Systems and methods for guiding spinal cord stimulation using evoked potentials

Abstract

Methods and systems for spinal cord stimulation (SCS) are disclosed. The methods and systems involve the use of electrode leads implanted within the spine of a patient to record nerve responses induced by a stimulus. The disclosed neural responses differ in various aspects from the electrical responses previously measured in the SCS context, such as stimulation artifacts and evoked compound action potentials (ECAPs). The disclosed neural responses typically occur at a later time after inducing the stimulation pulse. Another significant feature is that when the frequency of evoked stimulation is ultra-low, such as about 10 Hz or less, the disclosed neural response is most significantly observed at a consistent, relatively constant amplitude as a whole. The disclosed methods and systems may use these neural responses as indications of pain, treatment, and / or another clinically relevant dimension to guide / confirm stimulation placement, as well as feedback control for stimulation parameters.

Description

Technical Field

[0001] The present application relates to implantable medical devices (IMDs), and more particularly to sensing signals in implantable stimulator devices. Background Art

[0002] Implantable neurostimulator devices are implantable medical devices (IMDs) that generate and deliver electrical stimulation to the body's nerves and tissues to treat various biological disorders, such as pacemakers for treating cardiac arrhythmias, defibrillators for treating cardiac fibrillation, cochlear stimulators for treating deafness, retinal stimulators for treating blindness, muscle stimulators for producing coordinated limb movements, spinal cord stimulators for treating chronic pain, cortical and deep brain stimulators for treating movement and psychological disorders, and other neurostimulators for treating urinary incontinence, sleep apnea, shoulder subluxation, etc. The following description generally focuses on the use of the present invention in a spinal cord stimulation (SCS) system, such as disclosed in U.S. Patent 6,516,227. However, the present invention may find application in any implantable neurostimulator device system.

[0003] The SCS system typically includes an implantable pulse generator (IPG) 10 shown in FIG1 . The IPG 10 includes a biocompatible device housing 12 that houses a battery 14 and circuitry for powering the IPG. The IPG 10 is coupled to tissue stimulation electrodes 16 via one or more electrode leads forming an electrode array 17. For example, one or more percutaneous leads 15 may be used, having ring or split ring electrodes 16 carried on a flexible body 18. In another example, a paddle-shaped lead 19 provides electrodes 16 positioned on one of its generally flat surfaces. Lead wires 20 within the lead are coupled to the electrodes 16 and proximal contacts 21 in a lead connector 22 that can be inserted into a header 23 secured to the IPG 10, which header may include, for example, epoxy. Once inserted, the proximal contacts 21 connect to header contacts 24 within the lead connector 22, which in turn are coupled to stimulation circuitry 28 within the housing 12 by feedthrough pins 25 through a housing feedthrough 26.

[0004] In the illustrated IPG 10, there are 32 electrodes (E1-E32), split between four percutaneous leads 15 or contained in a single paddle lead 19, and therefore, the head 23 may include a 2x2 array of eight electrode lead connectors 22. However, the type and number of leads in an IPG, as well as the number of electrodes, are application specific and may therefore vary. The conductive housing 12 may also include electrodes (Ec). In SCS applications, one or more electrode leads are typically implanted in the patient's spinal cord near the dura mater, preferably spanning both the left and right sides of the patient's spine. Proximal contacts 21 are tunneled through the patient's tissue to a distal location, such as the buttocks where the IPG housing 12 is implanted, at which point they are coupled to the lead connectors 22. In other examples of IPGs designed for direct implantation at the site where stimulation is desired, the IPG may be leadless, with electrodes 16 instead present on the body of the IPG 10 for contacting the patient's tissue. In other solutions, one or more IPG leads may be integrated with and permanently connected to the IPG 10. The goal of SCS therapy is to provide electrical stimulation from the electrodes 16 to relieve a patient's symptoms, such as chronic back pain.

[0005] The IPG 10 may include an antenna 27a to allow it to communicate bidirectionally with a number of external devices used to program or monitor the IPG, such as a handheld patient controller or a clinician's programmer (CP), as described, for example, in U.S. Patent Application Publication 2019 / 0175915. The antenna 27a as shown includes a conductive coil within the housing 12, although the coil antenna 27a may also be present in the head 23. When the antenna 27a is configured as a coil, communication with the external device preferably occurs using near-field magnetic induction. The IPG 10 may also include a radio frequency (RF) antenna 27b. In FIG1 , the RF antenna 27b is shown within the head 23, but it may also be within the housing 12. The RF antenna 27b may include a patch, a slot, or a wire, and may operate as a monopole or a dipole. The RF antenna 27b preferably communicates using far-field electromagnetic waves and may operate according to any number of known RF communication standards such as Bluetooth, Zigbee, MICS, and the like.

[0006] Stimulation in the IPG 10 is typically provided by pulses, each of which may include multiple phases, such as 30a and 30b, as shown in the example of FIG2A. Stimulation parameters typically include amplitude (current I, although voltage amplitude V may also be used); frequency (F); pulse width (PW) of the pulse or its individual phases; electrodes 16 selected to provide stimulation; and the polarity of these selected electrodes, i.e., whether they act as anodes pulling (source) current to the tissue or cathodes sinking (sink) current from the tissue. These and possibly other stimulation parameters together comprise a stimulation program that the stimulation circuit 28 in the IPG 10 can execute to provide therapeutic stimulation to the patient.

[0007] In the example of FIG2A , electrode E4 has been selected as the anode (during its first phase 30 a) and has therefore provided a pulse that pulls a positive current of amplitude +I into the tissue. Electrode E5 has been selected as the cathode (also during the first phase 30 a) and has therefore provided a pulse that sinks a corresponding negative current of amplitude -I from the tissue. This is an example of bipolar stimulation, in which only two lead-based electrodes are used to provide stimulation to the tissue (one anode, one cathode). However, more than one electrode can be selected to act as the anode at a given time, and more than one electrode can be selected to act as the cathode at a given time. In the so-called monopolar case, the housing electrode Ec (12) can also be selected as an electrode or current loop.

[0008] As mentioned, the IPG 10 includes stimulation circuitry 28 to provide prescribed stimulation to the patient's tissue. FIG3 shows an example of stimulation circuitry 28, which includes one or more current sourcing circuits 40i and one or more current sinking circuits 42i. The sourcing circuits 40i and sinking circuits 42i may include digital-to-analog converters (DACs) and may be referred to as PDACs 40i and NDACs 42i, respectively, based on the positive (sourcing, anode) and negative (sinking, cathode) currents they source. In the example shown, the NDAC / PDAC 40i / 42i pair is dedicated (hardwired) to a specific electrode node ei 39. For reasons explained below, each electrode node ei 39 is connected to electrode Ei 16 via a DC blocking capacitor Ci 38. The stimulation circuitry 28 in this example also supports selection of the conductive housing 12 as the electrode (Ec12), which is typically selected for monopolar stimulation. The PDACs 40i and NDACs 42i may also include voltage sources.

[0009] Appropriate control of the PDACs 40i and NDACs 42i allows any electrode 16 to act as an anode or cathode to generate current through the patient's tissue R, hopefully with a therapeutic effect. In the illustrated example ( FIG. 2A ), during the first phase 30a (where electrodes E4 and E5 are selected as anode and cathode, respectively), the PDACs 404 and NDACs 425 are activated and digitally programmed to generate the desired current I with the correct timing (e.g., at a specified frequency F and pulse width PWa). During the second phase 30b (PWb), the PDACs 405 and NDACs 424 are activated to reverse the polarity of the current. More than one anode electrode and more than one cathode electrode can be selected simultaneously, and thus current can flow through the tissue R between two or more of the electrodes 16.

[0010] The stimulation circuit 28 is powered by a compliance voltage VH. As described in further detail in U.S. Patent Application Publication No. 2013 / 0289665, the compliance voltage VH can be generated by a compliance voltage generator 29, which can include circuitry for boosting the voltage (Vbat) of the battery 14 to a voltage VH sufficient to drive a prescribed current I through the tissue R. The compliance voltage generator 29 can include an inductor-based boost converter as described in the '665 publication, or can include a capacitor-based charge pump. Because the resistance of the tissue is variable, VH can also be variable, and in one example can be as high as 18 volts.

[0011] Other stimulation circuits 28 may also be used in the IPG 10. In an example not shown, a switch matrix may be interposed between one or more PDACs 40i and the electrode node ei 39, and between one or more NDACs 42i and the electrode node. The switch matrix allows one or more of the PDACs or one or more of the NDACs to be connected to one or more anode or cathode electrode nodes at a given time. Various examples of stimulation circuits can be found in U.S. Patents 6,181,969, 8,606,362, 8,620,436, and U.S. Patent Application Publications 2018 / 0071520 and 2019 / 0083796. Most of the stimulation circuitry 28 of FIG3 (including the PDAC 40i and NDAC 42i, the switch matrix (if present), and the electrode nodes ei 39) can be integrated on one or more application-specific integrated circuits (ASICs), as described in U.S. Patent Application Publications 2012 / 0095529, 2012 / 0092031, and 2012 / 0095519, incorporated herein by reference. As explained in these references, one or more ASICs can also contain other circuits useful in the IPG 10, such as telemetry circuitry (for interfacing off-chip with telemetry antennas 27a and / or 27b), compliance voltage generator 29, various measurement circuits, and the like. The stimulation circuitry described herein provides multiple independent current controls (MICCs) (or multiple independent voltage controls) to guide the estimation of the current fractionalization between multiple electrodes and estimate the total amplitude that provides the desired intensity. In other words, the total anodic current can be split between two or more electrodes and / or the total cathodic current can be split between two or more electrodes, thereby allowing adjustment of the stimulation location and the resulting field shape. For example, a "virtual electrode" can be created at a location between two physical electrodes by subdividing the current between the two physical electrodes. In other words, the virtual electrode is not co-located with either of the physical electrodes.

[0012] Also shown in FIG3 are DC blocking capacitors Ci 38 placed in series in the electrode current path between electrode node ei 39 and each of electrodes Ei 16 (including housing electrode Ec 12). The DC blocking capacitors 38 serve as a safety measure to prevent DC current from being injected into the patient, which could occur, for example, if there is a circuit fault in the stimulation circuit 28. The DC blocking capacitors 38 are typically provided off-chip (outside of one or more ASICs) and may alternatively be provided in or on a circuit board in the IPG 10 that is used to integrate its various components, as explained in U.S. Patent Application Publication 2015 / 0157861.

[0013] Although not shown, the circuits in the IPG 10, including the stimulation circuit 28, may also be included in an external trial stimulator (ETS) device that is used to simulate the operation of the IPG during a trial period and before the IPG 10 is implanted. The ETS device is typically used after the electrode array 17 has been implanted in the patient. The proximal ends of the leads in the electrode array 17 pass through the patient's incision and connect to an externally worn ETS, allowing the ETS to provide stimulation to the patient during the trial period. More details regarding the ETS device are described in USP 9,259,574 and US Patent Application Publication 2019 / 0175915.

[0014] Referring again to FIG. 2A , the stimulation pulses shown are biphasic, with each pulse at each electrode comprising a first phase 30a followed by a second phase 30b of opposite polarity. Biphasic pulses help actively restore any charge that may be stored on capacitive components in the electrode current path (such as DC blocking capacitors 38, the electrode / tissue interface, or within the tissue itself). In order to restore all charge (Vc4=Vc5=0V) by the end of the second pulse phase 30b of each pulse, the first phase 30a and the second phase 30b are preferably charge-balanced at each electrode, wherein the phases comprise equal amounts of charge but opposite polarity. In the example shown, this charge balance is achieved by using the same pulse width (PWa=PWb) and the same amplitude (|+I|=|-I|) for each of the pulse phases 30a and 30b. However, as is known, the pulse phases 30a and 30b can also be charge-balanced if the product of the amplitude and pulse width of the two phases 30a and 30b is equal.

[0015] FIG3 shows that the stimulation circuit 28 may include a passive recovery switch 41i, which is further described in U.S. Patent Application Publications 2018 / 0071527 and 2018 / 0140831. Passive recovery switches 41i can be attached to each of the electrode nodes 39 and are used to passively recover any charge remaining on the DC blocking capacitor Ci 38 after the second pulse phase 30b is issued—that is, to recover the charge without actively driving current using the DAC circuit. Passive charge recovery can be cautious because non-idealities in the stimulation circuit 28 may result in pulse phases 30a and 30b that are not completely charge balanced. By closing the passive recovery switch 41i, passive charge recovery typically occurs during at least a portion 30c (FIG. 2A) of the quiet period between pulses. As shown in FIG3, the other end of the switch 41i not coupled to the electrode node 39 is connected to a common reference voltage, which in this example includes the voltage Vbat of the battery 14, but another reference voltage may also be used. As explained in the references cited above, passive charge recovery tends to balance the charge on the DC blocking capacitor 38 and other capacitive components by placing the capacitor in parallel between the reference voltage (Vbat) and the patient tissue. Note that passive charge recovery is shown as a small exponential decay curve during 30c in FIG2A, which can be positive or negative, depending on whether the pulse phase 30a or 30b has a charge advantage at a given electrode.

[0016] FIG4 illustrates various external devices that can communicate wirelessly with the IPG 10 and / or ETS 80, including a patient, a handheld external controller 45, and a clinician programmer 50. Devices 45 and 50 can both be used to wirelessly transmit stimulation programs to the IPG 10 or ETS 80, i.e., to program their stimulation circuits 28 and 44 to generate pulses of the desired shape and timing as described above. Devices 45 and 50 can also be used to adjust one or more stimulation parameters of a stimulation program currently being executed by the IPG 10 or ETS 80. Devices 45 and 50 can also receive information from the IPG 10 or ETS 80, such as various status information.

[0017] For example, the external controller 45 may be as described in U.S. Patent Application Publication 2015 / 0080982 and may include a dedicated controller configured to work with the IPG 10. The external controller 45 may also include a general-purpose mobile electronic device (such as a mobile phone) that has been programmed with a Medical Device Application (MDA) to allow it to operate as a wireless controller for the IPG 10 or ETS 80, as described in U.S. Patent Application Publication 2015 / 0231402. The external controller 45 includes a user interface that includes means for inputting commands (e.g., buttons or icons) and a display 46. The user interface of the external controller 45 enables the patient to adjust stimulation parameters, although its functionality may be limited compared to the more powerful clinician programmer 50 described later.

[0018] The external controller 45 may have one or more antennas capable of communicating with the IPG 10 and the ETS 80. For example, the external controller 45 may have a near-field magnetic induction coil antenna 47a capable of wirelessly communicating with the coil antenna 27a or 42a in the IPG 10 or ETS 80. The external controller 45 may also have a far-field RF antenna 47b capable of wirelessly communicating with the RF antenna 27b or 42b in the IPG 10 or ETS 80.

[0019] The external controller 45 may also have a control circuit 48, such as a microprocessor, microcomputer, FPGA, other digital logic structure, etc., which is capable of executing instructions in the electronic device. The control circuit 48 can, for example, receive the patient's adjustments to the stimulation parameters and create a stimulation program to be wirelessly transmitted to the IPG 10 or ETS 80.

[0020] The clinician programmer 50 is further described in U.S. Patent Application Publication 2015 / 0360038 and is only briefly explained here. The clinician programmer 50 may include a computing device 51, such as a desktop, laptop or notebook computer, tablet computer, mobile smartphone, Personal Data Assistant (PDA) type mobile computing device, etc. In Figure 4, the computing device 51 is shown as a laptop computer, which includes typical computer user interface devices such as a screen 52, a mouse, a keyboard, speakers, a stylus, a printer, etc., for convenience, not all of which are shown. Also shown in Figure 4 are auxiliary devices of the clinician programmer 50, which are generally specific to its operation as a stimulation controller (such as a communication "stick" 54 and a joystick 58), which can be coupled to appropriate ports on the computing device 51, such as a USB port 59.

[0021] The antenna used in the clinician programmer 50 for communicating with the IPG 10 or ETS 80 can depend on the type of antenna included in these devices. If the patient's IPG 10 or ETS 80 includes a coil antenna 27a or 82a, the wand 54 can also include a coil antenna 56a to establish near-field magnetic induction communication over a short distance. In this case, the wand 54 can be attached near the patient, such as by placing the wand 54 in a wearable belt or holster that the patient wears and close to the patient's IPG 10 or ETS 80. If the IPG 10 or ETS 80 includes an RF antenna 27b or 82b, the wand 54, the computing device 51, or both can also include an RF antenna 56b to establish communication with the IPG 10 or ETS 80 at a longer distance. (In this case, the wand 54 may not be needed). The clinician programmer 50 can also establish communication with other devices and networks (such as the Internet) wirelessly or via a wired link provided at an Ethernet or network port.

[0022] In order to program the stimulation program or parameters of the IPG 10 or ETS 80, the clinician interacts with a clinician programmer graphical user interface (GUI) 64 provided on the display 52 of the computing device 51. As will be appreciated by those skilled in the art, the GUI 64 can be rendered by executing clinician programmer software 66 on the computing device 51, which can be stored in the device's non-volatile memory 68. Those skilled in the art will also recognize that a controller circuit 70 (such as a microprocessor, microcomputer, FPGA, other digital logic structures, etc.) capable of executing programs in a computing device can facilitate the execution of the clinician programmer software 66 in the computing device 51. In one example, the controller circuit 70 can include any of the i5 core processors manufactured by Intel Corporation. In addition to executing the clinician programmer software 66 and rendering the GUI 64, such a controller circuit 70 can also communicate via antenna 56a or 56b to communicate the stimulation parameters selected through the GUI 64 to the patient's IPG 10.

[0023] Although GUI 64 is shown as operating in clinician programmer 50 , the user interface of external controller 45 may provide similar functionality as external controller 45 may have similar controller circuitry, software, etc. Summary of the Invention

[0024] Disclosed herein is a method for providing electrical stimulation to a patient's spinal cord using a pulse generator (PG) connected to one or more electrode leads implanted in the patient's spinal cord, each electrode lead comprising a plurality of electrodes, the method comprising: using a first one or more electrodes of the plurality of electrodes as stimulation electrodes to apply an induced stimulation to the patient's spinal cord, using a second two or more electrodes of the plurality of electrodes as recording electrodes to record a neural response induced in the patient's spinal cord by the induced stimulation, comparing the recorded induced neural responses at each of the recording electrodes, and using the comparison to evaluate the placement of the electrode leads relative to the spinal cord. According to some embodiments, the induced stimulation has a frequency of 10 Hz or less. According to some embodiments, the induced neural response occurs at least 2 milliseconds after the induced stimulation. According to some embodiments, the induced neural response indicates synaptic activity within the patient's spinal cord. According to some embodiments, comparing the recorded induced neural responses comprises extracting one or more features of the recorded neural responses. According to some embodiments, the extracted one or more features comprise one or more of peak amplitude, area under the curve, and curve length. According to some embodiments, comparing the recorded evoked neural responses includes determining a reversal location on the lead where the polarity of the evoked neural response switches between positive and negative polarity. According to some embodiments, the method further includes determining a first stimulation configuration using one or more patient metrics, the first stimulation configuration configured to provide optimized stimulation to the patient; applying the optimized stimulation as the evoked stimulation using a first one or more electrodes of the plurality of electrodes; and determining a first value of one or more characteristics of the recorded evoked neural response associated with the first stimulation configuration. According to some embodiments, the one or more patient metrics include pain level and / or pain-paresthesia overlap. According to some embodiments, the one or more patient metrics include patient posture. According to some embodiments, the one or more patient metrics are determined using one or more sensors and / or input received from the patient via an external device. According to some embodiments, the one or more sensors include an accelerometer. According to some embodiments, the one or more sensors include a wearable sensor. According to some embodiments, the one or more characteristics of the recorded evoked neural response include one or more of the following: peak amplitude, area under the curve, curve length, and a reversal location on the lead where the polarity of the evoked neural response switches between positive and negative polarity. According to some embodiments, the method further comprises determining a change in first values ​​of one or more characteristics of the recorded evoked neural response and adjusting the first stimulation configuration based on the change. According to some embodiments, the PG is an implantable pulse generator (IPG). According to some embodiments, the PG is an external trial stimulator (ITS).

[0025] Also disclosed herein is a non-transitory computer-readable medium comprising instructions, which, when executed on a computer, configure the computer to perform the method according to any of the above embodiments.

[0026] Also disclosed herein is a system for providing electrical stimulation to a patient's spinal cord using a pulse generator (PG) connected to one or more electrode leads implanted in the patient's spinal cord, each electrode lead comprising a plurality of electrodes, the system comprising: a control circuit configured to: use a first one or more electrodes of the plurality of electrodes as stimulation electrodes to apply evoked stimulation to the patient's spinal cord, use a second two or more electrodes of the plurality of electrodes as recording electrodes to record a neural response evoked in the patient's spinal cord by the evoked stimulation, compare the recorded evoked neural responses at each of the recording electrodes, and use the comparison to evaluate the placement of the electrode leads relative to the spinal cord. According to some embodiments, the evoked stimulation has a frequency of 10 Hz or less. According to some embodiments, the evoked neural response occurs at least 2 milliseconds after the evoked stimulation. According to some embodiments, the evoked neural response indicates synaptic activity within the patient's spinal cord. According to some embodiments, comparing the recorded evoked neural responses comprises extracting one or more features of the recorded neural responses. According to some embodiments, the extracted one or more features comprise one or more of peak amplitude, area under the curve, and curve length. According to some embodiments, comparing the recorded evoked neural responses includes determining a reversal location on the lead at which the polarity of the evoked neural response switches between positive and negative polarity. According to some embodiments, the control circuit is further configured to: determine a first stimulation configuration using one or more patient metrics, the first stimulation configuration configured to provide optimized stimulation to the patient; apply the optimized stimulation as the evoked stimulation using a first one or more electrodes of the plurality of electrodes; and determine a first value of one or more characteristics of the recorded evoked neural response associated with the first stimulation configuration. According to some embodiments, the one or more patient metrics include pain level and / or pain-paresthesia overlap. According to some embodiments, the one or more patient metrics include patient posture. According to some embodiments, the one or more patient metrics are determined using one or more sensors and / or input received from the patient via an external device. According to some embodiments, the one or more sensors include an accelerometer. According to some embodiments, the one or more sensors include a wearable sensor. According to some embodiments, the one or more characteristics of the recorded evoked neural response include one or more of the following: peak amplitude, area under the curve, curve length, and a reversal location on the lead at which the polarity of the evoked neural response switches between positive and negative polarity. According to some embodiments, the control circuit is further configured to determine a change in the first value of one or more characteristics of the recorded evoked neural response and adjust the first stimulation configuration based on the change. According to some embodiments, the PG is an implantable pulse generator (IPG) configured to be implanted in a patient, and wherein the control circuit is configured within the IPG. According to some embodiments, the control circuit is configured within an external computing system that is configured to transmit control commands to the PG. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 shows an implantable pulse generator (IPG) according to the prior art.

[0028] 2A and 2B illustrate examples of stimulation pulses that may be generated by an IPG according to the prior art.

[0029] FIG3 shows a stimulation circuit that may be used in an IPG according to the prior art.

[0030] FIG. 4 shows an external device capable of communicating with an IPG according to the prior art.

[0031] Figure 5 An improved IPG is shown that has the ability to stimulate and sense electrospinogram (ESG) signals, which may include evoked compound action potentials (ECAPs) caused by stimulation.

[0032] Figure 6 Stimulation artifacts, ECAPs and evoked synaptic potentials (ESPs), are shown separately and combined in the ESG.

[0033] Figure 7 An algorithm for characterizing the ESP and using the characteristics for closed-loop feedback control of the SCS is presented.

[0034] Figure 8 Stimuli used to induce and record ESP are shown.

[0035] Figure 9 Stimuli used to induce and record ESP are shown.

[0036] Figure 10 A GUI showing ESPs recorded at different locations is shown.

[0037] Figure 11 The workflow for optimizing stimulation geometry and waveform is shown.

[0038] Figure 12 Graphs correlating recorded ESP behavior with stimulation location and patient metrics are shown.

[0039] Figure 13 A diagram is shown for maintaining a therapy window using ESP characteristics as a function of stimulation location and patient metrics.

[0040] Figure 14 A decision matrix relating changes in neural responses to possible causes and consequences is shown.

[0041] Figure 15The logical relationship between changes in neural responses and possible causes and effects is shown.

[0042] Figure 16 A pulse program illustrating the threshold of neural responses at increasing amplitudes is shown.

[0043] Figure 17A and Figure 17B It is shown how a pulse procedure at increasing frequency can be used to illustrate ESP roll-off.

[0044] Figure 18A and Figure 18B An example of correlating posture changes with ESP feature changes is shown. DETAILED DESCRIPTION

[0045] An increasingly interesting development in pulse generator systems, and particularly in spinal cord stimulator (SCS) pulse generator systems, is the addition of sensing capabilities to supplement the stimulation provided by such systems. Figure 5 An IPG 100 is shown that includes both stimulation and sensing functionality. An ETS as previously described may also include stimulation and sensing functionality, and Figure 5 The circuit shown.

[0046] For example, it may be beneficial to sense neural responses in neural tissue that receives stimulation from the IPG 100. One such neural response is the evoked compound action potential (ECAP). The ECAP comprises the cumulative response provided by the neural fibers recruited by the stimulation and essentially comprises the sum of the action potentials of the recruited neural elements (ganglia or fibers) as they "fire." Figure 5 , and includes multiple peaks, which are conventionally labeled with P for positive peaks and N for negative peaks, where P1 includes the first positive peak, N1 includes the first negative peak, P2 includes the second positive peak, N2 includes the second negative peak, etc. Note that not all ECAPs will have such peaks. Figure 5 The exact shape and number of peaks shown in are not known because the shape of the ECAP is a function of the number and type of neural elements that are recruited and involved in its conduction. ECAPs are typically small signals and may have peak-to-peak amplitudes of the order of hundreds of microvolts or even higher.

[0047] Figure 5Also shown is an electrode array 17, which (in this example) includes a single percutaneous lead 15, and shows the use of electrodes E3, E4, and E5 to generate pulses in a tripolar stimulation mode, wherein (during the first phase 30a) E3 and E5 comprise anodes and E4 comprises a cathode. Other electrode arrangements (e.g., bipolar, etc.) may also be used. Such stimulation generates an electric field 130 in a volume of patient tissue centered around the selected electrode. Some nerve fibers within the electric field 130 (particularly those close to the cathode electrode E4) will be recruited and ignited, forming an ECAP, which can travel headward toward the brain and caudally away from the brain. The ECAP passes through the spinal cord via neural conduction at a speed that depends on the nerve fibers involved in the conduction. In one example, the ECAP can move at a speed of approximately 5 cm / 1 ms. U.S. Patent Application Publication 2020 / 0155019 describes a lead that can be used to detect the ECAP.

[0048] ECAP can be sensed at one or more sensing electrodes, which can be selected from electrodes 16 in the electrode array 17. Sensing preferably occurs in a differential manner, with one electrode (e.g., S+, E8) used for sensing and another (e.g., S-, E9) used as a reference. This can also be reversed, with E8 providing a reference (S-) for sensing at electrode E9 (S+). Although not shown, the housing electrode Ec (12) can also be used as a sensing reference electrode S-. The sensing reference S- can also include a fixed voltage provided by the IPG 100 (e.g., Vamp discussed below), such as ground, in which case the sensing will be referred to as single-ended rather than differential.

[0049] Figure 5 The waveform appearing at the sensing electrode E8 (S+) is shown, which includes the stimulation artifact 134 and the ECAP. The stimulation artifact 134 includes the voltage developed in the tissue as a result of the stimulation (i.e., as a result of the electric field 130 generated in the tissue by the stimulation). As described in U.S. Patent Application Publication 2019 / 0299006, the voltage in the tissue can vary between ground and the compliance voltage VH used to power the DAC, so the stimulation artifact 134 can be on the order of volts and therefore significantly higher than the amplitude of the stimulation-induced ECAP. In general, the waveform sensed at the sensing electrode can be referred to as an electromyogram (ESG) signal, which includes the ECAP, the stimulation artifact 134, and other background signals that may be generated by the neural tissue even in the absence of stimulation. Note that Figure 5 The ESG signal displayed at the sensing electrode S+ is idealized. The figure in US Provisional Patent Application Publication 2022 / 0323764 shows the actual recorded ESG trace.

[0050] The magnitude of the stimulation artifact 134 and the ECAP at the sensing electrodes S+ and S- depend on many factors, such as the intensity of the stimulation and the distance of the sensing electrodes from the stimulation. The ECAP tends to decrease in magnitude as the stimulation-to-sensing distance increases because they are dispersed in the tissue. The magnitude of the stimulation artifact 134 also decreases as the stimulation-to-sensing distance increases because the electric field 130 is weaker at greater distances. Note that the stimulation artifact 134 is also typically larger during the delivery of the pulse, and may still exist even after the pulse (i.e., the last phase 30b of the pulse) has ceased due to the capacitive properties of the tissue or the capacitive properties of the drive circuit (i.e., the DAC). Therefore, the electric field 130 may not dissipate immediately after the pulse stops.

[0051] It may be useful to sense features of either or both of the ECAP or stimulation artifact 134 contained in the sensed ESG signal in the IPG 100, as such features can be used for useful purposes. For example, neural response features can be used for feedback (such as closed-loop feedback) to adjust the stimulation provided by the IPG 100. See, for example, USP 10,406,368; U.S. Patent Application Publications 2019 / 0099602, 2019 / 0209844, 2021 / 0252287, 2021 / 0252289, 2019 / 0070418, 2020 / 0147393, and 2022 / 0347479. ECAP assessment can also be used to infer the type of neural elements or fibers recruited, which in turn can be used to adjust stimulation to selectively stimulate such elements. See, for example, U.S. Patent Application Publication 2019 / 0275331. Assessment of ECAP features can also be used to determine cardiovascular effects, such as the patient's heart rate. See, for example, U.S. Patent Application Publication 2019 / 0290900. To the extent that one wishes to assess features of the ECAP that are masked by stimulation artifacts, U.S. Patent Application Publication 2019 / 0366094 discloses techniques that can be used to extract ECAP features from ESG signals. As discussed in some of these references, the detected ECAP may also depend on the patient's posture or activity, and thus assessment of the ECAP features may be used to infer the patient's posture, which in turn may be used to adjust the stimulation provided by the IPG 10.

[0052] It may also be useful to detect characteristics of the stimulation artifact 134 (value in itself). For example, U.S. Patent Application Publication 2022 / 0323764 describes that characteristics of the stimulation artifact can be used to determine patient posture or activity, which in turn can be used to adjust the stimulation provided by the IPG 100.

[0053] Figure 51 shows further details of the circuitry in the IPG 100 that can provide stimulation and sensing of electrospinal cord (ESG) signals. The IPG 100 includes a control circuit 102, which can include a microcontroller, such as part number MSP430 manufactured by Texas Instruments, Inc., which is described in the data sheet at http: / / www.ti.com / microcontrollers / msp430-ultra-low-power-mcus / overview.html, which is incorporated herein by reference. Other types of controller circuits can also be used in place of a microcontroller, such as a microprocessor, FPGA, DSP, or a combination of these. The control circuit 102 can also be formed in whole or in part in one or more application-specific integrated circuits (ASICs), such as those described and incorporated herein.

[0054] The IPG 100 also includes stimulation circuitry 28 to generate stimulation at the electrodes 16, which may include the stimulation circuitry 28 previously shown (FIG. 3). The bus 118 provides signals to one or more PDACs 40. i or NDAC 42 i Digital control signals are provided from the control circuit 102 (and possibly from the feature extraction algorithm 140, as described below) to generate currents or voltages of specified amplitude (I) with correct timing (PW, F) at the selected electrodes for the stimulation pulses. As previously mentioned, the DACs can be powered between the compliance voltage VH and ground. Also as previously mentioned but not shown in FIG4 , a switch matrix can be interposed between the PDACs and the electrode node 39 and between the NDACs and the electrode node 39 to route their outputs to one or more of the electrodes (including the conductive shell electrode 12 (Ec)). The control signals for the switch matrix, if present, can also be carried by the bus 118. Note that the current path to the electrode 16 includes the previously described DC blocking capacitor 38, which provides safety by preventing inadvertent supply of DC current to the electrode and to the patient tissue. Passive recovery switch 41 i (Figure 3) can also exist, but for simplicity, Figure 5 Not displayed in .

[0055] The IPG 100 also includes a sensing circuit 115, and one or more of the electrodes 16 may be used to sense ESG signals. In this regard, each electrode node 39 may also be coupled to a sense amplifier circuit 110. Under the control of the bus 114, the multiplexer 108 may select one or more electrodes to operate as sensing electrodes (S+, S-) by coupling one or more electrodes to the sense amplifier circuit 110 at a given time, as further explained below. Although Figure 5Only one multiplexer 108 and sense amplifier circuit 110 is shown, but there may be more than one. For example, there may be four multiplexer 108 / sense amplifier circuit 110 pairs, each of which can operate in one of the four timing channels supported by the IPG 100 to provide stimulus. The sense signal output by the sense amplifier circuit is preferably converted to a digital signal by one or more analog-to-digital converters (ADCs) 112, which can sample the output of the sense amplifier circuit 110 at, for example, 50 kHz. The ADC(s) 112 can also reside within the control circuit 102, particularly if the control circuit 102 has A / D inputs. The multiplexer 108 can also provide a fixed reference voltage, Vamp, to the sense amplifier circuit 110, as this is useful in single-ended sensing mode (i.e., setting S- to Vamp).

[0056] In order not to bypass the safety provided by the DC blocking capacitor 38, the input to the sense amplifier circuit 110 is preferably taken from the electrode node 39. However, the DC blocking capacitor 38 will pass the AC signal component (while blocking the DC component), and therefore, AC components in the ESG signal being sensed (such as ECAP and stimulation artifacts) will still be readily sensed by the sense amplifier circuit 110. In other examples, the signal can be sensed directly at the electrode 16 without passing through the intervening capacitor 38.

[0057] As described above, the ESG signal is preferably sensed differentially. In this regard, the sense amplifier circuit 110 includes a differential amplifier that receives a sense signal S+ (e.g., E8) at its non-inverting input and a sense reference S- (e.g., E9) at its inverting input. As will be appreciated by those skilled in the art, the differential amplifier will subtract S- from S+ at its output, thereby canceling any common-mode voltage from the two inputs. This can be useful, for example, when sensing ECAP, as in this case it may be useful to subtract (as much as possible) the relatively large stimulus artifact 134 from the measurement. That said, note that differential sensing will not completely eliminate stimulus artifacts, as the voltages at the sense electrodes S+ and S- will not be exactly the same. For example, each will be located at a slightly different distance from the stimulus and, therefore, will be located at a different location in the electric field 130. Thus, even when differential sensing is used, stimulus artifacts 134 may still be sensed. Examples of sense amplifier circuits 110 and ways to use such circuits can be found in U.S. Patent Application Publications 2019 / 0299006, 2020 / 0305744, 2020 / 0305745, and 2022 / 0233866.

[0058] The digitized ESG signals from one or more ADCs 112 (including any detected ECAPs and stimulation artifacts) are received at a feature extraction algorithm 140 programmed into the control circuitry 102 of the IPG. The feature extraction algorithm 140 analyzes the digitized sensed signals to determine one or more ECAP features and one or more stimulation artifact features, as described, for example, in U.S. Patent Application Publication 2022 / 0323764. Such features may generally indicate the magnitude and shape of the associated signal, but may also indicate other factors (such as ECAP conduction velocity). Those skilled in the art will appreciate that the feature extraction algorithm 140 may include instructions that may be stored on a non-transitory machine-readable medium, such as a magnetic, optical, or solid-state memory within the IPG 100 (e.g., stored in association with the control circuitry 102).

[0059] For example, the feature extraction algorithm 140 may determine one or more neural response features (e.g., ECAP features), which may include, but are not limited to:

[0060] The height of any peak (e.g., N1);

[0061] The peak-to-peak height between any two peaks (e.g., from N1 to P2);

[0062] Peak height ratio (e.g., N1 / P2);

[0063] The peak width of any peak (e.g., the full width at half maximum of N1);

[0064] The area or energy under any peak;

[0065] Total area or energy, including the area or energy under positive peaks minus or plus the area or energy under negative peaks;

[0066] The length of any portion of the curve of the ECAP (e.g., the length of the curve from P1 to N2);

[0067] Any time that defines the duration of at least a portion of the ECAP (e.g., the time from P1 to N2);

[0068] The time delay from stimulation to the onset of the ECAP, which indicates the nerve conduction velocity of the ECAP, can vary in different types of neural tissue;

[0069] The conduction velocity of the ECAP (i.e., conduction rate), which can be determined by sensing the ECAP as it moves past different sensing electrodes;

[0070] The rate of change of any previous feature, i.e., how much the feature changes over time;

[0071] The power (or energy) determined in a specified frequency band (e.g., delta, alpha, beta, gamma, etc.) determined in a specified time window (e.g., a time window overlapping with neural responses, stimulation artifacts, etc.);

[0072] Any mathematical combination or function of these variables.

[0073] Such ECAP features can be approximated by the feature extraction algorithm 140. For example, the area under the curve can include the sum of the absolute values ​​of the sensed digital samples within a specified time interval. Similarly, the curve length can include the sum of the absolute values ​​of the differences between consecutive sensed digital samples within a specified time interval. ECAP features can also be determined within specific time intervals, which can be referenced to the onset of stimulation or referenced from the ECAP signal itself (e.g., reference peak N1).

[0074] In this disclosure, as described above, ECAP features are also referred to as neural features or neural response features. This is because such ECAP features contain information about how various neural elements are excited / recruited during stimulation, and how these neural elements spontaneously fire to produce spontaneous neural responses.

[0075] The feature extraction algorithm 140 may also determine one or more stimulation artifact features that may be similar to the ECAP features just described, but may also be different to account for the different shapes of the stimulation artifacts 134. The determined stimulation artifact features may include, but are not limited to:

[0076] The height of any peaks;

[0077] The peak-to-peak height between any two peaks;

[0078] Peak height ratio;

[0079] The area or energy under any peak;

[0080] Total area or energy, including the area or energy under positive peaks minus or plus the area or energy under negative peaks;

[0081] The length of any portion of the curve that is a stimulus artifact;

[0082] any time that defines the duration of at least a portion of the stimulation artifact;

[0083] The rate of change of any previous feature, i.e., how much the feature changes over time;

[0084] The power (or energy) determined in a specified frequency band (e.g., delta, alpha, beta, gamma, etc.) determined in a specified time window (e.g., a time window overlapping with neural responses, stimulation artifacts, etc.);

[0085] Delay and / or time delay at any critical points in the signal, such as positive peaks, negative peaks, zero crossings, etc.; and

[0086] Any mathematical combination or function of these variables.

[0087] Likewise, such stimulation artifact features may be approximated by the feature extraction algorithm 140 and may be determined relative to specific time intervals, which may be referenced as the start or end of stimulation, or referenced from within the stimulation artifact signal itself (e.g., referenced to specific peaks).

[0088] Once the feature extraction algorithm 140 determines one or more of these features, it can be used in the IPG 100 for any useful effect, and in particular can be used to adjust the stimulation provided by the IPG 100, for example by providing new data to the stimulation circuit 28 via the bus 118. This is further explained in some of the U.S. patents cited above. For example, if the distance between the stimulation electrode and the patient's spinal cord changes (e.g., due to posture changes, coughing, movement, etc.), the stimulation can be adjusted based on the extracted features to maintain optimized therapeutic stimulation.

[0089] The SCS / neurosensing patents and applications mentioned above primarily relate to ECAPs and / or stimulation artifacts. The inventors have discovered additional neural responses that can be sensed, recorded, and play a useful role during SCS. Without being bound by theory, the inventors hypothesize that the new neural responses originate at synapses and / or are evoked by synapses connecting dorsal column axons to neurons in the dorsal horn. The hypothesis of a synaptic origin for the newly observed signals is supported by the observation that CNQX, an AMPA receptor antagonist that inhibits synaptic activity, causes the new neural responses to disappear. Therefore, the new neural responses are referred to in this disclosure as evoked synaptic potentials (ESPs). Because ESPs originate from neurons, they can be used as biomarkers of pain, therapeutic windows, side effects, and / or paresthesias, as well as to guide appropriate placement and control of stimulation.

[0090] ESP differs from stimulation artifacts and ECAPs in several ways. One difference is that the ability to sense ESP is highly dependent on the location of the sensing and stimulating electrodes. Specifically, ESP is most easily sensed near the synapses where it originates. The location-sensitivity of ESP sensing contrasts with that of ECAPs and / or stimulation artifacts, which, as described above, propagate rostrally and caudally from their point of origin and can therefore be sensed at various locations along the electrode leads. In other words, ESP can also be sensed at multiple locations along the spinal cord (if dorsal column fibers have multiple synaptic entry points into the horns), but not in the spatially continuous manner that ECAPs and artifacts can be sensed. Therefore, the location of ESP sensing is much more constrained than the location at which ECAPs can be detected. Furthermore, ECAPs will exhibit evidence of progression (i.e., gradual changes in the N1 and P2 latency), but their morphology is relatively consistent. ESP can also change morphology or even reverse depending on the position of the sensing electrode relative to the neural substrate.

[0091] ESP also tends to appear with a longer delay after stimulation than ECAP and stimulation artifacts. Figure 6 The recorded stimulation artifact, ECAP, and ESP are shown, each independently, along with the ESG containing each of the three recorded signals. Note that the ESP occurs later than the artifact and ECAP. Accordingly, the contribution of the ESP to the ESG can be distinguished based on the time window during which the signal is recorded, as explained in more detail below.

[0092] Another distinguishing characteristic of ESP is that it is typically most prominently observed at very low induced stimulation frequencies (e.g., approximately 10 Hz or lower), with a consistent, relatively constant amplitude. At higher frequencies, the amplitude of ESP decreases significantly only after a few cycles, but sporadic occurrences may still occur. In some embodiments, the amplitude of ESP evoked by 50 Hz stimulation begins to decrease after approximately the fourth pulse and then remains at a smaller, stable amplitude. At 10 Hz stimulation, the amplitude decreases more slowly, if at all. This contrasts with ECAP, which retains its amplitude and morphology even when SCS is applied at relatively high frequencies (e.g., 50 Hz). Furthermore, ESP is correspondingly wider than ECAP. The width of ECAP (defined by the N1 to P2 width) can be only 1-2 ms, while the width of ESP, which is roughly defined as the width of the large positive phase, can be or exceed 4-10 ms, or even larger. ESP is typically elicited at stimulation amplitudes that exceed the ECAP but fall below the discomfort threshold (DT). For example, some experiments have shown that the ECAP threshold is approximately 30% of the motor threshold, while the ESP threshold is approximately 50% to 60% of the motor threshold. This suggests that the ECAP threshold requires the smallest stimulus amplitude, followed by the ESP threshold, which requires a slightly higher amplitude. The DT and motor thresholds require even higher stimulus amplitudes. These thresholds refer to the stimulus amplitudes required to elicit corresponding signals (such as ECAP, ESP, or motor activity).

[0093] Aspects of the present disclosure relate to methods and systems for sensing, recording, characterizing, and using ESP. For example, aspects of the present disclosure relate to using one or more features of ESP as feedback control variables to adjust stimulation parameters (as an indicator of pain) and / or determine appropriate placement of stimulation. For example, stimulation parameters and / or stimulation location can be adjusted to maximize the value of one or more features of ESP. Alternatively, parameters and / or stimulation location can be adjusted to minimize one or more features of ESP, for example, if the ESP features indicate side effects. According to some embodiments, ESP features can be used in combination with features of other sensed signals, such as ECAP and / or stimulation artifact signals, for feedback control.

[0094] Figure 7 An algorithm 700 for guiding an SCS using an ESP is shown. The algorithm includes a calibration aspect 701 and an implementation of closed-loop feedback (i.e., step 708). The calibration aspect can be performed in part or in whole using an external device for controlling the IPG (or ETS), such as a clinician programmer 50 and / or an external controller 45. The implementation of closed-loop feedback control can be performed in the IPG, for example, using the control circuitry of the IPG.

[0095] At step 702, stimulation can be provided to the patient's spinal cord using candidate stimulation parameter values. Examples of stimulation parameters are as described above and can include, for example, frequency, pulse width, amplitude, inter-phase interval, inter-pulse interval, and the like. Candidate stimulation parameters can also include the location of the stimulation, which can be determined based on the subdivision of the current provided to the selected active electrode contacts. For the purposes of this discussion, it is assumed that the stimulation parameter that algorithm 700 is seeking to optimize is stimulation amplitude. In that case, step 702 will involve providing stimulation with a first candidate amplitude.

[0096] At step 704, the ESP is measured. It should be noted that a precursor to measuring the ESP may include determining an optimal location (i.e., an optimized electrode contact or contacts) at which to measure the ESP. As explained above, the ESP is location-dependent, so it may be desirable to poll various electrode contacts to find the electrode contact or contacts that best sense the ESP.

[0097] As explained above, ESP exhibits a consistent and sustained amplitude when induced at frequencies <10 Hz, but can also be observed in response to stimulation having frequencies of 50 Hz or lower. ESP induced at higher frequencies may exhibit a decrease in amplitude over subsequent stimulation periods. If a candidate therapeutic stimulation waveform has such a frequency, then the ESP induced by the candidate therapeutic stimulation waveform can be measured. If the candidate therapeutic stimulation waveform has a higher frequency, then a different stimulation waveform may need to be applied for the purpose of inducing ESP, or ESP detected according to the above criteria may decay over subsequent stimulation periods. In the present disclosure, the term "therapeutic stimulation" means stimulation applied for therapeutic purposes, such as treating pain in a patient. The term "induced stimulation" applies to stimulation applied for the purpose of inducing ESP. The induced stimulation may have a frequency specifically configured to induce ESP, for example, below 10 Hz. According to some embodiments, the induced stimulation may comprise a single pulse.

[0098] Figure 8 An embodiment is shown in which therapeutic stimulation is applied at the first one or more electrode contacts of the electrode lead 15 (electrode contacts 802a and 802b in the illustration). In the context of step 704 of the algorithm 700 ( Figure 7 ), the therapeutic stimulus applied at electrode contacts 802a and 802b may be a candidate stimulus waveform having a candidate amplitude. An induced stimulus may be applied simultaneously at a second one or more electrode contacts (804a and 804b in the illustration). Note that the induced stimulus may have a lower frequency than the therapeutic stimulus. The induced stimulus may have an ultra-low frequency, for example, less than 10 Hz. One or more electrode contacts (electrode contact 806 in the illustration) may be used to sense ESP. Note that for clarity, the induced stimulus may be applied at a second one or more electrode contacts (804a and 804b in the illustration). Note that the induced stimulus may have a lower frequency than the therapeutic stimulus. The induced stimulus may have an ultra-low frequency, for example, less than 10 Hz. Figure 8Stimulation artifacts and ECAP signals were omitted from the ESP signal.

[0099] Figure 9 Another embodiment of applying both therapeutic and induced stimulation is shown. Figure 9 In the embodiment of the present invention, therapeutic stimulation is provided at a first electrode or electrodes (electrode contacts 802a and 802b in the illustration) for a first duration. A delay period is applied for a second duration. After the delay, evoked stimulation is delivered at one or more electrodes, which may or may not be the same as the first electrode or electrodes. The evoked stimulation is delivered for a third duration, during which ESP can be recorded at one or more recording electrode contacts (electrode contact 806 in the illustration). Therapeutic stimulation can resume after the evoked stimulation, which can be delayed for another interval.

[0100] Reference again Figure 7 , according to step 704, Figure 8 or Figure 9 Any of the embodiments shown in can be used to measure ESP in response to candidate stimulation parameters. Furthermore, recall that ESP typically occurs later in time after the evoked stimulus than other detectable responses (such as stimulation artifacts and / or ECAPs), e.g. Figure 6 As shown. Therefore, recording the ESP (step 704) may include applying a delay duration between the issuance of the evoked stimulus and the start of recording at the sensing electrode to (as far as possible / practical) avoid recording both the stimulation artifact and the ECAP and record only the ESP. According to some embodiments, the delay duration may be, for example, approximately 3 milliseconds, 2.5 milliseconds, or 2 milliseconds after the evoked stimulus. According to some embodiments, the timing of the recording may be keyed to characteristics of the sensed stimulation artifact or the sensed ECAP signal. For example, the algorithm may sense characteristics of the ECAP, such as the N1 peak of the ECAP, and then wait an additional 1 or 1.5 milliseconds before recording the ESP. Alternatively, the algorithm may sense characteristics of the stimulation artifact, such as the rising phase of the stimulation artifact, the settling phase of the artifact, and time the sensing of the ESP based on these artifact characteristics. Furthermore, as described above, the ESP is correspondingly wider than the ECAP. Therefore, some embodiments involve continuing sensing for 5-10 milliseconds or longer after the start of sensing, thereby capturing most or all of the ESP signal. According to some embodiments, if the ECAP signal is not present, the sensed presumed ESP signal may be rejected.

[0101] Step 704 also includes determining one or more values ​​for a characteristic of the ESP. The determined ESP characteristic may be similar to any of the characteristics described above that may be determined for stimulation artifacts and / or ECAP. Examples of ESP characteristics that may be determined may be peak height, area under the curve, curve length, curve shape (such as decay rate), or any of the above characteristics.

[0102] At step 706, the determined ESP characteristics are used to develop a relationship, or "transfer function," that relates one or more ESP characteristics to stimulation parameters consistent with treatment goals. Figure 7 An example of a transfer function 707 is shown, in which ESP characteristic values ​​(F) are plotted as a function of stimulation parameter values ​​(P). In the illustrated embodiment, stimulation parameters corresponding to an optimized therapeutic outcome can be determined. Examples of therapeutic outcomes may include pain relief, stimulation location, pain-paresthesia overlap, neural recruitment, and the like. In the figure, the values ​​of parameters (such as stimulation amplitude, pulse width, rate, total charge delivered per unit time, and / or parameter envelope function modulation factor) corresponding to an optimized therapeutic outcome (such as pain relief) can be represented as P(Opt.). For example, stimulation value P(Opt.) can represent the stimulation amplitude that results in optimized pain relief for the patient. The range of parameter values ​​(ΔP) between P1 and P2 can correspond to a range of stimulation amplitudes that provide acceptable pain relief. For example, the range (ΔP) can correspond to a therapeutic window. The transfer function associates stimulation parameter values ​​with corresponding values ​​of one or more ESP characteristics. In other words, the ESP characteristic value F(Opt.) corresponding to the optimized stimulation amplitude (and, accordingly, optimized pain relief) can be identified. The range of ESP characteristic values ​​(ΔF) corresponding to the range of stimulation parameter values ​​ΔP can also be identified. Steps 702 - 706 may be repeated until the transfer function is determined to be sufficiently accurate.

[0103] At step 708, the value of the ESP characteristic and the transfer function can be used for closed-loop feedback control of the stimulation. As described above, the control circuitry in the IPG can be programmed with one or more sets of instructions configured to cause the IPG to adjust stimulation parameters based on the ESP characteristic. According to some embodiments, the IPG can be configured to provide therapeutic stimulation and periodically emit induced stimulation. The therapeutic stimulation can be subperceptual or paresthesia or a combination of subperceptual and paresthesia. The induced stimulation and therapeutic stimulation can occur simultaneously, such as Figure 8 as shown, or occur at different times, such as Figure 9If delivered simultaneously, the device can be configured to stop the therapeutic stimulation long enough afterwards so that ESP can be sensed, for example if the therapeutic waveform is a high energy waveform. If the therapeutic stimulation is being delivered at a rate that is incompatible with ESP, the device can also be configured to pause the therapeutic stimulation for 1-2 seconds before delivering the inducing stimulation.

[0104] The IPG may include a closed-loop feedback control algorithm configured to use one or more ESP characteristic values ​​as control variables. Closed-loop feedback control is well known in the art and will not be discussed in detail herein, but the control scheme may involve a controller such as a PID controller, a Kalman filter, or the like. Figure 7 A simplified control diagram 709 is shown whereby a controller (e.g., an IPG control circuit) controls stimulation based on ESP characteristics sensed from the patient's spinal cord, as described above. A feedback control algorithm can adjust stimulation parameters to seek to keep the sensed ESP characteristics correlated with F(Opt.) or within a range of, for example, ΔF.

[0105] Aspects of the present disclosure are directed to leveraging the rostral-caudal spatial dependence of ESP signals to achieve useful effects. As mentioned above, previously evoked neural responses (such as ECAP) can be detected at many locations along the spinal cord because the responses propagate through the spinal cord. ESP, on the other hand, is spatially dependent due to its believed neural / synaptic origin. The amplitude and shape of ESP signals can vary depending on the spinal location at which the signals are sensed. Aspects of the present disclosure are directed to using ESP characteristics to provide information regarding electrode lead placement and to adjust stimulation configuration accordingly.

[0106] Figure 10 An embodiment of a GUI 1000 for detecting the spatial dependence of ESP signals is shown. For example, GUI 1000 can be displayed on the screen of a clinician programmer 50 ( FIG. 4 ). The illustrated embodiment includes a representation of a stimulation lead 1002 having multiple electrodes ( E1–E9 ). In the figure, E1 is assigned as the anode, E3 is the cathode, E2 is inactive, and E4–E9 are used as recording electrodes. The GUI can also include an indication of a vertebral level 1012 at which sensing and / or stimulation occurs. According to some embodiments, the vertebral level indication can be a representation of the patient's spinal cord.

[0107] The GUI can provide one or more ways to visualize and / or analyze the neural responses recorded at the recording electrodes. For example, the illustrated GUI includes a visualization panel 1004 in which various neural response signals can be displayed. According to some embodiments, the visualization panel can be configurable to distinguish different types of responses recorded. The illustrated visualization panel includes separate windows for the fastest responses 1006 (such as stimulation artifacts), fast neural responses 1008 (such as ECAP), and slower responses 1010 (such as ESP). The neural response signals can be displayed and matched to the electrodes that recorded them.

[0108] Figure 10 The neural response signals shown in Figure 3 demonstrate the properties of the recorded ESP, namely that both ESP amplitude and ESP polarity can vary depending on the recording location. In the illustration, very little ESP activity is recorded at electrodes E4 or E5. Electrode E6 records ESP with a strong positive amplitude. Note that the peak amplitude of the ESP signal decreases at E7 and is essentially absent at E8. Also note that the ESP signal at E9 has a strong negative peak. This behavior is referred to herein as "inversion." The illustrated ESP signal has an "inversion point," i.e., a point where the ESP signal reverses polarity, approximately at E8. Inversion and the use of inversion points will be discussed in more detail below.

[0109] The illustrated GUI also features a characteristic value indicator 1014 configured to display one or more characteristic values ​​of the ESP signal. In the illustrated embodiment, the characteristic value indicator is configured to show the peak amplitude of the ESP. The characteristic value indicator 1214 includes a heat map indicating the peak amplitude, ranging from –25 mV to +25 mV. Note that this voltage range can be adjustable, and different voltages can be used. Note that electrodes E4-E9 are color-coded based on the peak amplitude measured at the electrodes. Electrodes E4 and E8 are coded with colors corresponding to near-zero amplitude; electrode E6 is coded with a color corresponding to a strong positive peak amplitude; and electrode E9 is coded with a color corresponding to a strong negative peak amplitude. The characteristic value indicator can be configured to display and correlate values ​​of other characteristics, such as those discussed above, e.g., area under the curve, curve length delay, and the like. The curve itself can represent a single epoch, or it can represent an averaged, filtered, and otherwise processed epoch constructed from two or more saved individual epochs.

[0110] The GUI may also have one or more input displays for inputting and / or adjusting stimulation and / or sensing parameters. For example, the illustrated GUI features a stimulation mode selector 1016 for switching between induced stimulation and therapeutic stimulation and a parameter selector 1018 for inputting parameters for the applied electrical stimulation.

[0111] Figure 11 An embodiment of a workflow 1100 for determining an optimized electrode configuration for inducing an ESP signal is shown, for example, using the GUI 1000 ( Figure 10 At step 1102, a scan of a preselected electrode configuration is performed. Example electrode configurations may include bipolar, tripolar, contour bipolar, graded bipolar, or continuous bipolar, where the stimulation current is divided among three or more electrodes, among others. Essentially, step 1102 determines how the stimulation current should be divided among the stimulation electrodes to induce an ESP signal. This can be referred to as a "sweet spot search." Step 1102 may also involve trying various induced stimulation waveforms, such as those described above, for inducing an ESP signal. At step 1104, various recording electrodes may be tried to determine the optimal contact point for sensing the ESP signal. It should be noted that the order of steps 1104 and 1102 can be interchangeable, or the steps can be iterative. Step 1106 involves determining the ESP characteristics to be observed and the configuration that maximizes those characteristics. Any of the characteristics mentioned above can be used, including ESP amplitude, ACU, curve length, etc., as well as reversal points, as described below. The output of workflow 1100 is the optimized stimulation geometry and waveform for inducing an ESP signal 1108.

[0112] Once the optimal stimulation geometry for eliciting ESP signals is determined, the ESP signals can be used to monitor aspects of the treatment. In particular, the spatial specificity of the sensed ESP signals, their polarity, and reversal points can be used to monitor changes in stimulation lead position / geometry and distinguish such changes from other changes that may affect treatment outcomes. Figure 12 An embodiment of a three-dimensional graph correlating ESP signals with treatment metrics is shown. Vertical graph 1202 shows patient metrics plotted for the vertebral locations where stimulation is provided. The patient metrics are the patient-reported pain level (dashed line) and the patient-reported pain-paresthesia overlap (solid line). The pain-paresthesia overlap indicates the degree to which the perceived paresthesia from the stimulation overlaps with the dermatome where the patient feels pain. Typically, maximum overlap is desired. Note that when stimulation is applied near the T8 vertebral level, the patient experiences minimal pain and maximum pain-paresthesia overlap. This indicates that T8 is a good stimulation location under the conditions shown. Similarly, stimulation near T7 or near T9 provides suboptimal results.

[0113] Horizontal plot 1204 shows the ESP signals recorded at various recording locations as a function of stimulation location. Note that negative ESP amplitudes are plotted with dashed lines, and positive ESP amplitudes are plotted with solid lines. In the illustration, when stimulation is provided at T9, ESP shows a maximum positive amplitude sensed approximately halfway between T7 and T8, and a maximum negative amplitude sensed near T8. The ESP induced by stimulation at T9 has a reversal point (where ESP transitions from positive to negative polarity, marked by a circle) that can be sensed approximately three-quarters of the way between T7 and T8. The ESP induced by stimulation at T8 (i.e., the optimized stimulation identified above) shows a reversal point (marked by a square) sensed near T7.

[0114] Figure 12 The graph in shows that stimulation that provides optimal patient metrics corresponds to an ESP signal with a reversal point sensed near T7, while less optimal stimulation results in a reversal point near T8. This suggests that stimulation can be adjusted to keep the ESP reversal point near T8 to maintain optimal treatment.

[0115] Figure 12 The graph in can be considered a clinical effect graph that correlates ESP features with the clinical effect experienced by the patient. It should be noted that any other ESP features besides reversal points can also be expressed in a similar clinical effect graph. It should also be noted that other graphical representations can be used to express the clinical effect graph. Example graphical representations include cluster graphs, machine learning correlations, and the like. Figure 12 Another example of a clinical effectiveness graph is shown. Top graph 1202 is described above. Bottom graph 1302 shows how ESP characteristics vary as a function of stimulation site and recording site. The combination of graphs 1202 and 1302 correlates that variability with the clinical effectiveness of stimulation, providing an indication of how ESP progresses or changes position as stimulation and / or recording are dragged along the lead. Stimulation can be maintained so that ESP remains within an optimized spatial window, referred to herein as the spatial therapeutic window. If ESP characteristics move outside the spatial therapeutic window, stimulation may need to be readjusted.

[0116] ESP and its characteristics can be used to guide stimulation, as described above. ESP can be correlated with the patient's pain state. For example, ESP can indicate that stimulation is effective and therapeutic (positive correlation) or, in some embodiments, can be correlated with the presence of side effects (negative correlation). Due to their spatial dependence, ESP signals can be used to diagnose the cause of therapeutic decline. The time delay characteristics of the ESP signal can be used to determine whether the change in treatment is due to neural activity or due to a change in the position of the lead relative to the spinal cord. The amplitude / intensity characteristics can be used to distinguish between changes in the stimulation contact and changes in the sensing contact. If the distance changes only at the sensing contact, then the change in ESP may not indicate that stimulation adjustment is needed. If the distance changes only at the stimulation contact, then the change in ESP may require adjustment. If the distance changes at both the stimulation contact and the sensing contact, stimulation adjustment may be required, but with appropriate weighting.

[0117] Some disclosed embodiments involve using characteristics of both faster evoked neural responses (such as ECAP) and slower ESP to diagnose changes in therapy. Figure 14 A decision matrix is ​​shown that relates patient-reported declines in therapy to changes in ECAP and ESP characteristics. This decision matrix can be used to define control strategies for how the stimulation system will respond to various indicators derived from ECAP, ESP, and patient metrics. If a patient reports a decline in therapy but neither the ECAP nor the ESP characteristics have changed, the cause may be migration of the entire lead. In such cases, the patient can be prompted to run a recalibration procedure to correct the stimulation configuration. Changes in both the ECAP and ESP characteristics, but no change in the patient's therapy, may indicate that only the recording lead has changed. In such cases, the system can continue to monitor therapy but take no further action. Changes in the ECAP but no changes in the ESP, accompanied by a decline in therapy, may indicate that the stimulation contacts have migrated. In such cases, recalibration and / or adjustment of the stimulation position may be necessary. Changes in the ECAP but no changes in the ESP or patient response may indicate that the patient is being over- or under-dosed. The system can recommend stimulation parameter adjustments.

[0118] Figure 15 An embodiment of an interface 1500 is shown for configuring how the system Figure 14The decision matrix shown illustrates a control strategy responsive to various indicators derived from ECAP, ESP, and patient metrics. Observed changes in ECAP, ESP, and patient metrics are shown at the top (1502) and the results are shown at the bottom (1504). The color of the arrow indicates whether the result is possible, with white arrows indicating "yes" and black arrows indicating "no." The thickness of the arrow indicates the weight associated with the correlation represented by the arrow. In some embodiments, the user can reconfigure the layout of the arrows and the weights of the arrows. The defined relationships can be used to encode decision trees based on combinations of changes and based on mutual logic. Changes indicated in the top row of values ​​can trigger an interrupt within the control circuitry, causing the system to run a predefined or user-specified procedure, such as a recalibration procedure. For example, such a procedure can run an evoked stimulus known to induce ECAP and / or ESP and use the ECAP / ESP characteristics to infer stimulus and recording electrode changes and / or stimulus / target consistency. Various evoked stimulus waveforms are described above, and further evoked stimulus examples are discussed below.

[0119] As mentioned several times herein, the stimulation used to induce neural responses such as ECAP, ESP and the like can be the same as the therapeutic stimulation or it can be different. According to some embodiments, the induced stimulation can be interleaved with the therapeutic stimulation and / or it can be provided simultaneously or at a different time than the therapeutic stimulation.

[0120] According to some embodiments, one or more stimulation parameters can be titrated to determine an optimized evoked stimulation for eliciting various neural responses. Any stimulation parameter can be used as a basis for titration and the observable can be any of the evoked response characteristics described herein. Figure 16 An embodiment is shown in which the stimulation amplitude is titrated to determine amplitude thresholds for eliciting ECAP and ESP. A stimulation pulse or pulse packets are delivered, and the amplitude of the pulses is increased until various evoked responses are observed. The stimulation preferably has a frequency of less than 50 Hz, and more preferably less than 10 Hz. The amplitude can begin at 0 mA or some other low value, such as a fraction of the patient's perceptual threshold. As the stimulation amplitude increases, thresholds (such as the ECAP threshold, the patient's perceptual threshold (i.e., the minimum amplitude at which the patient experiences paresthesia), the ESP threshold, the patient's comfort threshold, etc.) can be noted. The relationship between the ESP and ECAP thresholds can be deterministic or patient-specific. According to some embodiments, the ESP threshold can be predictable based on the ECAP threshold, or vice versa, and / or the patient's perceptual / comfort threshold can be predictable based on one or more evoked neural responses. According to some embodiments, the amplitude can be stepped down rather than up.

[0121] Figure 17A and Figure 17BAn embodiment is shown in which the frequency of stimulation is titrated. As described above, ESP is induced at low frequencies and decays at higher frequencies. Therefore, frequency dependence can be used to confirm that the recorded signal is indeed attributable to ESP. According to some embodiments, morphology and / or features extracted from the ESP morphology can be plotted as a function of stimulation frequency. Various frequency-dependent morphological features can be tracked, and changes in such features can indicate the need for reprogramming, recalibration, or other action. Example morphological features include amplitude differences, frequency "roll-off" points, decay slope differences, final (high-frequency) ESP amplitude, and the like. The calibration curve can be checked against a common / preloaded reference of ESP characteristics to ensure that the signal is consistent with the ESP morphology. If the signal characteristics do not match, a flag or interrupt can be thrown. If there is no match, the overall amplitude of the signal should also be checked. Amplitudes above a certain factor (e.g., 125% or more) of the noise floor can result in a flag / interrupt, while if the signal amplitude drops to or below the noise floor, the signal is simply assumed to be undetectable (i.e., the characteristic value is set to 0 or the like).

[0122] According to some embodiments, the ESP and its features may be used or correlated with patient state metrics provided by sensors such as accelerometers (worn or configured within an IPG) or other wearable or implantable sensors. The patient state metrics may be anything that is shown to correlate with ESP features, such as respiratory cycle, heartbeat, blood pressure, posture, etc. Figure 18A and Figure 18B The correlation between the patient's posture (sitting vs. supine) and the ESP signature (amplitude) is shown. Patient posture can be measured, for example, using an accelerometer. Once the relationship between the patient's state and the ESP signature is established, the system can intervene when the sensor detects changes that affect the ESP signature. For example, the system can deliver induced pulses that vary inversely with the change in the ESP signature to maintain the ESP signature within a predetermined range.

[0123] As described above, embodiments of the present disclosure relate to using ESP features as observable control variables for closed-loop feedback control to maintain treatment. One embodiment relates to using ESP as an indicator to restore or assist balance and / or gait, for example in patients with Parkinson's disease. ESP can be associated with proprioceptive neurons (type I and type II myelinated fibers) that have a large diameter (e.g., larger than Aβ fibers). For patients with Parkinson's disease, ESP detection can be performed at the cervical spine and / or high thoracic spinal cord. Such applications can be performed similarly to the pain control model discussed above, whereby ESP features are correlated with the severity of motor symptoms and / or accelerometers rather than (or in addition to) pain.

[0124] According to some embodiments, ESP signatures can be correlated with side effects. If the ESP signature is a sign of discomfort rather than relief, then the ESP signature can inform stimulation to avoid. An ESP threshold can be determined based on a minimum stimulus to induce ESP. This can involve, for example, a minimum required stimulus amplitude, a minimum number of averaged runs required to identify / extract the ESP signature, etc. Stimulation can be titrated to maintain intensity at or below such thresholds (or predetermined fractions thereof). Associated methods can involve user-configured number of runs to average, range, signal-to-noise ratio (SNR), channels to highlight for avoidance, and the like.

[0125] While specific embodiments of the present invention have been shown and described, the foregoing discussion is not intended to limit the present invention to these embodiments. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, the present invention is intended to cover substitutions, modifications, and equivalents that may fall within the spirit and scope of the present invention as defined by the claims.

Claims

1. A system for providing electrical stimulation to a patient's spinal cord using a pulse generator (PG) connected to one or more electrode leads implanted in the patient's spine, each electrode lead comprising a plurality of electrodes, the system comprising: A control circuit, the control circuit being configured to: using a first one or more electrodes of the plurality of electrodes as stimulation electrodes to apply induced stimulation to the patient's spinal cord, using second two or more electrodes of the plurality of electrodes as recording electrodes to record neural responses evoked in the patient's spinal cord by the evoked stimulation, comparing the recorded evoked neural responses at each of the recording electrodes, and The comparison is used to assess the placement of the electrode leads relative to the spinal cord.

2. The system according to claim 1, wherein: The induced stimulation has a frequency of 10 Hz or less.

3. The system according to claim 1 or 2, wherein: The evoked neural response occurs at least 2 milliseconds after the evoked stimulus.

4. The system according to any one of claims 1 to 3, wherein: The evoked neural response is indicative of synaptic activity within the patient's spinal cord.

5. The system according to any one of claims 1 to 4, wherein: Comparing the recorded evoked neural responses includes extracting one or more features of the recorded neural responses.

6. The system according to claim 5, wherein: The one or more features extracted include one or more of: peak amplitude, area under the curve, and curve length.

7. The system according to any one of claims 1 to 6, wherein: Comparing the recorded evoked neural responses includes determining a reversal position on the lead at which the polarity of the evoked neural response switches between positive and negative polarity.

8. The system according to any one of claims 1 to 7, wherein: The control circuit is further configured to: determining a first stimulation configuration using one or more patient metrics, the first stimulation configuration configured to provide optimized stimulation for the patient, applying an optimized stimulus as the evoked stimulus using a first one or more electrodes of the plurality of electrodes, and First values ​​of one or more characteristics of the recorded evoked neural response associated with the first stimulation configuration are determined.

9. The system according to claim 8, wherein: The one or more patient metrics include pain level and / or pain-paresthesia overlap.

10. The system according to claim 8, wherein: The one or more patient measurements include patient posture.

11. The system according to claim 8, wherein: The one or more patient metrics are determined using one or more sensors and / or input received from the patient via an external device.

12. The system according to claim 11, wherein The one or more sensors include an accelerometer.

13. The system according to claim 11, wherein: The one or more sensors include wearable sensors.

14. The system according to claim 8, wherein The one or more characteristics of the recorded evoked neural response include one or more of: peak amplitude, area under the curve, curve length, and a reversal position on the lead at which the polarity of the evoked neural response switches between positive to negative polarity.

15. The system according to claim 8, wherein The control circuit is further configured to: determining a change in a first value of one or more characteristics of the recorded evoked neural response, and The first stimulation configuration is adjusted based on the change.

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