modified nerve cuff can be used without a microstimulator to deliver drug to a nerve. 
     In some embodiments, as shown in  FIG. 12A , the nerve cuff  2800  can have a refilling port  2810  in fluid communication with the reservoir  2802 . The refilling port  2810  can be used to refill the reservoir  2802  with drug (e.g., anesthetic). In some embodiments as shown in  FIG. 12A , the refilling port  2810  can be located on the outer surface of the nerve cuff  2800 , and a needle or catheter can be used to access the refilling port and deliver drug to the reservoir (depot) while the nerve blocking device remains within the body around the nerve  2806 . In some embodiments as shown in  FIG. 12B , the refilling port  2810  can be in fluid communication with a subcutaneous or subdermal access port  2812 , and a needle or catheter can be used to access the access port  2812  and deliver drug to the reservoir. For example, the access port  2812  can be located at a subcutaneous location, and tubing  2814  can connect the access port  2812  with the drug refilling port  2810  on the nerve cuff  2800 . 
     In some embodiments as shown in  FIG. 12C , one or more of the electrodes  2816  can be modified to include a lumen  2818  or channel for drug delivery. For example, the modified electrode  2816  can be a cuff type electrode, or a penetrating type electrode such as a needle electrode, or a combination of both. The modified electrode  2816  can deliver the drug from the reservoir to the nerve  2806  in a perifascicular or intrafascilular manner. Perifascicular delivery means delivery of the drug around a nerve or nerve bundle, while intrafascilular delivery means delivery of the drug into or inside the nerve or nerve bundle. In some embodiments, a modified cuff electrode  2816  can be used for perifascicular drug delivery, while a modified penetrating electrode can be used for intrafascilular drug delivery. In other embodiments, the device can have a dedicated drug delivery lumen or needle that is separate from the electrode. 
     In some embodiments, the drug can be delivered from the reservoir using a passive diffusion matrix drug delivery system. For example, the drug can be incorporated into a polymer matrix and can diffuse out of the matrix and/or be release as the matrix erodes. 
     In other embodiments as shown in  FIGS. 12A and 12B , the drug delivery system can use a pump  2820 , such as a screw pump or other small pump. The pump  2820  can deliver drug in a liquid form, a solid form such as a power, or a mixed form such as a paste or slurry, from the reservoir  2802  to the nerve  2806 . 
     In some embodiments, the modified electrodes can be electrically active and can be capable of delivering and/or detecting an electrical stimulus or signal to the nerve or other tissue. In other embodiments, the modified electrodes can be electrically inactive, and may only be used for drug delivery. 
     In some embodiments, a controller can be used to control the pump along with controlling the stimulation delivered by the electrodes and/or the signal detection and processing by the electrodes. The controller may be programmable and may drive the pump to deliver drug at a constant or intermittent rate. In some embodiments, the controller may enable manual drug dosing, where the user can communicate with the controller using wireless communications. In some embodiments, the controller may be programmed and/or communicate with a computing device, such as a tablet, smart phone, laptop, or desktop computer, using a wireless communication protocol, such as Bluetooth or WiFi. 
     In some embodiments, the controller provides closed loop control of the drug delivery. In some embodiments, the controller can adjust the dosage of drug, i.e. the amount and/or the rate of drug delivered, based on feedback received from a sensor. The sensor can be the electrode described above used for local detection of action potential activity in a nerve. Alternatively or additionally, the sensor can be a remotely located sensor that detects a physiological aspect of the patient, such as inflammation or pain. For example, one or more remote sensors can be placed at a different nerve that is remotely located from the nerve cuff but is part of the same sensory pathway. This allows the nerve cuff with drug delivery capabilities to be placed at an upstream, more central location that can potentially block pain signals from multiple nerves. Alternatively, this allows the sensors to be placed at upstream locations to improve detection of pain signals transmitted by the nerves while the drug delivery device is placed at one or more downstream locations to minimize or reduce the area affected by the drug. These remotely located sensors may communicate wirelessly with the controller in the nerve cuff, or the remote sensors may be directly connected to the nerve cuff using a wire. Local detection or remote detection of action potential activity in the any of the nerves in the pathway can trigger the delivery of drug from the reservoir. 
     In some embodiments, the sensor can measure electrical activity from the heart and can be used to measure an ECG signal. The controller can be used to process and analyze the ECG signal to determine heart rate and heart rate variability. In some embodiments, the drug dosage can be modified based on the heart rate and/or heart rate variability. 
     In some embodiments, the drug can be an anesthetic or analgesic or another type of painkiller One or more drugs can be used to provide a customizable dosing schedule tailored to the needs of the patient. The one or more drugs can be selected based in part on the desired wash out speed, volumetric optimization, and drug stability. The nerve cuff can include one or more reservoirs so that each drug can be contained in a separate reservoir, or the drugs can be mixed together and be placed into a single reservoir. Examples of drugs include ester based anesthetics such as procaine (novocaine), benzocaine, chloroprocaine cocaine, cyclomethycaine, dimethocaine, piperocaine, propoxycaine, proparacaine, and tetracaine; and amine based anesthetics such as lidocaine, bupivacaine (Marcaine), ropivacaine, cinchocaine, etidocaine, levobupivacaine, mepivacaine, articaine, prilocaine, and trimecaine. 
     In some embodiments, the drugs can be neurotrophic drugs with an effect on nerves. 
     Since the drugs may have different time constants, the pharmacokinetic profile of the drug or drug combination can be tailored to match the symptoms experienced by the patient, such as short term pain, chronic pain, or inflammation. For example, lidocaine has a time constant of about 1 hour and Marcaine has a time constant of about 4 hrs. Therefore, to treat inflammation or pain lasting greater than 2 hours, it may be desirable to include Marcaine, which persists longer than lidocaine. In contrast, to treat inflammation or pain of shorter durations, for example, less than 2 hours, it may be desirable to include lidocaine. In some embodiments, both a mixture of drugs having short and long time constants can be used. In addition, the device can be programmed to deliver drug at regular intervals, which can be determined based on the drug time constants and the degree of vascular profusion in the area, and/or in an on-demand fashion. In addition, as described above, the delivery of the drug can also be modified based on data received from a sensor, or in an on-demand fashion. 
     In some embodiments, the modified nerve cuff and electrode can be secured around the vagus nerve and both electrical stimulation and drug(s) can be delivered to the vagus nerve. For example, when using the nerve cuffs described herein, the slit on the nerve cuff can be opened to allow access to a channel for receiving the nerve. The nerve can be placed within the channel, and the slit can then be closed to secure the nerve within the channel of the nerve cuff. 
     In some embodiments, the nerve cuff and electrode can be secured in a similar manner around a nerve responsible for generating the sensation of pain in the patient. For example, to establish a nerve block in the upper extremities, one or more nerve cuffs and electrodes can be placed around or adjacent the interscalene nerve, supraclavicular nerve, infraclavicular nerve, and/or axillary nerve. An interscalene nerve block can be established for surgeries to the shoulder, clavicle, or upper arm; a supraclavicular nerve block can be established for surgeries to the upper arm to the hand; an infraclavicular nerve block can be established for surgeries to the elbow to the hand; and an axillary block can be established for surgeries to the elbow to the hand. To establish a nerve block in the chest and abdomen, one or more nerve cuffs and electrodes can be placed around or adjacent to the vertebral body in the paravertebral space and/or around or adjacent to nerves in the space between the internal oblique and the transversus abdominis muscles. To establish a nerve block in the lower extremities, one or more nerve cuffs and electrodes can be placed around or adjacent the lumbar plexus, the femoral nerve, and/or the sciatic nerve. 
     The sensors can be positioned at or around the nerves listed above, and on other nerves or neural structures which receive signals from these nerves or are formed in part from these nerves, such as the brachial plexus and lumbar plexus, or on nerves that transmit signals to these nerves. For example, as described herein, the nerve cuff can include an electrode for sensing electrical signals, such as action potentials, to measure nerve activity of the nerve attached to the nerve cuff. Alternatively or additionally, as described above, remote sensors can be placed away from the nerve cuff at remote locations to sense electrical activity in nerves or nerve locations described herein. In some embodiments, the remote locations may be closer to the source of pain, such as near or at the extremities and joints. 
     In addition or alternative to the use of drug agents as described above, any of these apparatuses may be configured to provide an electrical nerve block using a microstimulator held within the cuff. Electrical nerve bock may involve reversibly blocking peripheral nerves by applying high frequency alternating current directly on a nerve trunk. For example, a current ranging from 5 kHz to 50 kHz may be applied (high frequency, compared to a current of less than 1 kHz for low frequency). Efficacy of the high frequency alternating current therapy in acute non-human animal experiments (frog, cat) has been reported, e.g., U.S. Pat. Nos. 7,389,145 and 8,060,208 describe this electrical stimulation. 
     Reversibly blocking an action potential in a peripheral nerve having a diameter exceeding 3 mm and up to about 12 mm, e.g., a sciatic nerve, a tibial nerve, etc., may be applied by a neurostimulator held within any of the cuffs described herein, providing an electrical waveform for an interval of time sufficient to effect substantially immediate pain relief, defined generally as within about 10 min. One embodiment uses a waveform ranging from 5 kHz to 50 kHz. One embodiment uses a 10 kHz sinusoidal waveform at a current ranging from 4 mA to 26 mA. The electrode can be retained in the cuff encircling the desired peripheral nerve in which the action potential is to be blocked. The time interval may be about 10 minutes, but an interval may be selected by a magnitude sufficient to effect pain relief in the patient. In one embodiment, the electrical waveform to effect pain relief ranges from a voltage from 4 V to 20 V, or a current ranging from 4 mA to 26 mA. The time of increasing magnitude can range from about 10 seconds to about 60 seconds with a steady ramp up of voltage or current. The waveform may be provided by a waveform generator that is part of the apparatus. As mentioned above, the application of the nerve block (including electrical nerve block) may be triggered by activity on the nerve to which the cuff is attached. 
     Dual Clocking Apparatuses 
     As mentioned above, also described herein are methods and apparatuses for keeping highly accurate time in a implant (including, but not limited to the nerve block apparatuses described above) using very low power. In particular, described herein are methods and apparatuses for calibration of a first (e.g., low power) clock/clocking mechanism, where the calibration occurs periodically or based upon some event or signal being detected and through use of a second, more accurate clock/clocking mechanism. 
     In implantable devices, and many other electrical devices in general, there is great demand for having systems with lower power consumption as well as lower cost. Lower power expenditure may be achieved through having a process that does not draw as much power, but often this is at the expense of having less accurate outputs. In the case with a clocking system, the use of a less accurate clock signal may lead to lower power consumption compared to a more accurate clocking mechanism, but a less accurate clock having lower power consumption may result in providing output at imprecise or unpredictable times. 
     One way to compensate for having a systems clocking mechanism that is a less accurate clocking mechanism that will be periodically calibrated with a more accurate clocking system, including one which is present on/in the implant, but which may be deactivated or inactive until triggered. For example, disclosed herein is a first or central clocking mechanism that uses a semiconductor junction to generate a reference voltage that in turn charges an RC circuit to produce a time reference. Because these voltage references have significant variations due to integrated circuit characteristics and parameters and temperature, they tend to be less accurate, though they may require lower power. Other, typically lower power and/or lower cost clocks may be used as the primary clock. 
     To compensate for the lack in accuracy of the first clocking mechanism, a second more accurate clocking mechanism is employed. The second, more accurate clocking mechanism may be used to periodically recalibrate the first clocking mechanism. 
     More accurate clocking mechanism include real time clocks. Real time clocks are a type of computer clock in the form of integrated circuits. Most real time clocks use a piezoelectric crystal oscillator, where the oscillator frequency is 32.768 kHz, the same frequency as in quartz clocks and watches. 
     In one non-limiting example, a time reference clocking module error in the RC circuit may be measured over fixed intervals or based on a change in a pre-determined parameter (e.g. voltage or current). Deviations may be measured against a more accurate real time crystal oscillator clocking mechanism. Based on the measured deviation and time elapsed since the last calibration, the amount of time deviation in the time reference clocking module may be calculated and corrected. Correction of any time deviation may be occur through correcting the central clocking module. Alternatively, the central clocking module may be temporarily replaced with the more accurate real time crystal oscillator clocking mechanism to bring the central clocking module back to a correct value. 
     In another non-limiting example, the implantable device will run the central clocking mechanism continuously while a second, more accurate clocking mechanism remains in an OFF or standby mode. Upon the occurrence of a pre-determine event or time interval, the second, more accurate clocking mechanism may enter an active mode and re-calibrate the central clocking mechanism. Upon completion of the calibration routine, the second, more accurate clocking mechanism will again revert to an OFF or standby mode until the next calibration is triggered. 
       FIG. 13  shows a flowchart for visualizing the steps of implementing a clocking calibration routine  1300 . Presumably the clocking system for the implantable device, such as a neurostimulator, will be activated once the device is implanted in the patient. At  1302 , the systems clocking mechanism is running. At this point, the second, more accurate clocking mechanism is in a sleep or OFF mode ( 1308 ). At some point in time later, an even triggers a signal being sent to the second clocking mechanism ( 1304 ). The trigger may correspond to the beginning of a new cycle in the implantable device. In the case of an implantable neurostimulator, the trigger may be associated with the beginning of a stimulation session or a combination of features of the stimulation session (e.g. a time interval after the start of the stimulation session). A trigger for calibration may also be a circuit parameter that has exceeded or dropped below a threshold value. Once the trigger event has occurred ( 1304 ), a signal is sent to the second clocking module to turn from the OFF or standby mode to an active mode ( 1312 ). With the second clocking module in an active state, it will initiate the calibration routine ( 1310 ). Once the calibration routine ( 1310 ) has been performed, any deviation determined from running the calibration routine ( 1310 ) may be corrected in the following step ( 1314 ). Once the deviation has been corrected, a second signal may be sent to the second clocking module to return to an OFF or standby mode. In the final step, a third signal may be sent to the central clocking module to switch it from an OFF or standby mode to an active mode. These steps may be repeated based on a condition being satisfied, an event occurring, or a pre-determined period of time. Also, it may be possible to delay calibration to sometime past the triggering event. 
     Turning to  FIG. 14 , a sample calibration routine based on some feature or characteristic of the implanted device output is shown. In the case of an implantable neurostimulation device, calibration of the central clocking system may be tied to when a stimulation session begins. In this scenario, a sensor may be incorporated to sense when a current or voltage has increased above a certain value and that a calibration routine should be initiated immediately or after a set amount of time. To better visualize each component status,  FIG. 14  shows stacked signals in order from top to bottom: a series of neurostimulation outputs for a neurostimulator  1430 , the functional state of the first or central clocking module  1440 , and the functional state of the second clocking module  1450  that is able to perform the calibration routine. The horizontal axis from left to right indicates the passage of time and may be in units of minutes, hours, days, weeks, months, and so forth. 
     As the diagram arbitrarily shows a snapshot of the output of an implanted device. Initially, when the neurostimulation device is in an idle state ( 1431 ), the central clocking module  1440  is in an active mode  1441  and the second clocking module  1450  is in an OFF or standby mode ( 1451 ). The central clocking module  1440  will then continue to run for some period  1442  until a neurostimulation session begins ( 1432 ), at that point, signals are set to the both the central clocking module  1440  and the second clocking module  1450  when the neurostimulation output surpasses a certain threshold value. Upon reaching this state, the central clocking module will drop to an idle or OFF state  1442  while the second clocking module  1450  will switch from its OFF or standby mode  1451  to an active mode  1452 , where it will run a calibration routine  1453  either immediately or at a preset time in the future. Upon completion of the calibration routine  1453 , a signal is sent to the central clocking module to coordinate switching it from the standby mode  1442  back to an active mode  1441  and for the second clocking module to return from an active mode  1452  to an OFF or standby mode  1451  in a coordinated fashion. These steps will repeat based on some feature of the stimulating output from the implanted device. In some other variations, the calibration routine may be tied to some other feature of the stimulating output and not necessarily correspond to the beginning of the stimulation output. 
       FIG. 15  shows an alternative initiation of calibration routines in a system where a secondary, more accurate clocking module is used to calibrate and correct any deviations experienced by a less accurate central clocking module. In this arrangement, the implanted device output will provide output periodically, where the time periods may be the same or different and may be set by the doctor or other user. A calibration routine may occur that aligns with a given time period t, that repeats. As the diagram shows, during the evolution of time period t, the central clocking module is in an active state  1541 , while the second clocking module is in an OFF or inactive state  1551 . At the end of the time period t, the central clocking module will switch to an idle or OFF mode  1542  while the second clocking module will turn to an active mode  1552  to calibrate the less accurate central clocking module  1540  and adjust for any deviations that is measured. Upon completion of the calibration routine the second clocking module  1550  will return to an OFF or standby mode  151  while the central clocking module  1540  will return to an active mode  1541 . These steps will repeat based on a pre-defined time interval. In some examples the time period will be the same, but in other examples the time period may be different or may be based on some algorithm or known relation between the length of time and the amount of deviation expected. 
     The second clocking module may be linked to the calibration module that performs the actual calibration routine. The calibration module may be integrated into the circuitry of the implanted device. The systems clocking module is able to provide a central clocking signal that serves as a clock source. 
     In some other examples, the systems clocking module is configured to provide a tick signal that acts as a time keeper. Periods between device outputs may be defined by the number of tick counts. While the tick counts accuracy is based upon characteristics of the circuit parameters, and may be not be as accurate as some other timing keeping mode, certain methods may be implemented to accommodate any inaccuracies. For example, tick counts may be tied to the calibration module, which can be used to determine the duration of intervals between successive calibration routines. The start of a calibration routine is initialed by a signal which is configured to count the ticks from the central clocking module. The ticks may be counted until the calibration routine is complete and through a period where the central clocking module is keeping time. Tick counts may restart based upon the start of a new calibration routine. Every time the calibration routine is run, any deviations resulting from the tick counts may be corrected. In the example of an implantable neurostimulation device that has wireless recharging capabilities, the tick counts may be adjusted for accuracy using a more accurate time keeper located within the wireless transmitter unit. Thus, whenever the implanted neurostimulation device is being recharged, the tick counts may be matched with the more time keeping module within the wireless transmitter unit and any deviations may be corrected. The benefit of having a tick counting type time-keeping module is that a patient may move to different time zones without having to modify potentially salient circadian components of the stimulation output. 
     As alluded to above, the implanted device circuitry or controller will also be configured to detect a trigger or event that will commence a calibration routine. The trigger may be an increase in a threshold voltage or current value. The trigger may also be a combination or a pattern of changes in the voltage or current value in more complex arrangement of stimulating outputs. 
     The implantable device will also be configured to provide a series of signals that will coordinate the switching of the central clocking module from an active mode to an OFF or standby mode, while signals are also sent for switching the second clocking module from an OFF mode to an active mode for the calibration routine. 
     The implantable device may also include programs or algorithms that will be able to correct for any time drift that may be detected after the calibration routine is completed. In another variation, the step of calibrating the central clocking module and accounting for any deviation may be performed in one step. 
     In some non-limiting variations of the clocking calibration systems and methods, the implantable neurostimulation device may be able to retain information on the calibration results such as the amount of drift that the central clocking module has experienced since the previous calibration routine. This information may be sent wirelessly to a telecommunication device or may be sent to the wireless transmitter module during recharging events. 
     It should be noted that because the clocking system described herein is directed to use within an implantable device, there is minimal temperature variations that may cause further drifts in the clocking system. Because the implant is in a temperature stable environment, there may be no need for temperature compensation. The circuit&#39;s wafer to wafer and die to die variations may be calibrated to a fixed temperature and scaled to 37° C. during manufacturing of the implantable device, may be calibrated during the programming of the implantable device, or during the wireless charging process. 
     In yet other variations, the calibration routine and subsequent correction steps may be in response to a received voltage or current signal from a sensor via some data communication link, and compares the received voltage or current signal against a set of pre-programmed or learned variables and values to determine if the central clocking module needs to be recalibrated. While the calibration routine may occur at any time, it may be beneficial to run the calibration routine when there is no stimulating output being provided. This would prevent overtaxing the overall circuitry of the implanted device. 
     When a feature or element is herein referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when a feature or element is referred to as being “directly on” another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature. 
     Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items and may be abbreviated as “/”. 
     Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature&#39;s relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise. 
     Although the terms “first” and “second” may be used herein to describe various features/elements (including steps), these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention. 
     Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps. 
     In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and/or steps may alternatively be exclusive, and may be expressed as “consisting of” or alternatively “consisting essentially of” the various components, steps, sub-components or sub-steps. 
     As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word “about” or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and/or position to indicate that the value and/or position described is within a reasonable expected range of values and/or positions. For example, a numeric value may have a value that is +/−0.1% of the stated value (or range of values), +/−1% of the stated value (or range of values), +/−2% of the stated value (or range of values), +/−5% of the stated value (or range of values), +/−10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “X” is disclosed the “less than or equal to X” as well as “greater than or equal to X” (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. 
     Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims. 
     The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of this disclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.