Patent Publication Number: US-11395625-B2

Title: Pain management based on functional measurements

Description:
CLAIM OF PRIORITY 
     This application is a continuation of U.S. application Ser. No. 15/867,760, filed Jan. 11, 2018, which claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Ser. No. 62/445,075, filed on Jan. 11, 2017, which is herein incorporated by reference in its entirety. 
     CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is related to commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,053, entitled “PAIN MANAGEMENT USING CARDIOVASCULAR PARAMETERS”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/445,061, entitled “PAIN MANAGEMENT BASED ON BRAIN ACTIVITY MONITORING”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/445,069, entitled “PAIN MANAGEMENT BASED ON RESPIRATION-MEDIATED HEART RATES”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/445,082, entitled “PAIN MANAGEMENT BASED ON EMOTIONAL EXPRESSION MEASUREMENTS”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/445,092, entitled “PAIN MANAGEMENT BASED ON MUSCLE TENSION MEASUREMENTS”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/445,095, entitled “PATIENT-SPECIFIC CALIBRATION OF PAIN QUANTIFICATION”, filed on Jan. 11, 2017, U.S. Provisional Patent Application Ser. No. 62/395,641, entitled “METHOD AND APPARATUS FOR PAIN MANAGEMENT USING HEART SOUNDS”, filed on Sep. 16, 2016, U.S. Provisional Patent Application Ser. No. 62/400,313, entitled “SYSTEMS AND METHODS FOR CLOSED-LOOP PAIN MANAGEMENT”, filed on Sep. 27, 2016, U.S. Provisional Patent Application Ser. No. 62/400,336, entitled “METHOD AND APPARATUS FOR PAIN MANAGEMENT USING OBJECTIVE PAIN MEASURE”, filed on Sep. 27, 2016, U.S. Provisional Patent Application Ser. No. 62/412,587, entitled “METHOD AND APPARATUS FOR PAIN CONTROL USING BAROREFLEX SENSITIVITY DURING POSTURE CHANGE”, filed on Oct. 25, 2016, which are incorporated by reference in their entirety. 
    
    
     TECHNICAL FIELD 
     This document relates generally to medical systems and more particularly to systems, devices, and methods for pain management. 
     BACKGROUND 
     Pain is one of the most common and among the most personally compelling reasons for seeking medical attention, and consumes considerable healthcare resources each year. The relation between etiology, underlying mechanisms and the specific symptoms and signs related to painful disorders is complex. Pain in an individual patient may be produced by more than one mechanism. 
     Chronic pain, such as pain present most of the time for a period of six months or longer during the prior year, is a highly pervasive complaint and consistently associated with psychological illness. Chronic pain may originate with a trauma, injury or infection, or there may be an ongoing cause of pain. Chronic pain may also present in the absence of any past injury or evidence of body damage. Common chronic pain can include headache, low back pain, cancer pain, arthritis pain, neurogenic pain (pain resulting from damage to the peripheral nerves or to the central nervous system), or psychogenic pain (pain not due to past disease or injury or any visible sign of damage inside or outside the nervous system). 
     Chronic pain may be treated or alleviated using medications, acupuncture, surgery, and neuromodulation therapy such as local electrical stimulation or brain stimulation, among others. Examples of neuromodulation include Spinal Cord Stimulation (SCS), Deep Brain Stimulation (DBS), Peripheral Nerve Stimulation (PNS), and Functional Electrical Stimulation (FES). Implantable neuromodulation systems have been applied to deliver such a therapy. An implantable neuromodulation system may include an implantable neurostimulator, also referred to as an implantable pulse generator (IPG), which can electrically stimulate tissue or nerve centers to treat nervous or muscular disorders. In an example, an IPG can deliver electrical pulses to a specific region in a patient&#39;s spinal cord, such as particular spinal nerve roots or nerve bundles, to create an analgesic effect that masks pain sensation. 
     SUMMARY 
     By way of example, chronic pain management may involve determining appropriate treatment regimens such as SCS and evaluating therapy efficacy. Accurate pain assessment and characterization are desirable for managing patients with chronic pain. Currently, pain assessment generally relies on patient subjective report of pain symptoms, including severity, pattern, or duration of pain. Based on the patient reported pain sensation, a clinician may prescribe a pain therapy, such as to manually program an electrostimulator for delivering a neuromodulation therapy. However, the subjective description of pain sensation may be constrained by patient cognitive abilities. The subjective pain description may also be subject to intra-patient variation, such as due to a progression of a chronic disease, or a change in general health status or medication. Having a patient to report and describe each pain episode he or she has experienced is not efficient and may delay appropriate pain therapy. Additionally, for patients in an ambulatory setting who lack immediate access to medical assistance, manual adjustment of pain therapy by a clinician may not be feasible especially if immediate therapy titration is required. The present inventors have recognized that there remains a demand for improving pain management, such as systems and methods for objective pain assessment and automated closed-loop pain therapy based on objective pain assessment. 
     This document discusses, among other things, systems, devices, and methods for assessing pain of a subject. The system includes motion sensors to sense at least one functional signal indicative a physical state of the patient. The functional signal may include at least one signal of motor activity or sleep state. The system may extract from the functional signal one or more signal metrics indicative of patient motor control or kinetics, and generate a pain score using the one or more signal metrics. The pain score can be output to a patient or used for closed-loop control of a pain therapy. 
     Example 1 is a system for managing pain of a patient. The system comprises a sensor circuit, a pain analyzer circuit, and an output unit. The sensor circuit may be coupled to a motion sensor and configured to sense from the patient at least one functional signal indicative of a physical state of the patient. The pain analyzer circuit, coupled to the sensor circuit, may be configured to generate, from each of the sensed at least one functional signal, one or more signal metrics indicative of patient motor control or kinetics, and generate a pain score using the generated one or more signal metrics. The output unit may be configured to output the pain score to a user or a process. 
     In Example 2, the subject matter of Example 1 optionally includes an electrostimulator configured to generate electrostimulation energy to treat pain, and a controller circuit coupled to the pain analyzer circuit and the electrostimulator. The controller circuit may be configured to control the electrostimulator to deliver a pain therapy and to control the electrostimulation energy generated by the electrostimulator according to the pain score. 
     In Example 3, the subject matter of Example 2 optionally includes the electrostimulator that may be further configured to deliver at least one of: a spinal cord stimulation; a brain stimulation; or a peripheral nerve stimulation. 
     In Example 4, the subject matter of any one or more of Examples 2-3 optionally includes the controller circuit that may be further configured to deliver first electrostimulation to the patient in response to the pain score exceeding a threshold value, and to deliver second electrostimulation to the patient in response to the pain score falling below the threshold value. The first electrostimulation may differ from the second electrostimulation with respect to at least one of an electrostimulation energy, an electrostimulation pulse shape, or an electrostimulation pattern. 
     In Example 5, the subject matter of any one or more of Examples 1-4 optionally includes the at least one functional signal including at least one motor activity signal. 
     In Example 6, the subject matter of any one or more of Examples 1-5 optionally includes the at least one functional signal including at least one sleep state signal. 
     In Example 7, the subject matter of any one or more of Examples 1-6 optionally includes the motion sensor that may comprise an ambulatory sensor including at least one of: an accelerometer; a gyroscope; a magnometer; or a global positioning system (GPS) sensor. 
     In Example 8, the subject matter of Example 7 optionally includes the motion sensor that may be configured to be mounted on a garment or footwear. 
     In Example 9, the subject matter of any one or more of Examples 7-8 optionally includes the motion sensor disposed in a mobile device communicatively coupled to the pain analyzer circuit. 
     In Example 10, the subject matter of any one or more of Examples 1-9 optionally includes the motion sensor that may comprise a camera configured to produce image data of the physical state of the patient. The pain analyzer circuit may be further configured to generate, from the image data, a plurality of image features indicative of body motion, and to generate the pain score using the generated plurality of image features. 
     In Example 11, the subject matter of any one or more of Examples 1-10 optionally includes the sensor circuit that may be further configured to sense the at least one functional signal in response to a triggering event. 
     In Example 12, the subject matter of any one or more of Examples 1-11 optionally includes the pain analyzer circuit that may be further configured to generate the pain score using a combination of a plurality of the signal metrics weighted by their respective weight factors. 
     In Example 13, the subject matter of any one or more of Examples 1-12 optionally includes the pain analyzer circuit that may be further configured to generate the pain score using a combination of comparisons between a plurality of the signal metrics and their respective threshold value. 
     In Example 14, the subject matter of any one or more of Examples 1-13 optionally includes the output unit that may be further configured to produce an alert based on the generated pain score. 
     In Example 15, the subject matter of any one or more of Examples 2-14 optionally include an implantable neuromodulator device (IND) that includes one or more of the sensor circuit, the pain analyzer circuit, or the electrostimulator. 
     Example 16 is a method for managing pain of a patient using an implantable neuromodulator device (IND). The method comprises: sensing at least one functional signal from the patient via a sensor circuit, the at least one functional signal indicative of a physical state of the patient; generating, from each of the sensed at least one functional signal, one or more signal metrics indicative of patient motor control or kinetics; generating a pain score based on the one or more signal metrics; and outputting the pain score to a user or a process. 
     In Example 17, the subject matter of Example 16 optionally includes delivering a pain therapy via the IND. The pain therapy may include electrostimulation energy determined according to the pain score. 
     In Example 18, the subject matter of any one or more of Examples 16-17 optionally includes the at least one functional signal including at least one motor activity signal. 
     In Example 19, the subject matter of Example 18 optionally includes the at least one motor activity signal that may include at least one of: a physical activity signal; a posture signal; a gait signal; a balance signal; or a range of motion signal. 
     In Example 20, the subject matter of any one or more of Examples 16-19 optionally includes the at least one functional signal including at least one sleep state signal. 
     In Example 21, the subject matter of Example 20 optionally includes the sleep state signal which may include at least one of: a sleep incline; a sleep pattern disruption; or a sleep position switch. 
     In Example 22, the subject matter of any one or more of Examples 16-21 optionally includes capturing an image of the physical state of the patient using a camera. The one or more signal metrics may include image features indicative of body motion. 
     In Example 23, the subject matter of any one or more of Examples 16-22 optionally includes generating the pain score using a combination of a plurality of the signal metrics weighted by their respective weight factors. 
     The pain score generated based on the functional signals, such as based on the motor activity or sleep state signals as discussed in this document, may improve medical diagnostics of automated characterization of patient pain, as well as individualized therapies to alleviate pain and to reduce side effects. The systems, devices, and methods discussed in this document may also enhance the performance and functionality of a pain management system or device. A device or a system programmed with the sensor-based pain assessment methods can have improved automaticity in medical diagnostics. More efficient device memory or communication bandwidth usage may be achieved by storing or transmitting medical information more relevant to clinical decisions. Additionally, through improved pain therapy based on patient individual need and therapy efficacy, battery longevity of an implantable device may be enhanced, or pain medication volume may be saved. 
     This summary is intended to provide an overview of subject matter of the present patent application. It is not intended to provide an exclusive or exhaustive explanation of the disclosure. The detailed description is included to provide further information about the present patent application. Other aspects of the disclosure will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which are not to be taken in a limiting sense. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Various embodiments are illustrated by way of example in the figures of the accompanying drawings. Such embodiments are demonstrative and not intended to be exhaustive or exclusive embodiments of the present subject matter. 
         FIG. 1  illustrates, by way of example and not limitation, a neuromodulation system and portions of an environment in which the neuromodulation system may operate. 
         FIG. 2  illustrates, by way of example and not limitation, a block diagram of a pain management system. 
         FIG. 3  illustrates, by way of example and not limitation, a block diagram of another pain management system. 
         FIG. 4  illustrates, by way of example and not limitation, a portion of a pain management system for sensing functional signal indicative a physical state of the patient. 
         FIG. 5  illustrates, by way of example and not limitation, a method for managing pain of a patient. 
         FIG. 6  illustrates, by way of example and not limitation, a block diagram of an example machine upon which any one or more of the techniques discussed herein may perform. 
     
    
    
     DETAILED DESCRIPTION 
     In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which is shown by way of illustration specific embodiments in which the invention may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is to be understood that the embodiments may be combined, or that other embodiments may be utilized and that structural, logical and electrical changes may be made without departing from the spirit and scope of the present invention. References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description provides examples, and the scope of the present invention is defined by the appended claims and their legal equivalents. 
     Clinically, chronic pain may affect a patient&#39;s motion control. As a result, patients in pain may present with poor or unbalanced posture, abnormal gait pattern, restrained range of motion, or decreased intensity or duration of physical activities. Pain may also cause body to compensate, such that muscles, ligaments and nerves may move differently to adapt to the pain. Over time, some muscles may become chronically tight while other muscles weaken, and ligaments may stretch to accommodate uneven body motion. The compensatory changes in posture and the unbalanced motion pattern may gradually exacerbate the chronic pain and cause recurring injuries, resulting in a vicious pain cycle. In addition to motion control disorders, some patients in chronic pain may experience high incidence of sleep disturbance, such as poor sleep quality, shorter sleep duration, or frequent body position switches during sleep. Sleep disturbance is correlated to greater pain intensity, disability, depression, and other physical symptoms. Moreover, sleep disturbance may aggravate the pain symptoms. Therefore, close monitoring of patient motor control or sleep disturbance may provide an objective assessment of pain, and may be used to improve pain therapy efficacy. 
     Disclosed herein are systems, devices, and methods for or assessing pain of a subject, and optionally programming pain therapy based on the pain assessment. In various embodiments, the present system may include sensors configured to sense functional signals indicative a physical state of the subject. The functional signals may include signals of motor activities or sleep state. A pain analyzer circuit may generate a pain score using signal metrics extracted from the functional signals. The system may include a neurostimulator that can deliver a pain therapy according to the pain score. 
     The present system may be implemented using a combination of hardware and software designed to provide a closed-loop pain management regimen to increase therapeutic efficacy, increase patient satisfaction for neurostimulation therapies, reduce side effects, and/or increase device longevity. The present system may be applied in any neurostimulation (neuromodulation) therapies, including but not limited to SCS, DBS, PNS, FES, and Vagus Nerve Stimulation (VNS) therapies. In various examples, instead of providing closed-loop pain therapies, the systems, devices, and methods described herein may be used to monitor the patient and assess pain that either occurs intrinsically or is induced by nerve block procedures or radiofrequency ablation therapies, among others. The patient monitoring may include generating recommendations to the patient or a clinician regarding pain treatment. 
       FIG. 1  illustrates, by way of example and not limitation, an example of a neuromodulation system  100  for managing pain of a subject such as a patient with chronic pain, and portions of an environment in which the neuromodulation system  100  may operate. The neuromodulation system  100  may include an implantable system  110  that may be associated with a body  199  of the subject, and an external system  130  in communication with the implantable system  110  via a communication link  120 . 
     The implantable system  110  may include an ambulatory medical device (AMD), such as an implantable neuromodulator device (IND)  112 , a lead system  114 , and one or more electrodes  116 . The IND  112  may be configured for subcutaneous implant in a patient&#39;s chest, abdomen, or other parts of the body  199 . The IND  112  may be configured as a monitoring and diagnostic device. The IND  112  may include a hermetically sealed can that houses sensing circuitry to sense physiological or functional signals from the patient via sensing electrodes or ambulatory sensors associated with the patient and in communication with the IND  112 . In some examples, the sensing electrodes or the ambulatory sensors may be included within the IND  112 . The physiological or functional signals, when measured during a pain episode, may be correlative to severity of the pain. The IND  112  may characterize and quantify the pain, such as to determine onset, intensity, severity, duration, or patterns of the pain experienced by the subject. The IND  112  may generate an alert to indicate occurrence of a pain episode, pain exacerbation, or efficacy of pain therapy, and present the alert to a clinician. 
     The IND  112  may alternatively be configured as a therapeutic device for treating or alleviating the pain. In addition to the pain monitoring circuitry, the IND  112  may further include a therapy unit that can generate and deliver energy or modulation agents to a target tissue. The energy may include electrical, magnetic, or other types of energy. In some examples, the IND  112  may include a drug delivery system such as a drug infusion pump that can deliver pain medication to the patient, such as morphine sulfate or ziconotide, among others. 
     The IND  112  may include electrostimulation circuitry that generates electrostimulation pulses to stimulate a neural target via the electrodes  116  operably connected to the IND  112 . In an example, the electrodes  116  may be positioned on or near a spinal cord, and the electrostimulation circuitry may be configured to deliver SCS to treat pain. In another example, the electrodes  116  may be surgically placed at other neural targets such as a brain or a peripheral neutral tissue, and the electrostimulation circuitry may be configured to deliver brain or peripheral stimulations. Examples of electrostimulation may include deep brain stimulation (DBS), trigeminal nerve stimulation, occipital nerve stimulation, vagus nerve stimulation (VNS), sacral nerve stimulation, sphenopalatine ganglion stimulation, sympathetic nerve modulation, adrenal gland modulation, baroreceptor stimulation, or transcranial magnetic stimulation, spinal cord stimulation (SCS), dorsal root ganglia (DRG) stimulation, motor cortex stimulation (MCS), transcranial direct current stimulation (tDCS), transcutaneous spinal direct current stimulation (tsDCS), pudendal nerve stimulation, multifidus muscle stimulation, transcutaneous electrical nerve stimulation (TENS), tibial nerve stimulation, among other peripheral nerve or organ stimulation. The IND  112  may additionally or alternatively provide therapies such as radiofrequency ablation (RFA), pulsed radiofrequency ablation, ultrasound therapy, high-intensity focused ultrasound (HIFU), optical stimulation, optogenetic therapy, magnetic stimulation, other peripheral tissue stimulation therapies, other peripheral tissue denervation therapies, or nerve blocks or injections. 
     In various examples, the electrodes  116  may be distributed in one or more leads of the lead system  114  electrically coupled to the IND  112 . In an example, the lead system  114  may include a directional lead that includes at least some segmented electrodes circumferentially disposed about the directional lead. Two or more segmented electrodes may be distributed along a circumference of the lead. The actual number and shape of leads and electrodes may vary according to the intended application. Detailed description of construction and method of manufacturing percutaneous stimulation leads are disclosed in U.S. Pat. No. 8,019,439, entitled “Lead Assembly and Method of Making Same,” and U.S. Pat. No. 7,650,184, entitled “Cylindrical Multi-Contact Electrode Lead for Neural Stimulation and Method of Making Same,” the disclosures of which are incorporated herein by reference. The electrodes  116  may provide an electrically conductive contact providing for an electrical interface between the IND  112  and tissue of the patient. The neurostimulation pulses are each delivered from the IND  112  through a set of electrodes selected from the electrodes  116 . In various examples, the neurostimulation pulses may include one or more individually defined pulses, and the set of electrodes may be individually definable by the user for each of the individually defined pulses. 
     Although the discussion herein with regard to the neuromodulation system  100  focuses on an implantable device such as the IND  112 , this is meant only by way of example and not limitation. It is within the contemplation of the present inventors and within the scope of this document, that the systems, devices, and methods discussed herein may also be used for pain management via subcutaneous medical devices, wearable medical devices (e.g., wrist watch, patches, garment- or shoe-mounted device), or other external medical devices, or a combination of implantable, wearable, or other external devices. The therapy, such as electrostimulation or medical therapies, may be used to treat various neurological disorders other than pain, which by way of example and not limitation may include epilepsy, obsessive compulsive disorder, tremor, Parkinson&#39;s disease, or dystonia, among other movement and affective disorders. 
     The external system  130  may be communicated with the IND  112  via a communication link  120 . The external system  130  may include a dedicated hardware/software system such as a programmer, a remote server-based patient management system, or alternatively a system defined predominantly by software running on a standard personal computer. The external system  130  may be configured to control the operation of the IND  112 , such as to program the IND  112  for delivering neuromodulation therapy. The external system  130  may additionally receive via the communication link  120  information acquired by IND  112 , such as one or more physiological or functional signals. In an example, the external system  130  may determine a pain score based on the physiological or functional signals received from the IND  112 , and program the IND  112  to deliver pain therapy in a closed-loop fashion. Examples of the external system and neurostimulation based on pain score are discussed below, such as with reference to  FIGS. 2-3 . 
     The communication link  120  may include one or more communication channels and intermediate devices between the external system and the IND, such as a wired link, a telecommunication link such as an internet connection, or a wireless link such as one or more of an inductive telemetry link, a radio-frequency telemetry link. The communication link  120  may provide for data transmission between the IND  112  and the external system  130 . The transmitted data may include, for example, real-time physiological or functional signals acquired by and stored in the IND  112 , therapy history data, data indicating device operational status of the IND  112 , one or more programming instructions to the IND  112  which may include configurations for sensing physiologic signal or stimulation commands and stimulation parameters, or device self-diagnostic test, among others. In some examples, the IND  112  may be coupled to the external system  130  further via an intermediate control device, such as a handheld external remote control device to remotely instruct the IND  112  to generate electrical stimulation pulses in accordance with selected stimulation parameters produced by the external system  130 . 
     Portions of the IND  112  or the external system  130  may be implemented using hardware, software, firmware, or combinations thereof. Portions of the IND  112  or the external system  130  may be implemented using an application-specific circuit that may be constructed or configured to perform one or more particular functions, or may be implemented using a general-purpose circuit that may be programmed or otherwise configured to perform one or more particular functions. Such a general-purpose circuit may include a microprocessor or a portion thereof, a microcontroller or a portion thereof, or a programmable logic circuit, or a portion thereof. For example, a “comparator” may include, among other things, an electronic circuit comparator that may be constructed to perform the specific function of a comparison between two signals or the comparator may be implemented as a portion of a general-purpose circuit that may be driven by a code instructing a portion of the general-purpose circuit to perform a comparison between the two signals. 
       FIG. 2  illustrates, by way of example and not limitation, an example of a pain management system  200 , which may be an embodiment of the neuromodulation system  100 . The pain management system  200  may assess pain of a subject using functional signals that indicate the patient&#39;s physical state, and program a pain therapy based on the pain assessment. As illustrated in  FIG. 2 , the pain management system  200  may include a sensor circuit  210 , a pain analyzer circuit  220 , a memory  230 , a user interface  240 , and a therapy unit  250 . 
     The sensor circuit  210  may be coupled to a motion sensor to sense from the patient at least one functional signal. The sensor circuit  210  may include sense amplifier circuit that may pre-process the sensed signals, including, for example, amplification, digitization, filtering, or other signal conditioning operations. The motion sensor may be an ambulatory sensor, such as an implantable or wearable sensor associated with the patient. Additionally or alternatively, the motion sensor may be a stationary sensor, such as mounted in a room or attached to furniture, to detect one or more functional signals from the patient when the patient enters, or remains within, an environment of patient daily life. In an example, the functional signal may include a motor activity signal. Examples of the motor activity signal may include, but are not limited to, patient posture, gait, balance, or physical activity signals, among others. In another example, the functional signal may include a sleep state signal that contains information about sleep disturbance. Chronic pain patients may experience frequent disrupted sleep or change of sleep patterns. The motion sensor may detect frequency or duration of sleep position switch, sleep incline, or other indicators of sleep quality. Examples of the motor activity signals and sleep state signals are discussed below, such as with reference to  FIG. 4 . 
     The pain analyzer circuit  220  may generate a pain score using at least the functional signals received from the sensor circuit  210 . The pain analyzer circuit  220  may be implemented as a part of a microprocessor circuit, which may be a dedicated processor such as a digital signal processor, application specific integrated circuit (ASIC), microprocessor, or other type of processor for processing information including physical activity information. Alternatively, the microprocessor circuit may be a general purpose processor that may receive and execute a set of instructions of performing the functions, methods, or techniques described herein. 
     The pain analyzer circuit  220  may include circuit sets comprising one or more other circuits or sub-circuits that may, alone or in combination, perform the functions, methods or techniques described herein. In an example, hardware of the circuit set may be immutably designed to carry out a specific operation (e.g., hardwired). In an example, the hardware of the circuit set may include variably connected physical components (e.g., execution units, transistors, simple circuits, etc.) including a computer readable medium physically modified (e.g., magnetically, electrically, movable placement of invariant massed particles, etc.) to encode instructions of the specific operation. In connecting the physical components, the underlying electrical properties of a hardware constituent are changed, for example, from an insulator to a conductor or vice versa. The instructions enable embedded hardware (e.g., the execution units or a loading mechanism) to create members of the circuit set in hardware via the variable connections to carry out portions of the specific operation when in operation. Accordingly, the computer readable medium is communicatively coupled to the other components of the circuit set member when the device is operating. In an example, any of the physical components may be used in more than one member of more than one circuit set. For example, under operation, execution units may be used in a first circuit of a first circuit set at one point in time and reused by a second circuit in the first circuit set, or by a third circuit in a second circuit set at a different time. 
     As illustrated in  FIG. 2 , the pain analyzer circuit  220  may include a signal metrics generator  221  and a pain score generator  225 . The signal metrics generator  221  may generate one or more functional signal metrics  222  from the sensed at least one functional signal. The signal metrics may include statistical parameters extracted from the sensed signal, such as signal mean, median, or other central tendency measures or a histogram of the signal intensity, among others. The signal metrics may additionally or alternatively include morphological parameters such as maximum or minimum within a specific time period such as a cardiac cycle, positive or negative slope or higher order statistics, or signal power spectral density at a specific frequency range, among other morphological parameters. The signal metrics may additionally include timing information such as a time interval between a first characteristic point in one signal and a second characteristic point in another signal. In various examples, the signal metrics generator  221  may generate from the sensed motor activity signal a plurality of signal metrics indicative of patient motor control or kinetics, such as physical activity metrics, posture metrics, range of motion metrics, gait metrics, among others. Additionally or alternatively, the signal metrics generator  221  may generate from the sensed sleep state signal a plurality of sleep state signal metrics. The motor control signal metrics and/or the sleep state signal metrics may be used to quantify the pain experienced by the patient. Examples of the signal metrics for pain quantification are discussed below, such as with reference to  FIG. 4 . 
     The pain score generator  225  may generate a pain score using the measurements of the signal metrics generated by the signal metrics generator  221 . The pain score can be represented as a numerical or categorical value that quantifies the patient&#39;s overall pain symptom. In an example, a composite signal metric may be generated using a combination of a plurality of the signal metrics respectively weighted by weight factors. The combination can be linear or nonlinear. The pain score generator  225  may compare the composite signal metric to one or more threshold values or range values, and assign a corresponding pain score (such as numerical values from 0 to 10) based on the comparison. 
     In another example, the pain score generator  225  may compare the signal metrics to their respective threshold values or range values, assign corresponding signal metric-specific pain scores based on the comparison, and compute a composite pain score using a linear or nonlinear fusion of the signal metric-specific pain scores weighted by their respective weight factors. In an example, the threshold can be inversely proportional to signal metric&#39;s sensitivity to pain. A signal metric that is more sensitive to pain may have a corresponding lower threshold and a larger metric-specific pain score, thus plays a more dominant role in the composite pain score than another signal metric that is less sensitive to pain. Examples of the fusion algorithm may include weighted averages, voting, decision trees, or neural networks, among others. The pain score generated by the pain score generator  225  may be output to a system user or a process. 
     In various examples, in addition to the functional signals such as motor control signals or sleep state signals, the sensor circuit  210  may sense one or more physiological signals. The physiological signals, such as cardiac, pulmonary, neural, or biochemical signals, may reveal characteristic signal properties in response to an onset, intensity, severity, duration, or patterns of pain. In an example, the sensor circuit  210  may sense one or more physiological signals when the sensed functional signal satisfy a specific condition, such as when the functional signal metric falls within a specified value range that indicates an onset of a pain episode. The signal metrics generator  221  may generate physiological signal metrics from the sensed cardiac, pulmonary, or biochemical signals, and the pain score generator  225  may determine the pain score using a linear or nonlinear combination of functional signal metrics  222  and the physiological signal metrics. Examples of the cardiac signals may include an electrocardiograph (ECG), intracardiac electrogram, gyrocardiography, magnetocardiography, a heart rate signal, a heart rate variability signal, a cardiovascular pressure signal, or a heart sounds signal, among others. Examples of the pulmonary signals may include a respiratory signal, a thoracic impedance signal, or a respiratory sounds signal. Examples of the biochemical signals may include blood chemistry measurements or expression levels of one or more biomarkers such as B-type natriuretic peptide (BNP) or N-terminal pro b-type natriuretic peptide (NT-proBNP), serum cytokine profiles, P2X4 receptor expression levels, gamma-aminobutyric acid (GABA) levels, TNFα and other inflammatory markers, cortisol, adenosine, Glial cell-derived neurotrophic factor (GDNF), Nav 1.3, Nav 1.7, or Tetrahydrobiopterin (BH4) levels, among other biomarkers. The signal metrics generator  221  may generate physiological signal metrics from functional signals, and the pain score generator  225  may determine the pain score using a linear or nonlinear combination of the functional parameters and the physiological signal metrics. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,053, entitled “PAIN MANAGEMENT BASED ON CARDIOVASCULAR PARAMETERS” describes cardiovascular parameters such as arterial pulsatile activity and electrocardiography for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,061, entitled “PAIN MANAGEMENT BASED ON BRAIN ACTIVITY MONITORING” describes information of brain activity for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,061, entitled “PAIN MANAGEMENT BASED ON BRAIN ACTIVITY MONITORING” describes information of brain activity for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,069, entitled “PAIN MANAGEMENT BASED ON RESPIRATION-MEDIATED HEART RATES” describes information of respiration-mediated heart rate for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,082, entitled “PAIN MANAGEMENT BASED ON EMOTIONAL EXPRESSION MEASUREMENTS” describes measurements of patient emotional expressions for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,092, entitled “PAIN MANAGEMENT BASED ON MUSCLE TENSION MEASUREMENTS” describes measurements of patient muscle tension including electromyography for use in pain analysis, the disclosure of which is incorporated herein by reference in its entirety. One or more of these additional signals or measurements may be used by the pain analyzer circuit  220  to generate a pain score. 
     The memory  230  may be configured to store sensor signals or signal metrics such as generated by the sensor circuit  210  and the signal metrics generator  221 , and the pain scores such as generated by the pain score generator  225 . Data storage at the memory  230  may be continuous, periodic, or triggered by a user command or a specific event. In an example, as illustrated in  FIG. 2 , the memory  230  may store weight factors, which may be used by the pain score generator  225  to generate the composite pain score. The weight factors may be provided by a system user, or alternatively be automatically determined or adjusted such as based on the corresponding signal metrics&#39; reliability in representing an intensity of the pain. Examples of the automatic weight factor generation are discussed below, such as with reference to  FIG. 3 . 
     The user interface  240  may include an input circuit  241  and an output unit  242 . In an example, at least a portion of the user interface  240  may be implemented in the external system  130 . The input circuit  241  may enable a system user to program the parameters used for sensing the physiological signals, generating signal metrics, or generating the pain score. The input circuit  241  may be coupled to one or more input devices such as a keyboard, on-screen keyboard, mouse, trackball, touchpad, touch-screen, or other pointing or navigating devices. In some example, the input device may be incorporated in a mobile device such as a smart phone or other portable electronic device with a mobile application (“App”). The mobile App may enable a patient to provide pain description or quantified pain scales during the pain episodes. In an example, the input circuit  241  may enable a user to confirm, reject, or edit the programming of the therapy unit  250 , such as parameters for electrostimulation, as to be discussed in the following. 
     The output unit  242  may include a display to present to a system user such as a clinician the pain score. The output unit  242  may also display information including the physiological and functional signals, trends of the signal metric, or any intermediary results for pain score calculation such as the signal metric-specific pain scores. The information may be presented in a table, a chart, a diagram, or any other types of textual, tabular, or graphical presentation formats, for displaying to a system user. The presentation of the output information may include audio or other human-perceptible media format. In an example, the output unit  242  may generate alerts, alarms, emergency calls, or other forms of warnings to signal the system user about the pain score. 
     The therapy circuit  250  may be configured to deliver a therapy to the patient based on the pain score generated by the pain score generator  225 . The therapy circuit  250  may include an electrostimulator configured to generate electrostimulation energy to treat pain. In an example, the electrostimulator may deliver spinal cord stimulation (SCS) via electrodes electrically coupled to the electrostimulator. The electrodes may be surgically placed at a region at or near a spinal cord tissue, which may include, by way of example and not limitation, dorsal column, dorsal horn, spinal nerve roots such as the dorsal nerve root, and dorsal root ganglia. The SCS may be in a form of stimulation pulses that are characterized by pulse amplitude, pulse width, stimulation frequency, duration, on-off cycle, pulse shape or waveform, temporal pattern of the stimulation, among other stimulation parameters. Examples of the stimulation pattern may include burst stimulation with substantially identical inter-pulse intervals, or ramp stimulation with incremental inter-pulse intervals or with decremental inter-pulse intervals. In some examples, the frequency or the pulse width may change from pulse to pulse. The electrostimulator may additionally or alternatively deliver electrostimulation to other target tissues such as peripheral nerves tissues. In an example, the electrostimulator may deliver transcutaneous electrical nerve stimulation (TENS) via detachable electrodes that are affixed to the skin. 
     The therapy circuit  250  may additionally or alternatively include a drug delivery system, such as an intrathecal drug delivery pump that may be surgically placed under the skin, which may be programmed to inject medication or biologics through a catheter to the area around the spinal cord. Other examples of drug delivery system may include a computerized patient-controlled analgesia pump that may deliver the prescribed pain medication to the patient such as via an intravenous line. In some examples, the therapy circuit  250  may be delivered according to the pain score received from the pain score generator  225 . 
       FIG. 3  illustrates, by way of example and not limitation, another example of a pain management system  300 , which may be an embodiment of the neuromodulation system  100  or the pain management system  200 . The pain management system  300  may include an implantable neuromodulator  310  and an external system  320 , which may be, respectively, embodiments of the IND  112  and the external system  130  as illustrated in  FIG. 1 . The external system  320  may be communicatively coupled to the implantable neuromodulator  310  via the communication link  120 . 
     The implantable neuromodulator  310  may include several components of the pain management system  200  as illustrated in  FIG. 2 , including the sensor circuit  210 , the pain analyzer circuit  220 , the memory  230 , and the therapy unit  250 . As discussed with reference to  FIG. 2 , the pain analyzer circuit  220  includes the pain score generator  225  that determines a pain score using weight factors stored in the memory  230  and the signal metrics from the signal metrics generator  221  which may also be included in the pain analyzer circuit  220 . The implantable neuromodulator  310  may include a controller circuit  312 , coupled to the therapy unit  250 , which controls the generation and delivery of pain therapy, such as neurostimulation energy. The controller circuit  312  may control the generation of electrostimulation pulses according to specific stimulation parameters. The stimulation parameters may be provided by a system user. Alternatively, the stimulation parameters may be automatically determined based on the intensity, severity, duration, or pattern of pain, which may be subjectively described by the patient or automatically quantified based on the physiological or functional signals sensed by the sensor circuit  210 . For example, when a patient-described or sensor-indicated quantification exceeds a respective threshold value or falls within a specific range indicating elevated pain, the electrostimulation energy may be increased to provide stronger pain relief. Increased electrostimulation energy may be achieved by programming a higher pulse intensity, a higher frequency, or a longer stimulation duration or “on” cycle, among others. Conversely, when a patient-described or sensor-indicated pain quantification falls below a respective threshold value or falls within a specific range indicating no pain or mild pain, the electrostimulation energy may be decreased. The controller circuit  312  may also adjust stimulation parameters to alleviate side effects introduced by the electrostimulation of the target tissue. 
     Additionally or alternatively, the controller circuit  312  may control the therapy unit  250  to deliver electrostimulation pulses via specific electrodes. In an example of pain management via SCS, a plurality of segmented electrodes, such as the electrodes  116 , may be distributed in one or more leads. The controller circuit  312  may configure the therapy unit  250  to deliver electrostimulation pulses via a set of electrodes selected from the plurality of electrodes. The electrodes may be manually selected by a system user or automatically selected based on the pain score. 
     The implantable neuromodulator  310  may receive the information about electrostimulation parameters and the electrode configuration from the external system  320  via the communication link  120 . Additional parameters associated with operation of the therapy unit  250 , such as battery status, lead impedance and integrity, or device diagnostic of the implantable neuromodulator  310 , may be transmitted to the external system  320 . The controller circuit  312  may control the generation and delivery of electrostimulation using the information about electrostimulation parameters and the electrode configuration from the external system  320 . Examples of the electrostimulation parameters and electrode configuration may include: temporal modulation parameters such as pulse amplitude, pulse width, pulse rate, or burst intensity; morphological modulation parameters respectively defining one or more portions of stimulation waveform morphology such as amplitude of different phases or pulses included in a stimulation burst; or spatial modulation parameters such as selection of active electrodes, electrode combinations which define the electrodes that are activated as anodes (positive), cathodes (negative), and turned off (zero), and stimulation energy fractionalization which defines amount of current, voltage, or energy assigned to each active electrode and thereby determines spatial distribution of the modulation field. 
     In an example, the controller circuit  312  may control the generation and delivery of electrostimulation in a closed-loop fashion by adaptively adjusting one or more stimulation parameters or stimulation electrode configuration based on the pain score. For example, if the score exceeds the pain threshold (or falls within a specific range indicating an elevated pain), then the first electrostimulation may be delivered. Conversely, if the composite pain score falls below a respective threshold value (or falls within a specific range indicating no pain or mild pain), then a second pain therapy, such as second electrostimulation may be delivered. The first electrostimulation may differ from the second electrostimulation with respect to at least one of the stimulation energy, pulse amplitude, pulse width, stimulation frequency, duration, on-off cycle, pulse shape or waveform, electrostimulation pattern such as electrode configuration or energy fractionalization among active electrodes, among other stimulation parameters. In an example, the first electrostimulation may have higher energy than the second electrostimulation, such as to provide stronger effect of pain relief. Examples of increased electrostimulation energy may include a higher pulse intensity, a higher frequency, or a longer stimulation duration or “on” cycle, among others. 
     The parameter adjustment or stimulation electrode configuration may be executed continuously, periodically at specific time, duration, or frequency, or in a commanded mode upon receiving from a system user a command or confirmation of parameter adjustment. In some examples, the closed-loop control of the electrostimulation may be further based on the type of the pain, such as chronic or acute pain. In an example, the pain analyzer circuit  220  may trend the signal metric over time to compute an indication of abruptness of change of the signal metrics, such as a rate of change over a specific time period. The pain episode may be characterized as acute pain if the signal metric changes abruptly (e.g., the rate of change of the signal metric exceeding a threshold), or as chronic pain if the signal metric changes gradually (e.g., the rate of change of the signal metric falling below a threshold). The controller circuit  312  may control the therapy unit  250  to deliver, withhold, or otherwise modify the pain therapy in accordance with the pain type. For example, incidents such as toe stubbing or bodily injuries may cause abrupt changes in certain signal metrics, but no adjustment of the closed-loop pain therapy is deemed necessary. On the contrary, if the pain analyzer circuit  220  detects chronic pain characterized by gradual signal metric change, then the closed-loop pain therapy may be delivered accordingly. 
     The external system  320  may include the user interface  240 , a weight generator  322 , and a programmer circuit  324 . The weight generator  322  may generate weight factors used by the pain score generator  225  to generate the pain score. The weight factors may indicate the signal metrics&#39; reliability in representing an intensity of the pain. A sensor metric that is more reliable, or more sensitive or specific to the pain, would be assigned a larger weight than another sensor metric that is less reliable, or less sensitive or specific to the pain. In an example, the weight factors may be proportional to correlations between a plurality of quantified pain scales (such as reported by a patient) and measurements of the measurements of the signal metrics corresponding to the plurality of quantified pain scales. A signal metric that correlates with the pain scales is deemed a more reliable signal metric for pain quantification, and is assigned a larger weight factor than another signal metric less correlated with the quantified pain scales. In another example, the weight generator  322  may determine weight factors using the signal sensitivity to pain. The signal metrics may be trended over time, such as over approximately six months. The signal sensitivity to pain may be represented by a rate of change of the signal metrics over time during a pain episode. The signal sensitivity to pain may be evaluated under a controlled condition such as when the patient posture or activity is at a specific level or during specific time of the day. The weight generator  322  may determine weight factors to be proportional to signal metric&#39;s sensitivity to pain. 
     The programmer circuit  324  may produce parameter values for operating the implantable neuromodulator  310 , including parameters for sensing physiological and functional signals and generating signal metrics, and parameters or electrode configurations for electrostimulation. In an example, the programmer circuit  324  may generate the stimulation parameters or electrode configurations for SCS based on the pain score produced by the pain score generator  225 . Through the communication link  120 , the programmer circuit  324  may continuously or periodically provide adjusted stimulation parameters or electrode configuration to the implantable neuromodulator  210 . By way of non-limiting example and as illustrated in  FIG. 3 , the programmer circuit  324  may be coupled to the user interface  234  to allow a user to confirm, reject, or edit the stimulation parameters, sensing parameters, or other parameters controlling the operation of the implantable neuromodulator  210 . The programmer circuit  324  may also adjust the stimulation parameter or electrode configuration in a commanded mode upon receiving from a system user a command or confirmation of parameter adjustment. 
     The programmer circuit  324 , which may be coupled to the weight generator  322 , may initiate a transmission of the weight factors generated by the weight generator  322  to the implantable neuromodulator  310 , and store the weight factors in the memory  230 . In an example, the weight factors received from the external system  320  may be compared to previously stored weight factors in the memory  230 . The controller circuit  312  may update the weight factors stored in the memory  230  if the received weight factors are different than the stored weights. The pain analyzer circuit  220  may use the updated weight factors to generate a pain score. In an example, the update of the stored weight factors may be performed continuously, periodically, or in a commanded mode upon receiving a command from a user. In various examples, weight factors may be updated using a fusion model. Commonly assigned U.S. Provisional Patent Application Ser. No. 62/445,095, entitled “PATIENT-SPECIFIC CALIBRATION OF PAIN QUANTIFICATION” describes systems and methods for calibrating a fusion model, such as adjusting weights for signal metrics, using a reference pain quantification, the disclosure of which is incorporated herein by reference in its entirety. 
     In some examples, the pain score may be used by a therapy unit (such as an electrostimulator) separated from the pain management system  300 . In various examples, the pain management system  300  may be configured as a monitoring system for pain characterization and quantification without delivering closed-loop electrostimulation or other modalities of pain therapy. The pain characterization and quantification may be provided to a system user such as the patient or a clinician, or to a process including, for example, an instance of a computer program executable in a microprocessor. In an example, the process includes computer-implemented generation of recommendations or an alert to the system user regarding pain medication (e.g., medication dosage and time for taking a dose), electrostimulation therapy, or other pain management regimens. The therapy recommendations or alert may be based on the pain score, and may be presented to the patient or the clinician in various settings including in-office assessments (e.g. spinal cord stimulation programming optimization), in-hospital monitoring (e.g. opioid dosing during surgery), or ambulatory monitoring (e.g. pharmaceutical dosing recommendations). 
     In an example, in response to the pain score exceeding a threshold which indicates elevated pain symptom, an alert may be generated and presented at the user interface  240  to remind the patient to take pain medication. In another example, therapy recommendations or alerts may be based on information about wearing-off effect of pain medication, which may be stored in the memory  230  or received from the user interface  240 . When the drug effect has worn off, an alert may be generated to remind the patient to take another dose or to request a clinician review of the pain prescription. In yet another example, before a pain therapy such as neurostimulation therapy is adjusted (such as based on the pain score) and delivered to the patient, an alert may be generated to forewarn the patient or the clinician of any impending adverse events. This may be useful as some pain medication may have fatal or debilitating side effects. In some examples, the pain management system  300  may identify effect of pain medication addiction such as based on functional and physiological signals. An alert may be generated to warn the patient about effects of medication addiction and thus allow medical intervention. 
       FIG. 4  illustrates, by way of example and not limitation, an example of a portion of a pain management system for sensing functional signal indicative a physical state of the patient. The system portion may generate signal metrics including motor activity metrics and sleep state metrics, which may be used by the pain management system  200  or  300  to characterize and quantify pain of a patient. The system portion may include one or more motion sensors  401  through  405 , the sensor circuit  210 , and a functional signal metrics generator  420  which is an embodiment of the signal metrics generator  221 . 
     One or more types of motion sensors may be used to sense the functional signals such as a posture signal, a gait signal, a balance signal, or a range of motion signal, among other motor activity signals. According to the manner of interaction with the patient, the motion sensors may include, by way of example and not limitation, one or more of an implantable sensor  401 , a wearable sensor  402 , an apparel-mounted sensor  403 , a mobile device sensor  404 , or a stationary sensor  405 . The implantable sensor  401  may be subcutaneously implanted at various body locations. The wearable sensor  402  may be worn on the head, wrist, hand, foot, ankle, waist, or other parts of the body. The apparel-mounted sensor  403  may be mounted on a garment, a footwear, a headwear, or one or more accessories carried by the patient, such as a pendant, a necklace, or a bracelet. In an example, the apparel-mounted sensor  403  may include insole force sensor for placement inside a shoe or a boot. The insole force sensor may take the form of a strain gauge, piezoelectric sensor, or capacitive sensor, among others. The insole force sensor may be wirelessly coupled to the IND  310  or the pain analyzer circuit  220 . The sensor circuit  210  may analyze force distribution on a patient&#39;s foot, and generate an indicator of gait. 
     The mobile device sensor  404  is a sensor incorporated in a mobile device. Examples of the mobile device may include a smart phone, a wearable device, a fitness band, a portable health monitor, a tablet, a laptop computer, or other types of portable computerized device. In an example, embedded in a mobile device may include motion sensors such as an accelerometer, a gyroscope, a magnometer, a GPS sensor or other location services, or a camera that sense motor activity signals. The mobile device may be communicatively coupled to the IND  310  or the pain analyzer circuit  220  via a communication link such as a universal serial bus (USB) connection, a Bluetooth protocol, Ethernet, IEEE 802.11 wireless, an inductive telemetry link, or a radio-frequency telemetry link, among others. 
     The stationary sensor  405  may be positioned in an environment of patient&#39;s daily life such as at a bedside, in a room at patient home, or in a testing room at a clinic or medical facility. In an example, the motion sensors may be mounted on a chair, a bed (e.g., under or attached to a mattress), or a fixture in a patient&#39;s environment. Unlike the implantable, wearable, or apparel-mounted sensors which are ambulatory in nature, the stationary sensor  405  are configured to detect one or more functional signals when the patient enters, or remains within, an environment within the scope of surveillance of the stationary sensor  405 . Examples of the stationary sensor  405  may include a camera or a video recorder configured to capture an image, an image sequence, or a video of the patient at a specific physical state, such as sitting, standing, walking, or doing physical activities. In an example, the camera may be an infrared camera. In an example, the camera is a digital camera that may generate digital data representation of an image or a video sequence. The functional signal metrics generator  420  may generate from the image data image features associated with patient posture, gait, balance, range of motion, etc. 
     The sensor circuit  210  may be coupled to the one or more motion sensors  401 - 405  via a wired or wireless connection. The sensor circuit  210  may include sense amplifier circuit that may pre-process the sensed functional signal. From the processed functional signals, the functional signal metrics generator  420  may extract one or more motor activity metrics  421 , and one or more sleep state metrics  422 . By way of example and not limitation, the motor activity metrics  421  may include features of posture, gait, physical activity, balance, or range of motion. In an example, the sensor circuit  210  may be coupled to a posture sensor to detect signals of a posture, a state of balance, or a range of motion of the patient. Examples of the posture sensor may include a tilt switch or a single- or multi-axis accelerometer configured to be affiliated with the patient in one of the sensor types  401 - 405 . For example, the posture sensor may be disposed external to the body or implanted inside the body. Posture may be represented by, for example, a tilt angle. In some examples, posture or physical activity information may be derived from thoracic impedance information. The functional signal metrics generator  420  may generate from the posture signal one or more signal metrics including body position during sitting, standing, or walking. Additionally or alternatively, the sensor circuit  210  may be coupled to a motion sensor positioned on the extremities or the trunk of patient body to detect range of motion. The functional signal metrics generator  420  may generate signal metrics of lumbar forward flexion, shoulder flexion, elbow flexion, rotation of arm and elbow joint, trunk-pelvis rotation, or other motor control and kinematic metrics. The range of motion metrics may also include indicators of smoothness of motion, such as a rate or a pattern of change in motion with respect to time, or with respect to angular velocity, etc. A decrease in activity intensity or duration from an activity baseline such as established using patient historical activity signals, or less frequent transition or an increase in transition time from one activity to another may indicate pain suffered by the patient. 
     In another example, the sensor circuit  210  may be coupled to an accelerometer to sense a physical activity signal. The accelerometer may be single-axis or multi-axis accelerometer configured to be one of the types of  401 - 405 . The functional signal metrics generator  420  may generate from the physical activity signal one or more signal metrics including activity intensity, activity duration, or a transition time between different types of activities. A decrease in activity intensity or duration from an activity baseline such as established using patient historical activity signals, or less frequent transition or an increase in transition time from one activity to another may indicate pain suffered by the patient. 
     The sensor circuit  210  may be coupled to a gait sensor to detect gait of the patient. The sensors may be configured to be worn or attached to various parts of the patient&#39;s body, such as on the foot, ankle, leg, waist, or other parts on the torso or the extremities. Examples of the gait sensors may include accelerometer, gyroscope (which may be a one-, two-, or three-axis gyroscope), magnetometer (e.g., a compass), inclinometers, goniometers, electromagnetic tracking system (ETS), a global positioning system (GPS) sensor or other location services, sensing fabric, force sensor, strain gauges, and sensors for electromyography (EMG). The functional signal metrics generator  420  may generate gait signal metrics based on signals acquired from a single sensor type or a combined sensor system of multiple types of sensors. Examples of gait signal metrics may include velocity, time to peak velocity, step length, stride length, stride width, swing time, single limb support time, double limb stance, gait autonomy, cadence, among other measurements. 
     The sensor circuit  210  may detect a sleep state of the patient. The sensor circuit  210  may be coupled to one or more accelerometer, piezoelectric sensor, biopotential electrodes and sensors, or other sensors to detect the sleep state. The functional signal metrics generator  420  may generate sleep state metrics, which may include, by way of example and not limitation, sleep incline, sleep sidedness, frequency of sleep position switch, or other sleep quality or sleep disturbance metrics. For example, an increase in sleep incline, or enhanced frequency of body position switches during sleep, or reduced sleep duration are indicators of increase pain. The sleep state metrics, when satisfying a condition that indicates occurrence or aggravation of a pain episode, may trigger one or more other sensors to sense physiological or functional signals. In an example, if the frequency of sleep position switch exceeds a threshold, or if the sleep duration at a sleep position falls below a threshold (e.g., less than 5-15 seconds), sleep disturbance is indicated, which may trigger other sensors for sensing heart rate, respiration rate, jaw clench, or other physiological or functional responses. The sensed response may be used to distinguish between normal sleep patterns (e.g., sleep position change) and abnormal sleep patterns caused by or otherwise associated with acute pain. 
       FIG. 5  illustrates, by way of example and not limitation, a method  500  for managing pain of a patient. The method  500  may be implemented in a medical system, such as the pain management system  200  or  300 . In an example, at least a portion of the method  500  may be executed by a neuromodulator device (IND) such as the implantable neuromodulator  310 . In an example, at least a portion of the method  500  may be executed by an external programmer or remote server-based patient management system, such as the external system  320  that are communicatively coupled to the IND. The method  500  may be used to provide neuromodulation therapy to treat chronic pain or other disorders. 
     The method  500  begins at step  510 , where one or more functional signals may be sensed from the patient. The functional signals sensed at  510  may include motor activity signals, or sleep state signals containing information about sleep disturbance. Examples of the motor activity signals may include, but not limited to, patient posture, gait, balance, range of motion, or physical activity signals, among others. Examples of the sleep state signals may include pain indicators during sleep, such as frequency or duration of sleep position switch, sleep incline, or other indicators of sleep quality or change of sleep pattern. Chronic pain patients may present with poor or unbalanced posture, abnormal gait pattern, restrained range of motion, or decreased intensity or duration of physical activities. Pain may also cause frequent sleep disturbance and poor sleep quality. Monitoring patient motor control or sleep disturbance may provide an objective assessment of pain, and may be used to improve pain therapy efficacy. The functional signals may be sensed using electrodes or ambulatory sensors, such as one or more motion sensors  401 - 405  associated with patient in different manners, as illustrated in  FIG. 4 . 
     In some examples, in addition to the functional signals, one or more physiological signals may be sensed at  510 . The physiological signals, such as cardiac, pulmonary, neural, or biochemical signals, may reveal characteristic signal properties in response to an onset, intensity, severity, duration, or patterns of pain. In an example, the one or more physiological signals may be sensed when the sensed functional signal satisfy a specific condition, such as the functional signal metric falling with a specific value range thus indicative of occurrence or worsening of a pain episode. 
     At  520 , one or more signal metrics may be generated from the sensed functional or physiological signals. The signal metrics may include statistical, morphological, or temporal metric extracted from functional signals. In an example, the functional signal metrics may include posture and balance signal metrics including one or more of body positions during sitting, standing, or walking. In another example, the functional signal metrics may include range of motion signal metrics including one or more of lumbar forward flexion, shoulder flexion, elbow flexion, rotation of arm and elbow joint, trunk-pelvis rotation, a rate or a pattern of change in motion with respect to time, or with respect to angular velocity, or other indicators of motion smoothness. The functional signal metrics may also include physical activity signal metrics including one or more of an intensity or a duration of a physical activity, or a transition time between different types of activities. The functional signal metrics may further include gait signal metrics including one or more of velocity, time to peak velocity, step length, stride length, stride width, swing time, single limb support time, double limb stance, gait autonomy, cadence, among other gait measurements. In various examples, the functional signal metrics may include sleep state metrics including one or more of sleep incline, sleep sidedness, frequency of sleep position switch, or other sleep quality or sleep disturbance metrics. For example, an increase in sleep incline, or enhanced frequency of body position switches during sleep, or reduced sleep duration are indicators of increase pain. The sleep state metrics, when satisfying a condition that indicates occurrence or aggravation of a pain episode, may trigger one or more other sensors to sense physiological or functional signals. 
     At  530 , a pain score may be generated using the measurements of the signal metrics such as one or more functional signal metrics. The pain score may be represented as a numerical or categorical value that quantifies overall pain quality in the subject. In an example, a composite signal metric may be generated using a combination of the signal metrics weighted by their respective weight factors. The composite signal metric may be categorized as one of a number of degrees of pain by comparing the composite signal metric to one or more threshold values or range values, and a corresponding pain score may be assigned based on the comparison. In another example, the signal metrics may be compared to their respective threshold values or range values and a corresponding signal metric-specific pain score may be determined. A composite pain score may be generated using a linear or nonlinear fusion of the signal metric-specific pain scores each weighted by their respective weight factors. In some examples, the pain score may be computed using a subset of the signal metrics selected based on their temporal profile of pain response. Signal metrics with quick pain response (or a shorter transient state of response) may be selected to compute the pain score during a pain episode. Signal metrics with slow or delayed pain response (or a longer transient state of response before reaching a steady state) may be used to compute the pain score after an extended period following the onset of pain such as to allow the signal metrics to reach steady state of response. In some examples, patient demographic information such as patient age or gender may be used in computing the pain score. A higher pain threshold for the composite signal metric may be selected for male patients than for female patients. Additionally or alternatively, the respective weight factors may be determined based on patient demographic information. The weight factors for the signal metrics may be tuned to a lower value than the weight factors for the same signal metric in a female patient. 
     At  542 , the pain score may be output to a user or to a process, such as via the output unit  242  as illustrated in  FIG. 2 . The pain score, including the composite pain score and optionally together with metric-specific pain scores, may be displayed on a display screen. Other information such as the functional signals and the signal metrics extracted from the functional signals may also be output for display or for further processing. In some examples, alerts, alarms, emergency calls, or other forms of warnings may be generated to signal the system user about occurrence of a pain episode or aggravation of pain as indicated by the pain score. 
     The method  500  may include, at  544 , an additional step of delivering a pain therapy to the patient according to the pain score. The pain therapy may include electrostimulation therapy, such as spinal cord stimulation (SCS) via electrodes electrically coupled to the electrostimulator. The SCS may be in a form of stimulation pulses that are characterized by pulse amplitude, pulse width, stimulation frequency, duration, on-off cycle, waveform, among other stimulation parameters. Other electrostimulation therapy, such as one or a combination of DBS, FES, VNS, TNS, or PNS at various locations, may be delivered for pain management. The pain therapy may additionally or alternatively include a drug therapy such as delivered by using an intrathecal drug delivery pump. 
     In various examples, the pain therapy (such as in the form of electrostimulation or drug therapy) may be delivered in a closed-loop fashion. Therapy parameters, such as stimulation waveform parameters, stimulation electrode combination and fractionalization, drug dosage, may be adaptively adjusted based at least on the pain score. The pain-relief effect of the delivered pain therapy may be assessed based on the signal metrics such as the cardiovascular parameters, and the therapy may be adjusted to achieve desirable pain relief. The therapy adjustment may be executed continuously, periodically at specific time, duration, or frequency, or in a commanded mode upon receiving from a system user a command or confirmation of parameter adjustment. In an example, if the pain score exceeds the pain threshold (or falls within a specific range indicating an elevated pain), then the first electrostimulation may be delivered. Conversely, if the composite pain score falls below a respective threshold value (or falls within a specific range indicating no pain or mild pain), then a second pain therapy, such as second electrostimulation may be delivered. The first electrostimulation may differ from the second electrostimulation with respect to at least one of the stimulation energy, pulse amplitude, pulse width, stimulation frequency, duration, on-off cycle, pulse shape or waveform, electrostimulation pattern such as electrode configuration or energy fractionalization among active electrodes, among other stimulation parameters. The method  500  may proceed at  510  to sense functional signals in response to the therapy delivered at  544 . In some examples, the responses of the signal metrics to pain therapy delivered at  544  may be used to gauge composite pain score computation such as by adjusting the weight factors. In an example, weight factors may be determined and adjusted via the weight generator  322  as illustrated in  FIG. 3 , to be proportional to signal metric&#39;s sensitivity to pain. 
       FIG. 6  illustrates generally a block diagram of an example machine  600  upon which any one or more of the techniques (e.g., methodologies) discussed herein may perform. Portions of this description may apply to the computing framework of various portions of the LCP device, the IMD, or the external programmer. 
     In alternative embodiments, the machine  600  may operate as a standalone device or may be connected (e.g., networked) to other machines. In a networked deployment, the machine  600  may operate in the capacity of a server machine, a client machine, or both in server-client network environments. In an example, the machine  600  may act as a peer machine in peer-to-peer (P2P) (or other distributed) network environment. The machine  600  may be a personal computer (PC), a tablet PC, a set-top box (STB), a personal digital assistant (PDA), a mobile telephone, a web appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by that machine. Further, while only a single machine is illustrated, the term “machine” shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein, such as cloud computing, software as a service (SaaS), other computer cluster configurations. 
     Examples, as described herein, may include, or may operate by, logic or a number of components, or mechanisms. Circuit sets are a collection of circuits implemented in tangible entities that include hardware (e.g., simple circuits, gates, logic, etc.). Circuit set membership may be flexible over time and underlying hardware variability. Circuit sets include members that may, alone or in combination, perform specific operations when operating. In an example, hardware of the circuit set may be immutably designed to carry out a specific operation (e.g., hardwired). In an example, the hardware of the circuit set may include variably connected physical components (e.g., execution units, transistors, simple circuits, etc.) including a computer readable medium physically modified (e.g., magnetically, electrically, movable placement of invariant massed particles, etc.) to encode instructions of the specific operation. In connecting the physical components, the underlying electrical properties of a hardware constituent are changed, for example, from an insulator to a conductor or vice versa. The instructions enable embedded hardware (e.g., the execution units or a loading mechanism) to create members of the circuit set in hardware via the variable connections to carry out portions of the specific operation when in operation. Accordingly, the computer readable medium is communicatively coupled to the other components of the circuit set member when the device is operating. In an example, any of the physical components may be used in more than one member of more than one circuit set. For example, under operation, execution units may be used in a first circuit of a first circuit set at one point in time and reused by a second circuit in the first circuit set, or by a third circuit in a second circuit set at a different time. 
     Machine (e.g., computer system)  600  may include a hardware processor  602  (e.g., a central processing unit (CPU), a graphics processing unit (GPU), a hardware processor core, or any combination thereof), a main memory  604  and a static memory  606 , some or all of which may communicate with each other via an interlink (e.g., bus)  608 . The machine  600  may further include a display unit  610  (e.g., a raster display, vector display, holographic display, etc.), an alphanumeric input device  612  (e.g., a keyboard), and a user interface (UI) navigation device  614  (e.g., a mouse). In an example, the display unit  610 , input device  612  and UI navigation device  614  may be a touch screen display. The machine  600  may additionally include a storage device (e.g., drive unit)  616 , a signal generation device  618  (e.g., a speaker), a network interface device  620 , and one or more sensors  621 , such as a global positioning system (GPS) sensor, compass, accelerometer, or other sensor. The machine  600  may include an output controller  628 , such as a serial (e.g., universal serial bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate or control one or more peripheral devices (e.g., a printer, card reader, etc.). 
     The storage device  616  may include a machine readable medium  622  on which is stored one or more sets of data structures or instructions  624  (e.g., software) embodying or utilized by any one or more of the techniques or functions described herein. The instructions  624  may also reside, completely or at least partially, within the main memory  604 , within static memory  606 , or within the hardware processor  602  during execution thereof by the machine  600 . In an example, one or any combination of the hardware processor  602 , the main memory  604 , the static memory  606 , or the storage device  616  may constitute machine readable media. 
     While the machine readable medium  622  is illustrated as a single medium, the term “machine readable medium” may include a single medium or multiple media (e.g., a centralized or distributed database, and/or associated caches and servers) configured to store the one or more instructions  624 . 
     The term “machine readable medium” may include any medium that is capable of storing, encoding, or carrying instructions for execution by the machine  600  and that cause the machine  600  to perform any one or more of the techniques of the present disclosure, or that is capable of storing, encoding or carrying data structures used by or associated with such instructions. Non-limiting machine readable medium examples may include solid-state memories, and optical and magnetic media. In an example, a massed machine readable medium comprises a machine readable medium with a plurality of particles having invariant (e.g., rest) mass. Accordingly, massed machine-readable media are not transitory propagating signals. Specific examples of massed machine readable media may include: non-volatile memory, such as semiconductor memory devices (e.g., Electrically Programmable Read-Only Memory (EPROM), Electrically Erasable Programmable Read-Only Memory (EEPROM)) and flash memory devices; magnetic disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROM and DVD-ROM disks. 
     The instructions  624  may further be transmitted or received over a communications network  626  using a transmission medium via the network interface device  620  utilizing any one of a number of transfer protocols (e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.). Example communication networks may include a local area network (LAN), a wide area network (WAN), a packet data network (e.g., the Internet), mobile telephone networks (e.g., cellular networks), Plain Old Telephone (POTS) networks, and wireless data networks (e.g., Institute of Electrical and Electronics Engineers (IEEE) 802.11 family of standards known as WiFi®, IEEE 802.16 family of standards known as WiMax®), IEEE 802.15.4 family of standards, peer-to-peer (P2P) networks, among others. In an example, the network interface device  620  may include one or more physical jacks (e.g., Ethernet, coaxial, or phone jacks) or one or more antennas to connect to the communications network  626 . In an example, the network interface device  620  may include a plurality of antennas to wirelessly communicate using at least one of single-input multiple-output (SIMO), multiple-input multiple-output (MIMO), or multiple-input single-output (MISO) techniques. The term “transmission medium” shall be taken to include any intangible medium that is capable of storing, encoding or carrying instructions for execution by the machine  600 , and includes digital or analog communications signals or other intangible medium to facilitate communication of such software. 
     Various embodiments are illustrated in the figures above. One or more features from one or more of these embodiments may be combined to form other embodiments. 
     The method examples described herein can be machine or computer-implemented at least in part. Some examples may include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device or system to perform methods as described in the above examples. An implementation of such methods may include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code may include computer readable instructions for performing various methods. The code can form portions of computer program products. Further, the code can be tangibly stored on one or more volatile or non-volatile computer-readable media during execution or at other times. 
     The above detailed description is intended to be illustrative, and not restrictive. The scope of the disclosure should, therefore, be determined with references to the appended claims, along with the full scope of equivalents to which such claims are entitled.