Side effect prediction using clinical effect maps in application of deep brain stimulation

Abstract

Methods and systems for predicting side effects in deep brain stimulation therapy for a patient having a neuromodulation system. Therapy parameters, specifically a position and amplitude combination, predicted to result in a side effect are mapped. The map may be populated with a border indicating the threshold position and amplitude combination likely to result in side effects. The border may be adjusted to account for new stimulation data, historical data, anatomical data, or in reaction to verification processes.

Description

[0001] BSC File No.: 24-0612W001

[0002] Atty. Docket No.: 2001.3828111 SIDE EFFECT PREDICTION USING CLINICAL EFFECT MAPS IN APPLICATION OF DEEP BRAIN STIMULATION

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 751,443 filed on January 30, 2025, the disclosure of which is incorporated herein by reference.

[0005] BACKGROUND

[0006] Deep brain stimulation (DBS) involves the use of a pulse generator attached to the proximal end of a lead; the distal end of the lead being positioned inside the head of a patient. Neuromodulation can be achieved by, for example, issuing therapy pulses to the sub-thalamic nucleus or other neural structure in the brain to provide various forms of treatment. DBS may, for example, reduce tremor for a patient having Parkinson’s disease. Other neural structures and conditions may be treated, with a number of potential therapies under development or clinical research and study, such as for cognitive disorders, tremors, Alzheimer’s, depression and other diseases.

[0007] Modern systems have a plurality of electrodes on the lead allowing spatial selection of structures to receive therapy pulses. A lead may have segmented electrodes about its perimeter to allow such spatial control. This may be called directional therapy and may use current or voltage steering with multiple current or voltage sources. Various other parameters (repetition rate, pulse width / duty cycle, and amplitude, among others) can be modified. The physician may have thousands of options for therapy delivery.

[0008] The existing standard of care for DBS includes a significant amount of trial and error to determine, in a fitting process for a given patient, parameters that provide the clinical benefits and side effects of neuromodulation when delivered to the brain. Other neuromodulation implants, such as spinal cord, occipital nerve, sacral nerve, and peripheral nerve modulation systems likewise rely on trial and error to determine benefit and side effects of stimulation delivered at different positions, amplitude and / or other parameters. New and alternative methods and systems to predict the positions where side effects occur, thus streamlining the fitting process, are desired.BSC File No.: 24-0612W001

[0009] Atty. Docket No.: 2001.3828111 OVERVIEW

[0010] The present inventors have recognized, among other things, that a problem to be solved is the need for new and / or alternative methods and systems for streamlining the fitting process are desired.

[0011] In an example, a system for predicting side effects in deep brain stimulation may include a clinician programmer having a graphical user interface, a controller, and a first communication circuit, along with an implanted system comprising a pulse generator and a lead adapted for placement in a patient's brain, wherein the pulse generator has a second communication circuit configured to communicate with the first communication circuit. The clinician programmer may be configured to receive a first side effect data point corresponding to a first stimulation setting, present the first side effect data point on a map of electrode positions on the graphical user interface, the map having an amplitude level as a first axis and an electrode level as a second axis, define a first anchor point at a higher amplitude value than the first side effect data point as determined by a first predefined equation, define a second anchor point at a lower amplitude value than the first side effect data point as determined by a second predefined equation, generate a border on the map by connecting the first and second anchor points and the first side effect data point, the border representing threshold amplitude values and electrode levels expected to result in side effects and the region, define the region beyond the border, further along the first axis, as a side effect region, and at least one of recommend a test setting to confirm no side effect by use of the border, or recommend an upper limit to patient adjustments of therapy by use of the border.

[0012] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be further configured to transmit, via the first communication circuit to the second communication circuit, test stimulation parameters for use by the implantable pulse generator, receive stimulation response data indicating whether side effects occurred, and update the border based on the received stimulation response data.

[0013] Alternatively or additionally to any of the examples above, in another example, the lead may comprise a plurality of electrodes along a distal portion thereof, and the electrode levels may correspond to positions of the plurality of electrodes along the distal portion, and wherein the first communication circuit may be configured to issue an instruction toBSC File No.: 24-0612W001

[0014] Atty. Docket No.: 2001.3828111 the second communication circuit to generate a deep brain stimulation through the plurality of electrodes, and the pulse generator may be configured to issue electrical signals via selected ones of the plurality of electrodes in response to the instruction to generate deep brain stimulation.

[0015] Alternatively or additionally to any of the examples above, in another example, the electrode levels may indicate a lowest level at a distal tip of the lead, and a highest level spaced from the distal tip of the lead, and the border may be positioned to indicate, at a lower electrode level, a relatively lesser amplitude expected to cause a side effect as compared to a relatively higher amplitude at a higher electrode level.

[0016] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be further configured to receive an indication of a non-side effect point within the side effect region, generate a new estimated side effect point at a predetermined amplitude above the non-side effect point, and update the border by generating a new line connecting the new estimated side effect point with at least one of the first and second anchor points.

[0017] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to receive an indication of an additional side effect point at a lower electrode level than the first side effect data point, update the side effect region by extending the border to connect to the additional side effect point at the lower electrode level, and maintain the original border for electrode levels above the first side effect data point.

[0018] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to receive anatomical information including a location of the lead in the patient and a location of one or more neural structures near the lead.

[0019] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to receive at least one expected anatomical neural structure associated with side effects and historical side effect data point, and update the border based on the expected anatomical neural structures and historical side effect data points.BSC File No.: 24-0612W001

[0020] Atty. Docket No.: 2001.3828111 Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to identify the expected anatomical neural structure associated with side effects, and issue a testing instruction to the pulse generator for a second data point within the side effect region predicted to be near the expected anatomical neural structure.

[0021] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to determine whether the electrode level is within a defined target region based on the anatomical information, and one of: regenerate the border with decreased amplitude thresholds when the electrode level is within the defined target region, and regenerate the border to create a larger side effect region when the electrode level is outside the defined target region.

[0022] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be further configured to at least one of confirm the border based on receiving an indication of the side effect at the second data point, or regenerate the border based on a lack of indication of side effect.

[0023] Alternatively or additionally to any of the examples above, in another example, the first and second anchor points may be established using predefined equations that account for variation of threshold levels in relation to the electrode level.

[0024] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be configured to extrapolate the border into extended regions by calculating a stimulation field model that defines areas of tissue activation around stimulation points, determining where the model would overlap with the side effect region, and generating an additional boundary extending outward along the first axis based on a calculated degree of stimulation field model overlap.

[0025] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be further configured to display the border in a heat map with varying colors representing at least one of different intensities of predicted side effects or varying confidence levels in the predictions based on proximity to verified side effect points.

[0026] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may be further configured to receive a plurality of side effect dataBSC File No.: 24-0612W001

[0027] Atty. Docket No.: 2001.3828111 points from multiple stimulation settings, generate an average border based on the plurality of side effect data points and their corresponding first and second anchor points, present the average border on the map of electrode positions on the graphical user interface, and transmit, via the first communication circuit to the second communication circuit, updated stimulation parameters based on the average border.

[0028] In another example, a method of using a deep brain stimulation system may include an implantable pulse generator, a lead coupled to the implantable pulse generator, and a clinician programmer including a graphical user interface and a communication circuit for communicating with the implantable pulse generator. At the clinician programmer, the method may include providing a suggested initial testing parameter set including an electrode level and an amplitude level, receiving one or more first testing instructions, and communicating first stimulation commands to the implantable pulse generator. At the implantable pulse generator, the method may include delivering deep brain stimulation therapy in response to the first stimulation commands. At the clinician programmer, the method may include receiving an indication that at least one of the testing instructions resulted in a side effect, presenting, on the graphical user interface, a map of the side effect on a graph having an amplitude level as a first axis and an electrode level as a second axis, displaying on the map each of a first tested point illustrating the electrode level and the amplitude level of the testing instruction that resulted in the side effect, and a line indicating amplitude and electrode levels which are expected to result in side effects, based on the first tested point, wherein the line has a slope indicating amplitude is determined as a function of electrode level, and at least one of recommending a test setting to confirm no side effect by use of the line, or recommending an upper limit to patient adjustments of therapy by use of the line.

[0029] Alternatively or additionally to any of the examples above, in another example, the lead may have a plurality of electrodes along a distal portion thereof, and the electrode levels of the map may correspond to positions of the plurality of electrodes along the distal portion.

[0030] Alternatively or additionally to any of the examples above, in another example, the method may include receiving an indication of a non-side effect point within a region beyond the line, the non-side effect point corresponding to a tested amplitude of stimulusBSC File No.: 24-0612W001

[0031] Atty. Docket No.: 2001.3828111 delivery at a tested electrode level which has been tested without a side effect being observed, generating a new estimated side effect point at a predetermined amplitude above the non-side effect point at the tested electrode level, and updating the line to connect to the new estimated side effect point.

[0032] Alternatively or additionally to any of the examples above, in another example, the method may include receiving an indication of an additional side effect point at a lower electrode level than the first tested point, updating the line by extending it to connect to the additional side effect point at the lower electrode level, and maintaining the original line position for electrode levels above the first tested point.

[0033] Alternatively or additionally to any of the examples above, in another example, the method may include determining whether the electrode level is within a defined target region based on anatomical data, modifying the line with decreased amplitude thresholds when the electrode level is within the defined target region, and modifying the line to create a larger region beyond the line when the electrode level is outside the defined target region.

[0034] Alternatively or additionally to any of the examples above, in another example, the method may include identifying an expected anatomical neural structure associated with side effects, receiving a testing instruction for a second data point within a region beyond the line predicted to be near the expected anatomical neural structure, and at least one of: confirming the line based on receiving an indication of the side effect at the second point, or modifying the line based on a lack of side effect at the second point.

[0035] In another example, a method implemented by a controller of a clinician programmer at a fitting procedure for a deep brain stimulation therapy may include providing a suggested initial testing parameter set including an electrode level and an amplitude, generating at least one testing instruction from the suggested initial testing parameter set, the testing instruction being delivered to an implantable pulse generator configured to deliver the deep brain stimulation therapy using at least one testing instruction, receiving an indication that at least one of the testing instructions resulted in a side effect, generating a map on a graph with axes illustrating at least one testing instruction, including an electrode level along a y-axis and an amplitude level along an x-axis, the map further comprising: a data point corresponding to the testing instruction that resulted in the side effect, at least one anchor point above the data point along the electrodeBSC File No.: 24-0612W001

[0036] Atty. Docket No.: 2001.3828111 level axis, and at least one anchor point below the data point along the electrode level axis, generating, on the map, a line connecting the anchor point above the data point, the anchor point below the data point, and the data point, the line indicating a threshold of amplitude and electrode levels expected to result in side effects, having a slope indicating amplitude determined as a function of electrode level, defining the region beyond the line, further along the amplitude level axis, as a side effect region.

[0037] Alternatively or additionally to any of the examples above, the method may include receiving an indication of a non-side effect point within the side effect region, generating a new estimated side effect point at a predetermined amplitude above the non-side effect point, and updating the side effect region by generating a new line connecting the new estimated side effect point with at least one of the anchor points.

[0038] Alternatively or additionally to any of the examples above, the method may include receiving an indication of an additional side effect point at a lower electrode level than the data point, updating the side effect region by extending the line to connect to the additional side effect point at the lower electrode level, and maintaining the original side effect region for electrode levels above the data point.

[0039] Alternatively or additionally to any of the examples above, the method may include determining whether a particular electrode level is within a defined target region based on anatomical data, regenerating the line with a decreased amplitude threshold when the particular electrode level is within the defined target region, and regenerating the line to create a larger side effect region when the particular electrode level is outside the defined target region.

[0040] Alternatively or additionally to any of the examples above, the method may include identifying an expected anatomical neural structure associated with side effects, and receiving a testing instruction for a second data point within the side effect region predicted to be near the expected anatomical neural structure, and at least one of confirming the line based on receiving an indication of the side effect at the second point, or regenerating the line based on a lack of side effect at the second point.

[0041] In another example, a system for predicting side effects in deep brain stimulation may include a lead implanted in a patient at a location near neural structures, the lead having a proximal end, a distal end, and a plurality of electrodes near the distal end, anBSC File No.: 24-0612W001

[0042] Atty. Docket No.: 2001.3828111 implantable pulse generator having operational circuitry therein for generating electrical outputs, and adapted to receive the proximal end of the lead such that the operational circuitry can issue the electrical outputs to the patient via the lead, and a clinician programmer in communication with the implantable pulse generator, having a controller, a graphical user interface, and machine-readable instructions executable by the controller for the programmer to perform the following: receive a first side effect data point corresponding to a first stimulation setting, present the first side effect data point on a map of electrode positions on the graphical user interface, the map having an amplitude level as a first axis and an electrode level as a second axis, define a first anchor point at a higher amplitude value than the first side effect data point as determined by a first predefined equation, define a second anchor point at a lower amplitude value than the first side effect data point as determined by a second predefined equation, generate a border on the map by connecting the first and second anchor points and the first side effect data point, the border representing threshold amplitude values and electrode levels expected to result in side effects and the region, define the region beyond the border, further along the first axis, as a side effect region, and at least one of recommending a test setting to confirm no side effect by use of the border, or recommending an upper limit to patient adjustments of therapy by use of the border.

[0043] Alternatively or additionally to any of the examples above, the electrode levels may correspond to positions of the plurality of electrodes along the distal portion of the lead.

[0044] Alternatively or additionally to any of the examples above, the electrode levels may indicate a lowest level at a distal tip of the lead, and a highest level spaced from the distal tip of the lead, and the slope may indicate, at a lower electrode level, a relatively lesser amplitude expected to cause a side effect as compared to a relatively higher amplitude at a higher electrode level.

[0045] Alternatively or additionally to any of the examples above, the programmer may be configured to receive anatomical information including a location of the lead in the patient, and a location of one or more neural structures near the lead and historical side effect data points, further wherein the controller may be configured by the machine-readable instructions to generate the border to include historical side effect points and use the one or more neural structures to estimate at least one side effect point.BSC File No.: 24-0612W001

[0046] Atty. Docket No.: 2001.3828111 Alternatively or additionally to any of the examples above, the controller may be further configured to extrapolate the border into extended regions by calculating a stimulation field model that defines areas of tissue activation around stimulation points, determining where the model would overlap with the side effect region, and generate an additional boundary extending outward along the first axis based on a calculated degree of stimulation field model overlap.

[0047] Alternatively or additionally to any of the examples above, the clinician programmer may further comprise machine-readable instructions to receive an indication of a non-side effect point within the side effect region, generate a new estimated side effect point at a predetermined amplitude above the non-side effect point, and update the border by generating a new line connecting the new estimated side effect point with at least one of the first and second anchor points.

[0048] Alternatively or additionally to any of the examples above, the clinician programmer may further comprise machine-readable instructions to receive an indication of an additional side effect point at a lower electrode level than the first side effect data point, update the side effect region by extending the border to connect to the additional side effect point at the lower electrode level, and maintain the original border for electrode levels above the first side effect data point.

[0049] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may further comprise machine-readable instructions to determine whether the electrode level is within a defined target region based on anatomical data, regenerate the border with decreased amplitude thresholds when the electrode level is within the defined target region, and regenerate the border to create a larger side effect region when the electrode level is outside the defined target region.

[0050] Alternatively or additionally to any of the examples above, in another example, the clinician programmer may further comprise machine-readable instructions to identify an expected anatomical neural structure associated with side effects, receive a testing instruction for a second data point within the side effect region predicted to be near the expected anatomical neural structure, and at least one of confirm the line based on receiving an indication of the side effect at the second point, or regenerate the border based on a lack of side effect at the second point.BSC File No.: 24-0612W001

[0051] Atty. Docket No.: 2001.3828111 This overview is intended to provide an introduction to the subject matter of the present patent application. It is not intended to provide an exclusive or exhaustive explanation. The detailed description is included to provide further information about the present patent application.

[0052] BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In the drawings, which are not necessarily drawn to scale, like numerals may describe similar components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0054] Figure 1 show an illustrative DBS system in a patient;

[0055] Figure 2 shows a directional lead in relation to neural structures associated with clinical benefits and side effects;

[0056] Figure 3 illustrates an exemplary clinical effects map;

[0057] Figure 4A-4D show illustrative processes of populating a clinical effects map; Figure 5A illustrates a stimulation field model;

[0058] Figure 5B shows an illustrative process of pre-populating a clinical effects map; Figure 6 illustrates modification of a clinical effects map;

[0059] Figures 7A-7D illustrates processes of extrapolating data in a clinical effects map; Figure 8 illustrates use of a pre-populated clinical effects map;

[0060] Figures 9A-9B show an illustrative method in block flow form.

[0061] DETAILED DESCRIPTION FIG. 1 shows an illustrative DBS system implanted in a patient. The system comprises an implantable pulse generator (IPG) 10, shown implanted in the pectoral region of a patient 16. The IPG 10 is coupled to a lead 12 which extends subcutaneously to the head of the patient 16, through a burr hole formed in the patient’s skull, and then into the brain. In the example shown, the lead 12 includes a plurality of electrodes positioned near the distal end 14 of the lead.BSC File No.: 24-0612W001

[0062] Atty. Docket No.: 2001.3828111 The lead 12 may be placed at any suitable location of the brain where a target for therapy is identified. For example, a lead 12 may be positioned so that the distal end 14 is near the mid-brain and / or various structures therein that are known in the art for use in providing neuromodulation to treat various diseases. A lead used in DBS may include a combination of segmented and ring electrodes, if desired, such as disclosed in US Pat. Nos.

[0063] 8,483,237 and 8,321,025, the disclosures of which are incorporated herein by reference.

[0064] The IPG 10 may include separate circuits, sometimes referred to as operational circuitry, including a microcontroller (which may also be implemented as part of a microprocessor if desired), which controls operations of the IPG at a high level. The IPG can include a power source, typically a battery (rechargeable or primary cell, as desired), though some systems may be adapted to operate without a battery by receiving power inductively or through other link (such as radiofrequency) and issuing therapy using the received power without long-term storage. The microcontroller may include memory for storing operational instructions in a non-transitory media, such as a Flash memory, RAM, ROM, etc. The IPG includes stimulation circuitry. At a high level, the stimulation circuitry may include a plurality of current sources and current sinks (for a current-controlled system; a plurality of voltage sources may be used in voltage-controlled systems instead), and control circuitry including for example one or more analog ASICs, as well as switch arrays that implement steering instructions and / or electrode selections. US Patent 10,716,932 provides illustrative details for both current and planned future implementations of the stimulation circuitry and is incorporated herein by reference.

[0065] The IPG 10 may include a conductive outer housing that can serve as a return electrode or indifferent electrode during therapy delivery, as desired. A header provides feedthrough circuitry allowing the IPG 10 to couple to a lead 12, with separate electrical connections to each of the electrodes. The IPG header and housing provide a hermetic sealed environment for the operational circuitry. In some examples, a plurality of programs can be set for therapy delivery by the IPG 10. Each program may operate according to a schedule and individual program parameters.

[0066] DBS may be targeted, for example, and without limitation, at neuronal tissue in the thalamus, the globus pallidus, the subthalamic nucleus, the pedunculopontine nucleus, substantia nigra pars reticulate, the cortex, the globus pallidus extemus, the medialBSC File No.: 24-0612W001

[0067] Atty. Docket No.: 2001.3828111 forebrain bundle, the periaquaductal gray, the periventricular gray, the habenula, the subgenual cingulate, the ventral intermediate nucleus, the anterior nucleus, other nuclei of the thalamus, the zona incerta, the ventral capsule, the ventral striatum, the nucleus accumbens, and / or white matter tracts connecting these and other structures. Data related to DBS may include the identification of neural tissue regions determined analytically to relate to side effects or benefits observed in practice. “Targets” as used herein are brain structures associated with therapeutic benefits, in contrast to avoidance regions or “Avoid” regions which are brain structures associated with side effects.

[0068] Conditions to be treated may include dementia, Alzheimer’s disease, Parkinson’s disease, dyskinesia, epilepsy, seizure, tremor, depression, anxiety or other mood disorder, sleep related conditions, etc. Therapeutic benefits may include, for example, and without limitation, improved cognition, alertness, and / or memory, enhanced mood or sleep, elimination, avoidance or reduction of pain, seizure or tremor, reduction in motor impairments, and / or preservation of existing function and / or cellular structures, such as preventing loss of tissue and / or delaying cell death. Therapeutic benefits may be monitored using, for example, patient surveys, imaging studies, performance tests, and / or physical monitoring such as monitoring gait, tremor, etc. Side effects can include a wide range of issues such as, for example, and without limitation, reduced cognition, neuroinflammation, alertness, and / or memory, degraded sleep, depression, agitation or anxiety, unexplained weight gain or loss, tinnitus, pain, seizure, tremor, etc. These are just examples, and the discussion of ailments, benefits and side effects is merely illustrative and not exhaustive.

[0069] The illustrative system described below includes various external devices. A clinician programmer (CP) 20 may be used to determine / select therapy programs. The CP 20 can be used by a physician to manipulate the outputs of the IPG 10 and / or an external test stimulator (ETS) 36. For example, the CP 20 can be used by the physician to define a therapy regimen or program for application to the patient. Multiple programs may be facilitated and stored by the IPG 10 or ETS 36; in some examples, a patient remote control (RC) 32 may store the programs to be used.

[0070] The CP 20 may be, for example and without limitation, a computer such as a laptop or tablet computer. The CP 20 therefore includes a microcontroller and / or microprocessor, shown as processor 22 and associated memory 24. The memory 24 may take any suitableBSC File No.: 24-0612W001

[0071] Atty. Docket No.: 2001.3828111 form (RAM, ROM, Flash, etc.), and stores machine readable instructions allowing the processor 22 to perform the methods disclosed herein. To the extent Bluetooth is used as a communications protocol, the RF circuitry may be included in the device as a communications circuitry 28, located internal to the CP 20. If some other communications technology (inductive or Medradio) is used, or if range is limited by the IPG for example, the communications circuit 28 may be provided via a wand having specialized circuitry (for Bluetooth, Medradio, or inductive telemetry) therein that couples, for example, to a USB port on the CP. The CP will include a user interface 26, such as a screen or touch screen, keyboard, mouse, trackball, etc. allowing the user to provide instructions and make choices. The RC may take the form of a dedicated device, a locked off-the shelf device (such as a smartphone) or may be a multi-use device such as a smartphone running an app.

[0072] The CP 20 may be used to determine stimulation parameters. Stimulation parameters may include amplitude of stimulation pulses, frequency or repetition rate of stimulation pulses, pulse width of stimulation pulses, and more complex parameters such as burst definition, as are known in the art. Biphasic square waves are commonly used, though nothing in the present invention is limited to biphasic square waves, and ramped, triangular, sinusoidal, monophasic and other stimulation types may be used as desired. The CP 20 can be used by a physician, or at the direction of a physician, to obtain data from and provide instructions to the IPG 10 via suitable communications protocols such as Bluetooth or MedRadio or other wireless communications standards, non-standard or proprietary RF, optical and / or via other modalities such as inductive telemetry.

[0073] The RC 32 can be used by the patient to perform various actions relative to the IPG 10. These may be physician defined options, and may include, for example, turning therapy on and / or off, entering requested information (such as answering questions about activities, therapy benefits and side effects), and making (limited) adjustments to therapy such as selecting from available therapy programs and adjusting, for example, amplitude and / or spatial / directional settings. The RC 32 can communicate via similar telemetry as the CP 20 to control and / or obtain data from the IPG 10. The patient RC 32 may also be programmable on its own or may communicate or be linked with the CP 20. The RC 32 may be a dedicated device, including a custom device, a locked off-the-shelf device withBSC File No.: 24-0612W001

[0074] Atty. Docket No.: 2001.3828111 specialized software to prevent other uses, or may be a multi-purpose device such as the patient’s smartphone or cell phone.

[0075] A charger 34 may be provided to the patient to allow the patient to recharge the IPG 10, if the IPG 10 is rechargeable. A primary cell IPG 10, which is not rechargeable may be used, and so the charger 34 may be omitted. The charger 34 can operate, for example, by generating a varying magnetic field to activate an inductor associated with the IPG 10 to provide power to recharge the IPG battery, using known methods and circuitry.

[0076] Some systems may include the ETS 36. The ETS 36 can be used to assess therapy programs after the lead 12 has been implanted in the patient to determine whether therapy will or can work for the patient 16. For example, an initial implantation of the lead 12 can take place using, for example, a stereotactic guidance system, with the IPG 10 temporarily left out. After a period of healing, the patient may return to the clinic for therapy configuration and testing. The lead 12 may have a proximal end (the end opposite where therapy electrodes are located in the brain) thereof connected to an intermediate connector (sometimes called an operating room (OR) cable) that couples to the ETS 36, and the ETS 36 can be programmed using the CP 20 with various therapy programs and stimulation parameters. Once therapy suitability for the patient is established to the satisfaction of the patient 16 and / or physician, the permanent IPG 10 is implanted and the lead 12 is connected thereto, with the ETS 36 and the OR cable then removed from use. Additional components, such as a remote monitoring system or bedside monitor (not shown) may also be included.

[0077] The figures and explanations herein focus primarily on use of the present invention for DBS purposes. That said, a clinical effects map and the related processes that are disclosed may also be used in other neural therapy systems, including any of Vagus nerve stimulation (VNS), spinal cord stimulation (SCS), occipital nerve therapy, sacral nerve therapy, etc.

[0078] Figure 2 shows a directional lead in relation to neural structures associated with clinical benefits and side effects. The lead has a distal tip 50 and carries a ring electrode 52, a tip electrode 53, and a number of segmented electrodes 54a, 54b, 54c (collectively, segmented electrodes 54). Each electrode 52, 53, 54 can be separately addressed using multichannel outputs, which can be voltage controlled or current controlled. Some systems may use multiple independent current control, as is known in the art.BSC File No.: 24-0612W001

[0079] Atty. Docket No.: 2001.3828111 As an example of a directional or spatially selective therapy, the use of only the electrodes level with electrode 54a may generate an electrical field that may be visualized as shown at 56, where the outer border of 56 represents an equipotential or equal-field line relative to a voltage or current controlled output using a distant or remote electrode, such as the housing of the pulse generator (not shown).

[0080] Neural structures are identified in relation to the lead 50. For example, avoid structures are illustrated at 60, 62, representing neural tissue that, if stimulated, may cause a side effect to the patient. Structures associated with clinical benefits, such as that shown at 70, may also be present in the vicinity of the lead 50. With the understanding that a DBS lead can positioned relative to neural structures associated with clinical benefits as well as neural structures associated with side effects, and further noting DBS therapy may be tailored to a particular patient, the programming of such a lead is important to therapy outcomes. It should also be noted that when programming for DBS, it is also desirable both for power consumption purposes (linked to battery longevity) and to avoid triggering new, unknown side effects, to limit the volume of tissue that is subject to electrical fields.

[0081] Using the visual representation of Figure 2 to explain the aims and complexities, it is desirable to deliver therapy to region 70, without causing stimulus in regions 60 and 62, while also minimizing the total volume of tissue that is subject to stimulation. However, when the lead is positioned in the brain, there is limited capability for understanding the exact borders of any of structures 60, 62, and 70 based solely on patient specific imaging, brain atlas data, and / or patient population data. Further, it may not be known how much stimulation of any such structures will cause therapeutic benefits and / or side effects, and the amplitude, intensity, frequency, pulse width, and / or pulse shape / type that will cause either benefits or side effects may vary from one patient to another.

[0082] A clinical effects map is utilized to provide an understanding of how stimulation at various lead electrodes with different strengths treats the patient. It illustrates the interaction of stimulation at different levels of the lead (vertical axis) at various stimulation intensities (i.e., amplitudes) and further shows benefit and side effects induced in the patient. To address the above noted limitations on precise knowledge of brain structures, as well as variation across patients, some degree of patient testing and trial and error isBSC File No.: 24-0612W001

[0083] Atty. Docket No.: 2001.3828111 typically needed. The clinical effects map has been developed as one tool for the patient testing process.

[0084] A populated clinical effects map is shown in Figure 3. The map shown would have been developed after testing the patient in a test session typically lasting at least twenty minutes and sometimes for up to ninety minutes or more depending, among other factors, on the patient’s condition and abilities. The clinical effects map 90 shows electrode position on the y-axis and amplitude on the x-axis. Each horizontal line 92 may indicate an electrode level at which electrodes reside on the lead. The lowest electrode level indicates the lowest level of electrodes at a distal tip of the lead; as the electrode level increases, so does the distance from the distal tip of the lead. However, a 1:1 correspondence is not needed for the horizontal lines to actual electrodes, and the line 92 may indicate halfway points between electrode edges, centers, etc., as desired. The map view may be rotated using icons 96, in keeping with the use of a cylindrical and directional lead as indicated in Figure 2. This map 90, as well as the other clinical effects maps shown below, may be displayed in the user interface 26, as determined by the processor 22 using instructions from memory 24, in the CP 20 (Figure 1).

[0085] A line is generated and displayed to visually represent a border 94 on the clinical effects map 90 at which side effects may be expected to occur. The border 94 of the predicted side effects region is, in the example shown, a closed border on a graph having amplitude and electrode position as axes. The border 94, is not directly an indication of a spatial location, but instead estimates an amplitude at which therapeutic pulses may be expected to cause a side effect at the corresponding electrode level. The individual points along the border 94 represent the minimum values for a selected electrode position and amplitude which may result to a side effect. In other words, the side effects border in the mapping as shown has a minimum amplitude above which side effects may be expected to occur. The region further along the x-axis (of higher amplitude at a given electrode position) from border 94 is a region to which side effects are predicted to occur. Values of lesser amplitude from border 94 at a given electrode position (to the left of border 94) define a region in which side effects are not predicted to occur. Having borders of this type available in the clinical effects map may be useful to streamline the testing process by allowing testing to be focused to some extent on the location of the border 94.BSC File No.: 24-0612W001

[0086] Atty. Docket No.: 2001.3828111 In some embodiments, not illustrated, a populated map may also show regions of no clinical benefit (generally corresponding to therapy strength / amplitude being too low) and regions where a clinical benefit (typically with varying degree of benefit based on stimulation strength / amplitude) has observed. Such additional borders may be useful to the physician as there is a minimum amplitude below which no therapy benefit (possibly no neural activation) occurs. In some, additional borders could be shown to indicate clinical benefits at specific positions and amplitudes.

[0087] While Figure 3 shows the results in a black and white drawings, a heat map may be used with one color representing the side effect region, and a second color varying in intensity / brightness across the rest of the clinical effects map, with varying intensity or brightness indicating predictions of higher likelihood and lower likelihood of therapeutic benefits. Additionally, rather than discrete lines as shown, gradients may be used in a color scheme for representing increasing likelihood of finding a location and amplitude of greater or lesser side effects.

[0088] Figure 4A illustrates an initial step of populating, a clinical effects map. A number of test therapies have been performed in this example, including for example, those highlighted in grey and black at 102, 104, 106, 110. Testing is performed by issuing (biphasic or, optionally, monophasic) stimulation using electrodes at a selected electrode level, with varying stimulation strength. The stimulation is sourced from an IPG or ETS (Figure 1), for example, coupled to the lead. For the testing process, the ETS offers an advantage of allowing physician or operator of the DBS system to deliver stimulation without surgical implantation of an IPG, creating the opportunity for a physician to determine whether DBS is a viable therapy for the patient without the bodily trauma of surgical implantation of an IPG.

[0089] Starting from a relatively low amplitude, a test is performed as indicated at 102. Subsequent iterations of testing at 104 and 106 are represented on the map with the dots as shown. In this example, the series of tests 102, 104, and 106 are conducted at the same electrode level or position with each iteration slowly increasing stimulus amplitude. The amplitude changes (steps) between tests 102, 104 and 106 are determined by the physician or operator, typically with an increase of 0.3 to 0.5 milliamps in between tests (for current controlled stimulation), though any step size may be used whether using current controlledBSC File No.: 24-0612W001

[0090] Atty. Docket No.: 2001.3828111 or voltage controlled stimulation. At each step, the selected stimulation may be held for approximately ten to thirty seconds followed by a break before the next test.

[0091] The operator of the clinician programmer enters data as steps are completed to indicate whether or not a particular output at a particular electrode level caused a side effect. Some examples may include automated inputs or other ways to indicate side effect occurrence, including communication from the implanted system (which may sense for action potentials or other electrical signals indicative of side effects, or may include an accelerometer or other sensing structure to detect a side effect, such as tremor motions), or communication to an external system such as a wearable device that detects movement or electrical signals, or any other measurable parameter (galvanic skin response, sweat, temperature, movement, twitch, EEG, ECG, respiration, muscle tone, etc.).

[0092] As amplitude increases, stimulation may be administered for a longer period and longer breaks between intervals are given to avoid adverse effects of stimulation. At higher amplitudes, the stimulation period increases to help capture or monitor for side effects that are more likely to occur at those higher amplitudes, allowing for a more accurate assessment of neuronal response and ensuring that any delayed or gradual side effects are properly identified. Longer breaks allow the brain and surrounding tissues to recover from the increased neuronal activation caused by higher amplitudes, helping to prevent overstimulation, tissue damage, and adverse side effects while giving the body time to adapt to the stronger stimulation.

[0093] Testing at increasing amplitudes iteratively continues until a side effect, represented by black dot 110 is observed. Observation of side effects are typically performed by the physician querying the patient for feedback for the purposes of identifying side effects. During each stimulation step at 102, 104, 106, 110, the patient is asked to report any sensations of discomfort, atypical sensory experience, or otherwise irregular or abnormal sensations. In Figure 4A, the gray dots of tests 102, 104, and 106 indicate that the patient has reported no side effects and / or the physician or operator has not observed any side effects.

[0094] Typical manifestations of side effects may include, but are not limited to, general discomfort, onset of agitation or anxiety, contraction or twitching of the eye muscles, double vision, blurry vision, paresthesia (a tingling or “pins and needles” sensation),BSC File No.: 24-0612W001

[0095] Atty. Docket No.: 2001.3828111 numbness, muscle spasms, dizziness, vertigo, altered speech, and vertigo. At times, a physician or operator may associate certain side effects with particular electrode positions or amplitude, or the DBS system may have some limited anatomy information, however side effects are often not specific to any one electrode position or target. In some embodiments, testing may continue past the first observation of a side effect 110 and continue testing and observing for side effect points until they reach a maximum stimulation amplitude at 115. In other examples, the testing can stop once a first side effect 110 is observed. The testing may be performed at different rotational positions (Figure 3) about the same electrode level, if desired, by reallocating voltage or current outputs to different combinations of electrodes.

[0096] Prior approaches to the creation of a clinical effects map would repeat the procedure just described in relation to Figure 4A for several electrode levels, repeatedly starting from a lower amplitude and increasing to a higher amplitude. This is time consuming. Randomly selecting relatively high amplitudes and testing at different electrode levels may, on the other hand, subject the patient to more side effect discomfort than is desired. It should be recalled that the fitting and testing procedure in which the clinical effects map is created is first performed when the patient has recently received the implant, meaning that the experiences of the patient during such testing may represent the patient’s first real experience of the system. Subjecting the patient to unpredicted side effects can increase patient anxiety and displeasure with the implanted system. Because patient mental health is a significant concern with active implantable medical devices, it is undesirable to have the patient experience apparently random side effects. A system that provides predictions of whether side effects will occur with selected stimulation settings, without extensive testing, is desired.

[0097] Figure 4B illustrates the creation of the border between the predicted non-side effect region and the predicted side effect region. Once a side effect 110 is identified (using the method of Figure 4A, for example), the processor of the clinician programmer executes computer readable code (a software program) to predict other points where a side effect may be observed based on side effect point 110. A first anchor point 112, of a higher electrode position than side effect point 110, and a second anchor point 112, of a lower electrode position than side effect point 110, are set in accordance with the softwareBSC File No.: 24-0612W001

[0098] Atty. Docket No.: 2001.3828111 program executed by the processor of the clinician programmer. The anchor points are considered predictive data points, with anchor point 112 representing the highest electrode position and anchor point 114 representing the lowest electrode position in this predictive illustration. The range of electrode positions between the side effect point 110 and either anchor point 112 or 114 defines the limit of the prediction 120. The distance from side effect point to either of points 112, 114 can be a system setting, and may be understood in terms of electrode level or actual distance in millimeters, for example.

[0099] Next, lines 130 and 134 are displayed. The position of the first anchor point 112 and second anchor point 114 can be calculated using a predetermined slope as well as the position of side effect point 110. A formula of this type may be used:

[0100] A(y)—f(y-yse, se)—Ase + B(y-yse)

[0101] Where position y is the position of the relevant anchor point on the vertical axis, yseis the electrode position for the side effect point, Aseis the amplitude of stimulation that led to the side effect noted at point 110, and B is a constant that defines the slope. If y is lower than ySe, then the amplitude A(y) will be less than Ase. If y is higher than yse, then the amplitude A(y) will be greater than Ase, at least in this example. The direction of the slope, tending toward lower amplitude predictions as the position on the lead becomes more distal (lower in the graph) is expected to be useful in most DBS applications, though this may be reversed in some DBS and / or other applications (for example, with SCS, a lower electrode position may suggest higher amplitude to yield a side effect).

[0102] Once the positions for the anchor points 112, 114 are determined, the lines 130 and 134 are positioned by connecting the dots, 112 to 110 and 110 to 114, with straight lines. Curves may be used instead if, for example, B is not a constant but is instead a more complex formula (such as a quadratic or other formula). The CP user interface then displays line 130 and line 134 as a continuous border. The region of lower amplitudes than the border (to the left of line 130 and 134) represents the predicted region of no side effects, and the region of higher amplitudes (the values of and to the right of line 130 and line 134) represents the predicted region of side effects.

[0103] Figure 4C illustrates the display of clinical effects map 100 after an additional test resulting in a side effect. In this example, a second side effect point 118 is observed at a lower electrode position and amplitude than the first side effect point 110. Once collected,BSC File No.: 24-0612W001

[0104] Atty. Docket No.: 2001.3828111 a third anchor point 114a, representing the lower value limit of prediction, is generated and connected to the second side effect point 118 to create line 134. The limit of prediction 120 remains unchanged. However, Figure 4C shows the limit of prediction 120 reaching its minimum value at a lower electrode position than in Figure 4B, because the second side effect point 118 was observed at a lower electrode position than the first (and only) side effect point 110 of Figure 4B. Line 132 is also demarcated between the first side effect point 110 and the second side effect point 118. Lines 130, 132, and 134 are then joined with 134 to create a continuous border of the predicted side effect region.

[0105] Additional testing may continue in the same manner. For example, additional tests may be conducted, for example, after rotating the view to account for the directional nature of the lead which may have segmented electrodes (see Figure 2) allowing targeting at various rotational angles relative to that shown in Figure 4B or Figure 4C.

[0106] The dashed and solid style of lines 130, 132, 134 may not appear as such on the clinician programmer’s user interface. For purposes of illustration, lines 130 and 134 are dashed to denote their predictive nature, and line 132 is solid to signify its empirical nature as a connection between two definitive side effect points.

[0107] Optionally, a similar method may be used to generate a region of no clinical effects, as shown in Figure 4D. Here, the location of the no clinical effects line may be estimated using a similar formula as above, based on establishing first one or more points (shown as filled with dots in Figure 4D) where no clinical effect is observed. In some examples, the development of the no clinical effects line may be performed over time as the patient uses the DBS or other neurostimulation system, since clinical effects may take longer to be demonstrated for some patients and / or conditions. For example, when treating dyskinesia or tremors, such as with Parkinson’s disease, clinical effects (cessation of tremor) may be observed very quickly, and so the no clinical effect line can be generated rather quickly. However, for other diseases, the period needed to observe clinical benefits may be longer and / or a wash-in period may be needed. Thus, the no effect line may be generated at patient follow-ups if, for example, the patient does not experience a clinical benefit at certain settings. Particularly when observation of clinical benefits takes hours or days, it may be useful to position observed (tested) points and then use a formula or other prediction based on those observed points to extrapolate and / or populate the rest of the no effect line.BSC File No.: 24-0612W001

[0108] Atty. Docket No.: 2001.3828111 Further supplementary data to the clinical effects map may be provided by stimulation field modeling (SFM). SFM of a directional lead is illustrated in Figure 5A. An SFM region is shown, encompassing the Active electrodes and a Target Structure. The SFM does not encompass nearby Avoid structures, as these represent regions of neural tissue which, if stimulated, are expected to cause side effects.

[0109] In SFM, the tissue is modeled, for example, using finite element models in which the lead body is treated as an insulator, surrounded by a thin encapsulation sheath, and surrounded by neural tissue. The neural tissue may be modeled as isotropic and homogenous, though more sophisticated modelling can also be used if desired. A set of model volumes are defined around the lead, breaking up the space into small blocks, each of which can be analyzed within the model. The outer boundaries of the SFM (i.e., the SFM radius) may be determined by using therapy parameters, such as stimulation amplitude, pulse width, and frequency. The surrounding anatomical structures, which contribute to accurate modeling, can be estimated on patient-specific imaging information and / or population-based data. In the context of DBS, stimulation field modeling helps predict the distribution of electrical activity from the implanted electrode. As illustrated in Figure 5A, an SFM can be generated as a three-dimensional surface surrounding a portion of the lead and encompassing a volume of neural tissue and a given stimulation current.

[0110] The positioning of the SFM relative to target and / or non-target (side-effect) neural structures may be determined for a given system using imaging modalities such as X-ray, CT scan, PET scan, MRI, f-MRI, etc., to identify lead position in the patient. Imaging system data for the patient may also be used to estimate the locations of neural structures in the patient including relative to the identified lead position. The imaging data may be merged or overlapped with general anatomical knowledge, such as from a brain atlas, which can help identify the particular structures that can be identified from imaging data. The use of SFM in association with a directional lead can allow therapy planning to precisely stimulate targeted tissue structures while avoiding excess stimulation of nontarget tissue and limiting stimulation of structures associated with adverse side effects. By accounting for both the geometry of the brain and the electrode placement, the SFM contributes to optimization of therapeutic outcomes and minimization of side effects.BSC File No.: 24-0612W001

[0111] Atty. Docket No.: 2001.3828111 In some embodiments, the SFM radius can be used to identify side effect points and to extrapolate above or below the anchor points, as shown in Figure 5B.

[0112] Figure 5B shows a display with an extended border to assist in creating a more comprehensive clinical effects map 100. In this example, the length of the lead extends beyond the limit of predictions of the previously generated clinical effects map.

[0113] For areas of the lead extending beyond the initial anchor points and limit of prediction, the clinician programmer processor uses an alternative logic. In some embodiments, the SFM radius is used to predict how stimulation at different points would overlap with the established side effect regions of the SFM. When extending predictions beyond the initial anchor points, the SFM radius may be used to identify areas where stimulation fields may partially overlap with known side effect points. This assumes that if stimulation at a certain amplitude activates tissue overlapping with a known side effect point, the amplitude would likely trigger a side effect, even if the stimulation originates from a different position on the electrode.

[0114] In this example, the upper anchor point 112 is presumed to be a true side effect point in the process of generating a line 140, which joins with line 130 and line 134 to create an extended border of the predicted side effect region. More specifically, anchor point 112 serves as a reference point of a known position and amplitude where side effects are expected to occur when extending predictions beyond the anchor point 112. The processor determines where activation areas of the presumed side effect point, anchor point 112, overlap with the activation areas determined by the SFM to create line 140 extending outward based on the calculated degree of overlap.

[0115] The anchor point 112 has the lowest values of line 140, having the lowest electrode position and lowest amplitude of line 140. As line 140 extends both in electrode position and amplitude of the anchor point 112, confidence in this extrapolation gradually decreases as it extends further away from the presumed side effect point, anchor point 112.

[0116] As was the initial generation of the side effect region between anchor point 112 and anchor point 114, the new predicted side effect region extending beyond border 140 in electrode position and amplitude, is considered to have lower confidence than the side effect region starting from the border from anchor point 112 and anchor point 114. Thus, the limit of prediction 120 in Figure 5B remains unchanged.BSC File No.: 24-0612W001

[0117] Atty. Docket No.: 2001.3828111 Historical data of side effect occurrences may be used in conjunction or alternatively to the SFM radius to generate line 140 or adjust border positioning more generally. In some examples, the lead is positioned within a defined target accompanied by data of historical side effect occurrences specific to that target. The addition of definitive and / or presumed side effect points raises confidence in the predicted side effect region. As a result, the limit of prediction 120 may expand. Longer leads may not have as much historical data to populate the clinical effects map 100, thus the integration of SFM radius data may play a higher role in establishing line 140 in some examples.

[0118] Border adjustment can be either a manual process or automated by the system using testing data. A formula approach as shown above, or, alternatively, a smoothing function, may be used to refine the border positions. In some embodiments, the clinician programmer may, upon determination that an electrode level or position falls within a defined avoid region, adjust the border to the left, lowering the amplitude threshold values of the border. Subsequently, the predicted side effect region is enlarged.

[0119] Additional testing, initiated by the physician, operator, or suggested by the clinician programmer, may also affect the position of the predicted side effect region's border. For example, in verifying the accuracy of the border calculation, a physician may test an amplitude in the predicted region of no side effects. If a side effect does not occur, the border remains unchanged. If a side effect occurs, the processor of the clinician programmer recalculates the border for display on the clinical effects map 100.

[0120] Figure 6 illustrates the effect on the border of the predicted side effect region if a non-side effect point is identified in the previously predicted side effect region. In some examples, a test 160 is performed in the previously predicted side effect region. In Figure 6, test 160 is selected at a higher amplitude than side effect point 110, upper anchor point 112, and lower anchor point 114 to confirm the predicted side effect region. In this example, no side effect was observed at test 160. Upon receiving the indication of a nonside effect point within the predicted side effect region, the processor then generates a new anchor point 162, representing the estimation of a side effect point at the same electrode position and placed to the right of the test point 160.BSC File No.: 24-0612W001

[0121] Atty. Docket No.: 2001.3828111 For example, the amplitude anchor point 162 may be offset or spaced from test 160 by a pre-determined value, for example, a fixed amount or an additional 5% in the amplitude of test 160.

[0122] Once a non-side effect point 160 has been identified and anchor point 162 is created, the lower anchor point 114 is also similarly adjusted in amplitude, shown as dot 114b. Subsequently, the pre-test (dashed-dotted) line 134 between side effect point 110 and lower anchor point 114 is removed, as it is no longer necessary, and new line 134a and line 134b are generated, with line 134a connecting side effect point 110 and anchor point 162 and line 134b connecting anchor point 162 and anchor point 114b. As before, lines 130, 134a, and 134b are then joined to form the border of the predicted side effect region.

[0123] Upon adjustment of the border, the physician or operator may then choose to test the newly created anchor point 162 for further verification. If a no side effect is found at anchor point 162, anchor point 162 may also be conservatively adjusted in amplitude, for example an additional 5% in amplitude from anchor point 162.

[0124] In some embodiments, anatomical neural structures associated with side effects (herein referred to as side effect structure) may be helpful in generating the border of the predicted side effect region of clinical effects map 200, as shown in Figure 7A. A relevant side effect structure 210 is first identified and prepopulated into the clinical effects map 100. The borders of side effect structure 210 within the map 200 are displayed in accordance with the range of amplitudes and electrode positions known to cause side effects for the specific target. To capture the threshold of the predicted side effect region, side effect point 212 and side effect point 214 are placed at the estimated upper and lower electrode positions (y-axis) of the side effect structure 210. An amplitude is estimated along the x-axis using, for example, estimated electrical field and neural activation thresholds of the relevant neural tissue type in the side-effect structure. Above and below the estimated position of the side effect structure 210, line 230 extends up toward an estimated anchor point 216 and line 234 extends down from the lower anchor point 214 to an anchor point at 218. The location of points 216 and 218 along the y-axis can be set using predetermined spacing or maximum distances that can be preset, such as by electrode levels (up one electrode spacing along the length of the lead, for example) or using a set distance (1.0 toBSC File No.: 24-0612W001

[0125] Atty. Docket No.: 2001.3828111 5.0 mm for example). The location of points 216 and 218 along the x-axis can be set using field propagation principles, similar to those used for developing an SFM.

[0126] Anatomical data used to inform the clinical effects map can be communicated to the clinician programmer from a server resource. For example, DBS system implant is often informed by the use of a “brain atlas,” comprised of population-based data that helps identify where brain structures are expected to be located in the brain, which is further cross referenced with one or more imaging studies of the brain (X-Ray, PET scan, CT, MRI, etc.) of the particular patient to estimate positions and borders of the structures in the brain, further referenced with post-implant imaging to determine where the lead is in relation to such structures. Position of the lead in relation to any of the above identified target structures in the brain for DBS therapy can be communicated to the clinician programmer to aid in the development of the clinical effects map.

[0127] Testing is then performed as shown in Figure 7B, as, for example, the physician, to confirm the side effect structure 210 position as well as amplitude that will stimulate it, performs a test at 220. If a side effect is observed at location 220, the system can treat this as confirming the position for the estimated anchor points at 212, 214. Because the side effect was predicted to occur, the patient can be warned in advance, reducing mental stress on the patient for whom the system can be understood as operating predictably.

[0128] Through additional testing, further spatial and electrical stimulation information of side effect structure 210 is developed, as shown in Figure 7C. In this example, stimulation 222 at a lower electrode position than the initially predicted side effect structure 210 leads to a side effect. The processor in turn adjusts the former anchor point 218 from Figure 7B to a new anchor point 218a. The representative area of the side effect structure is redrawn to include the additional area for the side effect structure 210. It should be noted that while Figure 7C shows an extension to the lower portion of the side effect structure 210, an extension to the upper portion of the side effect structure 210 could be achieved by delivering stimulation at an electrode position between the upper anchor point 212 and the upper anchor point 216.

[0129] Additional adjustments may be made to the clinical effects map 200 based on testing a point where no side effect occurs, as illustrated in Figure 7D. In this example, stimulation 224 is delivered within the predicted side effect region at an electrode positionBSC File No.: 24-0612W001

[0130] Atty. Docket No.: 2001.3828111 above point 212, and to the right thereof (higher amplitude). If delivery of stimulation 224 results in no side effect, the point 216 from Figures 7A-7C is moved, now represented as 216a, creating a smaller predicted side effect region and defining the upper extent of the side effect structure 210.

[0131] Figure 8 illustrates the validation of the predicted side effect region in clinical effects map 250. Additional stimulation within the predicted side effect region may be applied to increase confidence in the accuracy of previous assumptions and the validity of the side effect region and the limit of prediction 258. In this example, a strategic test point 260 is chosen, either by the physician / operator or the clinician programmer, within the predicted side effect region and within the limit of prediction 258. If stimulation at test point 260 induces about side effects, the clinician programmer gains greater confidence in the validity of the predicted side effect region.

[0132] Figures 9A-9B show an illustrative method in block flow form. This example may be executed by, for example, one or more of a clinician programmer operating on its own, or a clinician programmer operating in conjunction with a central server and computer system.

[0133] Starting in Figure 9A, as indicated in block 900, a DBS lead (or complete system) (see Figure 1) is implanted into the patient in a chosen brain region associated with the patient’s treatment needs and symptoms. The position of the lead is determined by which structures to avoid or benefit as indicated in post-operative imaging (or intraoperative imaging) where the lead is in relation to patient-specific landmarks. Patient imaging, such as a structural MRI, may be aligned with the lead location information, where the structural MRI may be useful to indicate where the structures of interest are likely found (structures associated with clinical benefits or structures associated with side effects). Approximately a month after implantation (or other period of time as determined by the clinical expertise and judgment of the physician or operator), a clinical effects map 915 is defined by testing various stimulation parameters to define regions of therapeutic benefit. Figure 9B covers the steps for block 915. This process of defining the clinical effects map may involve multiple sessions to optimize the settings prior to treatment. A patient therapy program is set at 975, and the patient uses the system as indicated at 985. The patient may giveBSC File No.: 24-0612W001

[0134] Atty. Docket No.: 2001.3828111 feedback at 995 to the physician, which includes observations of side effects. Programmed therapy can then be adjusted at 975.

[0135] Turning to Figure 9B, the clinical effect map is generated. Block 905 indicates that the clinician programmer suggests conducting a test at an initial low amplitude, increasing the amplitude in fixed intervals until a side effect is observed, as indicated at 910.

[0136] Upon reaching the first observation of a side effect, the clinical effects map may be pre-populated, as indicated at block 920. Once the first side effect point is reached, the clinician effect map may be prepopulated with the border of the predicted side effect region represented as a slope along the y-axis, based on the relationship between electrode position and amplitude. In some embodiments, the clinical effects map may also be prepopulated with additional information. For example, population-based data, informed by known features of interaction between stimulation and various brains structures and derived from healthy persons and patients having similar conditions to the patient being treated, patients who have previously received an implanted system having a lead, and the like, may be useful sources of data. In addition, the patient in whom a DBS system is implanted will typically undergo pre-operative imaging, such as with MRI (structural and / or functional), and one or more scans may take place as the lead is introduced in the patient’s brain as well as post-operative imaging which may also be taken. These various sources can be used to estimate the position of structures in the patient’s brain associated with clinical benefits and side effects, in relation to the lead. Additional borders or other visual markers may be utilized to represent this data on the display.

[0137] Testing the validity and refinement of the clinical effects map is then performed using the populated clinical effects map, as indicated at 930-960, as discussed in detail in the description of Figure 5B, Figure 6, Figure 7A-D, and Figure 8. To further refine the clinical effects map, the clinician programmer may suggest 925 or the physician may use their clinical judgment to select 930 an amplitude value to test at a selected electrode level at 940.

[0138] To the extent that the map formed at 920 turns out to be inaccurate relative to the patient’s actual response, pre-populated data can be adjusted 960. For example, see Figure 6, which shows adjustment of the clinical effects map if a side effect does not occur during the testing at a location on the map that does indicate side effect. In some examples, theBSC File No.: 24-0612W001

[0139] Atty. Docket No.: 2001.3828111 therapy map can be adjusted even if the therapy delivered in 940 causes a predicted effect (no effect, side effect, or therapy benefit) by modifying the border on the amp from being a likelihood to being a tested result, if desired.

[0140] Adjustments at 960 can be performed in various ways. First, the clinician programmer receives an indication of whether a side effect was or was not generated by a particular stimulus at an amplitude and electrode level. This may occur by user input via the user interface of the clinician programmer, using, for example, a keyboard, mouse, touchscreen, voice input, etc. A wearable device, whether consumer type (fitness watch, step counter, etc.), medical type (devices specifically designed for DBS patients to track gait, tremor, muscle contraction, etc.), or clinical (EEG or other signal capture system adapted for use in clinic, for example) may monitor patient response to therapy, and data from such systems can be communicated in wired or wireless fashion to the clinician programmer, or, alternatively, such data may be communicated to the cloud or a local server and then downloaded to the clinician programmer, if desired. In still other examples, an implant or wearable may monitor patient response, such as with an accelerometer in the implanted device, and communicates directly to the clinician programmer such as by use of Medradio, Bluetooth, other wireless RF communication, optical, inductive telemetry, or other communication mode. Each of these methods or steps can be understood as a way of the clinician programmer receiving an indication of whether a side effect occurred in response to a particular test.

[0141] Second, the side effect data can then be matched to the stimulation signals that were generated. This information is used to then update and adjust the map at 960 as illustrated in the preceding examples.

[0142] The process of adjustment 930-960 may be repeated at later stages of treatment. As treatment continues, the patient’s response to stimulation may change. For example, the changes may be due to disease progression, symptom improvement, the development of stimulation tolerance, or other changes in symptoms, new data, and new patient feedback.

[0143] At the physician’s option, or at a prompt from the system (such as after a selected number of tests, a quantity of tests at each electrode level, or passage of time), the testing stops as indicated at 962. The final clinical effects map after any adjustments at 960 may be stored as part of the patient’s medical records, such as in a central server, or on a CP, anBSC File No.: 24-0612W001

[0144] Atty. Docket No.: 2001.3828111 RC, or even in the memory of the patient’s IPG, as desired. In addition, the clinical effects map from 960 may be communicated to the database to provide further tailoring of the data stored therein. For example, gradients or boundaries of likelihood that are generated in the standard space may be based on clinical maps at 960. Such updates to the stored set of clinical effects map at 960 may, for example, be averaged to generate an “average” clinical effects map across a population of patients. Updates may also be issued to, for example, a database of lead placements and / or neuroanatomy data, as desired.

[0145] In an example, the clinical effect maps may be grouped into clusters based on anatomical, disease state, age, gender, or other similarities shared among a group of patients to facilitate selection of the “most relevant data”. For example, one or several characteristics of patients (head size, lead position, disease type, age, etc.) may be communicated in the process to determine which clinical effects maps or other data sets are a best fit to the patient.

[0146] Each of these non-limiting examples can stand on its own or can be combined in various permutations or combinations with one or more of the other examples. The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments that may be referred to herein as “examples.” Such examples can include elements in addition to those shown or described. However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0147] In the event of inconsistent usages between this document and any documents so incorporated by reference, the usage in this document controls. In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” Moreover, in the claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.BSC File No.: 24-0612W001

[0148] Atty. Docket No.: 2001.3828111 Method examples described herein can be machine or computer-implemented at least in part. Some examples can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods can include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code can include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code can be tangibly stored on one or more volatile, non-transitory, or nonvolatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic or optical disks, magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.

[0149] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to comply with 37 C.F.R. § 1.72(b), to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

[0150] Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, innovative subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the protection should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

BSC File No.: 24-0612W001Atty. Docket No.: 2001.3828111 What is claimed is:

1. A system for predicting side effects in deep brain stimulation, comprising:a clinician programmer having:a graphical user interface,a controller,a first communication circuit;an implanted system comprising a pulse generator and a lead, the lead adapted for placement in a patient’s brain, wherein the pulse generator has a second communication circuit configured to communicate with the first communication circuit;wherein the clinician programmer is configured to:receive a first side effect data point corresponding to a first stimulation setting;present the first side effect data point on a map of electrode positions on the graphical user interface, the map having an amplitude level as a first axis and an electrode level as a second axis;define a first anchor point at a higher amplitude value than the first side effect data point as determined by a first predefined equation;define a second anchor point at a lower amplitude value than the first side effect data point as determined by a second predefined equation;generate a border on the map by connecting the first and second anchor points and the first side effect data point, the border representing threshold amplitude values and electrode levels expected to result in side effects and the region;define the region beyond the border, further along the first axis, as a side effect region; and at least one of:a) recommend a test setting to confirm no side effect by use of the border; orb) recommend an upper limit to patient adjustments of therapy by use of the border.BSC File No.: 24-0612W001Atty. Docket No.: 2001.3828111 2. The system of claim 1, wherein the clinician programmer is further configured to:transmit, via the first communication circuit to the second communication circuit, test stimulation parameters for use by the implantable pulse generator;receive stimulation response data indicating whether side effects occurred; and update the border based on the received stimulation response data.

3. The system of claim 1 or 2, wherein the lead comprises a plurality of electrodes along a distal portion thereof, and the electrode levels correspond to positions of the plurality of electrodes along the distal portion, and wherein the first communication circuit is configured to issue an instruction to the second communication circuit to generate a deep brain stimulation through the plurality of electrodes, and the pulse generator is configured to issue electrical signals via selected ones of the plurality of electrodes in response to the instruction to generate deep brain stimulation.

4. The system of any one of claims 1-3, wherein the electrode levels indicate a lowest level at a distal tip of the lead, and a highest level spaced from the distal tip of the lead, and the border is positioned to indicate, at a lower electrode level, a relatively lesser amplitude expected to cause a side effect as compared to a relatively higher amplitude at a higher electrode level.

5. The system of any one of claims 1-4, wherein the clinician programmer is further configured to:receive an indication of a non-side effect point within the side effect region; generate a new estimated side effect point at a predetermined amplitude above the non-side effect point; andupdate the border by generating a new line connecting the new estimated side effect point with at least one of the first and second anchor points.

6. The system of any one of claims 1-5, wherein the clinician programmer is configured to:BSC File No.: 24-0612W001Atty. Docket No.: 2001.3828111 receive an indication of an additional side effect point at a lower electrode level than the first side effect data point;update the side effect region by extending the border to connect to the additional side effect point at the lower electrode level; andmaintain the original border for electrode levels above the first side effect data point.

7. The system of any one of claims 1-6, wherein the clinician programmer is configured to receive anatomical information including a location of the lead in the patient and a location of one or more neural structures near the lead.

8. The system of claim 7, wherein the clinician programmer is configured to:receive at least one expected anatomical neural structure associated with side effects and historical side effect data point; andupdate the border based on the expected anatomical neural structures and historical side effect data points.

9. The system of any one of claims 1-8, wherein the clinician programmer is configured to:identify the expected anatomical neural structure associated with side effects; and issue a testing instruction to the pulse generator for a second data point within the side effect region predicted to be near the expected anatomical neural structure.

10. The system of claim 9, wherein the clinician programmer is configured to:determine whether the electrode level is within a defined target region based on the anatomical information; and one of:regenerate the border with decreased amplitude thresholds when the electrode level is within the defined target region; andregenerate the border to create a larger side effect region when the electrode level is outside the defined target region.BSC File No.: 24-0612W001Atty. Docket No.: 2001.3828111 11. The system of any one of claims 9-10, wherein the clinician programmer is further configured to at least one of:confirm the border based on receiving an indication of the side effect at the second data point; orregenerate the border based on a lack of indication of side effect.

12. The system of any one of claims 1-11, wherein the first and second anchor points are established using predefined equations that account for variation of threshold levels in relation to the electrode level.

13. The system of any one of claims 1-12, wherein the clinician programmer is configured to extrapolate the border into extended regions by:calculating a stimulation field model that defines areas of tissue activation around stimulation points;determining where the model would overlap with the side effect region; and generating an additional boundary extending outward along the first axis based on a calculated degree of stimulation field model overlap.

14. The system of any one of claims 1-13, wherein the clinician programmer is further configured to display the border in a heat map with varying colors representing at least one of different intensities of predicted side effects or varying confidence levels in the predictions based on proximity to verified side effect points.

15. The system of any one of claims 1-14, wherein the clinician programmer is further configured to:receive a plurality of side effect data points from multiple stimulation settings; generate an average border based on the plurality of side effect data points and their corresponding first and second anchor points;present the average border on the map of electrode positions on the graphical user interface; andBSC File No.: 24-0612W001Atty. Docket No.: 2001.3828111 transmit, via the first communication circuit to the second communication circuit, updated stimulation parameters based on the average border.

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