Systems and methods for modulating neural immune system

Abstract

Methods and systems for modulating neural immune responses while monitoring biomarkers that may be directly or indirectly associated with neural immune function. Neural modulation therapy may be delivered and biomarker levels may be determined. Some biomarker levels are determined from bodily fluids collected from the patient and compared to predetermined threshold levels. Therapeutic stimulation is delivered to a patient using one or more electrode leads and / or optical fibers.

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 543,193, filed October 9, 2023, the disclosure of which is incorporated herein by reference. Background Technology

[0002] Many diseases involve neuroinflammation. Current medical treatments for neuroinflammation are primarily pharmacological, such as the use of anti-inflammatory drugs that target cytokine inhibition or microglial inhibition. Research indicates that neuromodulation can modulate the neuroimmune system. Historically, neuromodulation therapies have not been optimized to alleviate neuroinflammation. There is currently interest in optimizing neuromodulation therapies to target the neuroimmune response to reduce or otherwise treat neuroinflammation. Summary of the Invention

[0003] The inventors have recognized, among other things, the need to address the demand for non-pharmacological options for treating neuroinflammation. One solution is to optimize current neuromodulation devices for modulating the function of the neuroimmune system. Modulation of neuroimmune responses using electrical stimulation alone and / or in combination with phototherapy has been proposed, as well as monitoring levels of neuroimmune biomarkers. A closed-loop system, such as an SCS system, has also been proposed, which senses neuroinflammatory biomarkers in bodily fluids or receives data on such biomarkers and optimizes therapy over time. Some examples may include implantable neuromodulation systems that are used in conjunction with sensing or other diagnostic systems to obtain neuroinflammatory biomarkers, such as by measuring biomarkers using tissue fluid, blood, CSF, or other bodily interactions.

[0004] The first illustrative and non-limiting example takes the form of a system for optimizing neurotherapy targeting the function of the neuroimmune system, the system comprising: an output circuit housed in an implantable pulse generator configured to emit the neurotherapy; a sensor for sensing the levels of one or more biomarkers in a patient; and a controller configured to: instruct the output circuit to emit the first neurotherapy; instruct the sensor to measure the levels of one or more biomarkers after the first neurotherapy has been emitted by the implantable pulse generator; compare the measurement of the neuromodulated levels of one or more biomarkers with a threshold; and, if the measurement exceeds the threshold, instruct the output circuit to emit a second neurotherapy.

[0005] Alternatively or additionally, the implantable pulse generator includes a sensor and a controller. Alternatively or additionally, the controller is housed within the implantable pulse generator, and the sensor is separate from the implantable pulse generator and communicates with the controller. Alternatively or additionally, the controller is located in an external device having communication circuitry for communicating with the implantable pulse generator; optionally, the sensor is part of the external device.

[0006] Alternatively or additionally, the neurotherapy includes electrical pulses. Alternatively or additionally, the neurotherapy includes optical signals. Alternatively or additionally, the system further includes leads coupled to a pulse generator and adapted to extend from the pulse generator to target neural tissue, wherein: the leads include one or more electrodes for outputting electrical pulses; and / or the leads include an optical transducer for generating an optical output from an electrical signal emitted by an output circuit; and / or the leads include an optical fiber for transmitting optical signals from the output circuit.

[0007] Alternatively or additionally, the measurement result is the amplitude of the biomarker, and the threshold is a population-based threshold for the normal level of one or more biomarkers. Alternatively or additionally, the measurement result is the amplitude of the biomarker, and the threshold is a patient-specific reference for the biomarker. Alternatively or additionally, the measurement result is the trend of the biomarker.

[0008] Additionally or alternatively, the sensor is configured to analyze body fluids in the field, and the body fluids are one of tissue fluid, blood, cerebrospinal fluid, or intrathecal fluid.

[0009] Alternatively or additionally, one or more biomarkers include spleen tyrosine kinase. Alternatively or additionally, one or more biomarkers include regressor D1. Alternatively or additionally, one or more biomarkers are selected from pro-inflammatory mediators, anti-inflammatory mediators, immune cells, or regressor compounds. Alternatively or additionally, the implantable pulse generator includes circuitry for measuring electrical signals from the patient's brain to determine the patient's intrinsic gamma frequency, and the step of delivering neurotherapy to the patient includes emitting electrical pulses at a repetition rate determined based on the patient's intrinsic gamma frequency.

[0010] Another illustrative, non-limiting example takes the form of a method for optimizing neurotherapy targeting neuroimmune system function, the method comprising: delivering neurotherapy to a patient; determining the post-neuromodulation level of one or more biomarkers in the patient, wherein the level of one or more biomarkers is directly or indirectly related to neuroimmune system function; comparing the measurement of the post-neuromodulation level of one or more biomarkers to a threshold; finding that the threshold has been exceeded, and adjusting the neurotherapy settings in response.

[0011] Alternatively or additionally, the measurement result is the amplitude of the biomarker, and the threshold is a population-based threshold for the normal level of one or more biomarkers. Alternatively or additionally, the measurement result is the amplitude of the biomarker, and the threshold is a patient-specific reference for the biomarker. Alternatively or additionally, the measurement result is the trend of the biomarker.

[0012] Additionally or alternatively, the steps of delivering neurotherapy to a patient are performed by delivering electrical stimulation from an implanted device to the patient’s nerves, glial cells, and / or immune structures.

[0013] Additionally or alternatively, the steps for determining the post-neuromodulation level of one or more biomarkers include the on-site collection or analysis of body fluids. Additionally or alternatively, the body fluids are one of tissue fluid, blood, cerebrospinal fluid, or intrathecal fluid.

[0014] Alternatively or alternatively, one or more biomarkers may be spleen tyrosine kinase. Alternatively or alternatively, one or more biomarkers may be regression D1. Alternatively or alternatively, one or more biomarkers may be selected from pro-inflammatory mediators, anti-inflammatory mediators, immune cells, or regression compounds.

[0015] Additionally or alternatively, the steps of delivering neurotherapy to a patient may include sending optically modulated signals to the patient's neural tissue.

[0016] Additionally or alternatively, the method further includes measuring electrical signals from the patient's brain to determine the patient's intrinsic gamma frequency, and the step of delivering the neurotherapy to the patient includes emitting electrical pulses at a repetition rate determined based on the patient's intrinsic gamma frequency.

[0017] This overview is intended to provide an introduction to the subject matter of this patent application. It is not intended to provide an exclusive or exhaustive interpretation. A detailed description is included to provide further information about this patent application. Attached Figure Description

[0018] In accompanying drawings that are not necessarily drawn to scale, the same numbers may describe similar parts in different views. Similar numbers with different letter suffixes may represent different instances of similar parts. The accompanying drawings are illustrated in general terms by way of example and not limitation, of the various embodiments discussed in this document.

[0019] Figure 1 The deep brain stimulation (DBS) system is shown;

[0020] Figure 2 The spinal cord stimulation (SCS) system is shown; and

[0021] Figures 3A to 3B The methods used for patient treatment are shown in boxes. Detailed Implementation

[0022] Figure 1 An illustrative DBS system implanted in a patient is shown. The system includes an implantable pulse generator (IPG) 10, shown implanted in the pectoral muscle region of patient 16. The IPG 10 is coupled to a lead 12, which extends subcutaneously to the head of patient 16, through a drill hole formed in the patient's skull, and then into the brain. In the example shown, the lead 12 includes multiple electrodes positioned near its distal end 14. The lead 12 can be placed in any suitable location in the brain to identify therapeutic targets. For example, the lead 12 can be positioned such that the distal end 14 is close to the midbrain and / or various structures known in the art for providing stimulation to treat various diseases.

[0023] DBS can be targeted to neuronal tissue in, but not limited to, the following sites: thalamus, globus pallidus, subthalamic nucleus, pontine peduncle nucleus, substantia nigra reticularis, cortex, lateral globus pallidus, medial anterior tract, periaqueductal gray matter, periventricular gray matter, habenular nucleus, subgenual cingulate gyrus, ventral intermediate nucleus, anterior nucleus, other nuclei of the thalamus, zona indeterminate, ventral internal capsule, ventral striatum, nucleus accumbens, and / or white matter tracts connecting these and other structures. Data related to DBS may include the identification of neural tissue regions, as determined by analysis, that are associated with side effects or benefits observed in practice. The term "target" as used herein refers to brain structures associated with therapeutic benefits, as opposed to avoidance areas or "avoidance" areas, which are brain structures associated with side effects.

[0024] Conditions to be treated may include dementia, Alzheimer's disease, Parkinson's disease, movement disorders, tremors, depression, anxiety or other mood disorders, sleep-related disorders, etc. Treatment benefits may include, for example, but not limited to, improved cognition, alertness, and / or memory; enhanced mood or sleep; elimination, avoidance, or reduction of pain or tremors; reduction of movement disorders; and / or protection of existing functions and / or cellular structures, such as preventing tissue loss and / or cell death. Treatment benefits may be monitored using, for example, patient surveys, performance tests, and / or physical monitoring (such as monitoring gait, tremors, etc.). Side effects may include a wide range of problems, such as, for example, but not limited to, decreased cognition, neuroinflammation, alertness and / or memory, worsening sleep, depression, anxiety, unexplained weight gain / loss, tinnitus, pain, tremors, etc. These are merely examples, and the discussion of diseases, benefits, and side effects is illustrative and not exhaustive.

[0025] In addition to the above, some examples in this article use, for example... Figure 1The DBS system shown modulates neuroinflammation, such as by influencing neuroinflammation through the emission of therapeutic signals or combinations of therapeutic signals. Accompanying such treatments, biomarkers can be sensed, and these sensed biomarkers can be used to tailor or enhance the therapy.

[0026] Figure 1 The illustrative system includes various external devices. The Clinician Programmer (CP) 30 can be used to determine / select therapeutic procedures, including guidance (explained further below) and stimulation parameters. Stimulation parameters may include the amplitude of the stimulation pulse, the frequency or repetition rate of the stimulation pulse, the pulse width of the stimulation pulse, and more complex parameters known in the art, such as pulse train definition. Biphasic square waves are typically used, but nothing in this invention is limited to biphasic square waves, and ramp, triangle, sine, monophasic, and other stimulation types may be used as needed. In other examples, continuous wave energy may be delivered as a continuous output, for example, in the form of a sine wave or DC or duty cycle DC. The CP 30 can be used by a physician, or under the physician's guidance, to acquire data from and instruct the IPG 10 via a suitable communication protocol (such as Bluetooth or MedRadio or other wireless communication standards) and / or via other modes (such as inductive telemetry).

[0027] The patient remote control (RC) 32 can be used by the patient to perform various actions related to the IPG 10. These actions can be physician-defined options and may include, for example, turning the therapy on and / or off, entering requested information (such as answering questions about the activity, therapy benefits, and side effects), and making (limited) adjustments to the therapy, such as selecting from available therapy programs and adjusting, for example, amplitude settings. The RC 32 can communicate via telemetry technology similar to that of the CP 30 to control the IPG 10 and / or acquire data from it. The patient RC 32 itself can also be programmable or can communicate with or link to the CP 30.

[0028] If the IPG 10 is rechargeable, a charger 36 can be provided to the patient to allow the patient to charge the IPG 10. Some IPG 10s are non-rechargeable, and therefore the charger 36 can be omitted. The charger 36 can operate, for example, by using known methods and circuitry to generate a changing magnetic field to activate an inductor associated with the IPG 10, thereby providing power to charge the IPG battery.

[0029] Some systems may include an external testing stimulator (ETS) 38. After lead 12 has been implanted in the patient, ETS 38 can be used to test therapeutic procedures to determine whether or how effective the therapy will be for the patient 16. For example, initial implantation of lead 12 may be performed using, for instance, a stereotactic guidance system, with IPG 10 temporarily left external. After a healing period, the patient can return to the clinic for therapy configuration and testing. Lead 12 can be connected proximally to an intermediate connector (sometimes referred to as an operating room cable) coupled to ETS 38, and ETS 38 can be programmed with various therapeutic procedures and stimulation parameters using CP 30. Once the therapy's suitability for the patient is established to the satisfaction of the patient 16 and / or physician, a permanent IPG 10 is implanted and lead 12 is attached to it, and then ETS 38 is removed from use.

[0030] Figure 1 Additional features in the system may include a sensor 18 suitable for performing, for example, chemical tests. For example, an optical sensor may include a light source and a cooperating light sensor, each using wavelength-selective interrogation to determine the chemical composition of the surrounding fluid. In another example, a chemical sensor 18 may be provided as needed. Sensor 18 may be tethered to a separate element of IPG 10, or may reside on one of the leads 12. Sensor 18 may alternatively be provided separately from IPG 10 and may communicate as needed, such as via conductive communication, acoustic or ultrasonic signals, or wireless communication such as Bluetooth, Medradio, or other RF. The separately provided sensor 18 may operate in response to an interrogation or activation signal, such as by sensing or receiving power via RF or ultrasonic signals as needed. As previously described, sensor 18 may provide in-situ testing of bodily fluids to determine the levels of one or more biomarkers as described below. Instead of a separately housed sensor 18, IPG 10 may include circuitry and interrogation or collection devices, such as a chemical sensor or optical interface, for measuring and / or determining biomarker levels. Biomarker “amplitude” can indicate prevalence in bodily fluids (such as concentration, whether relative or absolute) and can be used with any suitable parameterization of the biomarker.

[0031] A vagus nerve stimulation system may be provided as shown in Figure 40, located near the vagus nerve. This may replace the IPG 10 and lead 12 if desired, or may be an additional stimulator for the patient 16. The stimulation device may be a microstimulator and may include or omit the lead as needed. Several example microstimulators are disclosed in U.S. Patent 8,127,424, the disclosure of which is incorporated herein by reference. Devices including microstimulators may be externally or internally powered as needed.

[0032] External sensing systems can be provided as indicated in 20. For example, external sensors can be used to acquire fluid samples, such as tissue fluid, blood, lymph, cerebrospinal fluid (CSF), etc., which can be analyzed to identify chemical components. The results can then be used as needed to adjust, trigger, or modulate / pause / delay therapy using the implanted system 10 / 12 or 40.

[0033] In some examples, the internal sensor 18 or the external sensing system 20 may be a fluid analyzer for determining the concentration or other measurable level of biomarkers in fluids obtained from a patient, such as blood or other fluids, saliva, urine, etc. Additionally or alternatively, either sensor 18, 20 may take the form of an optical analyzer or a combined optical interrogation and analysis system. For example, an optical interrogation and analysis system may use, for example, a light-emitting diode, a laser, a vertical-cavity surface-emitting laser, etc., to output light of one or more wavelengths and observe the refraction, reflection, or transmission of light in the patient's fluid or tissue. For example, the wavelength used may determine which analyte is being measured in the tissue or fluid. Any sensor capable of determining the concentration and / or trend of the biomarkers identified herein may be used as the internal sensor 18 or the external sensing system 20. It should be noted that some systems include only one of the two sensors 18, 20, but both may be included or used simultaneously, for example, for continuous monitoring and / or for periodic calibration or checking of the accuracy of the implanted sensor 18 using the external sensor 20. Some examples involve the “amplitude” of a biomarker; this should be understood broadly to refer to the measurable amount of a biomarker in the tissue or body fluid being analyzed, such as concentration or prevalence, or simply its presence.

[0034] An external sensing system 20, or alternatively a sensor 18 implanted in the patient, can communicate with an external controller (such as CP 30 or RC 32), which in turn sends command signals to the IPG 10 to adjust the therapy after the first therapy or to administer a second therapy, wherein “adjustment” can include any of changing therapy parameters, activating the therapy, or stopping the therapy. Thus, the external device contains a controller that communicates with both the sensor (18 or 20) and the IPG 10, wherein the IPG includes output circuitry for administering therapy (such as electrotherapy or phototherapy, or both, as described herein) to the patient. In another example, sensor 20 may be part of CP 30 or RC 32, if desired. Alternatively, the IPG may integrate sensor 18 and also include a controller that performs analysis to determine whether and when to administer further therapy or adjust the therapy in response to sensed biomarker data. In some other examples, the IPG 10 may have a controller and output circuitry for delivering neurotherapy to a patient, and the IPG may include communication circuitry for communicating with a sensor (implantable 18 or external 20) to receive biomarker data.

[0035] Figure 2 An illustrative spinal cord stimulation system has been implanted. In this example, the IPG 70 can be placed near the patient's hip or in the patient's abdomen, with or without a lead extension 72 for coupling to one or more leads 74 entering the spine. A region 76 approximately at the level of the lower thoracic or upper lumbar vertebrae can be used as an entry point into the spine, where the distal ends of the leads 74 with electrode arrays can be placed close to the spinal cord 80. Other locations for the IPG 70 and / or leads 74 can be used. For example, sacral nerve stimulation can be performed.

[0036] In similar Figures 1 to 2 In the system shown, the standard approach to therapy is via IPG 14 (and ETS 20), which can deliver current-controlled or voltage-controlled therapy, including biphasic or monophasic square waves with passive recovery. Generally, the current output from the electrodes should return to zero over time to avoid corrosion at the electrode-tissue interface. Therefore, biphasic pulses or monophasic pulses with a passive recovery period are typically used.

[0037] Most therapies delivered in DBS and / or SCS are provided without feedback or with only indirect feedback. Much of the feedback is also immediate and acute, which does not provide visibility into chronic or longer-term changes. For example, during some testing and configuration procedures, patients may consciously answer questions about the benefits or side effects of the therapy, which introduces both the delay time required for the patient to perceive the stimulus effect and adds uncertainty to the feedback due to subjectivity. Sensing and modulating neuroinflammatory information is highly desirable, and some examples in this paper use additional testing and / or sensing to achieve closed-loop neuroinflammatory therapy.

[0038] Many diseases involve neuroinflammation (e.g., chronic pain, Parkinson's disease, Alzheimer's disease, epilepsy, major depressive disorder, type 2 diabetes, rheumatoid arthritis, hypertension, irritable bowel syndrome, asthma, etc.). Optimizing existing neuromodulation devices to modulate neuroimmune responses against neuroinflammation would be beneficial. For example, some neuromodulation systems (DBS, SCS, vagus nerve, etc.) have been shown to modulate the neuroimmune system.

[0039] Figures 3A to 3B The illustrative process of delivering neurotherapy, sensing biochemical markers, comparing them to thresholds, and adjusting neurotherapy settings is shown in box form. From Figure 3A Initially, at box 100, the neurotherapy is delivered via the neuromodulation system described above. The therapy can be delivered alone as electrotherapy 102, as phototherapy 104, or as a combination of electrotherapy and phototherapy 106, or delivered in combination with other therapies (magnetic, ultrasound, etc.) as needed.

[0040] The therapeutic location in box 108 can be any of the previously mentioned "targets". For example, the therapy can be directed to brain structures such as the thalamus, globus pallidus, subthalamic nucleus, pontine peduncle nucleus, substantia nigra reticularis, cortex, lateral globus pallidus, medial anterior tract, periaqueductal gray matter, periventricular gray matter, habenular nucleus, subgenual cingulate gyrus, ventral intermediate nucleus, anterior nucleus, other nuclei of the thalamus, zona indeterminate, ventral internal capsule, ventral striatum, nucleus accumbens, and / or white matter tracts connecting these structures to other structures. Stimulation can instead be directed to the spinal cord, occipital nerve, vagus nerve, renal nerve, sacral nerve, or other locations. In some embodiments, the therapy can be delivered to more than one location 108.

[0041] Electrical stimulation 102, light stimulation 104, and / or combined stimulation can be defined by any suitable parameters or combinations thereof, and can be altered / controlled by the amplitude of the stimulation pulses, the frequency or repetition rate of the stimulation pulses, the pulse width of the stimulation pulses, and more complex parameters such as pulse train definition. Biphasic square waves can be used, and / or ramp, triangular, sine, polyphasic, monophasic, and other stimulation pulses or types may be used as needed, including continuous wave energy, which can be delivered as a continuous output, for example, in the form of a sine wave or DC or duty cycle DC, and can be used to reduce neuroinflammation when applied to any suitable neural structure. Light therapy 104, alone or in combination 106, can include any variation of a neuromodulation device, such as using a light source or one or more transducers at the end of a lead, or using a lead with an optical fiber passing through a pulse generator where one or more light sources are located. In some embodiments, the light source may be located on the body of the lead extension. In some embodiments, the light source may be configured to project light onto a target at wavelengths in the range of about 600 nanometers (nm) to 1300 nm, but longer or shorter wavelengths may also be used as needed.

[0042] Stimulations used for neuroinflammatory therapy purposes may occur on a different schedule than those used by some other systems. For example, neuroinflammatory therapy may be delivered with a duty cycle of, for example, 1% or less, instead of several hours of therapy per day. For instance, in some examples, stimulation may be delivered for about 1 to about 10 minutes per day, or it may be delivered less frequently than daily. In another example, stimulation may last for several hours, but only once every seven to thirty days. Other variations of low-duty-cycle stimulation may be used; “duty cycle” indicates the amount of time stimulation is on relative to the total repetition rate of a given therapy procedure.

[0043] At box 110, biochemical markers for sensing neuroinflammation are included. Biomarkers may include spleen tyrosine kinase (STK) 112, regression-inducing D1 (RvD1) 114, specific pro-regression mediators (SP mediators) 116, such as SP mediators derived from omega-3 polyunsaturated fatty acids, or other biomarkers 118 as needed. Other biomarkers 118 may include, for example, interleukin-1 beta and / or neutrophil-derived chemical markers S100-8B. Other biomarkers 118 may also include pro-inflammatory and anti-inflammatory mediators, such as chemokines and cytokines. Other biomarkers 118 may also include immune cells, such as monocytes, macrophages, T cells, phagocytes, and lymphocytes. Besides RvD1, other forms of regression can be used as biomarkers, such as regression E1, regression E3, regression E4, 17R-regression D1, regression D2, regression D3, 17R-regression D3, regression D4, and regression D5. Depending on the need, some biomarkers can be associated with the innate immune system.

[0044] These and other biomarkers can be used to determine levels of neuroinflammation and oxidative stress, as described in more detail below. In some embodiments, the wearable device can measure the levels of one or more biomarkers. In some embodiments, the levels of one or more biomarkers can be measured from a blood draw. In some embodiments, the levels of one or more biomarkers can be measured intrathecally. In some embodiments, the levels of biomarkers can be inferred from sympathetic or parasympathetic tone (blood pressure, heart rate, etc.). For example, an increased sympathetic response (high heart rate and / or blood pressure) may be associated with increased neuroinflammation. In some embodiments, biomarkers can be evaluated using computed tomography to assess local blood flow and / or oxygenation. In some embodiments, the levels of one or more biomarkers can be measured by a wearable device that emits a stimulus that causes electroporation and releases or increases the presence of tissue fluid, and the tissue fluid can be obtained for chemical analysis, such as via biomarker determination. In some embodiments, biomarker levels can be tested daily. In other embodiments, biomarker levels can be tested less frequently, such as every other day, weekly, etc. Biomarkers can be tested in response to events identified by the patient or device; for example, if a patient experiences a period of increased anxiety, the patient can respond by obtaining a biomarker sample using a wearable device. In some embodiments, biomarker levels can be tested frequently at the start of a new therapy setting, and then the frequency can be reduced over time.

[0045] Go to Figure 3BAt box 120, the measured level of the neuroinflammatory biomarker is compared to a predetermined threshold. Such a threshold can be external and / or absolute, such as using a population-based definition using “normal reference” or “normal range,” as indicated at box 122. In other examples, the threshold can be patient-specific, as indicated at box 124. For example, a patient-specific threshold can be determined by observing patient symptoms associated with the neuroinflammatory state and identifying the level of a given biomarker at the onset or resolution of symptoms, using the identified level as a threshold or target. The patient-specific threshold or reference value can include statistical measurements, such as the mean of the specific biomarker over time, plus or minus one or more of variance, standard deviation, etc. Trends 126 can also be assessed, such as trends that can be determined from the rate of change of neuroinflammatory biomarker levels, and the direction of change of the neuroinflammatory biomarker. For example, it can be determined whether the level of the biomarker is increasing at a high rate. This combination of analyses can be used, such as observing whether a biomarker is outside a population-based normal range 122, or whether it is outside a patient-specific expected range 124 and has a trend 126 toward the outer boundary of the normal range 122, either of which can be considered a triggering factor in this example. Trend 126 can also look for absolute changes in any biomarker of interest over a specific time period.

[0046] If the analysis at 120 crosses or exceeds any applicable threshold (based on population-based normal values ​​122, patient-specific 124, and / or trend 126), the therapeutic parameters can be adjusted, as indicated at 130. At box 130, the therapeutic parameters can be adjusted based on biomarker information. Adjustments may include changes to amplitude 132, pulse width 134, duty cycle (not shown), and frequency 136. As another type of adjustment at 130, stimulation can be started or stopped, or repeated. For example, combined stimulation of 60 Hz and 1 kHz with an arbitrarily induced pulse pattern can reduce neuroinflammation by increasing the generation and release of RvD1. In another example, 40 Hz stimulation can increase SYK levels and reduce neuroinflammation.

[0047] Therapies can be delivered at the patient's inherent gamma frequency to alleviate neuroinflammation, for example, by acquiring electrical signals emanating from the brain first through an implanted device (such as a lead) or through other invasive data collection (such as a sensing catheter advanced into a blood vessel in the brain), or through transcranial sensing. The patient's gamma frequency can then be determined through analysis, such as Fourier transform, principal component analysis, wavelet decomposition, and other methods that can identify frequencies of interest in the captured signal. For example, the therapy can be delivered in pulse repetition rate or continuous wave energy (such as a sine wave or other continuous output) or in any other waveform configured to match the patient's determined gamma frequency.

[0048] In another example, low-level red to near-infrared light irradiation (600 nm to 1300 nm) has been shown to have anti-inflammatory effects on the brain. In any such example, one or more of the following can be adjusted: frequency, duty cycle, duration of treatment, amplitude, pulse width, target location of treatment, etc. The treatment cycle can be considered a chronic therapy and therefore may be continuously updated and adjusted over time.

[0049] In some examples, not using Figures 3A to 3B The procedure adjusts the therapy, and this method can be used to trigger additional treatment. For example, if a biomarker is within a threshold, box 120 can return the process to box 110 to perform additional sensing of one or more biomarkers, such as after a waiting period (e.g., one or several days). When monitoring biomarkers, trends 126 in the biomarker data can be observed and used as a way to determine at box 120 whether an additional threshold has been exceeded. Multiple thresholds can be applied; for example, a first threshold can be related to determining whether the therapy was effective at the time of delivery, and a second threshold is used to determine when the therapy needs to be repeated after a successful initial treatment. When the second threshold is exceeded at box 120, it means the patient should receive additional therapy, and box 130 can include repeating the previously delivered therapy, as indicated at 138. This can be achieved by retaining existing therapy parameters and... Figure 3B / Box 130 returns to Box 110 and reissues the therapy to achieve this.

[0050] Throughout the process, biomarker levels can also be stored, and changes in biomarker levels following a change in neurotherapy can influence subsequent treatments. For example, if neurotherapy is adjusted to increase RvD1 levels, and the RvD1 levels increase slowly, treatment parameters can be adjusted to increase the rate of change. In another example, if red light is directed at a patient from near-infrared light, and neuroinflammatory biomarker levels do not change, treatment parameters can be adjusted to include another type of treatment, such as electrical stimulation. Such linked data can be reported to a central repository or database as needed to inform treatment decisions for other or future patients.

[0051] In some embodiments, the neuromodulation therapy regimen may be tailored to include the stimulation parameters described above at specific intervals. In some embodiments, the neurotherapy may be administered for only a few hours. In other embodiments, the neurotherapy may be administered at regular intervals (weekly, monthly, etc.). In yet another embodiment, the therapy may be delivered for several hours on days 1, 3, and 5 of the treatment cycle. In any of the above embodiments, biomarker monitoring may be performed post-therapy, which may trigger further therapeutic treatments or adjustments to the therapy parameters.

[0052] For example, biomarkers of neuroinflammation can be measured before treatment to establish a baseline for the patient's condition. Therapies can be prescribed to modulate the neuroinflammatory system, and biomarkers can be monitored after treatment to observe changes, which could be a reduction in neuroinflammatories or an increase in neuroinflammatories. As the observed changes begin to diminish and the patient returns to baseline, subsequent treatment can be triggered. Illustrative timeframes can vary depending on the therapy used and the baseline biomarkers monitored, ranging from minutes to hours, days, weeks, or even longer.

[0053] For example, if a given neuroinflammatory agent for a particular patient sets the normalized baseline metric to 10, therapy can reduce that metric to a normalized score, such as 1. After therapy, the metric can return towards the normalized baseline over time. When the metric reaches a predetermined threshold (such as 3, 5, 7, 9), therapy can be triggered again, depending on the physician's choice and / or the perceived effect of the agent represented by the metric (such as the onset of symptoms).

[0054] Conversely, if the normalized baseline metric is set to 0 for a given neuroinflammation inhibitor, the therapy can increase that metric to, for example, 10. After therapy, the metric can return to the normalized baseline over time. When the metric reaches a predetermined threshold (such as 6, 4, 3, 2), the therapy can be triggered again, depending on the physician's choice and / or the perceived effect of the agent represented by the metric (such as the onset of symptoms).

[0055] Some examples utilize therapies with relatively long-lasting effects. For instance, a combination of stimulating one tissue area with a relatively low frequency and stimulating a second tissue area with a relatively high frequency can have a lasting effect. The lower frequencies can be up to 100 Hz, or in the range of 40 to 60 Hz, lasting for minutes to hours, for example. The higher frequencies can exceed 200 Hz, 500 Hz, or 1000 Hz, for example, in the range of 1 kHz to 2 kHz or about 1.2 kHz, and can also be emitted for minutes to hours. Such combinations have been shown to provide modulating effects for up to several weeks. A specific combination could be an overlapping therapy that delivers a lower frequency signal of 40 to 60 Hz and a higher frequency signal of 1.2 kHz to neural tissue. These two therapies can be directed to a single tissue location or separate tissue locations as needed, such as a single location or more than one location along the spinal cord.

[0056] The communication circuitry may include, for example, an application-specific integrated circuit (ASIC), such as a commercially available Bluetooth and / or Bluetooth Low Energy chip, or a Medradio ASIC (also commercially available), or a set of discrete components, including at least an oscillator, an antenna, and tuning circuitry suitable for generating RF or other frequency level signals. Inductive telemetry or other telemetry circuitry using induction coils may be used instead, including either conducted communication and / or optical or mechanical (e.g., ultrasonic) communication. The controller may include microcontroller, microprocessor, or state machine logic associated with logic and / or memory for storing machine-readable instructions in tangible and / or non-transient formats (such as flash memory, RAM, ROM, etc.) to perform the methods described herein. The output circuitry may include, for example, current controllers or voltage-controlled output circuitry known in various commercially available SCS, DBS, and / or vagus nerve stimulation systems.

[0057] Each of these non-restrictive examples can exist independently or can be combined with one or more other examples in various permutations or combinations.

[0058] The above detailed description includes references to the accompanying drawings, which form part of the detailed description. The drawings illustrate specific embodiments by way of illustration. These embodiments are also referred to herein as "examples." These examples can also include elements other than those shown or described. However, the inventors also contemplate examples that provide only those elements shown or described. Furthermore, the inventors contemplate examples using any combination or arrangement of those elements (or one or more aspects thereof) shown or described, whether concerning a particular example (or one or more aspects thereof) or other examples (or one or more aspects thereof) shown or described herein.

[0059] In the event of any inconsistency between the usage in this document and any other document incorporated by reference, the usage in this document shall prevail.

[0060] In this document, the terms “a” or “an” (as is common in patent documents) include one or more, and are not related to any other example or use of “at least one” or “one or more”. Furthermore, in the claims, the terms “first,” “second,” and “third,” etc., are used merely as labels and are not intended to impose numerical requirements on their objects.

[0061] The methods described herein can be implemented, at least in part, by a machine or computer. Some examples can include computer-readable or machine-readable media encoded with instructions operable to configure an electronic device to perform the methods described in the examples above. Implementations of such methods can include code, such as microcode, assembly language code, high-level language code, etc. Such code can include computer-readable instructions for performing various methods. The code can form part of a computer program product. Furthermore, in one example, the code can be tangibly stored on one or more volatile, non-transient, or non-volatile tangible computer-readable media, such as during execution or at other times. Examples of such tangible computer-readable media can include, but are not limited to, hard disks, removable disks or optical discs, magnetic tape cassettes, memory cards or memory sticks, random access memory (RAM), read-only memory (ROM), and similar devices.

[0062] The above description is intended to be illustrative and not restrictive. For example, the above examples (or one or more aspects thereof) can be used in combination with each other. Other embodiments can be used, such as those used by those skilled in the art after reviewing the above description.

[0063] An abstract is provided to comply with 37 CFR § 1.72(b) so that the reader can quickly determine the nature of the technical disclosure. When submitting this abstract, it should be understood that it will not be used to interpret or limit the scope or meaning of the claims.

[0064] Furthermore, in the above detailed description, various features may be grouped together to simplify this disclosure. This should not be construed as meaning that unclaimed features are essential to any claim. Rather, the subject matter of the invention may reside in some features of a particular disclosed embodiment. Therefore, the following claims are incorporated herein by way of example or embodiment, wherein each claim exists independently as a separate embodiment, and these embodiments are contemplated to be combined with each other in various combinations or arrangements. The scope of protection should be determined with reference to the appended claims and the full scope of their equivalents.

Claims

1. A system for optimizing neurotherapy targeting neuroimmune system function, the system comprising: An implantable pulse generator housing an output circuit configured to emit neurotherapy signals; Sensors used to detect the levels of one or more biomarkers in a patient's body; The controller is configured to: The output circuit is instructed to emit the first neurotherapy. After the first neurotherapy is delivered by the implantable pulse generator, the sensor is instructed to measure the levels of the one or more biomarkers; The measurement results of the post-neuromodulation levels of the one or more biomarkers are compared with the threshold; and If the measurement result exceeds the threshold, the output circuit is instructed to issue a second neurotherapy.

2. The system according to claim 1, wherein, The implantable pulse generator includes the sensor and the controller.

3. The system according to claim 1, wherein, The controller is housed within the implantable pulse generator, and the sensor is separate from the implantable pulse generator and communicates with the controller.

4. The system according to claim 1, wherein, The controller is located in an external device having communication circuitry for communicating with the implantable pulse generator, wherein, optionally, the sensor is part of the external device.

5. The system according to claim 1, wherein, The neurotherapy includes electrical pulses.

6. The system according to claim 1, wherein, The neurotherapy includes light signals.

7. The system according to any one of claims 5 or 6, further comprising a lead coupled to the pulse generator and adapted to extend from the pulse generator to the target neural tissue, wherein: The lead includes one or more electrodes for outputting electrical pulses; and / or The leads include an optical transducer for generating an optical output from an electrical signal emitted by the output circuit; and / or The lead includes an optical fiber for transmitting optical signals from the output circuit.

8. The system according to any one of claims 1 to 7, wherein, The measurement result is the amplitude of the biomarker, and the threshold is a population-based threshold for the normal level of the one or more biomarkers.

9. The system according to any one of claims 1 to 7, wherein, The measurement result is the amplitude of the biomarker, and the threshold is a patient-specific reference for the biomarker.

10. The system according to any one of claims 1 to 7, wherein, The measurement results indicate the trend of the biomarker.

11. The system according to any of the preceding claims, wherein, The sensor is configured to analyze body fluids in the field, and the body fluids are one of tissue fluid, blood, cerebrospinal fluid, or intrathecal fluid.

12. The system according to any one of claims 1 to 11, wherein, One or more biomarkers include spleen tyrosine kinase.

13. The system according to any one of claims 1 to 11, wherein, The one or more biomarkers include desensitizing factor D1.

14. The system according to any one of claims 1 to 11, wherein, The one or more biomarkers mentioned are selected from pro-inflammatory mediators, anti-inflammatory mediators, immune cells, or regressive compounds.

15. The system according to any one of claims 1 to 11, wherein, The implantable pulse generator includes circuitry for measuring electrical signals from the patient's brain to determine the patient's intrinsic gamma frequency, and the step of delivering neurotherapy to the patient includes emitting electrical pulses at a repetition rate determined based on the patient's intrinsic gamma frequency.

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