Evoked response guided multi-site deep brain stimulation

Abstract

Systems and methods for providing evoked response guided multi-site deep brain stimulation (DSB) at various brain targets are disclosed. An exemplary system includes at least one multi-electrode lead, an electrical stimulator to provide electrical stimulation to a neural target, a sensing circuit to sense an evoked response (ER) to the electrical stimulation, and a controller circuit. In response to electrical stimulation of the first neural target in accordance with the first stimulation setting, the controller circuit collects the ER from the first sensing location and determines or adjusts a second stimulation setting for stimulating the second neural target based on the sensed ER at the first neural target. The second neural target may be stimulated according to the second stimulation setting to modulate the ER of the electrical stimulation at the first neural target and produce a desired therapeutic outcome in the patient.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 590,277, filed October 13, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] This document generally relates to medical systems, and more specifically, but not limited to, to multi-site deep brain stimulation (DBS) systems and methods based on evoked responses. Background Technology

[0004] Medical devices may include treatment delivery devices capable of delivering treatment to a patient and / or monitors configured to monitor a patient's condition via user input and / or sensors. For example, treatment delivery devices for mobile patients may include wearable and implantable devices, and may also include, but are not limited to, stimulators (such as electrical, thermal, or mechanical stimulators) and drug delivery devices (such as insulin pumps). Examples of wearable devices include, but are not limited to, transcutaneous electrical neural stimulators (TENS), such as patches that can be attached to glasses, clothing, or configured to adhere to the skin. Implantable stimulators can deliver electrical stimulation to treat a variety of biological disorders, such as pacemakers for treating arrhythmias, defibrillators for treating cardiac fibrillation, cardiac resynchronization therapy devices for heart failure, cochlear stimulators for treating deafness, retinal stimulators for treating blindness, muscle stimulators for generating coordinated limb movements, spinal cord stimulators (SCS) for treating chronic pain, cortical and deep brain stimulators (DBS) for treating motor and psychological disorders, peripheral nerve stimulation (PNS), functional electrical stimulation (FES), and other neurostimulators for treating urinary incontinence, sleep apnea, shoulder subluxation, etc. Neurostimulators (e.g., DBS, SCS, PNS, or TENS) can be configured to treat pain. By way of example, and not limitation, a DBS system can be configured to treat tremor, bradykinesia, and other movement disorders, as well as other movement disorders associated with Parkinson's Disease (PD).

[0005] The use of evoked potentials (also known as evoked responses or ERs) to guide neurostimulation therapy has been proposed. For example, evoked resonant neural activity (ERNA) has been proposed as a feedback signal for controlling DBS delivery. ERNA may also be referred to by other names, such as DBS Local Evoked Potential (DLEP), evoked oscillatory neural responses (EONR), and other terms. Evoked potentials including ERNAs can be present in other indications and anatomical structures or locations.

[0006] DBS can improve motor symptoms in some patients with advanced Parkinson's disease (PD) and other motor and non-motor disorders. Stimulating leads / electrodes for PD treatment are typically implanted in the subthalamic nucleus (STN) or globus pallidus internus (GPi), although other neural targets, such as the pedunculopontine nucleus (PPN) and posterior subthalamic area (PSA), have been shown to be effective targets for tremor control and other Parkinson's symptoms. However, the optimal target for DBS management of PD and other motor and non-motor disorders may vary from patient to patient, and there is no single, optimal "universal" DBS target. A DBS system capable of providing universal and flexible stimulation at multiple neural targets is needed to meet the needs of patients with different disease profiles. Summary of the Invention

[0007] This paper discloses systems and methods for multi-site neural modulation, particularly deep brain stimulation (DBS) targeting multiple brain targets, such as the STN and GPi. Multi-site DBS can recruit neural pathways associated with multiple neural targets, achieving a wider stimulation field than a single local target, and maximizing therapeutic efficacy and / or minimizing side effects. According to various embodiments, different neural targets can be stimulated substantially simultaneously (within a specific time delay), sequentially with a time offset, or according to a predetermined stimulation pattern. In response to electrical stimulation of the neural targets, evoked responses (ERs) can be sensed locally, at locations remote from the stimulation site, or both, and used to feedback control the DBS or determine optimal DBS settings. In one embodiment, the ER (hereinafter “ER1”) of stimulation at a first neural target can be used to determine or adjust stimulation settings at different second neural targets. Electrical stimulation at the second neural target can modulate ER1 and produce a “compound” ER, which can be analyzed to determine whether the desired therapeutic outcome, such as high therapeutic efficacy and low side effects, has been achieved. In one example, ER modulation could be: electrical stimulation of the second target enhances ER1, thereby producing an enhanced compound ER. In another example, electrical stimulation of the second target site can reduce ER1, thus producing a weakened composite ER. Multi-site DBS, as described in this article, can conveniently and more effectively establish an ideal composite ER, which can lead to better treatment outcomes for patients.

[0008] Examples of neural modulation systems (e.g., "Example 1") may include: at least one lead comprising a plurality of electrodes; an electrostimulator configured to deliver electrical stimulation to a neural target of a patient via one or more of the plurality of electrodes of the at least one lead; a sensing circuit configured to sense an evoked response (ER) to the electrical stimulation; and a controller circuit operatively connected to the electrostimulator and the sensing circuit, the controller circuit being configured to: collect ER sensed by the sensing circuit from a first sensing electrode positioned at a first sensing location in response to delivery of the electrical stimulation to the first neural target according to a first stimulation setting; determine or adjust a second stimulation setting for stimulating a second neural target of a patient different from the first neural target, based at least in part on the sensed ER sensed for the electrical stimulation at the first neural target; generate a control signal to the electrostimulator to deliver electrical stimulation at the second neural target according to the second stimulation setting, thereby modulating the sensed ER sensed for the electrical stimulation at the first neural target and producing a desired therapeutic outcome in the patient; and collect ER sensed by the sensing circuit for the electrical stimulation at the second neural target from a second sensing electrode positioned at the second sensing location.

[0009] In Example 2, the subject of Example 1 may optionally include controller circuitry that can be configured to control an electrical stimulator to substantially simultaneously deliver corresponding electrical stimulation to a first neural target and a second neural target, according to corresponding first and second stimulation settings.

[0010] In Example 3, any one or more of the subjects in Examples 1-2 may optionally include controller circuitry that can be configured to control an electrical stimulator to deliver corresponding electrical stimuli to a first neural target and a second neural target in a specific time offset sequence according to corresponding first and second stimulation settings.

[0011] In Example 4, any one or more of the subjects in Examples 1-3 may optionally include a first and a second neural target for electrical stimulation, which are different brain targets in a particular hemisphere of the brain.

[0012] In Example 5, the subject of Example 4 may optionally include the first neural target of electrical stimulation being the subthalamic nucleus (STN) target, and the second neural target of electrical stimulation being the globus pallidus nucleus (GPi) target.

[0013] In Example 6, the subject of Example 5 may optionally include a first sensing electrode of the ER that can be positioned at a GPi sensing location to sense electrical stimulation of the STN target, and a second sensing electrode of the ER that can be positioned at an STN sensing location to sense electrical stimulation of the GPi target.

[0014] In Example 7, any one or more of the subjects in Examples 1-6 may optionally include an external electrical stimulator operatively coupled to one or more cortical electrodes or one or more stereotactic electrodes to provide cortical stimulation, thereby modulating one or more of the sensed ER of electrical stimulation at a first neural target or the sensed ER of electrical stimulation at a second neural target, and producing the desired therapeutic outcome in the patient.

[0015] In Example 8, any one or more of the subjects in Examples 1-7 may optionally include an electrostimulator that can be electrically coupled to a multi-electrode lead, the electrostimulator being configured to provide electrical stimulation to a first neural target via a first electrode on the multi-electrode lead and to provide electrical stimulation to a second neural target via a second electrode on the same multi-electrode lead.

[0016] In Example 9, any one or more of the subjects in Examples 1-8 may optionally include at least one lead, which may include different first and second leads, each lead including one or more electrodes, wherein the electrostimulator is configured to provide electrical stimulation to a first neural target via a first electrode on the first lead and to provide electrical stimulation to a second neural target via a second electrode on the second lead.

[0017] In Example 10, the subject of any one or more of Examples 1-9 may optionally include at least one of a first sensing electrode or a second sensing electrode, which may be selected from a plurality of electrodes of at least one lead.

[0018] In Example 11, the subject of any one or more of Examples 1-10 may optionally include at least one of sensed ER of electrical stimulation at a first neural target or sensed ER of electrical stimulation at a second neural target, which may include electrocorticography (ECoG) or stereotactic electroencephalography (sEEG) sensed via one or more cortical electrodes or one or more stereotactic electrodes.

[0019] In Example 12, any one or more of the subjects in Examples 1-11 may optionally include controller circuitry that can be configured to determine or adjust a second stimulation setting such that electrical stimulation at a second neural target, according to the second stimulation setting, reduces the ER of electrical stimulation at a first neural target.

[0020] In Example 13, any one or more of the subjects in Examples 1-12 may optionally include controller circuitry that can be configured to determine or adjust a second stimulation setting such that electrical stimulation at a second neural target, according to the second stimulation setting, enhances the ER of electrical stimulation at a first neural target.

[0021] In Example 14, the subject matter of any one or more of Examples 1 to 13 may optionally include controller circuitry to determine or adjust a second stimulation setting based at least in part on the sensed ER of electrical stimulation at the first neural target, the controller circuitry being configured to: evaluate treatment outcomes using the sensed ER of electrical stimulation at the first neural target; and, based on the evaluation of the treatment outcomes, determine or adjust a second stimulation setting, the second stimulation setting including one or more stimulation parameters or one or more electrodes selected from a plurality of electrodes of at least one lead for electrical stimulation.

[0022] In Example 15, the subject matter of Example 14 may optionally include controller circuitry configured to evaluate treatment outcomes, including: comparing the spatial distribution of sensed ER at a first neural target with a desired spatial distribution of ER, and determining or adjusting a second stimulation setting to reduce the difference between the spatial distribution of sensed ER at a second neural target and the desired spatial distribution of ER.

[0023] Example 16 is a method for delivering neural stimulation to a neural target in a patient via a neural modulation system comprising an electrical stimulator and at least one lead coupled thereto. The method includes the steps of: delivering electrical stimulation to a first neural target using the electrical stimulator according to a first stimulation setting; sensing an evoked response (ER) to the electrical stimulation at the first neural target via a first sensing electrode positioned at a first sensing location; determining or adjusting a second stimulation setting for stimulating a second neural target in a patient, different from the first neural target, via a controller circuit, based at least in part on the sensed ER to the electrical stimulation at the first neural target; delivering electrical stimulation to the second neural target according to the second stimulation setting to modulate the sensed ER to the electrical stimulation at the first neural target and produce a desired therapeutic outcome in the patient; and sensing the ER to the electrical stimulation at the second neural target via a second sensing electrode positioned at the second sensing location.

[0024] In Example 17, the subject of Example 16 may optionally include electrical stimulation of a first neural target and electrical stimulation of a second neural target, which may be delivered substantially simultaneously or sequentially with a specific time offset, depending on the corresponding first and second stimulation settings.

[0025] In Example 18, any one or more of the topics in Examples 16-17 may optionally include a first neural target of electrical stimulation being the subthalamic nucleus (STN) target in the cerebral hemisphere, and a second neural target of electrical stimulation being the globus pallidus nucleus (GPi) target in the cerebral hemisphere.

[0026] In Example 19, the subject matter of any one or more of Examples 16-18 may optionally include providing cortical stimulation via an external electrical stimulator operatively coupled to one or more cortical electrodes or one or more stereotactic electrodes, the cortical stimulation modulating the sensed ER of electrical stimulation at a first neural target or the sensed ER of electrical stimulation at a second neural target, and producing a desired therapeutic outcome in the patient.

[0027] In Example 20, any one or more of the subjects in Examples 16-19 may optionally include at least one lead, which may include different first and second leads, each lead including one or more electrodes, wherein electrical stimulation of a first neural target is delivered via a first electrode on the first lead, and electrical stimulation of a second neural target is delivered via a second electrode on the second lead.

[0028] In Example 21, the subject matter of any one or more of Examples 16-20 may optionally include at least one of sensed ER of electrical stimulation at a first neural target or sensed ER of electrical stimulation at a second neural target, which may include electrocorticography (ECoG) or stereotactic electroencephalography (sEEG) sensed via one or more cortical electrodes or one or more stereotactic electrodes.

[0029] In Example 22, any one or more of the subjects in Examples 16-21 may optionally include a second stimulation setting, which may be determined or adjusted such that electrical stimulation at a second neural target according to the second stimulation setting produces a desired modulation of the ER of electrical stimulation at a first neural target, the desired modulation including reducing the ER of electrical stimulation at the first neural target or increasing the ER of electrical stimulation at the first neural target.

[0030] In Example 23, the subject matter of any one or more of Examples 16-22 may optionally include comparing the spatial distribution of the sensed ER at the first neural target with the desired spatial distribution of the ER, wherein a second stimulation setting is determined or adjusted to reduce the difference between the spatial distribution of the sensed ER at the second neural target and the desired spatial distribution of the ER.

[0031] This overview is a summary of some of the teachings of this application and is not intended to be exclusive or exhaustive of the subject matter. Further details regarding the subject matter can be found in the detailed description and the appended claims. Other aspects of this disclosure will be apparent to those skilled in the art upon reading and understanding the following detailed description and examining the accompanying drawings, each of which should not be considered limiting. The scope of this disclosure is defined by the appended claims and their legal equivalents. Attached Figure Description

[0032] Various embodiments are shown by way of example in the accompanying drawings. Such embodiments are exemplary and are not intended to be exhaustive or exclusive embodiments of the subject matter.

[0033] Figure 1 An electrical stimulation system that can be used to deliver DBS is shown as an example, not a limitation.

[0034] Figure 2 An implantable pulse generator (IPG) in a DBS system is shown as an example rather than a limitation.

[0035] Figures 3A-3B Leads that can be coupled to the IPG to deliver electrical stimulation, such as DBS, are shown as examples rather than limitations.

[0036] Figure 4A computing device for programming or controlling the operation of an electrical stimulation system is shown by way of example rather than limitation.

[0037] Figure 5 An example of an electrotherapy delivery system is shown.

[0038] Figure 6 The use of implantable medical devices (IMDs) is illustrated as an example, not a limitation. Figure 5 The monitoring system and / or electrotherapy delivery system.

[0039] Figure 7 A parasagittal section through the brain of a non-human primate is shown, revealing the major anatomical pathways involved in STN DBS.

[0040] Figure 8 A neuromodulation system that can provide ER-guided multisite DBS at a variety of brain targets is illustrated by way of example rather than limitation.

[0041] Figures 9A-9B Single-lead and double-lead configurations for providing multi-site DBS and sensing corresponding ERs are shown by way of example rather than limitation.

[0042] Figure 10 The comparison between user-defined ER target locations and calculated ER distribution centers is shown as an example rather than a limitation.

[0043] Figure 11A-11D Stimulation patterns between electrodes or groups of electrodes for multi-site DBS are shown by way of example rather than limitation.

[0044] Figure 12 Methods for providing ER-guided multisite DBS at various brain targets are illustrated by way of example rather than limitation.

[0045] Figure 13 A block diagram of an example machine is shown in general, on which any one or more of the techniques (e.g., methods) discussed in this article can be executed. Detailed Implementation

[0046] The following detailed description of this subject matter takes into account the accompanying drawings, which illustrate specific aspects and embodiments in which the subject matter can be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the subject matter. Other embodiments may be utilized, and structural, logical, and electrical changes may be made without departing from the scope of the subject matter. References to “a,” “an,” or “various” embodiments in this disclosure do not necessarily refer to the same embodiment, and these references contemplate more than one embodiment. Therefore, the following detailed description should not be considered limiting, and the scope is defined only by the appended claims and the full scope of their legal equivalents.

[0047] In device-based neuromodulation therapy, identifying the “optimal” stimulation target is an important but challenging technical problem. It is generally believed that there is no universally accepted optimal target or desired evoked response due to differences in patient condition or disease, anatomy (anatomical target), lead and trajectory, center (imaging device location, etc.), surgeons (how they implant and position the lead, their preferences for lead placement), or the symptom to be improved (e.g., from tremor to improvement in cognitive skills). In deep brain stimulation (DBS) for Parkinson's disease (PD) management, there is no consensus on the “optimal” DBS target across PD patients. While DBS effectively treats several motor symptoms of PD, limitations remain regarding the characterization of side effects, management of non-motor symptoms, accurate lead placement under intraoperative testing, and the selection of optimal stimulation parameters. For example, although STN and GPi are common DBS targets for PD treatment, and both GPi and STN DBS can improve patients' motor function and activities of daily living, some PD patients may benefit more from STNDBS than from GPi DBS, while others may benefit more from GPi DBS than from STN DBS. STN DBS typically allows for greater medication reduction in patients, but may cause motor side effects, such as speech and motor impairments in some patients. GPi DBS generally provides better relief of psychiatric symptoms, but may also produce certain side effects in some other patients. The inventors have recognized the unmet need for neuromodulation systems capable of delivering universal DBS to multiple targets in a controlled and selective manner to meet the specific needs of individual patients.

[0048] Evoked responses (ERs) have been used to guide implantation procedures (e.g., lead placement or electrode positioning) or to program device settings (e.g., sensing parameters or neurostimulation parameters). ERs are generated by neural activity responding to applied stimuli and reveal information about neural connectivity and function. ERs may be induced by diagnostic or therapeutic stimuli or both. Stimuli may be located where placing an evoked pulse yields a desired response (e.g., maximizing ERNA), where listening for a response yields a desired response (e.g., maximizing ERNA), where lead placement is desired (e.g., optimal for therapy), or where stimulation is desired to be placed on the lead (e.g., maximizing therapy and / or minimizing / counteracting side effects).

[0049] In deep brain stimulation (DBS) for PD management, DBS generates stimulation points (EPs) in local (subcortical) and distal (cortical) regions of the nervous system based on neuronal and axonal stimulation. Estimation response (ER) has shown potential to improve programming, elucidate relevant mechanisms, and identify circuits involved in DBS for PD. ER can be sensed at anatomical targets, such as volumes (e.g., STN), fiber assemblages, subregions (motor STN or dorsolateral STN), patient-specific brain-described or associated target areas of interest (e.g., from atlases or aggregated prior information), or “points” that can be described by optimizing stimulation location. ER can be used to optimize stimulation settings in multi-site DBS, including, for example, lead placement, electrode selection, and programming of sensing or neurostimulation parameters.

[0050] The various embodiments described in this document implement multi-site neural modulation, particularly multi-site deep brain stimulation (DBS) involving various brain targets such as the STN and GPi. As described herein, multi-site DBS can recruit neural pathways associated with multiple neural targets being stimulated, achieving a broader stimulation field rather than a single local target, and maximizing therapeutic efficacy and / or minimizing side effects. In one example, GPi DBS can enhance the stimulation field established by STN DBS, thereby producing a more appropriate therapeutic outcome. According to some examples, multi-site DBS can facilitate the establishment of a target or desired ER by modulating the properties and stimulation timing of multiple targets. For example, when STN DBS and GPi DBS are programmed to produce the same effect, STN DBS can establish a “baseline” ER, while GPi DBS can be programmed to enhance or maximize the baseline ER. Alternatively, STN DBS and GPi DBS can be programmed to produce opposite effects, such that GPi DBS can be programmed to reduce or minimize the baseline ER established by STN DBS. The desired ER can be mapped to an optimized therapeutic stimulation setting.

[0051] The multi-site DBS described in this article enables more general therapeutic control. Multi-site DBS (e.g., STN DBS and GPi DBS) can be delivered substantially simultaneously, sequentially with time offsets, or according to a predetermined stimulation pattern. Multi-site DBS can be implemented using stimulation of multiple different target areas (i.e., target sites) or multipolar stimulation. In some examples, one or more leads can be placed in the brain to deliver multi-site DBS. Stimulation settings, such as target site selection, time offsets between stimuli at different target sites, and stimulation parameter values, can be titrated for individual patients. ERs for stimulation at individual neural targets can be sensed at locations remote from the target sites. In one example, the ER for STN DBS can be sensed at or near a GPi site in the cerebral hemisphere, and the ER for GPi DBS can be sensed at or near a STN site in the same cerebral hemisphere. ERs can be used for feedback control of DBS and optimization of personalized multi-site DBS, including lead placement and stimulation parameter settings.

[0052] The multi-site DBS described in this article can also help compare and contrast various target candidates for new indications in DBS by exploring functional or structural connectivity patterns. For example, when DBS is used to treat patients with treatment-resistant depression (TRD), a challenge is to identify better DBS targets between the subcallosalcingulate cortex (SCC) and the ventral capsule / ventral striatum (VC / VS). The multi-site DBS implementation described in this article can provide a testing platform to evaluate and compare treatment outcomes associated with individual neural targets.

[0053] Figure 1An electrical stimulation system 100 for DBS delivery is illustrated by way of example, not limitation. The electrical stimulation system 100 typically includes one or more (two illustrated) implantable neural modulation leads 101, a waveform generator such as an implantable pulse generator (IPG) 102, an external controller (RC) 103, a clinician programmer (CP) 104, and an external trial modulator (ETM) 105. The IPG 102 may be physically connected to the neural modulation leads 101 via one or more percutaneous lead extensions 106, which carry a plurality of electrodes 116. When implanted in a patient, the electrodes form an electrode arrangement. As shown, the neural modulation leads 101 may be percutaneous leads, with the electrodes arranged in a straight line along the neural modulation leads or in a circle around the circumference of the neural modulation leads. Any suitable number of neural modulation leads may be provided, including only one, as long as the number of electrodes is greater than two (including the IPG housing function as housing electrodes) to allow for lateral current redirection. Alternatively, a surgical paddle wire may be used instead of one or more percutaneous wires. The IPG 102 includes a pulse generation circuit that delivers electrically modulated energy to the electrodes in the form of pulsed electrical waveforms (i.e., a time sequence of electrical pulses) according to a set of modulation parameters.

[0054] The ETM 105 can also be physically connected to the neural modulation lead 101 via the percutaneous lead extension 107 and the external cable 108. The ETM 105 may have a pulse generation circuit similar to that of the IPG 102 to deliver electrically modulated energy to the electrodes according to a set of modulation parameters. The ETM 105 is a non-implantable device that can be used experimentally, after the neural modulation lead 101 has been implanted and before the IPG 102 has been implanted, to test the responsiveness of the modulation to be provided. The functions described herein regarding the IPG 102 can also be performed with respect to the ETM 105.

[0055] RC 103 can be used to telemetry control ETM 105 via bidirectional RF communication link 109. RC 103 can also be used to telemetry control IPG 102 via bidirectional RF communication link 110. This control allows IPG 102 to be turned on or off and programmed with different sets of modulation parameters. IPG 102 can also be operated to modify the programmed modulation parameters to actively control the characteristics of the electrically modulated energy output by IPG 102. Clinicians can use CP 104 to program modulation parameters into IPG 102 and ETM 105 in the operating room and during follow-up.

[0056] CP 104 can communicate indirectly with IPG 102 or ETM 105 via RC 103, via IR communication link 111, or another link. CP 104 can also communicate directly with IPG 102 or ETM 105 via RF communication link or other links (not shown). The detailed modulation parameters provided by CP 104 can also be used to program RC 103 so that the modulation parameters can subsequently be modified by operating RC 103 in stand-alone mode (i.e., without the assistance of CP 104). Various devices can be used as CP 104. Such devices may include portable devices such as laptops, minicomputers, personal digital assistants (PDAs), tablets, telephones, or remote controls (RCs) with extended functionality. Therefore, the programming method can be performed by executing the software instructions contained in CP 104. Alternatively, firmware or hardware can be used to perform this programming method. In any case, CP 104 can actively control the characteristics of the electrical modulation generated by IPG 102 to allow the determination of desired parameters based on patient feedback or other feedback, and subsequently program IPG 102 with the desired modulation parameters. To allow the user to perform these functions, CP 104 may include user input devices (e.g., a mouse and keyboard) and a programming display screen housed within a housing. In addition to a mouse, or in lieu of a mouse, other directional programming devices may be used, such as a trackball, touchpad, joystick, touchscreen, or directional keys included as part of the keys associated with the keyboard. External devices (e.g., CPs) can be programmed to provide a display screen that, among other functions, allows clinicians to select or input patient profile information (e.g., name, date of birth, patient identity, physician, diagnosis, and address), input procedural information (e.g., programming / follow-up, implantation of experimental systems, implantation of IPGs, implantation of IPGs and leads, replacement of IPGs, replacement of IPGs and leads, replacement or modification of leads, transplantation, etc.), generate patient pain maps, define lead configuration and orientation, initiate and control the electrically modulated energy output from the neuromodulation leads, and select and program IPGs with modulation parameters (including electrode selection) in surgical and clinical settings. External devices (e.g., CPs and / or RCs) can be configured to communicate with other devices, including local and / or remote devices. For example, wired and / or wireless communications can be used for communication between devices.

[0057] The external charger 112 can be a portable device for percutaneous charging of the IPG 102 via a wireless link, such as inductive link 113. Once the IPG 102 is programmed and its power has been charged by the external charger or otherwise replenished, the IPG 102 can operate as programmed without RC 103 or CP 104.

[0058] Figure 2 IPG 202 in a DBS system is illustrated by way of example, not limitation. IPG 202 is as follows: Figure 1 An example of an IPG 102 in the illustrated electrical stimulation system 100 may include a biocompatible device housing 214 and a battery 215 housing circuitry for providing power to the IPG 102 for operation, although the IPG 102 may also operate without a battery and can be wirelessly powered by an external power source. The IPG 102 may be coupled to one or more leads, such as lead 201 shown herein. Lead 201 may each include multiple electrodes 216 for delivering electrical stimulation energy, recording electrical signals, or both. In some examples, lead 201 may be rotatable, allowing electrodes 216 to be aligned with a target neuron after neuron localization, such as based on recorded signals. Electrodes 216 may include one or more ring electrodes and / or one or more rows of segmented electrodes (or any other combination of electrodes), examples of which will be referenced below. Figure 3A and Figure 3B Let's have a discussion.

[0059] The lead 201 can be implanted near or inside the site of stimulation in the body. In one example for DBS surgery, access to the desired location in the brain can be achieved by drilling holes in the patient's skull or cranial bone with a skull drill (commonly referred to as a drill bit) and coagulating and cutting the dura mater or brain covering. The lead can then be inserted into the skull and brain tissue with the aid of a probe (not shown). For example, a stereotactic frame and a micro-drive motor system can be used to guide the lead to the target location in the brain. In some examples, the micro-drive motor system can be fully or partially automated. The micro-drive motor system can be configured to perform actions such as inserting, advancing, rotating, or retracting the lead.

[0060] Lead wires 217 within the lead can be coupled to electrodes 216 and a proximal contact 218, which can be inserted into a lead connector 219 in a header 220 fixed to the IPG 202. This header may be made of, for example, epoxy resin. Alternatively, the proximal contact 218 can be connected to a lead extension (not shown), which is then inserted into the lead connector 219. Once inserted, the proximal contact 218 connects to a connector contact 221 within the lead connector 219, which is then coupled to a stimulation circuit 224 within the housing 214 via a feedthrough pin 222 passing through a housing feedthrough 223. The type and number of leads in the IPG, as well as the number of electrodes, are application-specific and may therefore vary.

[0061] IPG 202 may include antenna 225, allowing it to communicate bidirectionally with multiple external devices. Antenna 225 may be a conductive coil within housing 214, although the coil of antenna 225 may also be present in connector 220. When antenna 225 is configured as a coil, communication with external devices can be achieved using near-field magnetic induction. IPG 202 may also include a radio frequency (RF) antenna. The RF antenna may include a patch, slot, or wire and may operate as a monopole or dipole antenna, preferably using far-field electromagnetic waves for communication, and may operate according to any number of known RF communication standards, such as Bluetooth, Zigbee, WiFi, medical implantable communication systems (MICS), and the like.

[0062] In DBS applications, such as those used to treat tremors in Parkinson's disease, the IPG 202 is typically implanted below the patient's clavicle (cervical bone). A lead 201 (which can be extended via a lead extension, not shown) can be tunneled through the neck and scalp and below it, with electrodes 216 implanted through holes drilled into the skull and positioned, for example, in the subthalamic nucleus (STN) in each hemisphere. The IPG 202 can also be implanted below the scalp, closer to the electrode implantation site. In other solutions, the lead 201 or its extension can be integrated with and permanently attached to the IPG 202.

[0063] Stimulation in the IPG 202 is typically provided by pulses, each pulse may include one or more phases. For example, a unipolar stimulation current may be delivered between a lead-based electrode (e.g., one of electrodes 216) and a shell electrode. A bipolar stimulation current may be delivered between two lead-based electrodes (e.g., two of electrodes 216). Stimulation parameters typically include current amplitude (or voltage amplitude), frequency, pulse width of the pulse or its respective phase; the selected electrode used to provide stimulation; and the polarity of this selected electrode, i.e., whether it acts as an anode to source current into the tissue or as a cathode to sink current into the tissue. Each electrode may be used (activated electrode) or not used (OFF). When an electrode is used, it may act as an anode or cathode and carry an anodic or cathodic current. In some cases, an electrode may be an anode for a period of time and a cathode for a period of time. These, along with other possible stimulation parameters, constitute a stimulation program that the stimulation circuitry 224 in the IPG 202 can execute to provide therapeutic stimulation to the patient.

[0064] In some examples, the measuring device, coupled to the muscle or other tissue stimulated by the target neuron, or the unit responding to the patient or clinician, can be coupled to the IPG 202 or micro-drive motor system. The measuring device, user, or clinician can instruct the target muscle or other tissue to respond to the stimulation or recording electrodes to further identify the target neuron and facilitate the localization of the stimulating electrodes. For example, if the target neuron is pointed to a muscle experiencing a tremor, the measuring device can be used to observe the muscle and indicate, for example, changes in the tremor frequency or amplitude in response to the stimulation of the neuron. Alternatively, the patient or clinician can observe the muscle and provide feedback.

[0065] Figures 3A-3B Leads that can be coupled to the IPG to deliver electrical stimulation, such as DBS, are shown as examples rather than limitations. Figure 3A A lead 301A is shown having an electrode 316A disposed at least partially around the circumference of the lead 301A. The electrode 316A can be positioned along the distal portion of the lead. As shown herein, the electrode 316A is a ring electrode spanning 360 degrees around the circumference of the lead 301A. The ring electrode allows current to be projected equally from the position of the electrode in every direction and typically does not enable stimulation current to be directed only from a specific angular position or a limited angular range around the lead. A lead consisting only of a ring electrode can be referred to as a non-directional lead.

[0066] Figure 3B A lead 301B with electrodes 316B is shown, including ring electrodes such as E1 at the proximal end and E8 at the distal end. Furthermore, the lead 301B also includes multiple segmented electrodes (also called split-ring electrodes). For example, one set of segmented electrodes E2, E3, and E4 are positioned longitudinally around a circumference, each spanning less than 360 degrees around the lead axis. In one example, each of electrodes E2, E3, and E4 spans 90 degrees, with each separated from the others by a 30-degree gap. Another set of segmented electrodes E5, E6, and E7 are positioned longitudinally around the circumference in a different location than the segmented electrodes E2, E3, and E4. Segmented electrodes such as E2-E7 can direct stimulation current to a selected angular range around the lead.

[0067] Segmented electrodes typically provide superior current diversion compared to ring electrodes because the target structure in DBS or other stimuli is typically asymmetrical about the axis of the distal electrode array. Instead, the target can be located on one side of a plane passing through the lead axis. By using a radially segmented electrode array, current diversion can be achieved not only along the length of the lead but also around the circumference of the lead. This provides precise three-dimensional targeting and delivery of current stimulation to the neural target tissue, while potentially avoiding stimulation of other tissues. In some examples, segmented electrodes can be used in conjunction with ring electrodes. A lead comprising at least one or more segmented electrodes can be referred to as a directional lead. In one example, all electrodes on the directional lead can be segmented electrodes. In another example, there can be a different number of segmented electrodes at different longitudinal positions.

[0068] Segmented electrodes can be grouped into multiple rows of segmented electrodes, each group positioned around a circumference at a specific longitudinal location on the directional lead. The directional lead can have any number of segmented electrodes in a given group of segmented electrodes. By way of example and not limitation, a given group can include any number between 2 and 16 segmented electrodes. In one example, all rows of segmented electrodes may contain the same number of segmented electrodes. In another example, a group of segmented electrodes may include a different number of electrodes than at least another group of segmented electrodes.

[0069] The size and shape of the segmented electrodes can vary. In some examples, the segmented electrodes all have the same size, shape, diameter, width, or area, or any combination thereof. In some examples, the size and shape of the segmented electrodes in each circumferential group (or even all the segmented electrodes arranged on the lead) can be identical. Rows of segmented electrodes can be positioned at irregular or regular intervals along the length of lead 201.

[0070] Figure 4 A computing device 426 for programming or controlling the operation of an electrical stimulation system 400 is shown by way of example and not limitation. The computing device 426 may include a processor 427, a memory 428, a display 429, and an input device 430. Optionally, the computing device 426 may be connected to the electrical stimulation system 400 (such as...) Figure 1 The system 100 is separately and communicatively coupled to the electrical stimulation system 400. Alternatively, the computing device 428 may be integrated with the electrical stimulation system 100, such as... Figure 1 A portion of IPG 102, RC 103, CP 104, or ETM 105 is shown. The computing device can be used to perform processes for sensing parameters.

[0071] Computing device 426, also known as a programming device, may be a computer, tablet, mobile device, or any other suitable device for processing information. Computing device 426 may be user-local or may include non-computer-local components, including one or both of processor 427 and memory 428 (or portions thereof). For example, a user may operate a terminal connected to a non-local processor or memory. The functionality associated with computing device 426 may be distributed among two or more devices, such as having two or more memory devices performing storage functions, two or more processors performing processing functions, two or more displays performing display functions, and / or two or more input devices performing input functions. In some examples, computing device 406 may include a watch, wristband, or smartphone, etc. Such a computing device can be integrated with other components of an electrical stimulation system (such as...). Figure 1 The computing device 426 (e.g., CP 104, RC 103, ETM 105, or IPG 102) communicates wirelessly. The computing device 426 can be used to collect patient information, such as general activity levels, or to ask the patient questions or perform tests to identify or rate pain, depression, stimulation effects or side effects, or cognitive abilities. In some examples, the computing device 426 can prompt the patient to perform periodic tests (e.g., daily) targeting cognitive abilities to monitor, for example, Alzheimer's disease. In some examples, the computing device 426 can detect or otherwise receive the patient's clinical response to electrical stimulation such as DBS, and use a closed-loop algorithm to determine or update stimulation parameters based on the patient's clinical response. Examples of patient clinical responses may include physiological signals (e.g., heart rate) or motor parameters (e.g., tremor, rigidity, bradykinesia). The computing device 426 can communicate with the CP 104, RC 103, ETM 105, or IPG 102 and direct changes in stimulation parameters to one or more of these devices. In some examples, the computing device 426 may be a wearable device used by the patient only during the programming session. Alternatively, the computing device 426 may be worn continuously and the stimulation parameters may be adjusted continuously or periodically. In one example, the closed-loop algorithm for determining or updating the stimulation parameters may be implemented in a mobile device (such as a smartphone) connected to the IPG or evaluation device (e.g., a wristband or watch). These devices may also record information and send it to the clinician.

[0072] Processor 427 may include one or more processors, which may be user-local or non-user-local or other components of computing device 426. Stimulation settings (e.g., parameter set) include electrode configuration and values ​​for one or more stimulation parameters. Electrode configuration may include information about the activated (ON) or deactivated (OFF) electrodes (ring electrodes and / or segmented electrodes) selected for delivering stimulation, the polarity of the selected electrodes, electrode positions (e.g., the longitudinal position of a ring electrode along the length of a non-directional lead, or the longitudinal and angular positions of a segmented electrode on the circumference at the longitudinal position of a directional lead), stimulation mode (such as monopolar pacing or bipolar pacing), etc. Stimulation parameters may include, for example, current amplitude values, transelectrode current subdivision, stimulation frequency, stimulation pulse width, etc.

[0073] Processor 427 can identify or modify stimulation settings through an optimization process until search criteria are met, such as until a best solution, desired, or acceptable patient clinical response is achieved. Electrical stimulation programmed with the settings can be delivered to the patient, clinical effects (including therapeutic effects and / or side effects, or motor symptoms such as bradykinesia, tremor, or rigidity) can be detected, and clinical responses can be assessed based on the detected clinical effects. When actual electrical stimulation is applied, the setting may be referred to as a test setting, and the clinical response may be referred to as a tested clinical response. In contrast, for a setting where no electrical stimulation is delivered to the patient, clinical effects can be predicted using a computational model based at least on clinical effects detected from the test setting, and the predicted clinical effects can be used to estimate the clinical response. When no electrical stimulation is delivered, the setting may be referred to as a predicted or estimated setting, and the clinical response may be referred to as a predicted or estimated clinical response.

[0074] In various examples, some of the functionality of processor 427 may be implemented as part of a microprocessor circuit. The microprocessor circuit may be a special-purpose processor, such as a digital signal processor, an application-specific integrated circuit (ASIC), a microprocessor, or other type of processor for processing information. Alternatively, the microprocessor circuit may be a processor capable of receiving and executing a set of instructions that perform the functions, methods, or techniques described herein.

[0075] Memory 428 may store instructions executable by processor 427 to perform various functions, including, for example, determining a reduced or restricted electrode configuration and parameter search space (also referred to as a “restricted search space”), creating or modifying one or more stimulation settings within the restricted search space, etc. Memory 428 may store the search space, stimulation settings including “tested” stimulation settings and “predicted” or “estimated” stimulation settings, clinical effects (e.g., therapeutic effects and / or side effects), and clinical responses to the settings.

[0076] Memory 428 may be a computer-readable storage medium, including, for example, non-volatile, non-transitory, removable, and non-removable media implemented in any method or technology for storing information such as computer-readable instructions, data structures, program modules, or other data. Examples of computer-readable storage media include RAM, ROM, EEPROM, flash memory or other storage technologies, CD-ROM, digital universal disk (“DVD”) or other optical storage, magnetic tape cassettes, magnetic tape, disk storage or other magnetic storage devices, or any other medium that can be used to store desired information and is accessible by a computing device.

[0077] Communication methods provide another type of computer-readable medium: a communication medium. A communication medium typically embodies computer-readable instructions, data structures, program modules, or other data in the form of modulated data signals (such as carrier waves, data signals, or other transmission mechanisms), and includes any information delivery medium. The terms "modulated data signal" and "carrier signal" include signals whose one or more characteristics are set or altered in a manner that encodes information, instructions, and data in the signal. As examples, communication media include wired media such as twisted-pair cables, coaxial cables, optical fibers, waveguides, and other wired media, and wireless media such as acoustic, RF, infrared, Bluetooth, near-field communication, and other wireless media.

[0078] Display 429 can be any suitable display or presentation device, such as a monitor, screen, or display, and may include a printer. Display 429 may be part of a user interface configured to display information about stimulus settings (e.g., electrode configuration and stimulus parameter values ​​and ranges) and user control elements for programming stimulus settings into the IPG. Computing device 426 may include other outputs, such as speakers and haptic outputs (e.g., vibration motors).

[0079] Input device 430 may be, for example, a keyboard, mouse, touchscreen, trackball, joystick, voice recognition system, or any combination thereof or similar. Another input device 430 may be a camera from which a clinician can observe the patient. Yet another input device 430 may be a microphone from which a patient or clinician can provide responses or inquiries.

[0080] The electrical stimulation system 400 may include, for example Figure 1 Any of the components shown. The electrical stimulation system 400 can communicate with the computing device 426 via a wired or wireless connection, or alternatively or additionally, a user can provide information between the electrical stimulation system 400 and the computing device 426 using a computer-readable medium or some other mechanism.

[0081] Figure 5 An example of an electrotherapy delivery system is illustrated by way of example. The illustrated system 531 includes an electrotherapy device 532 configured to deliver electrotherapy to electrodes 533 according to a programmed set of parameters 534 for treatment to treat a condition. System 531 may include a programming system 535, which may be used as at least part of a processing system that may include one or more processors 536 and a user interface 537. The programming system 535 may be used to program and / or evaluate the set of parameters for delivering treatment. The illustrated system 531 may be a DBS system.

[0082] In some embodiments, the system 531 shown may include an SCS system for treating pain and / or a system for monitoring pain. For example, the therapeutic objective of conventional SCS programming may be to maximize stimulation (i.e., recruit) of dorsal column (DC) fibers traveling in the white matter along the longitudinal axis of the spinal cord, and to minimize stimulation of other fibers (e.g., dorsal root fibers) traveling perpendicular to the longitudinal axis of the spinal cord.

[0083] Treatment can be delivered based on a set of parameters. This set of parameters can be programmed into the device to deliver a specific treatment using specific values ​​of multiple treatment parameters. For example, treatment parameters controlling the treatment may include pulse amplitude, pulse frequency, pulse width, and electrode configuration (e.g., selected electrodes, polarity, and fractional distribution). The parameter set includes specific values ​​for the treatment parameters. The number of available electrodes, combined with the ability to generate various complex electrical waveforms (e.g., pulses), provides clinicians or patients with a vast selection of modulation parameter sets. For example, if the neural modulation system to be programmed has 16 electrodes, millions of modulation parameter sets are available for programming into the neural modulation system. To facilitate this selection, clinicians typically program the modulation parameter set via a computer programming system to allow the determination of optimal modulation parameters based on patient feedback or other means, and subsequently program the desired modulation parameter set.

[0084] Figure 6 The use of implantable medical devices (IMDs) is illustrated as an example, not a limitation. Figure 5The system includes a monitoring system and / or an electrotherapy delivery system. The system 631 shown includes an external system 638, which may include at least one programming device. The external system 638 shown may include a clinician programmer 604 and a remote control device 603, the clinician programmer 604 being similar to... Figure 1 CP 104, configured for use by clinicians to communicate with and program the neural modulator, is similar to remote control device 603. Figure 1 The RC 103 is configured for use by the patient to communicate with and program the neural modulator. For example, the remote control device 603 may allow the patient to turn the treatment on and off, change or select programs, and / or may allow the patient to adjust patient-programmable parameters among multiple modulation parameters. Figure 6 IMD 639 is shown, although the monitor and / or treatment device may be an external device such as a wearable device. External system 638 may include a computer network, including a computer remotely located with IMD 639 capable of communicating with programmer 604 and / or remote control device 603 via one or more communication networks. The remotely located computer and IMD 639 may be configured to communicate with each other via another external device, such as programmer 604 or remote control device 603. Remote control device 603 and / or programmer 604 may allow a user (e.g., a patient and / or clinician or representative) to answer questions as part of a data collection process. External system 638 may include personal devices such as telephones or tablets 640, wearable devices such as watches 641, sensors, or treatment application devices. Watches may include sensors, such as sensors for detecting activity, movement, and / or posture. Other wearable sensors may be configured to detect patient activity, movement, and / or posture. External system 638 may include, but is not limited to, telephones and / or tablets. Notifications can be sent to patients, doctors, device representatives, or other users via external systems and through remote portals provided by remote systems (e.g., web-based portals).

[0085] This document describes deep brain stimulation (DBS) at several brain targets, such as the STN and GPi, for PD management. The anatomy of the neural circuit elements by which the basal ganglia connect to the thalamus and cortex is important for understanding the mechanisms involved in ER generation in response to DBS at neural targets, such as the STN and GPi. Figure 7This image shows a parasagittal section traversing the brain of a nonhuman primate. Reproduced from Devergnas and Wichmann Frontiers' work in *Frontiers in Systems Neuroscience* (2011), 5, 30, it illustrates the major anatomical pathways involved in the subthalamic nucleus (STN) deep brain structures (DBS), including the internal capsule (IC), the globus pallidus nucleus (GPi), and the globus pallidus externus (GPe). Excitatory glutamatergic junctions are shown as red lines, inhibitory GABAergic junctions as black lines, and dopaminergic junctions as green lines. Blue concentric lines symbolize the propagation of the STN DBS. Figure 7 As shown, the STN is located in a very crowded region of the brain. The STN is part of an “indirect” pathway of the basal ganglia. This pathway links the main input structures of the basal ganglia (i.e., the striatum) to the output structures (i.e., the GPi) and the substantia nigra pars reticulata (SNr) via the GPe and the outer segment of the STN. During DBS surgery, at least one lead can be implanted into the brain so that certain electrodes are close to brain regions such as the STN. Typically, STN DBS electrodes are implanted in the central STN. The most ventral electrodes tend to be implanted at the ventral border of the STN, or may extend to the dorsal SNr. Depending on the contact spacing of the specific electrodes used, the top contacts are either located in the zone of indeterminacy (ZI) or in the central thalamus. Subsequently, continuous high-frequency stimulation is delivered via an externally programmable IPG.

[0086] Figure 8 An example of a neuromodulation system 800 is shown, configured to provide ER-guided multisite deep brain stimulation (DBS) at various brain targets. System 800 includes sensing circuitry 810, controller circuitry 820, storage device 830, electrical stimulator 840, and user interface 850. Parts of system 800 may be implemented in IPG 102 or CP 104.

[0087] Sensing circuitry 810 can sense the ER (excitatory response) of deep brain stimulation (DBS) delivered to neural targets (such as the STN or GPi in the cerebral hemispheres) in the brain of patient 801. The ER can be sensed from a sensing location in the brain via one or more sensing electrodes or sensors. Sensing circuitry 810 can be electrically coupled to one or more leads and associated electrodes, such as loop electrodes or segmented electrodes on non-directional leads 301A or directional leads 301B. Loop electrodes and / or segmented electrodes can also be electrically coupled to an electrostimulator 840, which can provide multi-site DBS at various different neural targets. Loop electrodes and / or segmented electrodes can be configured as sensing electrodes for sensing the ER or as stimulating electrodes for delivering stimulation pulses. In various examples, the ER can be sensed according to a stimulation-sensing electrode configuration, which represents the correspondence between a stimulating electrode and a sensing electrode on the same lead for sensing the ER.

[0088] The stimulating electrode for delivering DBS and the sensing electrode for sensing ER can be selected from electrodes associated with the same lead, or alternatively from electrodes associated with different leads. (Reference) Figures 9A-9B As an example and not a limitation, single-lead and double-lead configurations are shown to provide multi-site DBS and sense the corresponding ER. Figure 9A An example of a single lead 910 that can be implanted in the cerebral hemisphere during DBS surgery is shown. The lead 910 can be positioned such that a first electrode or electrode group is located at or near a first stimulation target 920A (e.g., STN), and a second electrode or electrode group is located at or near a second stimulation target 920B (e.g., GPi) in the same hemisphere. DBS at the first stimulation target (e.g., STN) can be delivered according to a first stimulation setting. DBS at the second stimulation target (e.g., GPi) can be delivered according to a second stimulation setting. The first and second stimulation settings can each include values ​​for multiple stimulation parameters such as pulse amplitude, pulse width, pulse rate, or frequency. The first and second stimulation settings can also include corresponding timing for initiating stimulation. According to various embodiments, DBS at the first and second neural targets can be delivered substantially simultaneously, sequentially with a time offset, or according to a predetermined stimulation pattern. DBS at the first stimulation target 920A can establish a first stimulation field in the region surrounding the first stimulation target. DBS at the second stimulation target 920B can establish a second stimulation field in the region surrounding the second stimulation target. As will be discussed further below, the second stimulation setting can be determined based on the ER (ER1) of DBS under the first stimulation, and DBS at the second neural target can modulate ER1, such as by increasing ER1 to produce an enhanced compound ER, or alternatively by decreasing ER1 to produce a weakened compound ER.

[0089] One or more electrodes on lead 910 can be used at locations remote from the DBS stimulation target to sense the evoked response to DBS at a specific neural target. In one example, the ER to STNDBS can be sensed at or near the GPi. In another example, the ER to GPi DBS can be sensed at or near the STN in the same cerebral hemisphere. Figure 9B An example of dual leads 930A and 930B implanted in the same cerebral hemisphere is shown. Lead 930A is positioned such that a first electrode or electrode group is located at or near a first stimulation target 940A (e.g., STN). Lead 930B is positioned such that a second electrode or electrode group is located at or near a second stimulation target 940B (e.g., GPi) in the same hemisphere. One or more electrodes on leads 930A or 930B can be used at locations remote from the DBS stimulation target to sense an evoked response to DBS at a specific neural target. In one example, lead 930A can deliver STN DBS according to a first stimulation setting, which can establish a first stimulation field in the region surrounding the first stimulation target 940A, where the ER to the STN DBS can be sensed at or near a location on GPi via electrodes on leads 930A or 930B. Lead 930B can deliver GPiDBS according to a second stimulation setting, which can establish a second stimulation field in the region around the second stimulation target 940B, wherein the ER to GPiDBS can be sensed at or near the STN via electrodes on leads 930A or 930B.

[0090] In some examples, at least some sensing or stimulating electrodes may be selected from electrodes other than those on implantable leads (such as leads 910, 930A, or 930B), such as skin patch electrodes. In some examples, intracranial brain activity, such as intracranial electroencephalography (iEEG), may be recorded via electrodes placed directly on the neocortex to record electrocorticography (ECoG), or via electrodes placed within the cortex to record stereoelectroencephalography (sEEG). Other terms and methods describing evoking and recording electrodes may be used, including those involving multiple evoking electrodes with proportional or fractionally allocated currents, or multiple independent current control (MICC) to generate precise control to refine the size and shape of the stimulation field, designed to tailor treatment for individual patients.

[0091] In some examples, external electrical stimulators can be used to provide DBS. The external electrical stimulator can be operatively coupled to one or more cortical electrodes or one or more stereotactic electrodes to provide cortical stimulation. In some examples, electrodes used to record intracranial brain activity, such as ECoG electrodes placed on the neocortex or intracortical electrodes used to sense sEEG, can be coupled to the external electrical stimulator to provide multisite DBS at corresponding neural targets near those intracranial electrodes. As will be discussed further below, such cortical stimulation can be used to modulate the response via implantable leaded electrodes (such as... Figures 9A-9B The ERs of DBS (as shown) are delivered at the corresponding neural targets (e.g., STN and GPi) and produce the desired therapeutic outcome in the patient.

[0092] Return to reference Figure 8 The controller circuit 820 may include a circuit group comprising one or more other circuits or sub-circuits, such as a signal analyzer circuit 822 and a multi-site stimulation controller 826. The circuits or sub-circuits may perform the functions, methods, or techniques described herein individually or in combination. In one example, the hardware of the circuit group may be designed invariably to perform a specific operation (e.g., hard-wired). In one example, the hardware of the circuit group may include physically connected components (e.g., execution units, transistors, simple circuits, etc.) including physically modified computer-readable media (e.g., magnetic, electrical, movable placement of invariant aggregated particles, etc.) to encode instructions for a specific operation. When the physical components are connected, the basic electrical characteristics of the hardware components are altered, for example, from an insulator to a conductor, and vice versa. Instructions enable embedded hardware (e.g., execution units or loading mechanisms) to create members of the circuit group in the hardware via the variable connections to perform portions of a specific operation during operation. Thus, when the device is operational, computer-readable media are communicatively coupled to other components of the circuit group members. In one example, any of the physical components may be used in more than one member of more than one circuit group. For example, in operation, the execution unit may be used in the first circuit of the first circuit group at one point in time, and reused by the second circuit in the first circuit group or the third circuit in the second circuit group at different times.

[0093] In various examples, some functions of the controller circuit 820 may be implemented as part of a microprocessor circuit. The microprocessor circuit may be a special-purpose processor, such as a digital signal processor, an application-specific integrated circuit (ASIC), a microprocessor, or other type of processor for processing information including bodily activity information. Alternatively, the microprocessor circuit may be a general-purpose processor that can receive and execute a set of instructions to perform the methods or techniques described herein.

[0094] Signal analyzer circuit 822 may include ER feature extraction circuit 823, which can extract one or more ER features from the ER sensed by sensing circuit 810. Examples of ER features may include signal amplitude, magnitude, peak value, value range, signal curve length, or signal power or RMS value of the ER signal within a time window, such as epoch-average ER. The signal amplitude range or value range, also known as peak-to-peak (P2P) value, may be measured as the difference between the maximum or minimum values ​​of the dominant peaks in the sensed evoked response or epoch-average evoked response within a time window (also known as the "maximum P2P" amplitude). Alternatively, the P2P value may be measured as the difference between a negative peak (valley) and the immediately following positive peak (also known as the "N1-P2P2P" amplitude). The signal curve length may be measured as the cumulative difference in signal values ​​of the sensed evoked response (or epoch-average evoked response) within a continuous unit of time (e.g., a continuous data sampling interval) within a time window. Signal power can be measured as the area under the curve (AUC) of the sensed evoked response (or epoch-average evoked response) within a time window.

[0095] In some examples, signal analyzer circuit 822 can generate a spatial distribution of extracted signal features across sensing locations of sensing electrodes. For example, multiple sensing electrodes at or near a first brain target can each sense a corresponding ER, and the spatial distribution of ER features across multiple sensing electrodes can be determined. In some examples, the spatial distribution can be determined by fitting ER data to an ER distribution model, such as a Gaussian distribution model, a periodic or wrapped Gaussian distribution model, an exponential distribution model, a Poisson distribution model, a Weibull distribution, a regression model or a nonparametric model (such as a decision tree), a K-nearest neighbor model, a support vector machine (such as one employing a Gaussian kernel), or an artificial neural network. ER feature extraction circuit 823 can extract one or more features or parameters from the ER distribution model, including, for example, the mean or standard deviation of the ER features. In another example, model features or parameters can include morphological or statistical characteristics of the distribution model, such as the amplitude, spatial location, or width of the peak of the fitted model over a range defined by multiple sensing locations. In another example, model features or parameters may include one or more of the positive peak amplitude (or local maximum) or negative peak amplitude (or local minimum) of the fitted model within a range defined by multiple sensing locations. In yet another example, model features or parameters may include composite features, such as the ratio of the positive peak amplitude to the negative peak amplitude of the fitted model within a range defined by multiple sensing locations.

[0096] In some examples, sensing circuit 810 can sense the ER of the DBS at a first brain target (DBS1) according to a first stimulation setting, and ER feature extraction circuit 823 can extract features (hereinafter referred to as "ER1 features") from the ER of DBS1. The ER1 features can be used to guide the DBS at a second brain target (DBS2), as will be discussed below. Signal analyzer circuit 822 can compare the ER1 features (or the distribution of ER1 features, or ER1 distribution model features or parameters) with one or more acceptance criteria 832 to determine whether a match with the desired or target ER can be found. In some examples, acceptance criteria can be set, modulated, checked, and accepted by a clinical user, including before or during the procedure. In some examples, signal analyzer circuit 822 can accumulate sensed ERs obtained during multiple stimulation-ER recording sessions during which stimulation pulses are delivered via specific stimulation electrodes with different stimulation parameter settings (e.g., stimulation amplitude, frequency, or pulse width); determine an ER distribution model (or model features or parameters) from the accumulated ERs; and compare the ER distribution model or model features or parameters with acceptance criteria 832. Acceptance criteria 832 may be provided by the user, such as via user interface 850. Alternatively, acceptance criteria 832 may be predetermined and stored in a storage device 830 accessible by signal analyzer circuitry 822. In one example, acceptance criteria 832 may include user-provided acceptance limits for model features or parameters (e.g., upper and lower limits, location limits, attribute limits, such as the presence, absence, or value of a feature). In another example, acceptance criteria 832 may include a target ER distribution representing a patient-specific ER distribution or a population-based ER distribution. In one example, a target ER distribution may be selected to alleviate symptoms or for other purposes, such as lead placement for disease improvement treatment or combined treatment (e.g., lead for injecting drugs or light), and side effect avoidance. In some examples, acceptance criteria may include one of multiple candidate ER templates indexed by region, clinical institution, group, participant information, implanter information, or symptom relief purpose, and the target ER template may be selected from multiple candidate ER templates based at least in part on one or more of the identification of the institution where the patient was implanted or treated with electrical stimulation, group or participant information, identification of the implanter of the implanted lead, or an indication of sensed patient symptom relief.

[0097] The multi-site stimulation controller 826 can generate control signals to the electrical stimulator 840 to deliver multi-site DBS based on a comparison of ER1 characteristics (or the distribution of ER1 characteristics, or ER1 distribution model characteristics or parameters) with acceptance criteria 832. For example, if the signal analyzer circuit 822 determines that the ER1 characteristics (or the distribution of ER1 characteristics, or ER1 distribution model characteristics or parameters) do not match the desired or target ER (causing the acceptance criteria to be unmet), the multi-site stimulation controller 826 can adjust the second stimulation settings for the DBS at the second brain target (DBS2). This may include, for example, guiding the placement or selection of a second or more stimulation electrodes for stimulating the second brain target with a second lead, and / or optimizing the stimulation parameters at the second brain target. The first and second brain targets may be located in the same hemisphere of the brain. In one example, the first brain target is the STN, and the second target is the GPi in the same hemisphere of the brain. DBS for the first and second brain targets can be delivered via corresponding electrodes or groups of electrodes in the same lead or separate leads, as described above regarding Figures 9A-9B As stated above.

[0098] The DBS at the second brain target site (DBS2) may modulate ER1, producing a "compound" ER. The multi-site stimulation controller 826 can adjust the stimulation settings of DBS2 until the compound ER matches the desired or target ER, thus satisfying acceptance criterion 832. In one example, the second stimulation setting of DBS2 can be determined such that DBS2 will increase ER1, thus producing an enhanced compound ER. In another example, the stimulation setting of DBS2 can be determined such that DBS2 will decrease ER1, thus producing a weakened compound ER.

[0099] In some examples, the multi-site stimulation controller 826 can determine or adjust the DBS2 stimulation settings (e.g., lead placement, stimulation parameters, and electrode selection) based on treatment outcomes. Treatment outcomes can be evaluated by comparing the spatial distribution of ER with the desired spatial distribution of ER. For example, the multi-site stimulation controller 826 can adjust the DBS2 stimulation settings to reduce the difference between the spatial distribution of the composite ER (i.e., ER1 modulated by DBS at a second brain target) and the desired spatial distribution of ER. In one example, the distribution of sensed ER can be depicted as a two-dimensional (2D) hotspot view, which includes hotspots for the ER distribution. Hotspots represent the center of the ER distribution where the ER amplitude reaches its peak. The multi-site stimulation controller 826 can compare the measured hotspots based on DBS1 with user-defined target hotspots. Target hotspots represent the desired location and amplitude of the peak of the ER distribution and correspond to better treatment outcomes. (See below for reference.) Figure 10Furthermore, the difference between the measured hot spot and the target hot spot can be used to optimize DBS2, such as by adjusting the DBS2 stimulation settings until the measured composite ER hot spot matches the target hot spot (e.g., the difference in ER peak location and / or ER peak amplitude is reduced below a threshold). This ER-guided multi-site DBS can improve the therapeutic efficacy of multi-site DBS.

[0100] The multi-site stimulation controller 826 can be implemented as a proportional-integral (PI) controller, a proportional-integral-derivative (PID) controller, or other suitable controller to use a comparison of the sensed ER (or its characteristics or characteristic distribution) with the acceptance criterion 852 as feedback for stimulation setting adjustments. The data type and the recording used to generate the data may vary depending on the type of acceptance criterion and the operation employed. For example, the ER data used to drive decisions regarding electrode selection and configuration may differ from the data and evoked / recorded configuration used for comparison with the acceptance criterion and as control signals for amplitude adjustment. One ER measurement may be used to inform lead positioning (e.g., by sweeping a non-therapeutic sampling pulse across the space of the lead electrodes), and another ER measurement may be used to determine or adjust stimulation parameters (e.g., by sweeping a therapeutic sampling signal across the amplitude).

[0101] The electrical stimulator 840 can be configured to deliver electrical stimulation according to stimulation settings. Electrical stimulation can be delivered using a monopolar (far field) or bipolar (near field) configuration. Examples of treatment settings may include electrode selection and configuration, stimulation parameter values, including, for example: amplitude, pulse width, frequency, pulse waveform, active or passive charging mode, ON time, OFF time, treatment duration, and fractional distribution. In some examples, the electrical stimulator 840 can be configured to deliver multi-site DBS at corresponding brain targets (such as the STN and GPi) according to the appropriate stimulation settings. Multi-site DBS can be delivered substantially simultaneously, sequentially, or according to a predetermined pattern to the corresponding brain targets.

[0102] The electrical stimulator 840 can be an implantable module, such as integrated within the IPG 10. Alternatively, the electrical stimulator 840 can be an external stimulation device, such as integrated with the ETS 40. In some examples, the user can choose to send notifications for treatment reminders (e.g., to the RC 45 or the patient's smartphone), or automatically initiate or adjust neuromodulation therapy according to the adjusted treatment settings. If automatic treatment initiation is selected, the electrical stimulator 840 can deliver stimulation according to the adjusted treatment settings.

[0103] In some examples, the multi-site stimulation controller 826 can generate suggestions to the user to reposition the lead or adjust device settings (e.g., programmable parameters of the electrical stimulator 840). During the implantation procedure, lead repositioning or device setting adjustment can align the sensed ER with or more appropriately compare it to a acceptance criterion (e.g., an ER template). In some examples, the multi-site stimulation controller 826 can determine or modify the treatment stimulation settings based on the sensed ER or features or the distribution of those features. The electrical stimulator 840 can deliver treatment stimulation (e.g., DBS) based on the determined or modified treatment stimulation settings.

[0104] In some embodiments, the display may offer the user suggestions for adjusting stimulation parameters to more appropriately compare the generated response with acceptance criteria (e.g., ER templates). This suggestion may be displayed on a user interface 850. The user interface 850 may be a portable (e.g., handheld) device, such as an RC 45, or a smartphone (with an executable software application) that the patient can operate at home without requiring additional clinic visits or consultation with a device specialist. In another example, the user interface 850 may be a programmer device, such as a CP 50. In addition to suggestions for lead replacement, other information may be displayed on the user interface 850, by way of example and not limitation, including one or more of the following: sensed ER (including, for example, before and / or after filtering), ER characteristics, distribution of ER characteristics, acceptance criteria (e.g., one or more ER templates), or comparisons between sensed ER and acceptance criteria.

[0105] In some examples, user interface 850 allows physicians to remotely view treatment settings and treatment history, consult with patients to obtain information including side effects or symptoms associated with or caused by electrical stimulation, perform remote programming of the electrical stimulator 840, or provide patients with additional treatment options. User interface 850 may allow users (e.g., patients, physicians managing patients, or device specialists) to view, program, or modify device settings. For example, a user may use one or more user interface (UI) controls to provide or adjust values ​​for one or more device parameters, or select from a plurality of predefined stimulation programs for future use. Each stimulation program may include a set of stimulation parameters with corresponding predetermined values. In some examples, user interface 850 may include a display to display, in text or graphical form, information provided by the user via input units, and device settings, including, for example, feature selection, sensing configuration, signal preprocessing settings, treatment settings, optionally with any intermediate calculations. In one example, according to various embodiments discussed in this document, user interface 850 may present the user with a “optimal” or improved treatment setting, such as determined based on closed-loop or adaptive feedback control of electrical stimulation based on selected evoked response signal characteristics. In some examples, users can use the user interface 850 to provide feedback on neuromodulation therapy, including, for example, the occurrence or persistence of side effects or symptoms associated with nerve stimulation, or the severity of the symptoms or side effects.

[0106] Figure 10 The display 1000 on the user interface is shown by way of example, not limitation, showing a comparison between a user-defined ER target location 1025 and a calculated ER distribution center 1027, overlaid on a depiction of a portion of the electrodes on the lead 1020, such as ring electrodes T1 and T4, segmented electrodes T2a, T2b, T2c, and segmented electrodes T3a, T3b, T3c, as shown. Figure 10As shown. The user-defined ER target location 1025 is an example of the acceptance criterion 832 and can represent the target ER distribution center. The calculated ER distribution center 1027 can be determined based on the ER distribution sensed by the signal analyzer circuit 822. The sensed ER distribution can be estimated along the longitudinal direction and around the rotational direction. The sensed ER distribution can be depicted as a two-dimensional (2D) hotspot view 1026, which provides indicators for hotspots of the ER distribution (e.g., a heatmap displayed as a color map or grayscale image). The calculated ER distribution center 1027 can represent the peak amplitude of the ER distribution at the peak location, such as the peak of a Gaussian distribution. In one example, the calculated ER distribution center 1027 can be determined based on the ER distribution of the DBS for the first brain target (DBS1). Based on the comparison between the user-defined ER target location 1025 and the calculated ER distribution center 1027, suggestions 1028 can be provided to the user to adjust the stimulation settings of the DBS at a second brain target (DBS2) different from the first brain target. Adjustments to the DBS2 stimulation settings may include adjustments to lead placement or stimulation parameters such that the DBS2 delivered according to the adjusted stimulation settings modulates the ER against DBS1 (i.e., ER1) and makes the calculated ER distribution center 1027 more closely correspond to the user-defined ER target location 1025 (e.g., the calculated ER distribution center 1027 falls within a predetermined proximity range of the user-defined ER target location 1025). The user-defined ER target location 1025 may be presented on the representation of the lead electrode. In some examples, the user interface 850 may determine the distance between the calculated ER distribution center 1027 and the user-defined ER target location 1025 and provide said distance to the user. During lead implantation, the calculated ER distribution center 1027 may be updated substantially in real time as the DBS2 stimulation settings are adjusted. A comparison between the user-defined ER target location 1025 and the updated calculated ER distribution center 1027, including the distance between them, may be displayed to the user to guide lead implantation.

[0107] Figure 11A-11D Various stimulation modalities that can be used for multi-site DBS are illustrated by way of example, not limitation, such as delivery via corresponding electrodes or electrode groups distributed between two or more leads, as referenced above. Figures 9A-9B Specifically, Figure 11AThe diagram illustrates a DBS (Device Shift) to a first target point (“DBS1” 1130A) via a first electrode 1110A on lead 1100, and a DBS to a second target point (“DBC2” 1140A) via a second electrode 1120A on the same lead 1100. In this example, DBS1 1130A and DBS2 1140A have different pulse rates (also known as pulse frequencies, i.e., the number of pulses per unit time), but may have the same or different pulse widths. Figure 11B Similarly, stimulation patterns including DBS1 1130A targeting a first target via a first electrode 1110A and DBS2 1140B targeting a second target via a second electrode 1120A on the same lead 1100 are shown. DBS1 1130A and DBS2 1140B may have the same or different pulse widths. Figure 11A The stimulation patterns shown are opposite, with DBS1 1130A and DBS2 1140B having the same pulse rate. Figure 11C It shows Figure 11B The stimulation pattern shown is modified, where DBS is delivered to the two electrodes 1110A and 1110B at or near the first target site, instead of as... Figure 11B Only one electrode, 1110A, is shown. In this example, the DBS at electrodes 1110A and 1110B is delivered in a current-directed mode, where the stimulation current is delivered substantially simultaneously to two (or more) electrodes. In the example shown, DBS 1130A at electrode 1110A and DBS 1130C at electrode 1110B have the same pulse rate and timing but different stimulation amplitudes. Similar to... Figure 11B DBS2 1140B at the second target site is delivered via the second electrode 1120A. Figure 11D It shows Figure 11B Another modification to the multi-site DBS stimulation pattern shown. In this example, DBS1 1130A is delivered to the first target site via electrode 1110A. DBS2, delivered to the second target site via the second electrode 1120A, comprises two DBS pulse trains: as shown... Figure 11B Similarly, the DBS 1140B is shown, as well as another DBS 1140D with the same pulse rate as the DBS1 1130A but different pulse amplitudes and timings. The stimulation pattern at the second target is itself referred to as an interleaved pattern because the DBS 1140B and DBS 1140D are delivered to the same electrode (e.g., electrode 1120A) but at different times, and one pulse train is interleaved with the other. In some examples, three or more DBS pulse trains with the same pulse rate may be applied to the same electrode (e.g., electrode 1120A) in an interleaved pattern.

[0108] Figure 12 A method 1200 for providing evoked response (ER)-guided multisite deep brain stimulation (DBS) at various brain targets is illustrated by way of example, not limitation. Method 1200 can be performed using a medical system such as a neuromodulation system 800. In one example, method 1200 can be implemented in a programmer device (such as an RC 45 or CP 50) that communicates with an electrical stimulator (such as an IPG 10 or an electrical stimulator 840). In some examples, method 1200 can alternatively be used to provide ER-based multisite stimulation at other neural targets, such as spinal cord stimulation (SCS) at multiple spinal cord targets.

[0109] At 1210, electrical stimulation can be delivered to a first neural target according to a first stimulation setting. In the example of DBS, the first neural target can be a brain target, such as the STN or GPi. Electrical stimulation such as in DBS can be delivered via a stimulating electrode selected from electrodes associated with at least one lead (such as a non-directional lead 301A or a directional lead 301B).

[0110] At 1220, an evoked response (ER) to electrical stimulation at the first neural target can be sensed via a first sensing electrode positioned at the first sensing location. The first sensing electrode can be selected from electrodes associated with the same lead used to provide electrical stimulation, or alternatively, from electrodes associated with different leads, as described above regarding... Figures 9A-9B The first sensing electrode for sensing the ER of the DBS at the first neural target can be positioned away from the first neural target being stimulated. In one example, the first neural target being stimulated is an STN target, and the ER of the STN DBS can be sensed at or near the GPi. In another example, the first neural target being stimulated is a GPi target, and the ER of the GPi DBS can be sensed at or near the STN in the same cerebral hemisphere.

[0111] In some examples, at least some of the sensing or stimulating electrodes can be selected from electrodes other than those on implantable leads, such as skin patch electrodes. In some examples, intracranial brain activity, such as intracranial electroencephalography (iEEG), can be recorded via electrodes placed directly on the neocortex to record electrocorticography (ECoG), or via electrodes placed within the cortex to record stereotactic electroencephalography (sEEG).

[0112] At 1630, the second stimulation setting for stimulating a second neural target different from the first neural target can be determined or adjusted, at least in part, based on the sensed ER of electrical stimulation at the first neural target. In the case of multi-site DBS, the first and second neural targets can be targets in the same hemisphere of the brain. In one example, the first brain target is the STN, and the second target is the GPi in the same brain hemisphere.

[0113] Determining or adjusting the ER-guided second stimulation setup may involve extracting features (hereinafter referred to as "ER1 features") from the ER sensed by the DBS at the first brain target. Examples of ER features may include signal amplitude, magnitude, peak value, range, signal curve length, or signal power or RMS value of the ER signal within a time window, such as epoch-average ER. In some examples, the spatial distribution of the extracted signal features across the sensing locations of the sensing electrodes may be determined, and one or more features or parameters may be extracted from an ER distribution model, including, for example, the mean or standard deviation of the ER features. ER1 features (or the distribution of ER1 features, or ER1 distribution model features or parameters) may be compared with one or more acceptance criteria to determine whether a match with the desired or target ER can be found. Acceptance criteria may be provided by the user or predetermined and stored in a storage device. In one example, acceptance criteria may include user-provided acceptance limits for model features or parameters (e.g., upper and lower limits, location limits, attribute limits, such as the presence, absence, or value of the feature). In another example, acceptance criteria may include a target ER distribution representing a patient-specific ER distribution or a population-based ER distribution. In one example, a target ER distribution can be selected to relieve symptoms or for other purposes, such as lead placement for disease improvement or combination therapy (e.g., lead for injecting drugs or light), and side effect avoidance.

[0114] At 1640, electrical stimulation can be delivered to a second neural target according to a second stimulation setting to modulate the sensed ER at the first neural target and produce the desired therapeutic outcome in the patient. For example, if features extracted from ER1 (or from a distribution of ER1 features, or ER1 distribution model features or parameters) do not match the desired or target ER (and therefore do not meet the acceptance criteria), the second stimulation setting (for stimulating the second brain target) can be adjusted. This may include guided placement of a second lead or selection of a second or more stimulation electrodes for stimulating the second brain target, and / or optimization of stimulation parameters at the second brain target.

[0115] At 1650, the ER of electrical stimulation at the second neural target can be sensed via a second sensing electrode positioned at the second sensing location. In multi-site DBS, stimulation at the second brain target can modulate ER1, thereby producing a “composite” ER. The second stimulation setting (for stimulating the second brain target) can be adjusted until the composite ER matches the desired or target ER, thus meeting the acceptance criteria. In one example, the second stimulation setting can be determined such that DBS at the second brain target will enhance ER1, thus producing an enhanced composite ER. In another example, the second stimulation setting can be determined such that DBS at the second brain target will decrease ER1, thus producing a weakened composite ER. In some examples, the second stimulation setting (e.g., lead placement, stimulation parameters, and electrode selection) can be adjusted based on treatment outcomes. Treatment outcomes can be evaluated by comparing the spatial distribution of ER with the desired spatial distribution of ER. For example, the second stimulation setting can be adjusted to reduce the difference between the spatial distribution of the composite ER (i.e., ER1 modulated by DBS at the second brain target) and the desired spatial distribution of ER. In one example, the sensed ER distribution can be depicted as a two-dimensional (2D) hotspot view, including hotspots targeting the ER distribution. The measured ER1-based hotspots can be compared to user-defined target hotspots. The target hotspots represent the desired location and amplitude of the ER distribution peaks and correspond to better therapeutic outcomes. In some examples, the difference between the measured hotspots and the target hotspots can be used to optimize a secondary stimulation setup (for stimulating a secondary brain target), such as by adjusting one or more stimulation parameters or selecting different stimulation electrodes, until the measured composite ER hotspots match the target hotspots (e.g., the difference in ER peak location and / or ER peak amplitude falls below a threshold). As described above, ER-guided multi-site DBS can improve the therapeutic efficacy of DBS.

[0116] In some examples, the comparison between the spatial distribution of the ER and the desired spatial distribution of the ER (such as a comparison between a measured ER1-based hotspot and a user-defined target hotspot) can be presented to the user (e.g., a clinician), such as by displaying it on a user interface. Based on this comparison, suggestions can be provided to the user, such as suggestions to reposition at least one lead, such as pushing, pulling, moving, or rotating the lead to achieve the desired target response, or suggestions to adjust the stimulation settings. During the repositioning of at least one lead and / or adjustment of the stimulation settings, an evoked response can be sensed, and ER characteristics and / or distribution can be determined and updated substantially in real time with the comparison to acceptance criteria and displayed to the user. The user can continue to reposition at least one lead and / or adjust the stimulation settings until the sensed ER is more appropriately compared to the acceptance criteria. The sensed ER or characteristics, or the distribution of ER characteristics derived therefrom, can be used as feedback to further modify the therapeutic stimulation settings.

[0117] Figure 13 A block diagram of an example machine 1300 is shown in general, on which any one or more of the techniques (e.g., methods) discussed herein can be executed. The portions of this description can be applied to the computational framework of various parts of a neural modulation device or an external programmer device.

[0118] In alternative examples, machine 1300 may operate as a standalone device or may be connected (e.g., networked) to other machines. In a networked deployment, machine 1300 may operate as a server machine, a client machine, or both in a server-client network environment. In one example, machine 1300 may act as a peer machine in a peer-to-peer (P2P) (or other distributed) network environment. Machine 1300 may be a personal computer (PC), tablet PC, set-top box (STB), personal digital assistant (PDA), mobile phone, network device, network router, switch, or bridge, or any machine capable of executing instructions (sequential or otherwise) specifying actions to be taken by that machine. Furthermore, although only a single machine is shown, the term "machine" should also be considered to include any collection of machines, such as cloud computing, software as a service (SaaS), and other computer cluster configurations, that individually or jointly execute a set (or more) of instructions to perform any one or more of the methods discussed herein.

[0119] The examples described herein may include logic or multiple components or mechanisms, or those that can be operated by them. A circuit group is a collection of circuits implemented in a tangible entity, including hardware (e.g., simple circuits, gates, logic, etc.). Circuit group members can be flexible with time and the variability of the underlying hardware. A circuit group includes members that can perform a specified operation individually or in combination during operation. In one example, the hardware of a circuit group may be invariably designed to perform a specific operation (e.g., hardwired). In one example, the hardware of a circuit group may include physically connected components (e.g., execution units, transistors, simple circuits, etc.) that include physically modified computer-readable media (e.g., magnetic, electrical, movable placement of invariant aggregated particles, etc.) to encode instructions for a specific operation. When the physical components are connected, the basic electrical characteristics of the hardware components are changed, for example, from an insulator to a conductor, and vice versa. Instructions enable embedded hardware (e.g., execution units or loading mechanisms) to create members of the circuit group in the hardware via variable connections to perform portions of a specific operation during operation. Thus, when the device operates, computer-readable media are communicatively coupled to other components of the circuit group members. In one example, any one of the physical components can be used in more than one member of more than one circuit group. For example, in operation, an execution unit can be used in a first circuit of a first circuit group at one point in time and reused by a second circuit in the first circuit group or a third circuit in the second circuit group at different times.

[0120] Machine (e.g., computer system) 1300 may include a hardware processor 1302 (e.g., a central processing unit (CPU), graphics processing unit (GPU), hardware processor core, algorithm-specific ASIC, or any combination thereof), main memory 1304, and static memory 1306, some or all of which may communicate with each other via an interconnect (e.g., bus) 1308. Machine 1300 may also include a display unit 1310 (e.g., raster display, vector display, holographic display, etc.), an alphanumeric input device 1312 (e.g., keyboard), and a user interface (UI) navigation device 1314 (e.g., mouse). In one example, display unit 1310, input device 1312, and UI navigation device 1314 may be a touchscreen display. Machine 1300 may also include a storage device (e.g., drive unit) 1316, a signal generation device 1318 (e.g., speaker), a network interface device 1320, and one or more sensors 1321, such as a global positioning system (GPS) sensor, a compass, an accelerometer, or other sensors. Machine 1300 may include output controller 1328, such as serial (e.g., universal serial bus, USB), parallel or other wired or wireless (e.g., infrared, near field communication, NFC, etc.) connections, to communicate or control one or more peripheral devices (e.g., printers, card readers, etc.).

[0121] Storage device 1316 may include machine-readable medium 1322 on which one or more sets of data structures or instructions 1324 (e.g., software) are stored, which embody or utilize any one or more of the techniques or functions described herein. During execution of instructions 1324 by machine 1300, instructions 1324 may also reside wholly or at least partially in main memory 1304, static memory 1306, or hardware processor 1302. In one example, one or any combination of hardware processor 1302, main memory 1304, static memory 1306, or storage device 1316 may constitute a machine-readable medium.

[0122] Although machine-readable medium 1322 is shown as a single medium, the term "machine-readable medium" can include a single medium or multiple media (e.g., a centralized or distributed database and / or associated caches and servers) configured to store one or more instructions 1324.

[0123] The term "machine-readable medium" can include any medium capable of storing, encoding, or carrying instructions executable by machine 1300 and enabling machine 1300 to perform any one or more of the technologies disclosed herein, or any medium capable of storing, encoding, or carrying data structures used by or associated with those instructions. Examples of non-limiting machine-readable media can include solid-state memory as well as optical and magnetic media. In one example, a massed machine-readable medium includes a machine-readable medium having a plurality of particles having invariant (e.g., rest) masses. Therefore, a massed machine-readable medium is not a transient propagation signal. Specific examples of massed machine-readable media can include: non-volatile memory, such as semiconductor storage devices (e.g., electrically programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EPSOM)) and flash memory devices; disks, such as internal hard disks and removable disks; magneto-optical disks; and CD-ROMs and DVD-ROMs.

[0124] Various transmission protocols (e.g., Frame Relay, Internet Protocol (IP), Transmission Control Protocol (TCP), User Datagram Protocol (UDP), Hypertext Transfer Protocol (HTTP), etc.) can be used to further send or receive instructions 1324 via the communication network 1326 through the network interface device 1320 using the transmission medium. Example communication networks may include local area networks (LANs), wide area networks (WANs), packet data networks (e.g., the Internet), mobile phone networks (e.g., cellular networks), plain old telephone (POTS) networks, and wireless data networks (e.g., the Institute of Electrical and Electronics Engineers (IEEE) 802.11 standard family known as WiFi®, the IEEE 802.16 standard family known as WiMax®), the IEEE 802.15.4 standard family, peer-to-peer (P2P) networks, etc. In one example, network interface device 1320 may include one or more physical jacks (e.g., Ethernet, coaxial cable, or telephone jacks) or one or more antennas for connection to communication network 1326. In one example, network interface device 1320 may include multiple antennas for wireless communication using at least one of single-input multiple-output (SIMO), multiple-input multiple-output (MIMO), or multiple-input single-output (MISO) technologies. The term "transmission medium" should be considered to include any intangible medium capable of storing, encoding, or carrying instructions executed by machine 1300, and includes digital or analog communication signals or other intangible media to facilitate communication of such software.

[0125] Various examples are illustrated in the accompanying figures above. One or more features from one or more of these examples can be combined to form other examples.

[0126] The methods described herein can be implemented, at least in part, by a machine or computer. Some examples may include a computer-readable or machine-readable medium encoded with instructions operable to configure an electronic device or system to perform the methods described in the examples above. Implementations of these methods may include code, such as microcode, assembly language code, high-level language code, etc. Such code may include computer-readable instructions for performing various methods. The code may form part of a computer program product. Furthermore, the code may be tangibly stored on one or more volatile or non-volatile computer-readable media during execution or at other times.

[0127] The above detailed description is intended to be illustrative and not limiting. Therefore, the scope of this disclosure should be determined by reference to the appended claims and the full scope of their equivalents.

Claims

1. A neural modulation system, comprising: At least one lead, which includes multiple electrodes; An electrical stimulator configured to deliver electrical stimulation to a patient’s neural target via one or more of the plurality of electrodes via the at least one lead; A sensing circuit configured to sense the evoked response (ER) to the electrical stimulation. as well as A controller circuit, operably connected to the electrical stimulator and the sensing circuit, is configured to: In response to delivering the electrical stimulation to a first neural target according to a first stimulation setting, the ER sensed by the sensing circuit from a first sensing electrode located at a first sensing position; Based at least in part on the sensed ER of the electrical stimulation at the first neural target, a second stimulation setting for stimulating a second neural target of the patient that is different from the first neural target is determined or adjusted. A control signal is generated to the electrical stimulator to provide electrical stimulation at the second nerve target according to the second stimulation setting, thereby modulating the sensed ER of the electrical stimulation at the first nerve target and producing the desired therapeutic result in the patient. as well as The ER (eructogenic response) of the second neural target is collected from the second sensing electrode located at the second sensing position via the sensing circuit.

2. The neural modulation system according to claim 1, wherein, The controller circuit is configured to control the electrical stimulator to deliver corresponding electrical stimuli to the first neural target and the second neural target substantially simultaneously according to corresponding first and second stimulation settings.

3. The neural modulation system according to any one of claims 1-2, wherein, The controller circuit is configured to control the electrical stimulator to deliver corresponding electrical stimuli to the first and second nerve targets in a specific time offset sequence according to the corresponding first and second stimulation settings.

4. The neural modulation system according to any one of claims 1-3, wherein, The first and second neural targets of the electrical stimulation are different brain targets in specific hemispheres of the brain.

5. The neural modulation system according to claim 4, wherein, The first neural target of the electrical stimulation is the subthalamic nucleus (STN) target, and the second neural target of the electrical stimulation is the globus pallidus nucleus (GPi) target.

6. The neural modulation system according to claim 5, wherein: The first sensing electrode is positioned at the GPi sensing location to sense the ER of electrical stimulation of the STN target; and The second sensing electrode is positioned at the STN sensing location to sense the ER of electrical stimulation to the GPi target.

7. The neuromodulation system according to any one of claims 1-6 further includes an external electrical stimulator operatively coupled to one or more cortical electrodes or one or more stereotactic electrodes to provide cortical stimulation thereby modulating one or more of the following: sensed ER at the electrical stimulation at the first neural target, or sensed ER at the electrical stimulation at the second neural target, and producing a desired therapeutic outcome in the patient.

8. The neural modulation system according to any one of claims 1-7, wherein, The electrostimulator is electrically coupled to a multi-electrode lead, and the electrostimulator is configured to provide electrical stimulation to the first neural target via a first electrode on the multi-electrode lead and to provide electrical stimulation to the second neural target via a second electrode on the same multi-electrode lead.

9. The neural modulation system according to any one of claims 1-8, wherein, The at least one lead includes different first leads and second leads, each lead including one or more electrodes. The electrical stimulator is configured to provide electrical stimulation to the first nerve target via a first electrode on the first lead and to provide electrical stimulation to the second nerve target via a second electrode on the second lead.

10. The neural modulation system according to any one of claims 1 to 9, wherein, At least one of the first sensing electrode or the second sensing electrode is selected from the plurality of electrodes of the at least one lead.

11. The neural modulation system according to any one of claims 1-10, wherein, At least one of the sensed ER at the first neural target or the sensed ER at the second neural target includes: electrocorticography (ECoG) or electrostereoscopic electroencephalography (sEEG) sensed via one or more cortical electrodes or one or more stereotactic electrodes.

12. The neural modulation system according to any one of claims 1-11, wherein, The controller circuit is configured to determine or adjust the second stimulation setting such that electrical stimulation at the second nerve target site, according to the second stimulation setting, reduces the ER of electrical stimulation at the first nerve target site.

13. The neural modulation system according to any one of claims 1-12, wherein, The controller circuit is configured to determine or adjust the second stimulation setting such that the electrical stimulation at the second nerve target site according to the second stimulation setting enhances the ER of the electrical stimulation at the first nerve target site.

14. The neural modulation system according to any one of claims 1-13, wherein, In order to determine or adjust the second stimulation setting based at least in part on the sensed ER of the electrical stimulation at the first neural target, the controller circuit is configured to: The treatment outcome was assessed using the sensed ER (eructation response) of the electrical stimulation at the first neural target; and Based on the evaluation of the treatment results, the second stimulation settings are determined or adjusted, including one or more stimulation parameters for electrical stimulation or one or more electrodes selected from a plurality of electrodes of the at least one lead.

15. The neural modulation system according to claim 14, wherein, Evaluating the treatment outcome includes comparing the spatial distribution of the sensed ER at the first neural target site with the expected spatial distribution of ER. The controller circuit is configured to determine or adjust the second stimulation setting to reduce the difference between the spatial distribution of the sensed ER at the second neural target and the desired spatial distribution of ER.

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