# Patent

## Title
Devices and methods for optimizing electrode placement for anti-inflamatory stimulation

## Abstract

Described herein are methods, devices and system for selecting an optimum position of a stimulation electrode, and particularly methods, devices and systems for optimizing the position of a stimulation electrode for stimulating the inflammatory reflex and thereby inhibiting inflammation. The methods, devices and systems described herein may generally include the analysis of one or more artifact modalities arising after the application of a stimulation pulse. One or more of these artifact modalities (e.g., EMG, ECG, etc.) may be detected and used to generate a comparable indicator of the fitness of the position of the electrode relative to a target, such as a portion of the inflammatory reflex like the vagus nerve.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. 119 of U.S. Patent Application No. 61/115,806 filed Nov. 18, 2008, titled “DEVICES AND METHODS FOR OPTIMIZING ELECTRODE PLACEMENT FOR ANTI-INFLAMMATORY STIMULATION”.


INCORPORATION BY REFERENCE
All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
BACKGROUND OF THE INVENTION
Inflammation is a complex biological response to pathogens, cell damage, and/or biological irritants. Inflammation may help an organism remove injurious stimuli, and initiate the healing process for the tissue, and is normally tightly regulated by the body. However, inappropriate or unchecked inflammation can also lead to a variety of disease states, including diseases such as hay fever, atherosclerosis, arthritis (rheumatoid, bursitis, gouty arthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases, chronic inflammation, chronic prostatitis, glomerulonephritis, nephritis, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, transplant rejection, vasculitis, myocarditis, colitis, etc. In autoimmune diseases, for example, the immune system inappropriately triggers an inflammatory response, causing damage to its own tissues.
Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.
The nervous system, and particularly the Vagus nerve, has been implicated as a modulator of inflammatory response. The Vagus nerve is part of an inflammatory reflex, which also includes the splenic nerve, the hepatic nerve and the trigeminal nerve. The efferent arm of the inflammatory reflex may be referred to as the cholinergic anti-inflammatory pathway. For example, Tracey et. al., have previously reported that the nervous system regulates systemic inflammation through a Vagus nerve pathway. This pathway may involve the regulation of inflammatory cytokines and/or activation of granulocytes. Thus, it is believed that appropriate modulation of the Vagus nerve (or other portions of the inflammatory reflex) may help regulate inflammation. Inhibition of the inflammatory reflex is described more fully in U.S. Pat. No. 6,610,713, filed on May 15, 2001 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUS NERVE STIMULATION”; pending U.S. patent application Ser. No. 11/807,493, filed on Feb. 26, 2003 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY STIMULATION OF BRAIN MUSCARINIC RECEPTORS”; pending U.S. patent application Ser. No. 10/446,625, with a priority date of May 15, 2001 and titled “INHIBITION OF INFLAMMATORY CYTOKINE PRODUCTION BY CHOLINERGIC AGONISTS AND VAGUE NERVE STIMULATION”; and pending U.S. patent application Ser. No. 11/318,075, filed on Dec. 22, 2005 and titled “TREATING INFLAMMATORY DISORDERS BY ELECTRICAL VAGUS NERVE STIMULATION.” This provisional patent application may also be related to pending U.S. Provisional Patent Application Ser. No. 60/968,292, titled “DEVICES AND METHODS FOR INHIBITING GRANULOCYTE ACTIVATION BY NEURAL STIMULATION”, and Ser. No. 60/982,681, titled “TRANSCUTANEOUS VAGUS NERVE STIMULATION REDUCES SERUM HIGH MOBILITY GROUP BOX 1 LEVELS AND IMPROVES SURVIVAL IN MURINE SEPSIS”. Each of these patent and pending applications is herein incorporated by reference in its entirety.
A system for stimulating one or more nerves of the inflammatory reflex may include one or more electrical leads which may be implanted acutely or chronically, and may be positioned adjacent or in contact with the Vagus nerve or other nerves of the inflammatory reflex, and particularly the cholinergic anti-inflammatory reflex.
Unfortunately, stimulation of the inflammatory reflex is made difficult by artifacts and/or side-effects of stimulation. Most stimulation (neurostimulation) devices target neurons or muscles with electrodes that generate current to activate these organs. Ideally, such devices should stimulate only the target tissue or organ. Even more ideally, the stimulation of the target should be precise enough to avoid collateral stimulation. Furthermore, the stimulation should evoke the desired effect, without triggering other effects. In practice, localized stimulation has proven very difficult, and practically unrealizable. Unintentional stimulation of collateral organs from non-specific electrodes can be detrimental enough to prevent treatment and/or reduce the efficacy of treatment by requiring suboptimal stimulation.
Furthermore, the in-vivo stimulation environment may be very non-homogenous in electrical conductivity and organ activation characteristics (e.g. fiber diameter). The practical significance of this non-homogeneity is that positional changes in the stimulating electrodes can shift the path of the activating current, or change the characteristics of the stimulating current itself, such as the pulse width, rate, polarity, asymmetry, or the like. Control of electrode position and stimulation current characteristics is therefore critical for the success of neurostimulation therapies, particularly those in which collateral stimulation is an issue. Described herein are device and methods for optimal positioning of the electrode during surgery and optimization of stimulation parameters.
Currently available systems for stimulating nerves of the inflammatory reflex such as the Vagus nerve are generally not appropriate for stimulation of the Vagus nerve to regulate inflammation, because they would either be ineffective for inhibiting inflammation, or because they would result in undesirable side-effects. The configuration of the electrodes and stimulators, including the configuration of the stimulating electrodes of the electrical leads, in conjunction with the level, duration and frequency of stimulation, are critical to inhibiting or modulation of the inflammatory response appropriately (e.g., without desensitizing the inflammatory reflex).
For example, US Patent Application publication numbers 2006/0287678, US 2005/0075702, and US 2005/0075701 to Shafer describe a device and method of stimulating neurons of the sympathetic nervous system, including the splenic nerve to attenuate an immune response. Similarly, US Patent Application publication numbers 2006/0206155 and 2006/010668 describe stimulation of the Vagus nerve by an implanted electrode. US Patent Application publication number 2007/0027499 describes a device and method for treating mood disorders using electrical stimulation. US Patent Application publication number 2006/0229677 to Moffitt et al. describes transvascularly stimulating a nerve trunk through a blood vessel. U.S. Pat. No. 7,269,457 to Shafer et al. also describes a system for vagal nerve stimulation with multi-site cardiac pacing. All of these published patent applications and issued patents describe systems and methods for stimulating nerves, including the Vagus nerve. However, none of these publications teach or suggest stimulating the inflammatory reflex, including the Vagus nerve, using a system or method that would prevent desensitization of the inflammatory reflex, and would avoid undesirable effects or artifacts, such as muscle twitch or seizures, pain, cardiac effects (e.g., increase heart rate, etc.), hoarseness, or the like.
In practice, when a surgeon is inserting an electrode, the position of the electrode is necessarily crude, since implantation is often done via catheter or other minimally-invasive techniques, or done using indirect imaging techniques. Thus, it is often difficult for a doctor to precisely implant an electrode. In addition, we have found that the correct placement of an electrode may vary based on patient variability. This means that what an optimal position in one patient (e.g., a certain proximity to the vagus nerve) may be sub-optimal or non-functional in another patient. Thus, although stimulation systems, including those described above, may be applied by a surgeon using a known protocol, such insertion does not usually result in minimal stimulation artifact, particularly relative to the desired effect. To correct for this, stimulation levels may simply be increased (e.g., increasing the intensity or frequency) to attain a desired stimulation, often at the expense of an increased artifact or side-effect. Further, even when a stimulation electrode is implanted using a “trial and error” technique, it may be overly difficult or costly to examine the stimulation artifact in determining the optimal position, particularly in any reliable, reproducible manner.
Thus, there is a need for electrical leads and systems that include electrical leads are configured to appropriately modulate the inflammatory reflex without causing undesirable side effects or artifacts due to the stimulation.
SUMMARY OF THE INVENTION
Described herein are systems, devices and methods for optimizing the position of electrodes for stimulating the inflammatory reflex to inhibit or otherwise modulate inflammation. In particular, described herein are systems, devices and methods for optimizing the position of one or more electrodes relative to one or more portion of the inflammatory reflex, such as the vagus nerve, the splenic nerve, the hepatic nerve and the trigeminal nerve.
In some variations, the position of the stimulation electrode (or electrodes) is optimized by detecting and/or measuring “stimulation artifacts” during insertion/implantation and programming of the electrode. Certain of the devices, systems and methods allow for the feedback of information to the clinician or to an analysis device in real-time during or after implantation. Stimulation artifact is broadly defined as a signal or signals resulting from the electrode that is not part of the desired stimulation. For example, stimulation artifact may be electrical (e.g., ECG, EKG, EMG), muscle twitch, cramping, seizure, cardiac effects (heart rate variability, increase in heart rate, decrease in heart rate, etc.), or other undesirable effects, as described further below. Thus, the systems and methods described herein may include one or more sensors for detecting and/or measuring such stimulation artifact, and may further include the display and or analysis of this artifact. Information from certain of the stimulation artifact may be used to position the electrode, and/or to choose which electrodes on a device to use for stimulation.
In some variations, the stimulation artifact can be detected from the same electrodes that are applying stimulation, or from different electrodes on the same lead. The artifact can also be measured by a distant electrode/lead. The artifact can be measured simultaneously with applied stimulation, and/or it can be measured between stimulation pulses. Measured artifact can consist of any appropriate electrical phenomena such as EMG, EKG, EEG, and/or evoked potentials such as those evoked to or from a target organ such as the Spleen. Other sensors can be used to detect stimulation artifact, including temperature sensors, tissue resistance sensors, and chemical sensors.
In addition to sensing and/or measuring artifact to optimize electrode placement, the target devices, systems and methods described herein may also be used to maximize the target response and minimize artifact response (e.g. minimization of heart rate and maximization of splenic evoked potential).
Generally, separating a stimulation artifact from a stimulation is complicated by the fact that a stimulus is usually much larger than an evoked intentional or artifact signal. Several mechanisms are described herein to facilitate measurement in these conditions including: high bandwidth fast recovery amplifiers, analog gating signals, digital gating, signal processing such as averaging and autocorrelation.
In addition to the methods and devices for optimizing the position of the electrode, stimulation artifact may be controlled by optimizing the type of electrode and/or the stimulation parameters. For example, the electrode (or electrodes) used may be configured to optimize simulation of a portion f the inflammatory reflex (such as the vagus nerve, the splenic nerve, the hepatic nerve and the trigeminal nerve). In some variations, the level of stimulation applied may be particularly important to avoid overstimulation (e.g., desensitization) of the inflammatory reflex, preventing inhibition (or long-lasting inhibition) of the inflammatory reflex. For example, the intensity (voltage and/or current level), duration, frequency, or the like, may be optimized. Low-intensity or particularly infrequent stimulation may be particularly important. Any of the methods, devices and systems for optimizing position of the stimulation electrodes may also be used in conjunction with any of the optimized electrodes and/or stimulation protocols, or methods of optimizing the electrodes and/or stimulation protocols. In practice, the position of the electrode may be fundamental.
In general, the methods described herein include the real-time monitoring of one or more ‘artifacts’ during implantation. In some variations, the artifact monitored may be averaged. For example, EMG signals (muscle response) may be monitored. In some variations, EKG (e.g., from the chest) may also be used to measure changes in heart rate (e.g., heart rate variability). Changes in heart rate may be used to both confirm position relative to a portion of the inflammatory reflex such as the vagus nerve, and may also be used to determine undesirable artifact. In some variations, evoked potentials from either the target nerve (e.g., vagus nerve, splenic nerve, hepatic nerve, trigeminal nerve, etc.) or from nearby or adjacent nerves that are not part of the inflammatory reflex, may be monitored as stimulation artifact.
For example, a neuron may be stimulated using an implanted electrode in a first position, and the evoked potentials may be monitored as they propagate from the implantation site of the nerve. Multiple simulations can be performed and the evoked responses in one or more nerves (either target and/or non-target nerves) be averaged over these multiple stimulations. Monitoring the evoked potential may allow confirmation that the nerve is being stimulated, and that adjacent nerves are not being stimulated.
In one variation, a monitoring sensor (e.g., electrode) is used to detect stimulation artifact. In some variations, multiple modalities of artifact may be measured and used to optimize the position. For example, a first artifact modality may be EMG or muscle twitch. The measurement of EMG or muscle twitch may be measured off of one or more pair of the multipolar probe applying the stimulus. Thus, the EMG artifact may be measured near the location of the stimulation (e.g., the neck). A second artifact modality may be EKG, which may be used to measure one or more component of the cardiac cycle (e.g., heart rate, etc.). The same electrode or different electrodes may be used to measure EKG (e.g., chest electrodes). A third artifact modality (e.g., evoked potentials, or compound action potentials) may be measured. In practice, any combinations of these artifact modalities may be used, and they may be weighted. For example, the EMG or muscle twitch artifact may be weighted more than the EKG artifact (or vice versa).
Any appropriate type of stimulation electrode may be used, include one or more of a field effect electrode, multi-polar (e.g., bipolar, octopolar), cuff electrodes, hook electrodes, or the like. The techniques described herein are particularly useful for field effect electrodes whose position may be adjusted during surgery, or any probe including multiple contacts, or any stimulator that may be adjusted to modify the stimulation parameter (e.g., intensity, etc.).
Also described herein are amplifiers that are adapted to detect and/or measure one or more of these artifacts relative to the stimulation. For example, the stimulation (which is typically a high intensity signal), must be isolated appropriately from the relatively low-intensity stimulus artifact. For example, an amplifier may include a fast recovery amplifier that clamps the stimulus (e.g., 20 mV stimulus), so that the low-intensity response (stimulus artifact such as EMG). The amplifier may also include appropriate averaging capability that averages the artifact following the stimulation. The system may use this information to generate a metric, such as artifact power. For example, artifact power may be a measure of the total power (e.g., the area under the waveform) of the artifact measured. The electrodes may be placed or selected to minimize a metric such as artifact power. In one variation, the system includes a probe having multiple electrode pairs, and is configured to include an output of artifact power for each of the pairs.
In some variations, the optimization of electrode position includes the measurement of stimulation artifact between stimulation pulses. For example, the stimulation electrodes may be configured to both apply a stimulation signal and to detect an electrical signal. Electrical signals detected from these electrodes may be analyzed (e.g., by sending to an analysis module) to remove the stimulation and analyze any electrical signal between periods of stimulation. For example, the electrical signal measured from the electrodes may be locked with the stimulation signal so that it can be subtracted or gated to remove the stimulation signal from the received signal. Thus, the analysis module may block out the relatively high-intensity applied signal and amplify the relatively low-intensity recorded signal. The signal may be further filtered or conditioned. For example, when using an EMG stimulus artifact, the signal may be filtered at 20-450 Hz, a spectral range that may provide useful information when EMG is used. If the stimulus artifact measured is heart rate variability, the signal may be filtered to pass within the spectral range of 0.5 to 20 Hz.
In addition to measuring stimulation artifact, the system may also measure the desired effect, including one or more indicators of the inhibition of inflammation. For example, the system may include one or more sensors to detect and/or measure inhibition of inflammation based on body temperature, distribution of cell types (e.g., granulocyte distribution), levels of certain neurotransmitters (e.g., acetylcholine), and/or markers of inflammation such as CD11, etc. The system may thus be configured to optimize position based on either or both the artifact signal (e.g., muscle twitch, heart rate, nerve firing, etc.) and/or based on the desired signal (e.g., inhibition of inflammation).



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1. Illustrates the justification and hypothesis of artifact-guided placement and programming of percutaneous electrode leads.
FIG. 2 shows a strength-duration curve for a Rat stimulated at various (labeled) protocols.
FIG. 3 shows a schematic of one variation of an artifact-guided placement system (a system for optimizing the placement of one or more electrodes).
FIG. 4 illustrates one variation of schematics for an artifact-guided placement system as described herein.
FIG. 5 is a table of variations of artifacts that may be monitored as part of the placement systems described herein.
FIG. 6 is a partial schematic of one variation of a system for optimizing position using EMG artifact.



DETAILED DESCRIPTION OF THE INVENTION
Described herein are devices, systems, and methods for optimizing placement of one or more electrodes. For example, the position may be optimized to stimulate the inflammatory reflex and thereby inhibit inflammation, while minimizing or eliminating undesirable side effects. Side effects may include cardiac effects (depression or acceleration of heart rate, blood pressure or the like), dry mouth, muscle twitching or spasm, etc. Such side effects may result from stimulation artifacts, which may occur when stimulating nearby muscle, nerve or other organs, or may occur because of overstimulation. Although the devices, systems and methods for optimizing position described herein are primarily directed to optimizing stimulation of the inflammatory reflex (e.g., the vagus nerve), some of the devices, system and methods described herein may also be used to optimize the position of other body regions or systems.
As illustrated in FIG. 1, preliminary studies in rats using various electrode types (hook, field effect, and sheath cuff electrodes) implanted for stimulation of the vagus nerve, in order to inhibit inflammation via the inflammatory reflex. FIG. 1 describes the problem address by the devices, systems and methods for optimizing placement of electrodes (leads) for stimulation. Based on preliminary experiments, the most significant problem while stimulating in rats is the side effect of muscle twitching. Muscle twitching may occur because of the undesirable stimulation of nearby muscle fibers or nerves innervating muscle fibers. This stimulation artifact may be reduced by changing the position of the electrode. This is consistent with other anecdotal reports from implantation of nerve stimulation, in which the percutaneous insertion of electrodes requires significant manual tweaking or adjustment of individual electrodes to get efficacious stimulation (e.g., vagus stimulation or “VNS”). FIG. 2 shows strength duration curves from this preliminary rat study.
As mentioned briefly above, a system may include an electrode (or electrode lead having multiple electrodes), a stimulator (for applying energy from the electrode(s)), a controller (for controlling stimulation and/or optimization), and an analysis module for receiving input from the controller (and the electrode and/or other sensors) and detecting and analyzing the stimulation artifact due to the stimulation. The analysis module may be a separate component, or it may be part of the controller. The system may also include one or more additional sensors for detecting stimulation artifact. In some variations, the system also includes an output (e.g., a display, one or more LEDs, an audible output, a wireless output for communication with a computer, etc.), for presenting an index or factor of the artifact (such as the artifact power) for the electrode(s).
FIG. 3 illustrates one variation of a schematic for a method for optimizing electrode position based on feedback from stimulation artifact (“artifact guided placement and programming”). In FIG. 3, two components, surgical and programming, contribute to the method and system for optimizing electrode position. For example, the surgical methodology may include implanting a multipolar electrode (e.g., an octopolar electrode) adjacent to a subject's vagus nerve in the region of the subject's neck. The electrode lead (containing multiple electrodes) may be secured in a first position using one or more locking/unlocking anchors. In some variations, the lead is secured in position so that it can later be repositioned incrementally, or completely removed. In some variations, the lead is secured so that it does not substantially move (or allow slight adjustments). A re-positionable anchor may allow the lead to be implanted, held in a first position, and then adjusted to a second position, where it can again be locked in place. For example, the lead may include a re-positionable anchor that includes a plurality of retractable tines which may releasably engage the tissue. In some variations, the lead may include an inflatable/deflatable region. Other variations of locking/unlocking anchors may be used in embodiments allowing repositioning of the lead.
In some variations, the electrode or electrode lead used may be configured for both applying energy to inhibit the inflammatory reflex (e.g., by stimulating the vagus nerve) and for receiving a signal representative of the stimulation artifact (e.g., EMG, EKG, evoked potentials, etc.). In some variations the lead includes processing (e.g., filters, amplifiers, etc.) that facilitate this.
Once the multiple-electrode lead is implanted, various combinations of electrode pairs may be tested. For example, as shown in FIG. 3, pulsed electrode pairs (e.g., at 1-10 Hz) may be applied sequentially between different pairs of the electrodes, and the artifact measured (e.g., EMG, ECG, etc.) during the duration between stimulation. The artifact may be correlated to the stimulation pair so that an index (e.g., artifact power) may be calculated for each electrode pair. For example, for a six-electrode pair lead, all six combinations of electrodes may be tested, and a real-time artifact factor or index, such as artifact power, may be provided to the doctor, allowing her to determine which pair has the lowest stimulation artifact and/or allowing repositioning of the electrode. In this way an optimal pair of electrodes (or single electrode when monopolar stimulation is used) may be determined. The system may allow the optimal electrode(s) to be recorded or chosen by the system, so that further stimulation of the subject (after the optimizing stage) may be performed using this optimal electrode/electrode pair.
The system may include instructions (e.g., programming) for evoking and analyzing the artifact associated with the electrode(s). For example, the controller and/or analysis module may include instructions for filtering a signal received after application of the stimulation in order to determine the signaling artifact (e.g., evoked potential, EKG, EMG). In some variations, the programming may also determine an index representing the artifact. For example, artifact power corresponding to a particular electrode or set of electrodes may be determined by detecting and/or measuring the signal following stimulation from a particular electrode or pair of electrodes. The signal may be filtered to remove the stimulation pulse(s), and may be bandwidth filtered to a particular region of interest (e.g., 20-450 Hz or other range relevant to EMG, 0.5 to 20 Hz or other range relevant to heart rate variability, etc.). Averaging across multiple stimulations may also be performed, and the controller and/or analysis module may include instructions determining the appropriate averaging to be performed (and/or number of stimulations to be performed to achieve an acceptable result).
For example, in some variations, the system outputs an “artifact power” for the electrode(s). In some variations, the artifact power is the index of the stimulation artifact that is calculated from the area under the curve of the stimulation artifact. Other means of quantifying the stimulation artifact associated with an electrode may also be used. In some variations, the index for each electrode includes an indication of the magnitude of the desired effect (e.g., stimulation of the inflammatory reflex, inhibition of inflammation, etc.). The module may include inputs from one or more sensors, in addition to the electrode(s), and may use all or a subset of these inputs to determine the index.
As mentioned, the systems, devices and methods may both help optimize the position of the one or more electrodes and/or may help optimize the selection of one or more electrodes from a multi-electrode lead.
FIG. 4 shows a schematic of another variation (indicating exemplary parameters) of a system for optimizing electrode position. Two artifact modalities may be used. The primary modality is EMG and the secondary modality is ECG (and specifically, heart rate variability or HRV). In FIG. 4, the system provides a 1-10 Hz stimulation across any or all of the electrodes of a multi-electrode lead. The same electrodes applying the stimulation may be used to record the stimulation artifact immediately post-stimulation, as mentioned above. The post-stimulation (artifact) signal may be measured between stimulation pulses; in this example the artifact modality is EMG, and the stimulation artifact signal is filtered at a bandwidth of 20-450 Hz, and amplified to a gain of 100 or 1000×. The system is configured to have a rapid recovery from the stimulation of approximately 5 ms, and a sample rate for detecting the stimulation artifact of approximately 1-2 Hz at 12 bits. As mentioned, the sampling processing may occur at the level of the electrode(s), the controller, the analysis module, or any other appropriate portion of the system. The signal received may be recorded and stored, and may be used to average with other signals, or may be used for further processing (e.g., calculation of an index).
The second artifact modality which may additionally be used in the example shown in FIG. 4 is the ECG modality. In particular, in this example, the heart rate variability is used. For example, the heart rate variability is recorded against an electrode on the probe and an additional electrode (e.g., reference electrode) elsewhere on the subject's body. Any other appropriate sensor input may be used, including a traditional chest/skin ECG electrode. The system may measure the RR interval from the ECG (e.g., within plus/minus 2 ms), and may filter the artifact signal received using a bandwidth of about 0.5 and about 20 Hz, as indicated. The signal may also be amplified by 100 or 1000×, and the sample rate may be between about 250 and 1 KHz at 12 bits.
As illustrated above, in some variations, the system monitors EMG (and/or ECG) between stimulation pulses, allowing a surgeon to place and program electrode objectively to reduce artifact. Thus, the system may provide on-the-fly (e.g., real-time or semi-real time) indicators of an indicator or artifact (and/or artifact plus efficacy of target stimulus). This may help avoid risk when implanting and stimulating a subject, by reducing the reliance on the doctor's skill and experience. Preliminary animal tests may show whether the system or just electrode type is the dominate factor and potentially help select electrode types, and may also show whether the desired stimulation effect (e.g., TNF levels) and the artifact thresholds are independent or correlated.
As mentioned above, any appropriate artifact modality may be used. FIG. 5 illustrates some of the more common artifact modalities that may be used, particularly those useful for positioning or selecting electrodes for stimulating the inflammatory reflex. The “measurement” column indicates one way that the artifact modality may be measured. Other variations are intended to be incorporated. The “mechanism” column suggests some ways in which these artifacts may arise due to stimulation from electrodes targeting the inflammatory reflex.
FIG. 6 schematically illustrates another example of a system for optimizing electrode position using stimulation artifact. In this example, the artifact modality is EMG. On the left of the figure, a muscle is illustrated in relation to one portion of the inflammatory reflex, the vagus nerve (VN). In this example, the application of stimulation intended to reach the vagus nerve (from the stimulator on top, may result in collateral stimulation of the muscle, which may be detected. The module indicated on the lower right portion of the figure indicates one manner in which this stimulation artifact may be detected and thus analyzed. In FIG. 6, electrical signals from the muscle (EMG signal) are gated against the stimulation impulse to remove the high-level stimulation signal from the artifact signal. A bandwidth filter is further used to focus the spectrum of the artifact signal to a smaller region (e.g., the range particularly relevant to EMG signals), and may be amplified (resulting in the “data” indicated). The signal may further be digitized (ADC) for further analysis.
The optimization methods and steps described above may also be performed, or re-performed, after some period of operation of the device/system. For example, routine or regular re-optimization may be part of the stimulation system. The system may then automatically or semi-automatically select a new optimum electrode/electrode pair (e.g., when using a multi-electrode lead) or suggest repositioning of the electrode or lead, if the artifact index falls outside of a present or input range or threshold.
While the systems, devices and methods herein have been described in some detail by way of illustration and example, such illustration and example is for purposes of clarity of understanding only. It will be readily apparent to those of ordinary skill in the art in light of the teachings herein that certain changes and modifications may be made thereto without departing from the spirit and scope of the invention.

## Claims

1. A method of optimizing the position of an electrode relative to a subject's inflammatory reflex, the method comprising:
implanting an electrode in electrical communication with either the vagus nerve, the splenic nerve, the hepatic nerve or the trigeminal nerve so the electrode can be stimulated to inhibit inflammation:
applying an electrical stimulus to electrode;
detecting a stimulation artifact;
determining an indicator of the power of the stimulation artifact, wherein the step of determining an indicator of the power of the stimulation artifact includes calculating the power of the stimulation artifact and a second stimulation artifact; and
adjusting the position of the stimulation electrode based on the indicator of the power of the stimulation artifact.

2. The method of claim 1, wherein the step of detecting the stimulation artifact comprises detecting the stimulation artifact between the applied stimulation.

3. The method of claim 1, wherein the stimulation artifact is selected from the group consisting of: EMG, EKG, and evoked potentials.

4. The method of claim 1, further comprising detecting a second stimulation artifact.

5. The method of claim 1, further comprising displaying an indicator of the power of the stimulation artifact.

6. The method of claim 1, wherein the step of implanting the electrode comprises implanting a probe having a plurality of electrodes thereon.

7. The method of claim 1, further comprising applying an electrical stimulus to a second electrode and detecting a second stimulation artifact associated with the stimulus from the second electrode; further comprising determining an indicator of the power of the second stimulation artifact.

8. The method of claim 1, further comprising measuring one or more indicators of inflammation.

9. The method of claim 8, further comprising determining a level of inhibition of inflammation based on the measurement of one or more indicators of inflammation.

10. The method of claim 8, further comprising adjusting the position of the stimulation electrode based on the measurement of one or more indicators of inflammation.

11. The method of claim 8, wherein the one or more indicators of inflammation is the level of a biomarker.

12. The method of claim 11, wherein the biomarker is CD11.

13. The method of claim 8, wherein the one or more indicators of inflammation is the level of a neurotransmitter.

14. The method of claim 13, wherein the neurotransmitter is acetylcholine.

15. The method of claim 8, wherein the one or more indicators of inflammation is body temperature.

16. The method of claim 8, wherein the one or more indicators of inflammation is the distribution of cell types.

17. The method of claim 16, wherein the distribution of cell types include granulocyte distribution.

18. A method of optimizing the position of an electrode relative to a subject's inflammatory reflex, the method comprising:
implanting an electrode in electrical communication with either the vagus nerve, the splenic nerve, the hepatic nerve or the trigeminal nerve so the electrode can be stimulated to inhibit inflammation:
applying an electrical stimulus to electrode;
detecting a stimulation artifact;
determining an indicator of the power of the stimulation artifact;
adjusting the position of the stimulation electrode based on the indicator of the power of the stimulation artifact; and
repeating the steps of applying an electrical stimulus to the electrode and detecting the stimulation artifact; further wherein the step of determining the indicator of the power of the stimulation artifact comprises averaging the detected stimulation artifacts to determine the indicator of the power of the stimulation artifact.