ELECTRIC FIELD THERAPY

VIA IMPLANTABLE ELECTRODES

[0001] This application is a PCT application claiming priority to U.S. Provisional Patent Application No. 63/316,229, filed March 3, 2022, the entire contents of which is incorporated herein by reference.

TECHNICAL FIELD

[0002] This disclosure generally relates to electrical stimulation therapy using alternating electric fields.

BACKGROUND

[0003] Alternating electric field (AEF) therapy, is a type of electric field therapy which uses low-intensity electrical fields to treat brain tumors; glioblastoma in particular. Conventional cancer treatments include chemotherapy and radiation, which are associated with treatment- related toxicity' and high rates of tumor recurrence. AEF uses an alternating electric field to disrupt cell division in cancer cells, thereby inhibiting cellular replication and initiating apoptosis (cell death). AEF therapy is typically delivered via electrodes located external to the patient.

SUMMARY

[0004] In general, the disclosure describes devices, systems, and techniques related to planning, delivering, and adjusting electric and magnetic stimulation therapy, which includes electrical field therapy. Electric field therapy may include modulated electrical field therapy which may include types of electrical field modulation, such as alternating current stimulation which includes alternating electrical field (AEF) therapy and is discussed herein as one example of therapy. Other types of electric and magnetic stimulation therapy are described herein in various examples and combinations. For example, an implantable medical device (IMD) may be coupled to one or more leads carrying an array of electrodes. The IMD may alternate delivery of electrical fields from respective different electrode combinations utilizing some or all of the implanted electrodes. The IMD may generate these electrical fields using a constant frequency, a different frequency for the alternating electrical fields, or a frequency for the alternating electrical fields that changes over time. The IMD may also cycle the AEF therapy on and off according to a predetermined schedule or in response to one or more trigger events. The AEF therapy may be used for various reasons, such as reducing or preventing the growth of tumor cells, such as glioblastomas, or the reduction in growlh or proliferation or directional migration of non-tumorous cells within the body. Examples of cells may be within the following tissues: skin, muscle, pulmonary, laryngeal, nasopharyngeal, liver, gastric, splenic, renal, intestinal, pancreatic, or prostate. These manipulations of normal cells could be conducted to address pathological processes or to enhance efficiency of normal cellular functions, such as secretory, migratory, or differentiational activities. AEF therapy has been demonstrated to impact the microstructural elements within cells (e.g., microtubules and/or actin filaments) such that a system can precisely deliver AEF therapy to a subpopulation of cells in a targeted manner to direct or restrict cell migratory activities. In some examples, AEF therapy may be delivered to a patient to modulate fibroblasts and their role in scar tissue formation or modulate the proliferation of lymphocytes or leukocytes for patients with an auto-immune condition.

[0005] In some examples, the IMD or a different computing device may model the anatomy of the patient that will receive the AEF therapy. For example, the computing device may receive imaging data from one or more imaging modalities (e.g., magnetic resonance imaging (MRI), computed tomography (CT), etc.) and identify locations of various tissues and/or structures, such as a resection bed from which a tumor was removed. The computing device may generate a patient specific model of anatomy, such as brain tissue, based on the imaging data. The computing device may also predict electrical field strengths for AEF therapy using the model and recommend stimulation parameters (e.g., electrode combinations, amplitudes, frequencies, electrode implant locations, etc.) that define the AEF therapy based on the predictions. In some examples, the computing device may update the predictions based on sensed data obtained after delivery of the AEF therapy.

[0006] In one example, a system includes processing circuitry' configured to receive a request to deliver alternating electric field (AEF) therapy, determine therapy parameter values that define the AEF therapy, wherein the AEF therapy' comprises delivery of a first electric field and a second electric field, control an implantable medical device to deliver the first electric field from a first electrode combination of implanted electrodes, and control the implantable medical device to deliver, alternating with the first electric field, the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination. [0007] The details of one or more examples of the techniques of this disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques wall be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

[0008] FIG. 1 is a conceptual diagram illustrating an example system that includes an implantable medical device (IMD) configured to deliver alternating electric field (AEF) therapy to a patient according to an example of the techniques of the disclosure.

[0009] FIG. 2 is a block diagram of the example IMD of FIG. 1 for delivering AEF therapy according to an example of the techniques of the disclosure.

[0010] FIG. 3 is a block diagram of the external programmer of FIG. 1 for controlling delivery of AEF therapy according to an example of the techniques of the disclosure.

[0011] FIG 4 is a block diagram illustrating an example system that includes an external device, such as a server, and one or more computing devices that are coupled to an implantable medical device and external programmer shown in FIG. 1 via a network.

[0012] FIGS. 5A and 5B are conceptual diagrams of example leads with respective electrodes carried by the lead.

[0013] FIGS. 5C, 5D, 5E, and 5F are conceptual diagrams of example electrodes disposed around a perimeter of a lead at a particular longitudinal location.

[0014] FIG. 6 is a flowchart illustrating an example technique for delivering AEF therapy to a patient.

[0015] FIG. 7 is a flowchart illustrating an example technique for generating a model of anatomy for a patient for AEF therapy planning.

[0016] FIG. 8 is a flowchart illustrating an example technique for predicting electrical field strength for AEF therapy.

[0017] FIG. 9 is a flowchart illustrating an example technique for determining stimulation parameters for AEF therapy based on user input identifying target tissue.

[0018] FIG. 10 is a conceptual diagram of an example three-dimensional user interface for programming AEF therapy. [0019] FIG. 11 is a flowchart illustrating an example technique for determining stimulation parameters for AEF therapy based on histological data from tumor tissue.

[0020] FIG. 12 is a flowchart illustrating an example technique for identifying target tissue for AEF therapy based on water content determined from imaging data.

[0021] FIG. 13 is a flowchart illustrating an example technique for identifying target tissue based on impedance tomography data.

[0022] FIG. 14 is a flowchart illustrating an example technique for generating a map of AEF dosimetry for a patient.

[0023] FIG. 15A is a flowchart illustrating an example technique for sweeping through different frequencies for AEF therapy.

[0024] FIGS. 15B and 15C include graphs of example relationships between certain cell characteristics.

[0025] FIG. 16 is a conceptual diagram of an example three-dimensional user interface for planning implantation of electrodes for AEF therapy.

[0026] FIG. 17 is a flowchart illustrating an example technique for adjusting stimulation parameters for AEF therapy based on sensed electrical signals.

[0027] FIG. 18A is a flowchart illustrating an example technique for switching polarity of electrodes for AEF therapy.

[0028] FIG. 18B is a conceptual drawing illustrating an example progression of polarity switching for AEF therapy.

[0029] FIG. 19A is a flowchart illustrating an example technique for switching polarity between electrode pairs of a cube configuration for AEF therapy.

[0030] FIG. 19B is a conceptual drawing illustrating an example progression of paired electrode selection using cube configurations for AEF therapy.

[0031] FIG. 20 is a flowchart illustrating an example technique for displaying user selectable electrode configurations for AEF therapy.

[0032] FIG. 21 is a conceptual diagram illustrating an example implantable medical device for delivering AEF therapy.

[0033] FIG. 22 is a conceptual diagram illustrating example implantable medical devices disposed within burr holes for delivering AEF therapy. [0034] FIG. 23 is a conceptual diagram of an example three-dimensional user interface for planning implantation of electrode arrays for AEF therapy.

[0035] FIG. 24 is a conceptual diagram illustrating example subcutaneous electrodes for use in delivering AEF therapy.

[0036] FIG. 25 is a conceptual diagram illustrating example cutaneous electrodes and an external medical device for use in combination with an IMD for delivering AEF therapy.

[0037] FIG. 26 is a flowchart illustrating an example technique for scheduling electrical field sensing based on patient activity.

[0038] FIG. 27 is a conceptual diagram illustrating example implantable coils for delivering alternating magnetic field (AMF) therapy.

[0039] FIG. 28 is a flowchart illustrating an example technique for delivering AMF therapy using multiple implantable coils.

[0040] FIG. 29 is a flowchart illustrating an example technique for cycling AEF therapy based on sensed temperatures of patient tissue.

[0041] FIG. 30 is a flowchart illustrating an example technique for synchronizing AEF therapy to cell cycle phases.

[0042] FIG. 31 is a flowchart illustrating an example technique for cycling through different frequencies for AEF therapy.

[0043] FIG. 32 is a flowchart illustrating an example technique for delivering AEF therapy that includes different frequencies from different electrode combinations.

[0044] FIG. 33 is a flowchart illustrating an example technique for adjusting the frequency of AEF therapy in response to detecting a trigger event.

[0045] FIG. 34 is a flowchart illustrating an example technique for adjusting the frequency of AEF therapy in response to tissue changes indicated by image data.

[0046] FIG. 35 is a flowchart illustrating an example technique for delivering AEF therapy to activate an exogenous agent injected into the patient.

[0047] FIG. 36 is a flowchart illustrating an example technique for delivering a voltage bolus configured to irreversible electroporation of cells in a target tissue.

[0048] FIG. 37 is a flowchart illustrating an example technique for adjusting a parameter of AEF therapy based on migration state of one or more cell types. [0049] FIG. 38 is a flowchart illustrating an example technique for determining a change in geometry of response to electrical stimulus that indicates a change in target tissue.

[0050] FIG. 39 is a conceptual diagram illustrating an example lead to deliver electrical energy and a drug to a target tissue.

[0051] FIG. 40 is a conceptual diagram illustrating an example lead with ports configured to deliver a drug to a target tissue.

[0052] FIG. 41 is a flowchart illustrating an example technique for delivering AEF therapy and a drug from a lead.

[0053] FIG. 42 is a flowchart illustrating an example technique for delivering an electrical stimulus configured to increase drug uptake by a target tissue.

[0054] FIG. 43 is a flowchart illustrating an example technique for creating liquid metal electrodes on target tissue for AEF therapy.

[0055] FIG. 44 is a flowchart illustrating an example technique for delivering AEF therapy and direct current stimulation.

[0056] FIG. 45 is a flowchart illustrating an example technique for delivering AEF therapy and a single electrical stimulus to elicit T cell response.

[0057] FIG. 46 is a flowchart illustrating an example technique for delivering AEF therapy and nanopulse electrical stimuli.

[0058] FIG. 47 is a flowchart illustrating an example technique for delivering AEF therapy and stimulation via a capacitive electrode.

[0059] FIG. 48 is a flowchart illustrating an example technique for updating parameter values that define AEF therapy using machine learning.

[0060] FIG. 49 is a flowchart illustrating an example technique for updating parameter values that define AEF therapy using machine learning.

[0061] FIGS. 50-61 are conceptual screenshots of an example user interface that facilitates interaction with a system configured to deliver of AEF therapy to a patient.

[0062] FIG. 62-69 are conceptual screenshots of an example user interface configured to plan and set up AEF therapy. DETAILED DESCRIPTION

[ 0063] This disclosure describes various devices, systems, and techniques for planning and/or delivering modulated electrical field therapy (which may include the example of AEF therapy) to a patient via implanted electrodes. Alternating electric field application is a cancer treatment type with the potential to reduce treatment related toxicity. In alternating electric field application, an alternating electric field is applied to a cancerous region of the brain, which may disrupt cellular division for rapidly-dividing cancer cells. To administer alternating electric field treatment to a patient, an external system can be applied near the anatomy of interest, such as around the cranium of the patient, in order to deliver the alternating electric field to the patient. However, there are various challenges to external delivery of AEF therapy. For example, external AEF therapy requires that hair be removed from the scalp of the patient. As another example, electrical fields delivered from the external electrodes for extended periods of time required for AEF therapy may cause increased tissue heating and potential burns on the skin of the patient. In addition, external electrodes may prevent localized treatment of tumors within the brain.

[0064] As described herein, a system may deliver electric field therapy (also referred to as AEF therapy in some examples) from implanted electrodes at a location and strength specific for the patient. Electric field therapy may generally refer to therapy in which electrical fields are modulated to provide some therapeutic response. For example, alternating electric field therapy- described herein includes a system that modulates electric fields by alternating between different electrode combinations, different field directions, and/or other parameters that define the electric field therapy). This internal AEF therapy may act to inhibit cellular division and/or initiate apoptosis of cancer cells at the targeted treatment location. The implanted electrodes may be selected to target tissue identified as including cancerous cells or tissue around a resection area where a previous tumor was removed. In this manner, the system may operate to deliver AEF therapy to reduce cancerous cells in the patient and/or prevent reoccurrence of cancer after resection. A computing device may be used for planning implantation of electrodes and/or selection of stimulation parameters based on imaging data obtained for the patient used to generate a model of patient tissue. In some examples, the computing device and/or IMD may adjust one or more stimulation parameters that define the AEF therapy. The system may adjust the one or more stimulation parameters based on various feedback variables, such as impedance tomography, histological analysis, patient activity, sensed temperature, and the like. In this manner, the IMD may operate in a closed-loop manner based on one or more feedback variables obtained from the patient. The AEF therapy described herein may facilitate patient-specific AEF therapy directed to specific target tissue. Using implanted electrodes may enable the system to operate over larger periods of time without impacting most patient daily activities. These and other advantages may be realized by the systems and examples described herein.

[0065] Although this disclosure is directed to delivery of AEF therapy to the brain for the purpose of treating glioblastoma, the systems, devices, and techniques described herein may similarly operate to deliver AEF therapy or similar electric-field therapies to other tissue areas and/or to treat different types of cancer. For example, a system may be implanted to treat and/or prevent cancer in the spine, pelvis, abdomen, or any other location. Some examples of target tissue may include regions of expected metastatic elements, such as lymph nodes, to reduce the spread of cells from a different tumor cite. Moreover, a human patient is described for example purposes herein, but similar systems, devices, and techniques may be used for other animals in other examples.

[0066] Electric field therapy described herein may include several different types of therapy in which different electric fields are delivered to a patient. These therapies may include modified electric field therapy, modulated electric field therapy, alternating electric field (AEF) therapy, or other therapies in which different electric fields are delivered to a patient. In some examples, these different electric fields change over time in a symmetric, non-symmetric, continuous, and/or non-continuous manner. While reference is primarily made to AEF in the examples described herein, other types of electric field therapy can be applied in the various example devices, systems, and techniques described herein.

[0067] FIG. 1 is a conceptual diagram illustrating an example system 100 that includes an implantable medical device (IMD) 106 configured to deliver therapy to patient 112 according to an example of the techniques of the disclosure. This therapy may be AEF therapy or another therapy based on applied electrical fields. As shown in the example of FIG. 1, example system 100 includes medical device programmer 104, implantable medical device (IMD) 106, lead extension 110, and leads 114A and 114B with respective sets of electrodes 116, 118. In the example shown in FIG. 1, electrodes 116, 118 of leads 114A, 114B are positioned to deliver electrical stimulation to a tissue site within brain 120, such as a deep brain site under the dura mater of brain 120 of patient 112. In some examples, delivery of electric fields (e.g., electrical stimulation) to one or more regions of brain 120, such as a region that contains a tumor such as glioblastoma, or region from which a glioblastoma was resected (removed). This location where the tumor was removed, e.g., the tumor bed, may be or be part of the target tissue for AEF therapy. The tumor bed may be of various sizes, but may be between approximately 1 mm to 3 mm m diameter in some examples. Some or all of electrodes 116, 118 also may be positioned to sense neurological brain signals within brain 120 of patient 112. In some examples, some of electrodes 116, 118 may be configured to sense neurological brain signals, impedance, etc., and some or all of electrodes 116, 118 may be configured to deliver electrical stimulation to brain 120 in the form of AEF therapy. In other examples, all of electrodes 116, 118 are configured to both sense electrical signals and deliver electrical stimulation to brain 120.

[0068] IMD 106 includes a therapy module (e.g., which may include processing circuitry', signal generation circuitry or other electrical circuitry configured to perform the functions attributed to IMD 106) that includes a stimulation generator configured to generate and deliver electrical stimulation therapy (e.g., AEF therapy) to patient 112 via a subset of electrodes 116, 118 of leads 114A and 114B, respectively. The subset of electrodes 116, 118 that are used to deliver electrical stimulation to patient 112, and, in some cases, the polarity of the subset of electrodes 116, 118, may be referred to as a stimulation electrode combination. As described in further detail below, the stimulation electrode combination can be selected for a particular patient 112 and target tissue site (e.g., selected based on the patient condition or based on the determined location of a tumor or other tissue of interest). The group of electrodes 116, 118 includes at least one electrode and can include a plurality of electrodes.

[0069] In some examples, the plurality of electrodes 116 and/or 118 may have a complex electrode geometry such that two or more electrodes of the lead are located at different positions around the perimeter of the respective lead (e.g., different positions around a longitudinal axis of the lead). In this manner, electrodes at different perimeter locations may be used to generate different electrical fields. For example, anodes on a first side of a first lead and cathodes on a second side of a second lead, wherein the first sides and second side face opposing directions, may be used to generate a first electric field. The second electric field may be generated with cathodes on the second side of the first lead and anodes on the first side of the second lead. In this manner, alternating between the first and second electric fields may generate electrical current that changes the polarities of cellular components to disrupt cell division. Although two leads 14 are shown in the example of FIG. 1, a single lead, three leads, four leads, five leads, or more leads may be implanted in different examples. In any case, the combination of leads may provide an overall array of electrodes that can be programmed to deliver alternating electrical fields to a target tissue. These complex electrode geometries can also enable directional sensing that can measure the orientation of electric fields generated in tissue. For example, the sy stem may measure electrical potentials between electrodes at different locations on a lead or between different leads to determine a gradient of electrical potentials and a gradient of the delivered electrical field. The system can then determine electric field spread and configure the electric fields and/or calibrate a predictive model of field spread based on the sensed gradient of electrical potentials.

[0070] In some examples, the neurological signals (e.g., an example type of electrical signals) sensed within brain 120 may reflect changes in electrical current produced by the sum of electrical potential differences across brain tissue. Examples of neurological brain signals include, but are not limited to, electrical signals generated from local field potentials (LFP) sensed within one or more regions of brain 120, electroencephalogram (EEG) signals, or electrocorticogram (ECoG) signals. Any of these sensed signals may be intrinsic signals generated by physiological neural activity and/or evoked signals generated in response to a delivered stimulus (e.g., a delivered electrical stimulation signal). It is noted that modulated electric field therapy (e.g., AEF therapy) may not evoke neuron propagation or affect other normal neurological function. However, the system may deliver signals intended to affect neurological processes in order to sense signals that may be indicative of physiological states or the response to modulated electric field therapy. In some examples, the system may utilize any electrode combinations to directly sense the electrical field (e.g., field strengths, field locations, or other characteristics) delivered by other electrode combinations. In this manner, the system may confirm expected electrical field strengths, adjust one or more stimulation parameters that define the electrical fields to effect target tissue (e.g., to match a desired stimulation model), and/or adjust the model of stimulation to reflect the reality of tissue characteristics. In some examples, the system may adjust the stimulation parameters defining the electrical fields to accommodate for tissue changes over time and/or lead movement within the patient after surgery or over time. The system may adjust any of these parameters in response to reviewing previously stored data and/or in real-time as sensed data is received or generated.

[0071] In some examples, the neurological brain signals that are used to select a stimulation electrode combination may be sensed within the same region of brain 120 as the target tissue site for the electrical stimulation and/or from a region different (e.g., adjacent to or outside of) than the target tissue site. The system may be configured to compute or predict the electrical field at the target tissue based on the signals sensed within the target tissue and/or at a region different than the target tissue. The specific target tissue sites and/or regions within brain 120 may be selected based on the patient condition or location, size, depth, and/or volume of a tumor or resection bed. Thus, due to these differences in target locations, in some examples, the electrodes used for delivering electrical stimulation may be different than the electrodes used for sensing neurological brain signals. In other examples, the same electrodes may be used to deliver electrical stimulation and sense brain signals. However, this configuration of using the same electrodes could require the system to switch between stimulation generation and sensing circuitry and may reduce the time the system can sense brain signals. In some examples, the system may be configured to deliver electrical signals to generate the electrical fields from the same electrode configurations (or using at least some of the same electrodes) in an at least partially interleaved basis.

[0072] Electrical stimulation generated by IMD 106 may be configured to manage a variety of disorders and conditions. In some examples, the stimulation generator of IMD 106 is configured to generate and deliver electrical stimulation pulses to patient 112 for AEF therapy via electrodes of a selected stimulation electrode combination. However, in other examples, the stimulation generator of IMD 106 may be configured to generate and deliver a continuous wave signal, e.g,, a sine wave or triangle wave of specified amplitude (peak to peak) and frequency as part of the electrical fields of the AEF therapy. Generally, modulated electric field therapy (e.g., AEF therapy) may include the delivery of the continuous wave signal(s), but the waveforms may be symmetric, asymmetric, non-continuous, continuous, cycled, interleaved between different combinations, constant, or otherwise changing over time at random or predetermined sequences. In either case, a stimulation generator within IMD 106 may generate the AEF therapy according to a therapy program that is selected at that given time in therapy. In examples in which IMD 106 delivers electrical stimulation in the form of stimulation pulses, a therapy program may include a set of therapy parameter values (e.g., stimulation parameters), such as a stimulation electrode combination for delivering different electrical fields to patient 112, pulse frequency, pulse width, and a current or voltage amplitude of the pulses or continuous signals. As previously indicated, the electrode combination may indicate the specific electrodes 116, 118 that are selected to deliver stimulation signals to tissue of patient 112 and the respective polarities of the selected electrodes. IMD 106 may deliver electrical stimulation intended to contribute to a therapeutic effect. In some examples, IMD 106 may also, or alternatively, deliver electrical stimulation intended to be sensed by other electrode and/or elicit a physiological response, such as an evoked compound action potential (ECAP), that can be sensed by electrodes.

[0073] IMD 106 may be implanted within a subcutaneous pocket above the clavicle, or, alternatively, on or within cranium 122 or at any other suitable site within patient 112 such as a lower abdominal or high buttock location. Other configurations might include IMD 106 implanted at multiple locations, such as near a site of tumor occurrence and remote sites of likely tumor transmission or spread. Generally, IMD 106 is constructed of a biocompatible material that resists corrosion and degradation from bodily fluids. IMD 106 may comprise a hermetic housing to substantially enclose components, such as a processor, therapy module, and memory. Other implant locations for IMD 106 may be utilized for treatment of the brain or other tissues. Example alternative implantation sites for IMD 106 may include the lower back, shoulder, neck, abdomen, or any other location.

[0074] As shown in FIG. 1, implanted lead extension 110 is coupled to IMD 106 via connector 108 (also referred to as a connector block or a header of IMD 106). In the example of FIG. 1 , lead extension 110 traverses from the implant site of IMD 106 and along the neck of patient 112 to cranium 122 of patient 112 to access brain 120. In the example shown in FIG. 1, leads 114A and 114B (collectively “leads 114”) are implanted within the right and left hemispheres, respectively, of patient 112 in order deliver AEF therapy to one or more regions of brain 120, which may be selected based on the patient condition or disorder controlled by therapy system 100. The specific target tissue site and the stimulation electrodes used to deliver stimulation to the target tissue site, however, may be selected, e.g., according to the locations of a tumor or resection bed and/or other sensed patient parameters. Other lead 114 and IMD 106 implant sites are contemplated. For example, IMD 106 may be implanted on or within cranium 122, in some examples. Or leads 114 may be implanted within the same hemisphere or IMD 106 may be coupled to a single lead implanted in a single hemisphere. Although leads 114 may have ring electrodes at different longitudinal positions as shown in FIG. 1, leads 114 may have electrodes disposed at different positions around the perimeter of the lead (e.g., different circumferential positions for a cylindrical shaped lead) as shown in the examples of FIGS. 5 A and 5B.

[0075] Leads 114 illustrate an example lead set that include axial leads carrying ring electrodes disposed at different axial positions (or longitudinal positions). In other examples, leads may be referred to as “paddle” leads carrying planar arrays of electrodes on one side of the lead structure or a “grid” of electrodes that enable the placement of electrical elements at a variety of locations around the tissue. In addition, as described herein, complex lead array geometries may be used in which electrodes are disposed at different respective longitudinal positions and different positions around the perimeter of the lead.

[0076] Although leads 114 are shown in FIG. 1 as being coupled to a common lead extension 110, in other examples, leads 114 may be coupled to IMD 106 via separate lead extensions or directly to connector 108. Leads 114 may be positioned to deliver electrical stimulation to one or more target tissue sites within brain 120. Leads 114 may be implanted to position electrodes 116, 118 at desired locations of brain 120 through respective holes, or a common hole, in cranium 122. Leads 114 may be placed at any location within brain 120 such that electrodes 116, 118 are capable of providing electrical stimulation to target tissue sites within brain 120 during treatment. For example, electrodes 116, 118 may be surgically implanted under the dura mater of brain 120 or within the cerebral cortex of brain 120 via a burr hole in cranium 122 of patient 112, and electrically coupled to IMD 106 via one or more leads 114.

[0077] In the example shown in FIG. 1 , electrodes 116, 118 of leads 114 are shown as ring electrodes. Ring electrodes may be used in AEF therapy applications because they are relatively simple to program and are capable of delivering an electrical field to any tissue adjacent to electrodes 116, 118. In other examples, electrodes 116, 118 may have different configurations. For example, in some examples, at least some of the electrodes 116, 118 of leads 114 may have a complex electrode array geometry that is capable of producing electrical fields of various shapes and electrical fields directed to different directions with respect to the lead. The complex electrode array geometry may include multiple electrodes (e.g., partial ring or segmented electrodes) around the outer perimeter of each lead 114, rather than one ring electrode, such as shown in FIGS. 5A and 5B. In this manner, electrical stimulation may be directed in a specific direction, such as alternating directions for alternating electrical fields, from leads 114 to provide AEF therapy. In some examples, one or more leads 114 may include insulation on a portion of the lead that may enable electrical field directionality such that the electrical current is directed to certain circumferential locations other than the insulated portion. In some examples, fewer electrodes may be used to generate smaller electrical fields specifically selected to affect target tissue during the AEF delivery while avoiding subjecting other tissues to the electric fields. In some examples, a housing of IMD 106 may include one or more stimulation and/or sensing electrodes. In alternative examples, leads 114 may have shapes other than elongated cylinders as shown in FIG. 1. For example, leads 114 may be paddle leads, spherical leads, bendable leads, or any other type of shape effective in treating patient 112 and/or minimizing invasiveness of leads 114.

[0078] In this manner, any electrode arrays may be designed to be placed surgically in a tumor void or bed and deliver electric fields to cover the interior volume of the debulked void therein. These electrode arrays may include conformable grids, volumetric “balloons,” multiple small electrodes placed individually within the void, surface anchorable electrodes applied with sutures or glue to the inside surface of the void, very long linear arrays wrapped around the circumference of the void or spiraled within, spring formed structures (nitinol or other compliant material) to expand to fill the volume, and hybrid arrays with paddle and/or grid elements to cover void surface and penetration elements to extend field perpendicular to the tissue surface. In other examples, an electrode array may include conductive fluid electrodes (e.g., an “injectrode” or something similar) or electrodes designed and created via rapid manufacturing techniques to fit a patient’s specific tumor void. Alternatively, an electrode application technique involving utilization of a spray liquid metal masking technique could be utilized to generate custom electrode configurations, in a variety of manners: external to the patient’s body to be later implanted, external to the patient’s body such as on the skin, internal to the patient’s body along the surface of a particular organ or body compartment such as the brain, liver, lung, or peritoneal compartment. In another example, the spray liquid metal masking technique for electrode generation could be used either external or internal to the patient’s body and then be combined with a more traditional implantable electrode or an adherent cutaneous grid of material configured to deliver electrical stimulation.

[0079] In the example shown in FIG. 1, IMD 106 includes a memory to store a plurality of therapy programs that each define a set of therapy parameter values. In some examples, IMD 106 may select a therapy program from the memory based on various parameters, such as sensed patient parameters and the identified patient behaviors. IMD 106 may generate electrical or magnetic stimulation based on the selected therapy program to deliver effective AEF therapy that reduces or prevents cancerous cell division, enhances apoptosis of cancer cells, facilitates immune-mediated cell death, or modulates other cellular functions , such as cell differentiation or de-differentiation, or secretory vesicle release. In other examples, AEF therapy may be delivered for additional or alternative benefits. For example, the system may target AEF therapy to fibroblasts in order to inhibit scar formation within a wound. For a patient with an auto- immune disease, the system may deliver AEF therapy to lymphatic channels, the spleen, thymus, or other anatomical location within the patient to modulate the proliferation of lymphocytes or leukocytes.

[0080] External programmer 104 wirelessly communicates with IMD 106 as needed to provide or retrieve therapy information. Programmer 104 is an external computing device that the user, e.g., a clinician and/or patient 112, may use to communicate with IMD 106. For example, programmer 104 may be a clinician programmer that the clinician uses to communicate with IMD 106 and program one or more therapy programs for IMD 106. Alternatively, programmer 104 may be a patient programmer that allows patient 112 to select programs and/or view and modify therapy parameters. The clinician programmer may include more programming features than the patient programmer. In other words, more complex or sensitive tasks may only be allowed to be completed by the clinician programmer to prevent an untrained patient from making undesirable changes to IMD 106. IMD 106 may also transmit notifications to programmer 104 for delivery to a user m response to detecting one or more problems with stimulation and/or detection of one or more trigger events for patient 112. Programmer 104 may enter a new programming session for the user to select new stimulation parameters for subsequent therapy. External programmer 104 may display estimated locations of target tissue locations and/or suggested stimulation parameter values for delivering electrical stimulation that affects the target tissue location. [0081] When programmer 104 is configured for use by the clinician, programmer 104 may be used to transmit initial programming information to IMD 106. This initial information may include hardware information, such as the type of leads 114 and the electrode arrangement, the position of leads 114 within brain 120, the configuration of electrode array 116, 118, initial programs defining therapy parameter values, and any other information the clinician desires to program into IMD 106. Programmer 104 may also be capable of completing functional tests (e.g., measuring the impedance of electrodes 116, 118 of leads 114 or the electric field strength at a strategic location on one of leads 114). In some examples, programmer 104 may receive sensed signals or representative information and perform the same techniques and functions attributed to IMD 106 herein. In other examples, a remote server (e.g., a standalone server or part of a cloud service as shown in FIG. 4) may perform the functions attributed to IMD 106, programmer 104, or any other devices described herein.

[0082] Programmer 104 may also be configured for use by patient 112. When configured as a patient programmer, programmer 104 may have limited functionality (compared to a clinician programmer) in order to prevent patient 112 from altering critical functions of IMD 106 or applications that may be detrimental to patient 112. In this manner, programmer 104 may only allow patient 112 to adjust values for certain therapy parameters or set an available range of values for a particular therapy parameter. In one example, a patient programmer may only allow for functions such as turning AEF therapy on or off and/or decreasing stimulation intensity. In some examples, programmer 104 may present an indication of delivery time for the patient, such as a screen that indicates the amount of time that the therapy is delivered and/or time the therapy has been off for each day, week, month, etc. For example, programmer 104 may present that “AEF therapy has been delivered for 85% of the time during the last week” or “AEF therapy has been delivered during 6 of the last 7 days.” In addition, programmer 104 may present remaining therapy time available before recharge is required when IMD 106 operates using a rechargeable power source. In some examples, the user interface may present a map of the cranium with the electrode configuration represented and one or more zones of tissue that receive a specified therapeutic parameter (such as V/cm). In some examples, the user interface may be configured to receive user input manipulating the orientation of the field and/or adjustment of other stimulation parameter values. [0083] Programmer 104 may also provide an indication to patient 112 when therapy is being delivered, when patient input has triggered a change in therapy or when the power source within programmer 104 or IMD 106 needs to be replaced or recharged. For example, programmer 112 may include an alert LED, may flash a message to patient 112 via a programmer display, generate an audible sound or somatosensory cue to confirm patient input was received, e.g., to indicate a patient state or to manually modify a therapy parameter.

[0084] Therapy system 100 may be implemented to provide chronic stimulation therapy to patient 112 over the course of several months or years. However, system 100 may also be employed on a trial basis to evaluate therapy before committing to full implantation. If implemented temporarily, some components of system 100 may not be implanted within patient 112. For example, patient 112 may be fitted with an external medical device, such as a trial stimulator, rather than IMD 106. The external medical device may be coupled to percutaneous leads or to implanted leads via a percutaneous extension. If the trial stimulator indicates AEF system 100 provides effective treatment to patient 112, the clinician may implant a chronic stimulator within patient 112 for relatively long-term treatment with AEF therapy.

[0085] Although IMD 106 is described as deli vering electrical stimulation therapy to brain 120, IMD 106 may be configured to direct electrical stimulation to other anatomical regions of patient 112 in other examples. In other examples, system 100 may include an implantable drug pump in addition to, or in place of, IMD 106. Further, an IMD may provide other electrical stimulation such as spinal cord stimulation to treat other types of cancer or other diseases or disorders. In some embodiments, the therapy delivered by IMD 106 is designed to enhance the ability of particular drugs to pass through the blood-brain barrier, through for example, delivering therapy at a specific parameter set such as a frequency of 100kHz, or is designed to enable particular drugs to pass through the blood-brain barrier. The therapy may function by either specification of opening diameter within the blood brain barrier or by the transcriptomic manipulation of the cells composing the blood brain barrier to impact the cellular receptors within the region adjacent to the blood brain barrier. Example drugs or substances may include viral vectors or contrast agents (e.g., substances that my facilitate imaging or intraoperative visualization). In other embodiments, the therapy delivered by IMD 106 is designed to enhance and/or enable cell membrane permeabilization for the purpose of mediating cell transfection by enhancing viral delivery to target cells, enhancing the bioavailability of serologically available pharmaceuticals, enhancing the delivery of tumor-specific marker agents, such as 5- aminolevulinic acid (5-ALA), or for combinatorial efficacy with additional therapy modalities through imparting cellular stress on those cells selectively vulnerable to permeabilization. By being designed to achieve these goals, IMD 106 may be configured (via specific stimulation parameter values) to deliver electrical field therapy that increases blood-brain barrier permeabilization and/or enhances cell membrane permeabilization.

[0086] According to the techniques of the disclosure, system 100 may include processing circuitry configured to receive a request to deliver alternating electric field (AEF) therapy, determine therapy parameter values that define the AEF therapy, wherein the AEF therapy comprises delivery of a first electric field and a second electric field, control IMD 106 to deliver the first electric field from a first electrode combination of implanted electrodes, and control IMD 106 to deliver, alternating with the first electric field, the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination. The request may be via user input and/or an automated system request to start AEF therapy delivery. .

[0087] The electrical fields that IMD 106 alternates over time to produce the AEF therapy may involve different electrode combinations and/or different methods for alternating the electrical fields between different electrode combinations (e.g., different electrodes and/or different polarities of the same or different electrodes). In one example, the first electrode combination includes a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes, and the second electrode combination includes the first set of electrodes defined as anodes and the second set of electrodes defined as cathodes.

[0088] In one example in which IMD 106 utilizes 4 different implantable leads, the first electrode combination includes a first set of anodes carried by a first lead, the second electrode combination includes a first set of cathodes carried by a second lead different than the first lead, the third electrode combination includes a second set of anodes carried by a third lead different than the first lead and the second lead, and the fourth electrode combination includes a second set of cathodes carried by a fourth lead different than the first lead, the second lead, and the third lead. The first and second electrical fields may generally be orthogonal or oblique to each other. In another example in which two leads are used to deliver AEF therapy, the first electrode combination includes a first set of anodes carried by a first lead, the second electrode combination includes a first set of cathodes carried by a second lead different than the first lead, the third electrode combination comprises a second set of anodes carried by the second lead, and the fourth electrode combination comprises a second set of cathodes carried by the first lead. In some examples, the AEF therapy may include alternating or switching between the first electrode combination and the second electrode combination, where some or all of electrodes of the first lead switch between operating as anodes in the first electrode combination and operating as cathodes in the second electrode combination, and electrodes of the second lead switch between operating as cathodes in the first electrode combination and operating as anodes in the second electrode combination. In other examples, the first and second electrode combinations may utilize completely different electrodes for each anodes and cathodes. In other examples, each electrode combination may utilize one lead for anodes and a different lead for cathodes. The different electrode combinations used to alternate electric fields may share leads or utilize separate leads for each electrode combination. These are only some of the different methods for generating alternating electric fields from an array of implanted electrodes, as other examples are also contemplated. For example, IMD 106 may instead alternate, or sweep through, three or more different electrical fields generated from respective electrode combinations. These larger number of electrical fields may effectively treat a larger number of cells depending on the location of the cells within respect to the location of the implanted electrodes.

[0089] Although alternating electric field therapy is generally described as delivering two different electric fields, three or more electric fields may be delivered in other examples. For example, IMD 106 may be configured to deliver three electric fields that are all orthogonal to each other. In other examples, four or more different electric fields may be delivered to the cells in order to affect cells oriented in a variety of different directions. In this manner, IMD 106 may deliver tens or hundreds of different electric fields having different vectors (limited only by the available electrode combinations for delivering the electric fields) by sweeping through a sequence of these electric fields or otherwise delivering these different electric fields in order to affect cells having different orientations. Three electric fields with all different directional vectors may enable three dimensional electrical field treatment of the target tissue.

[0090] In some examples, IMD 106 is configured to cycle the AEF therapy on and off according to a predetermined schedule. This predetermined cycle may be set according to the speed of tumor cell division in order to cycle the AEF therapy at a rate that enables the tumor cells are guaranteed to experience a relevant field at least once per cell divisional time to inhibit the division of the cells. In other examples, IMD 106 may be configured to receive temperature data indicative of a temperature of tissue that receives the AEF therapy, determine that the temperature exceeds a threshold temperature, responsive to determining that the temperature exceeds the threshold temperature, terminate delivery of the AEF therapy. This temperature monitoring may reduce the risk of tissue damage due to electrical field induced tissue heating. [0091] IMD 106 may generally use the same pulse or signal frequency for generating the first and second electrical fields of the AEF therapy. In one example, the frequency may be approximately 150 kHz. In another example, the frequency may be approximately 200 kHz. In general, the frequency may be selected from a range of approximately 100 kHz through 300 kHz, but frequencies higher or lower than this range may be used in other examples. In some examples, the frequencies employed by IMD 106 are selected based on the types of cells targeted for treatment. For example, if targeting cancer cells of a certain size (e.g., 13 micrometers in diameter), the IMD 106 delivers therapy with a frequency (e.g., 200 kHz) at which therapy will be more effective for that cell size. In some examples, the frequency or range of frequencies at which the electrical fields are delivered may be selected based on a workup of a patient biopsy or based on a lookup table according to the tumor type and associated distributions of cell sizes. In some examples, the minimum or maximum frequencies may be selected in order to avoid affecting sizes of healthy cells within the electric fields that may differ from the size of the tumor cells. Example relationships between possible frequencies of electric fields and the size of cells are provided in FIGS. 15B and 15C.

[0092] In some examples, the stimulation frequency at which the maximum force (f _max ) can be imparted on a spherical particle housed within a dividing cell is inversely related to the relaxation time (τ) possessed by the membrane charging voltage. The relaxation time (τ) can be described by this equation:

The terms within the above formula are as follows: (r) is the relaxation time of the membrane charging voltage, r is the radius of the cell, C _p is the membrane capacitance, and σ _i and σ _e are the conductivity of the cytoplasm and external medium respectively. Given σ _i and σ _e are nearly identical, this equation can be simplified to:

Given that within an individual cell the values for r and C _p will remain approximately constant within an example frequency range for AEF therapy (100-500kHz), and again keeping in mind that the frequency at which a maximum force (f _max ) is imparted on particles within the dividing cell is inversely related to the relaxation time (τ), it can be said that f _max is directly related to the cytoplasmic, conductivity σ _i . With that relationship in mind, simulation results are indicative of a relationship between the radius of the cell (r) and f _max as follows:

The terms within this above formula are as follows: fmax is the frequency at which maximum force is imparted on a spherical particle within a dividing cell, a represents a constant which was calculated from simulation results within the literature equivalent to 2155 kHz * m * μm/S/nm, σ _i is the cytoplasmic conductivity, r is the radius of the dividing cell, and is the membrane thickness represented in nanometers. With this relationship between the frequency for imparting maximal force and cell radius in mind, it can then be determined that with an increase in the cell size, the frequency for affecting the cell will decrease. As in the example of glioblastoma, the standardized cell lines possess an average diameter of approximately 17μm (or a radius of 8.5μm ), cell membrane thickness is somewhat variable but is reported anywhere between 4 to 10nm (7nm for the purposes of this example), and the cytoplasmic conductivity extrapolated from data attained within a melanoma cancer cell, 0.1 S/m. With those values and the value for a mentioned above the resulting optimal frequency to achieve a maximal force on cytoplasmic particles would be 177 kHz (or approximately 200kHz) This can be compared with a larger cancer cell such as pancreatic cancer which possesses a diameter of 18-22μm (for the purposes of this example, 20μm ), with all other variables remaining constant, and solving for the equation above the resulting optimal electric field frequency to achieve the maximal force on intracytoplasmic particles would be 151kHz (or approximately 150kHz). Both these frequencies are shown to be effective, suggesting validity to the relationship between the variables highlighted above. Therefore, if a particular cell type can be selectively impacted by a specific TTF therapy (or AEF therapy) frequency, it is feasible for a system to selectively avoid the impact on normal cell types that possess differing values of cell radius or cytoplasmic conductivity.

[0093] Given that AEF therapy has been demonstrated to impart an increase in cell volume within those cancer cells experiencing the therapy, in part due to the enhanced proportion of cells that occupy the G ₀ /G ₁ phase of the cell cycle, and that the optimal frequency for maximal efficacy of AEF therapy if cell size dependent (as above), the sy stem may deliver a sweep of different frequencies such as an interleaved or continuously sweeping protocol ranging between 100kHz to 250kHz would provide an optimal treatment for the diverse ceil population of the tumor.

[0094] In some examples, IMD 106 may swatch between two or more different frequencies during delivery of the AEF therapy. In one example, IMD 106 may be configured to adjust a frequency of the first electric field and the second electric field according to a predetermined schedule. In this manner, IMD 106 can employ a variety of frequencies to target a variety of cell sizes during a treatment cycle. In one example, IMD 106 can sweep through different frequencies in order to treat cells of various sizes that may react to different frequencies, as described further herein. The force acting on intracellular components can be modeled based on an intracellular particle being assumed to have a diameter of approximately 1 -micrometer, such that tiie particle will experience differential force dependent on the characteristics of the dividing cell, such as cell radius,, membrane thickness, and cytoplasmic dielectric properties. With the modelling observation over an increasing cell radius from 2 to 12 micrometers that the maximal force will be exerted at a lower value of AEF frequency (as described above), and the in vitro observation that such a phenomenon of increasing cell size is observed following the application of AEF therapy, the resulting conclusion is that the system can deliver electrical fields using a sweep of frequency to permit the maximal dielectric force on cytoplasmic particles. The sweep of frequency may be set to operate between the optimally determined baseline frequency, such as 200kHz, to a frequency value mathematically correlated with a doubling of the cell radius, such as 100kHz. This range can be determined, by the system of user, based on tumor profiling conducted by in vitro analysis of specific tumor types in advance of clinical application. This can permit characterization of the tumor cell composition geometry.

[0095] In other examples, IMD 106 may be configured to receive an indication that a trigger event occurred, and responsive to receiving the indication that the trigger event occurred, adjust a frequency of the first electric field and the second electric field. The trigger event may be patient activity (e.g., the patient is moving or the patient is sleeping - to target circadian timing of the patient and possibly associated cell growth cycles), detected brain activity, or any other type of trigger event that may indicate AEF therapy should or should not be delivered. Other trigger events may include therapeutic events such as delivery of another therapy (e.g., chemotherapy or other moderation therapy) in order to synchronize the effectiveness of each therapy or the totality of the therapies. In some examples, the first electric field is defined by a first frequency, and the second electric field is defined by a second frequency different than the first frequency.

[0096] In some examples, system 100 may be configured to determine, or recommend for user approval, one or more stimulation parameters that at least partially define the AEF therapy. For example, programmer 104 may include a user interface configured to receive user input indicative of target tissue to receive AEF therapy. Programmer 104 may be configured to determine, based on the user input, the first electrode combination and the second electrode combination. In this manner, system 100 can achieve therapy of desired tissue, such as a glioblastoma tumor or other tissue of concern. Alternatively, or in addition, programmer 104 may include a user interface configured to receive user input indicative of tissue to avoid receiving AEF therapy. Since programmer 104 may be a patient or clinician programmer, the user interface may be configured to receive input from a clinician or a patient. However, in some examples, the user interface may provide additional options or expanded customizability for clinicians when compared to patients. In some embodiments, the IMD 106 is configured to determine, e.g., using signals sensed by the electrodes, that electric fields are reaching a particular tissue structure. In some examples, one or more of the electrodes may be located in or near a non-target tissue to indicate the presence of electric fields at the non-target tissue (e.g., a specific recording electrode(s)). The IMD 106 (either alone or in combination with external devices) can adjust the applied therapy to enhance, reduce, or eliminate the applied electric fields (or the effects of the applied electric fields) at that particular tissue structure.

[0097] To accomplish the enhancement of AEF therapy, the electrode near or within the non- target tissue could be paired to the local stimulating electrodes in a 180° or π radians phase shifted configuration along the stimulation sinusoidal waveform. In doing so, the resulting electric field magnitude experienced by the non-target tissue may be higher due to the larger peak-to-peak differential in voltage between the two electrodes. To accomplish a reduction or elimination of AEF therapy within the non-target tissue region, the system may implement a 0° or Oπ radians phase shifting configuration between the local electrode and the remote stimulating electrode. By delivering the stimulation in this manner, there is less permissible of differential established in the peak-to-peak voltage experienced by the local tissue and therefore a reduction in the resulting electric field. Programmer 104 may then determine, based on the user input, the first electrode combination and the second electrode combination. System 100 can then atempt to reduce the effect of AEF therapy on non-target tissues. In some examples, system 100 may receive user input indicative of target tissue and/or tissue to avoid from a remote device over a network to support remote programmer options for system 100.

[0098] System 100 may also determine stimulation parameters based on feedback regarding the state of patient 112 and/or tissue of the patient. For example, programmer 104 and/or IMD 106 may adjust one or more stimulation parameters that at least partially defines the AEF therapy based on histological data obtained from a sample of tissue affected by the AEF therapy. In another example, programmer 104 and/or IMD 106 may determine target tissue for AEF therapy based on water content data obtained from magnetic resonance imaging (MRI) data, and determine, based on the target tissue, the first electrode combination and the second electrode combination for delivery' of the AEF therapy. In some examples, determining the electrode combinations may include determining the location, e.g., based on predictive computational models of electric field intensity in tissue, at which one or more leads should be located in order to deliver AEF therapy to the target tissue. As another example, programmer 104 and/or IMD 106 may determine target tissue for AEF therapy based on impedance tomography data obtained from sensed electrical potentials sensed from two or more of the implanted electrodes (and/or external electrodes disposed to record electric fields), and determine, based on the target tissue, at least the first electrode combination and the second electrode combination to deliver the AEF therapy. System 100 may also map AEF features to anatomy to inform AEF therapy planning and/or adjustments over time. For example, programmer 104 may be configured to generate an AEF dosimetry metric for anatomy that receives the AEF therapy and map the AEF dosimetry across target tissue of the anatomy. This AEF dosimetry' map may inform which tissues within the anatomy are receiving different strengths of the electrical fields. Programmer 104 may also display the map of the AEF dosimetry with respect to the anatomy. [0099] IMD 106 may alternate the electrical fields in AEF therapy by delivering the electrical fields from different electrodes and/or electrodes with different polarities. In one example, IMD 106 may continually shift the polarities of the electrodes in one direction with respect to the electrode array. The first electrode combination may include a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes, the second electrode combination may include a third set of electrodes defined as anodes and a fourth set of electrodes defined as cathodes, where the third set of electrodes are adjacent to the first set of electrodes in one direction on a first lead, and the fourth set of electrodes are adjacent to the second set of electrodes in the one direction on a second lead. In some examples, electrode combinations adjacent each other may be 180 degrees out of phase with each other in order to provide a maximum amount of change in voltage between the tissue separating the adjacent electrode contacts. In another example, the electrode combinations may be selected from a cube configuration where the selectable electrodes for each electrode combination form the eight vertices of a cube. In this example, the first electrode combination includes a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes in a first paired configuration from the cube configuration, and the second electrode combination includes the first set of electrodes defined as anodes and the second set of electrodes defined as cathodes in a second paired configuration from the cube configuration.

[0100] As shown in FIG. 1, the electrodes (e.g., at least two electrodes) used to deliver the AEF therapy are carried by an electrode array positioned adjacent a resection bed of tissue. In some examples, at least two electrodes of the implanted electrodes used to deliver AEF therapy are subcutaneous electrodes (e.g., electrodes implanted beneath the skin and superficial of the bone). In some examples, one or more electrodes may be implanted on the inside of the removed skull portion during surgery in order to provide a relatively easy implantation of electrodes within the skull but outside of the brain. In other examples, a system may deliver the AEF therapy using a plurality of external cutaneous electrodes in combination with a plurality of implanted electrodes. For example, a first electrical field of the AEF therapy may be delivered between two or more external electrodes and the second electrical field of the AEF therapy is delivered between two or more implanted electrodes. In other example, two or more electrical fields that create the AEF therapy each utilize one or more external electrodes. In some examples, the current passes between only external electrodes or between only implanted electrodes. In other examples, one or more electrical fields may be created between any combination of external and implanted electrodes. An external device may deliver current to the external electrodes, either independent controlled or controlled based on communication between the external device and IMD 106.

[0101] Generally, AEF therapy is described herein as a treatment to already present tumors, such as glioblastomas. In other examples, the application of AEF therapy can reduce the extent of metastatic tumor burden and seeding of tumors from a remote tumor source. Therefore, AEF treatment could be delivered to protect tissue regions from metastatic spread. For example, AEF could be utilized to provide global brain protection in the setting of a known malignant tumor within the body, particularly those that have a propensity for cerebral dissemination (e.g., Melanoma). AEF could be delivered to prevent additional metastatic spread of tumor within the organ system of current metastatic dissemination. In addition, AEF implant planning could be provided for the protection of certain neurological function (e.g., motor function), such that the implant system 100 would be focused on treatment to the pre-central gyrus and/or corticospinal tract to preserve its function and avoid seeding.

[0102] An AEF delivery implant (e.g., IMD 106 and leads 114) could be utilized to prophylactically treat a body region that is expected to have a high risk for metastatic dissemination (e.g., a presumed location where tumor would progress next). An example of this is the axillary lymph nodes in the setting of a newly diagnosed breast cancer. Lymphatic channels have predictable flow and are common highways for metastatic dissemination.

Therefore, implantation strategies that focus on the systematic treatment of these highways could meaningfully impact the propensity and capability for tumors to metastatically spread.

[0103] AEF delivery could also utilize electrodes within arteries to permit wider control of metastatic spread. Put another way, AEF delivery could reduce the likelihood of metastatic tumor cells to exit the blood stream and seed other regions within the body. In one example, treatment of the carotid arteries could reduce the ability for tumor cells to exit the bloodstream and invade the cerebral tissue. AEF delivery within the arteries could provide advantageous pharmacokinetic impacts on drugs within the tumor region and therefore justify intra-arterial placement of electrodes for AEF delivery. In this manner, AEF therapy described herein may be applied to numerous different tissues and for numerous different reasons. For example, AEF therapy or other modulated electric field therapy may be provided as a preventative therapy to tissue not yet diagnosed as cancerous but at risk for tumor occurrence based on one or more characteristics such as genetic markers, environmental factors, or any other risk factors.

[0104] The architecture of system 100 illustrated in FIG. 1 is shown as an example. The techniques as set forth in this disclosure may be implemented in the example system 100 of FIG. 1, as well as other types of systems not described specifically herein. Nothing in this disclosure should be construed so as to limit the techniques of this disclosure to the example architecture illustrated by FIG. 1.

[0105] System 100 is generally described as including IMD 106 and external programmer 104. However, in other examples, an external medical device may be configured to perform any of the techniques described herein or described with respect to IMD 106. The external medical device may be coupled to percutaneous leads or other devices that pass through the skin in order to dispose implanted electrodes at various locations within patient for at least partially delivering electric field therapy and/or sensing signals as described herein. Additionally, or alternatively, the external device may be coupled to external electrodes configured to at least partially deliver electric field therapy and/or sense signals as described herein. The external medical device may be configured to communicate with programmer 104 and/or partially or fully incorporate structures to perform the various functionality described with respect to programmer 104.

[0106] FIG. 2 is a block diagram of the example IMD 106 of FIG. 1 for delivering AEF therapy. In the example shown in FIG. 2, IMD 106 includes processing circuitry' 210, memory' 211, stimulation generator 202, sensing module 204, switch module 206, telemetry module 208, sensor 212, and power source 220. Each of these modules may be or include electrical circuitry configured to perform the functions attributed to each respective module. For example, processing circuitry 210 may include processing circuitry/, switch module 206 may include switch circuitry, sensing module 204 may include sensing circuitry, and telemetry module 208 may include telemetry circuitry. Switch module 206 may not be used for multiple current source and sink configurations, but one or more switches may still be used to disconnect sensing module 204 from the source and sinks in such a configuration. Memory 211 may include any volatile or non-volatile media, such as a random-access memory (RAM), read only memory (ROM), non- volatile RAM (NVRAM), electrically erasable programmable ROM (EEPROM), flash memory, and the like. Memory 211 may store computer-readable instructions that, when executed by processing circuitry 210, cause IMD 106 to perform various functions. Memory 211 may be a storage device or other non-transitory medium.

[0107] In the example shown in FIG. 2, memory 211 stores therapy programs 214 that include respective stimulation parameter sets that define AEF therapy. Each stored therapy program 214 defines a particular set of electrical stimulation parameters (e.g., a therapy parameter set), such as a stimulation electrode combination, electrode polarity , current or voltage amplitude, pulse width, and pulse rate. In some examples, individual therapy programs may be stored as a therapy group, which defines a set of therapy programs with which stimulation may be generated.

[0108] Memory 211 may also include parameter selection instructions 217 and notification instructions 218. Parameter selection instructions 217 may include instructions that control processing circuitry 210 selecting different stimulation parameter values such as electrode combinations, amplitudes, pulse frequencies, or other parameter values for compensating for various locations of target tissue or feedback related to changes in patient condition or tissue state. Parameter selection instructions 217 may include instructions for processing circuitry 210 to select parameter values based on various feedback variables. Notification instructions 218 may define instructions that control processing circuitry 210 actions such as transmitting an alert or other notification to an external device, such as programmer 104, that therapy is on or off, or if changes to AEF therapy have been made or are recommended.

[0109] In some examples, the sense and stimulation electrode combinations may include the same subset of electrodes 116, 118, a housing of IMD 106 functioning as an electrode, or may include different subsets or combinations of such electrodes. Thus, memory 211 can store a plurality of sense electrode combinations and, for each sense electrode combination, store information identifying the stimulation electrode combination that is associated with the respective sense electrode combination. The associations between sense and stimulation electrode combinations can be determined, e.g., by a clinician or automatically by processing circuitry 210. In some examples, corresponding sense and stimulation electrode combinations may comprise some or all of the same electrodes. In other examples, however, some or all of the electrodes in corresponding sense and stimulation electrode combinations may be different. For example, a stimulation electrode combination may include more electrodes than the corresponding sense electrode combination in order to increase the efficacy of the AEF therapy. [0110] Stimulation generator 202, under the control of processing circuitry 210, generates stimulation signals for delivery to patient 112 via selected combinations of electrodes 116, 118. An example range of electrical stimulation parameters believed to be effective in AEF therapy to manage cellular activity include:

1. Frequency (e.g., waveform frequency or pulse rate): between approximately 50 kHz and approximately 500 kHz, such as between approximately 100 kHz to 300 kHz, or such as approximately 150 kHz or 200 kHz.

2. In the case of a voltage controlled system, Voltage Amplitude: between approximately 0.1 volts and approximately 50 volts, such as between approximately 2 volts and approximately 10 volts.

3. In the alternative case of a current controlled system, Current Amplitude: between approximately 0.2 milliamps to approximately 100 milliamps, such as between approximately 1.3 milliamps and approximately 2.0 milliamps.

4. Pulse Width: between approximately 1 microseconds and approximately 10 microseconds, such as between approximately 1 microseconds and approximately 5 microseconds, or between approximately 2 microseconds and approximately 10 microseconds.

5. Cycle time (e.g., communication time), which is the time a waveform remains consistent before switching off or switching to a new waveform. The cycle time may be selected from a range of 30 seconds and 30 minutes, or within a range from 1 minute to 10 minutes. Shorter and longer cycle times may be used in other examples.

[0111] Accordingly, in some examples, stimulation generator 202 generates electrical stimulation signals in accordance with the electrical stimulation parameters noted above. Other ranges of therapy parameter values may also be useful, and may depend on the target stimulation site within patient 112, While stimulation pulses are described, stimulation signals may be of any form, such as continuous-time signals (e.g., sine waves) or the like. Stimulation signals configured to elicit ECAPs or other evoked physiological signals may be similar or different from the above parameter value ranges. In addition, sensing circuitry 204 may be configured to sense signals via one or more electrode combinations on one or more leads 114 (e.g., the same or different electrodes may deliver stimulation and sense electrical signals).

[0112] Processing circuitry 210 may include fixed function processing circuitry and/or programmable processing circuitry, and may comprise, for example, any one or more of a microprocessor, a controller, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field-programmable gate array (FPGA), discrete logic circuitry, or any other processing circuitry configured to provide the functions attributed to processing circuitry 210 herein may be embodied as firmware, hardware, software or any combination thereof. Processing circuitry 210 may control stimulation generator 202 according to therapy programs 214 stored in memory 211 to apply particular stimulation parameter values specified by one or more of programs, such as voltage amplitude or current amplitude, pulse width, or pulse rate.

[0113] In the example shown in FIG. 2, the set of electrodes 116 includes electrodes 116A, 116B, 116C, and 116D, and the set of electrodes 118 includes electrodes 118A, 118B, 118C, and 118D. Processing circuitry 210 also controls switch module 206 to apply the stimulation signals generated by stimulation generator 202 to selected combinations of electrodes 116, 118. In particular, switch module 204 may couple stimulation signals to selected conductors within leads 114, which, in turn, deliver the stimulation signals across selected electrodes 116, 118. Switch module 206 may be a switch array, switch matrix, multiplexer, or any other type of switching module configured to selectively couple stimulation energy to selected electrodes 116, 118 and to selectively sense neurological brain signals with selected electrodes 116, 118. Hence, stimulation generator 202 is coupled to electrodes 116, 118 via switch module 206 and conductors within leads 114. In some examples, however, IMD 106 does not include switch module 206, such as if each electrode is assigned a respective current and sink (e.g., independent current source).

[0114] Stimulation generator 202 may be a single channel or multi-channel stimulation generator. In particular, stimulation generator 202 may be capable of delivering a single stimulation pulse, multiple stimulation pulses, or a continuous signal at a given time via a single electrode combination or multiple stimulation pulses at a given time via multiple electrode combinations. In some examples, however, stimulation generator 202 and switch module 206 may be configured to deliver multiple channels on a time-interleaved basis. For example, switch module 206 may serve to time divide the output of stimulation generator 202 across different electrode combinations at different times to deliver multiple programs or channels of stimulation energy to patient 112 (e.g., cycling between regimes of stimulation on a fixed or variable sequence). Alternatively, stimulation generator 202 may comprise multiple voltage or current sources and sinks that are coupled to respective electrodes to drive the electrodes as cathodes or anodes. In this example, IMD 106 may not require the functionality of switch module 206 for time-interleaved multiplexing of stimulation via different electrodes.

[0115] Electrodes 116, 118 on respective leads 114 may be constructed of a variety of different designs. For example, one or both of leads 114 may include two or more electrodes at each longitudinal location along the length of the lead, such as multiple electrodes at different perimeter locations around the perimeter of the lead at each of the locations A, B, C, and D. On one example, the electrodes may be electrically coupled to switch module 206 via respective wires that are straight or coiled within the housing or the lead and run to a connector at the proximal end of the lead. In another example, each of the electrodes of the lead may be electrodes deposited on a thin film. The thin film may include an electrically conductive trace for each electrode that runs the length of the thin film to a proximal end connector. The thin film may then be wrapped (e.g., a helical wrap) around an internal member to form the lead 114. These and other constructions may be used to create a lead with a complex electrode geometry. [0116] Although sensing module 204 is incorporated into a common housing with stimulation generator 202 and processing circuitry 210 in FIG. 2, in other examples, sensing module 204 may be in a separate housing from IMD 106 and may communicate with processing circuitry 210 via wired or wireless communication techniques. Example neurological brain signals include, but are not limited to, a signal generated from local field potentials (LFPs) within one or more regi ons of brain 28. EEG and ECoG signals are examples of other types of electrical signals that may be measured within brain 120 and/or outside of brain 120. Other examples include sensed signals representative of electric field or voltage gradients caused by a remote electrode as recorded by a proximal electrode or electrode pair. Instead of, or in addition to, LFPs, IMD 106 may be configured to detect patterns of single-unit activity and/or multi-unit activity. IMD 106 may sample this activity at rates above 1 ,000 Hz, and in some examples within a frequency range of 6,000 Hz to 500,000 Hz. IMD 106 may identify the wave-shape of single units and/or an envelope of unit modulation that may be features used to differentiate or rank electrodes. In some examples, this technique may include phase-amplitude coupling to the envelope or to specific frequency bands in the LFPs sensed from the same or different electrodes. In some examples, the sampling technique may be set to identify the electric field strength at any location. For example, IMD 106 may include a peak following circuitry that holds the amplitude of a field of a specific frequency for later sampling. Alternatively, the response of a resonant circuit may be tuned to the AEF frequency might sampled to infer the field strength of the desired signal. In some examples, IMD 106 may be configured to detect a geometric response within the network of 114 electrodes in response to a single-pulse electrical stimulation generated within the system. The utilization of a basis profile curve algorithm to analyze this geometric response as sensed within the multitude of 114 electrodes within the system can permit diagnostics, such as demonstration of patters indicative of depression, anxiety, or tumor progression within the cerebral environment. IMD 106 may conduct this real-time diagnostic modality in an interleaved manner to permit ongoing stimulation with periodic analysis. [0117] Sensor 212 may include one or more sensing elements that sense values of a respective patient parameter, such as patient activity (e.g., movement and/or sleep). For example, sensor 212 may include one or more accelerometers, optical sensors, chemical sensors, temperature sensors, pressure sensors, or any other types of sensors. Sensor 212 may output patient parameter values that may be used as feedback to control delivery of AEF therapy. IMD 106 may include additional sensors within the housing of IMD 106 and/or coupled via one of leads 114 or other leads. In addition, IMD 106 may receive sensor signals wirelessly from remote sensors via telemetry module 208, for example. In some examples, one or more of these remote sensors may be external to patient (e.g., carried on the external surface of the skin, attached to clothing, or otherwise positioned external to the patient).

[0118] Telemetry module 208 supports wireless communication between IMD 106 and an external programmer 104 or another computing device under the control of processing circuitry 210. Processing circuitry 210 of IMD 106 may receive, as updates to programs, values for various stimulation parameters such as magnitude and electrode combination, from programmer 104 via telemetry module 208. The updates to the therapy programs may be stored within therapy programs 214 portion of memory 211. In addition, processing circuitry 210 may control telemetry module 208 to transmit alerts or other information to programmer 104 that indicate a lead moved with respect to tissue. Telemetry module 208 in IMD 106, as well as telemetry modules in other devices and systems described herein, such as programmer 104, may accomplish communication by radiofrequency (RF) communication techniques. In addition, telemetry module 208 may communicate with external medical device programmer 104 via proximal inductive interaction of IMD 106 with programmer 104. Accordingly, telemetry module 208 may send information to external programmer 104 on a continuous basis, at periodic intervals, or upon request from IMD 106 or programmer 104.

[0119] Power source 220 delivers operating power to various components of IMD 106. Power source 220 may include a small rechargeable or non-rechargeable battery and a power generation circuit to produce the operating power. Recharging may be accomplished through proximal inductive interaction between an external charger and an inductive charging coil within IMD 220. In some examples, power requirements may be small enough to allow IMD 220 to utilize patient motion and implement a kinetic energy-scavenging device to trickle charge a rechargeable battery. In other examples, traditional batteries may be used for a limited period of time. In other examples, IMD 106 may include a power receiving antenna an corresponding circuitry to continually receive external power that enables IMD 106 to deliver electric field therapy indefinitely without possible internal power source drain.

[0120] According to the techniques of the disclosure, processing circuitry 210 of IMD 106 delivers, electrodes 116, 118 interposed along leads 114 (and optionally swatch module 206), electrical stimulation therapy to patient 112. The AEF therapy is defined by one or more therapy programs 214 having one or more parameters stored within memory 211. For example, the one or more parameters include a current amplitude (for a current-controlled system) or a voltage amplitude (for a voltage-controlled system), a pulse rate or frequency, and a pulse width, or quantity of pulses per cycle. In examples where the electrical stimulation is delivered according to a “burst” of pulses, or a series of electrical pulses defined by an “on-time” and an “off-time,” the one or more parameters may further define one or more of a number of pulses per burst, an on-time, and an off-time.

[0121] In some examples, the plurality of electrode combinations includes at least one electrode combination comprising electrodes disposed at different positions around a perimeter of the lead. In some examples, at least one electrode combination includes electrodes disposed at different positions along a longitudinal axis of the lead implanted m the patient. In this manner, the plurality of electrode combinations may include electrode combinations where each electrode combination has electrodes at different positions around the perimeter of the lead, electrode combinations where each electrode combination has electrode at different positions along the longitudinal axis of the lead, or electrode combinations that include both electrode combinations with electrodes at different positions around the perimeter of the lead and different positions along the longitudinal axis of the lead.

[0122] The one or more features determined from the sensed electrical signals may include or represent different characteristics of the sensed electrical signals. Example features of the sensed electrical signals may include voltage (peak or average), orientation of resulting electric field, impedance, spectral power, one or more frequencies, one or more frequency bands, or any other characteristics of the sensed signals. In this manner, the one or more features may be features in the time domain, frequency domain, or any other signal domain relevant to identify the sensed signals. For example, processing circuitry 210 may be configured to determine the one or more features by at least determining a sensed voltage for each electrode combination of the plurality of electrode combinations. In some examples, processing circuitry 210 may be configured to determine the one or more features by at least determining at least one of a power, a frequency band, a time domain feature, and/or a frequency domain feature of each signal of the plurality of signals from respective electrode combinations of the plurality of electrode combinations.

[0123] Processing circuitry 210 may be configured to control a user interface to display various elements and aspects related to the planning and delivery of AEF therapy. For example, processing circuitry 210 may transmit sensed data related to AEF therapy such as impedance tomography, stimulation parameters, patent activity, and any other data to programmer 104 for display to the user via the user interface. In some examples, processing circuitry 210 may be configured to receive user selection of a value for one or more stimulation parameters that at least partially defines AEF therapy. For example, the user interface may present a visual indication of the estimated location of the target tissue and electrical field strength variations over different locations of the target tissue.

[0124] FIG. 3 is a block diagram of the external programmer 104 of FIG. 1 for planning and/or controlling delivery of AEF therapy according to an example of the techniques of the disclosure. Although programmer 104 may generally be described as a hand-held device, programmer 104 may be a larger portable device or a more stationary device. In some examples, programmer 104 may be referred to as a tablet computing device or a smart phone computing device. In addition, in other examples, programmer 104 may be included as part of a bed-side monitor, an external charging device or include the functionality of an external charging device. As illustrated in FIG. 3, programmer 104 may include a processing circuitry 310, memory 311, user interface 302, telemetry module 308, and power source 320. Memory 311 may store instructions that, when executed by processing circuitry 310, cause processing circuitry 310 and external programmer 104 to provide the functionality ascribed to external programmer 104 throughout this disclosure. Each of these components, or modules, may include electrical circuitry that is configured to perform some or all of the functionality described herein. For example, processing circuitry 310 may include processing circuitry configured to perform the processes discussed with respect to processing circuitry 310.

[0125] In general, programmer 104 comprises any suitable arrangement of hardware, alone or in combination with software and/or firmware, to perform the techniques attributed to programmer 104, and processing circuitry 310, user interface 302, and telemetry module 308 of programmer 104. In various examples, programmer 104 may include one or more processors, which may include fixed function processing circuitry and/or programmable processing circuitry, as formed by, for example, one or more microprocessors, DSPs, ASICs, FPGAs, or any other equivalent integrated or discrete logic circuitry, as well as any combinations of such components. Programmer 104 also, in various examples, may include a memory 311, such as RAM, ROM, PROM, EPROM, EEPROM, flash memory, a hard disk, a CD-ROM, comprising executable instructions for causing the one or more processors to perform the actions attributed to them. Moreover, although processing circuitry 310 and telemetry module 308 are described as separate modules, in some examples, processing circuitry 310 and telemetry module 308 may be functionally integrated with one another. In some examples, processing circuitry 310 and telemetry module 308 correspond to individual hardware units, such as ASICs, DSPs, FPGAs, or other hardware units.

[0126] Memory 311 (e.g., a storage device) may store instructions that, when executed by processing circuitry 310, cause processing circuitry 310 and programmer 104 to provide the functionality ascribed to programmer 104 throughout this disclosure. For example, memory 311 may include instructions that cause processing circuitry 310 to obtain a parameter set from memory, present a model of patient anatomy for predicting electrical field strengths, provide an interface that recommends or otherwise facilitates parameter value selection, or receive a user input and send a corresponding command to IMD 106, or instructions for any other functionality. In addition, memory 311 may include a plurality of programs, where each program includes a parameter set that defines stimulation therapy.

[0127] User interface 302 may include a button or keypad, lights, a speaker for voice commands, a display, such as a liquid crystal (LCD), light-emitting diode (LED), or organic light-emitting diode (OLED). In some examples the display may be a presence-sensitive screen, such as a touch screen. User interface 302 may be configured to display any information related to the delivery of stimulation therapy, detected trigger events, progression of therapy, suggested stimulation parameter values, sensed patient parameter values, or any other such information. User interface 302 may also receive user input via user interface 302. The input may be, for example, in the form of pressing a button on a keypad or selecting an icon from a touch screen. [0128] Telemetry module 308 may support wireless communication between IMD 106 and programmer 104 under the control of processing circuitry 310. Telemetry' module 308 may also be configured to communicate with another computing device via wireless communication techniques, or direct communication through a wired connection. In some examples, telemetry module 308 provides wireless communication via an RF or proximal inductive medium. In some examples, telemetry module 308 includes an antenna, which may take on a variety of forms, such as an internal or external antenna. In some examples, IMD 106 and/or programmer 104 may communicate with remote servers via one or more cloud-services in order to deliver and/or receive information between a clinic and/or programmer.

[0129] Examples of local wireless communication techniques that may be employed to facilitate communication between programmer 104 and IMD 106 include RF communication according to the 802.1 1 or Bluetooth specification sets or other standard or proprietary telemetry protocols. Security protocols and encryption techniques may be applied to enhance the security of the communication techniques. In addition, other external devices may be capable of communicating with programmer 104 without needing to establish a secure wireless connection. As described herein, telemetry module 308 may be configured to transmit a spatial electrode movement pattern or other stimulation parameter values to IMD 106 for delivery of stimulation therapy.

[0130] FIG. 4 is a block diagram illustrating an example system 124 that includes an external device, such as a server 130, and one or more computing devices 132A-132N, that are coupled to IMD 106 and external programmer 104 shown in FIG. 1 via a network 126. In this example, IMD 106 may use its telemetry circuit to communicate with external programmer 104 via a first wireless connection, and to communication with an access point 128 via a second wireless connection.

[0131] In the example of FIG. 4, access point 128, external programmer 104, server 130, and computing devices 132A-132N are interconnected, and able to communicate with each other, through network 126. In some cases, one or more of access point 128, external programmer 104, server 130, and computing devices 132A-132N may be coupled to network 126 through one or more wireless connections. IMD 106, external programmer 104, server 130, and computing devices 132A-132N may each comprise one or more processors, such as one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), programmable logic circuitry, or the like, that may perform various functions and operations, such as those described in this disclosure.

[0132] Access point 128 may comprise a device, such as a home monitoring device, that connects to network 126 via any of a variety of connections, such as telephone dial-up, digital subscriber line (DSL), or cable modem connections. In other embodiments, access point 128 may be coupled to network 126 through different forms of connections, including wired or wireless connections.

[0133] During operation, IMD 106 may collect and store various forms of data. For example, IMD 106 may collect sensed posture state information during therapy that indicate how patient 112 moves throughout each day. IMD 106 may store usage statistics (e.g., delivery times in hours per day, percentage of on time, compliance to the dosing schedule, etc.) for later presentation to a user or otherwise evaluating therapy and/or patient compliance. In some cases, IMD 106 may directly analyze the collected data to evaluate the status of the patient and the delivery of AEF therapy or any other aspects of the patient. In other cases, however, IMD 106 may send stored data relating to AEF therapy to external programmer 104 and/or server 130, either wirelessly or via access point 128 and network 126, for remote processing and analysis. [0134] For example, IMD 106 may sense, process, trend and evaluate sensed data and/or AEF therapy information. This communication may occur in real time, and network 126 may allow a remote clinician to review the data representative of AEF therapy by receiving a presentation of the data on a remote display, e.g., computing device 132A. Alternatively, processing, trending and evaluation functions may be distributed to other devices such as external programmer 104 or server 130, which are coupled to network 126. In addition, AEF therapy data may be archived by any of such devices, e.g., for later retrieval and analysis by a clinician.

[0135] In some cases, server 130 may be configured to provide a secure storage site for archival of AEF therapy information that has been collected from IMD 106 and/or external programmer 104. Network 126 may comprise a local area network, wade area network, or global network, such as the Internet. In other cases, external programmer 104 or server 130 may assemble AEF therapy information in web pages or other documents for viewing by trained professionals, such as clinicians, via viewing terminals associated with computing devices 132A- 132N. System 124 may be implemented, in some aspects, with general network technology and functionality similar to that provided by the Medtronic CareLmk® Network developed by Medtronic, Inc., of Minneapolis, MN.

[0136] Although some examples of the disclosure may involve AEF therapy information and data, system 124 may be employed to distribute any information relating to the treatment of patient 112 and the operation of any device associated therewith. For example, system 124 may allow therapy errors or device errors to be immediately reported to the clinician. In addition, system 124 may allow the clinician to remotely intervene in the therapy and reprogram IMD 106, patient programmer 104, or communicate with patient 112. In an additional example, the clinician may utilize system 124 to monitor multiple patients and share data with other clinicians in an effort to coordinate rapid evolution of effective treatment of patients..

[0137] FIGS. 5 A and 5B are conceptual diagrams of example leads 400 and 410, respectively, with respective electrodes carried by the lead. As shown in FIGS. 5A and 5B, leads 400 and 410 are embodiments of leads 114 shown in FIG. 1. As shown in FIG. 5 A, lead 400 includes four electrode levels 404 (includes levels 404A-404D) mounted at various lengths of lead housing 402. Lead 400 is inserted into through cranium 122 to a target position within brain 18. In some examples, external electrodes may be used instead of, or in addition to, leads such as lead 400.

[0138] Lead 400 is implanted within brain 120 at a location determined by the clinician that may be near an anatomical region to receive AEF therapy, such as a tumor location or resection bed. Electrode levels 404A, 404B, 404C, and 404D are equally spaced along the axial length of lead housing 402 at different axial positions. Each electrode level 404 may have one, two, three, or more electrodes located at different angular positions around the circumference (e.g., around the perimeter) of lead housing 402. As shown in FIG. 5 A, electrode level 404A and 404D include a single respective ring electrode, and electrode levels 404B and 404C each include three electrodes at different circumferential positions. This electrode pattern may be referred to as a 1- 3-3-1 lead in reference to the number of electrodes from the proximal end to the distal end of lead 400. Electrodes of one circumferential location may be lined up on an axis parallel to the longitudinal axis of lead 400. .Alternatively, electrodes of different electrode levels may be staggered around the circumference of lead housing 402. In addition, lead 400 or 410 may include asymmetrical electrode locations around the circumference, or perimeter, of each lead or electrodes of the same level that have different sizes. These electrodes may include semi- circular electrodes that may or may not be circumferentially aligned between electrode levels. [0139] Lead housing 402 may include a radiopaque stripe or other one or more radiopaque marker (not shown) along the outside of the lead housing. The radiopaque stripe corresponds to a certain circumferential location that allows lead 400 to be imaged and reliably localized when implanted in patient 112. Using the images of patient 112, the clinician can use the radiopaque stripe as a marker for the exact orientation of lead 400 within the brain of patient 112. Orientation of lead 400 may be needed to easily program the stimulation parameters by generating the correct electrode configuration to match the stimulation field defined by the clinician. In other embodiments, a marking mechanism other than a radiopaque stripe may be used to identify the orientation of lead 400. These marking mechanisms may include something similar to a tab, detent, or other structure on the outside of lead housing 402. In some embodiments, the clinician may note the position of markings along a lead wire during implantation to determine the orientation of lead 400 within patient 112. In some examples, programmer 104 may update the orientation of lead 400 in visualizations based on the movement of lead 400 from sensed signals.

[0140] FIG. 5B illustrates lead 410 that includes multiple electrodes at different respective circumferential positions at each of levels 414A-414D. Similar to lead 400, lead 410 is inserted through a burr hole, craniostomy, or craniotomy in cranium 122 to a target location within brain 120. Lead 410 includes lead housing 412. Four electrode levels 414 (414A-414D) are located at the distal end of lead 410. Each electrode level 414 is evenly spaced from the adjacent electrode level and includes two or more electrodes. In one embodiment, each electrode level 414 includes three, four, or more electrodes distributed around the circumference of lead housing 412. Therefore, lead 410 includes 414 electrodes in a preferred embodiment. Each electrode may be substantially rectangular in shape. Alternatively, the individual electrodes may have alternative shapes, e.g., circular, oval, triangular, rounded rectangles, or the like.

[0141] In alternative embodiments, electrode levels 404 or 414 are not evenly spaced along the longitudinal axis of the respective leads 400 and 410. For example, electrode levels 404C and 404D may be spaced approximately 3 millimeters (mm) apart while electrodes 404A and 404B are 10 mm apart. Variable spaced electrode levels may be useful in reaching target anatomical regions deep within brain 120 while avoiding potentially undesirable anatomical regions. The variable spacing may also be utilized to enhance the resulting AEF therapy generated between a pair of electrodes carried on any of leads 400 or 410. Further, the electrodes in adjacent levels need not be aligned in the direction as the longitudinal axis of the lead, and instead may be oriented diagonally with respect to the longitudinal axis.

[0142] Leads 400 and 410 are substantially rigid to prevent the implanted lead from varying from the expected lead shape. Leads 400 or 410 may be substantially cylindrical in shape. In other embodiments, leads 400 or 410 may be shaped differently than a cylinder. For example, the leads may include one or more curves to reach target anatomical regions of brain 120. In some embodiments, leads 400 or 410 may be similar to a flat paddle lead or a conformable lead shaped for patient 112. Also, in other embodiments, leads 400 and 410 may any of a variety of different polygonal cross sections (e.g., triangle, square, rectangle, octagonal, etc.) taken transverse to the longitudinal axis of the lead.

[0143] As shown in the example of lead 400, the plurality of electrodes of lead 400 includes a first set of three electrodes disposed at different respective positions around the longitudinal axis of the lead and at a first longitudinal position along the lead (e.g., electrode level 404B), a second set of three electrodes disposed at a second longitudinal position along the lead different than the first longitudinal position (e.g., electrode level 404C), and at least one ring electrode disposed at a third longitudinal position along the lead different than the first longitudinal position and the second longitudinal position (e.g., electrode level 404A and/or electrode level 404D). In some examples, electrode level 404D may be a bullet tip or cone shaped electrode that covers the distal end of lead 402. [0144] FIGS. 5C-5F are transverse cross-sections of example stimulation leads having one or more electrodes around the circumference of the lead. As shown in FIGS. 5C-5F, one electrode level, such as one of electrode levels 404 and 414 of leads 400 and 410, are illustrated to show electrode placement around the perimeter, or around the longitudinal axis, of the lead. FIG. 5C shows electrode level 500 that includes circumferential electrode 502. Circumferential electrode 502 encircles the entire circumference of electrode level 500 and may be referred to as a ring electrode in some examples. Circumferential electrode 502 may be utilized as a cathode or anode as configured by the user interface. Any of the electrodes of FIGS. 5A-5F may be configured to act as a sensing electrode, or as part of a sensing electrode combination, within a tissue environment.

[0145] FIG. 5D shows electrode level 510 which includes two electrodes 512 and 514. Each electrode 512 and 514 wraps approximately 170 degrees around the circumference of electrode level 510. Spaces of approximately 10 degrees are located between electrodes 512 and 514 to prevent inadvertent coupling of electrical current between the electrodes. Smaller or larger spaces between electrodes (e.g., between 10 degrees and 30 degrees) may be provided in other examples. Each electrode 512 and 514 may be programmed to act as an anode or cathode.

[0146] FIG. 5E shows electrode level 520 which includes three equally sized electrodes 522, 524 and 526. Each electrode 522, 524 and 526 encompass approximately 110 degrees of the circumference of electrode level 520. Similar to electrode level 510, spaces of approximately 10 degrees separate electrodes 522, 524 and 526. Smaller or larger spaces between electrodes (e.g., between 10 degrees and 30 degrees) may be provided in other examples. Electrodes 522, 524 and 526 may be independently programmed as an anode or cathode for stimulation.

[0147] FIG. 5F shows electrode level 530 which includes four electrodes 532, 534, 536 and 538. Each electrode 532, 534, 536 and 538 covers approximately 80 degrees of the circumference with approximately 10 degrees of insulation space between adjacent electrodes. Smaller or larger spaces between electrodes (e.g., between 10 degrees and 30 degrees) may be provided in other examples. In other embodiments, up to ten or more electrodes may be included within an electrode level. In alternative embodiments, consecutive electrode levels of lead 114 may include a variety of electrode levels 500, 510, 520, and 530. For example, lead 114 (or any other lead described herein) may include electrode levels that alternate between electrode levels 510 and 530 depicted in FIGS. 5D and 5F. In this manner, various stimulation field shapes may be produced within brain 120 of patient 112. Further the above-described sizes of electrodes within an electrode level are merely examples, and the invention is not limited to the example electrode sizes.

[0148] Also, the insulation space, or non-electrode surface area, may be of any size. Generally, the insulation space is between approximately 1 degree and approximately 20 degrees. More specifically, the insulation space may be between approximately 5 and approximately 15 degrees. In other examples, insulation space may be between approximately 10 degrees and 30 degrees or larger. Smaller insulation spaces may allow a greater volume of tissue to be stimulated. In alternative embodiments, electrode size may be varied around the circumference of an electrode level. In addition, insulation spaces may vary in size as well. Such asymmetrical electrode levels may be used in leads implanted at tissues needing certain shaped stimulation fields. In some examples, the insulation region of the lead may include a projection that extends radially outward from the lead body. Although not shown, any lead or electrode array may include one or more fixation elements (e.g., tines, screws, electrode shapes, adhesives, etc.) that enable the lead or electrodes to be relatively fixed in position with respect to surrounding tissue.

[0149] FIG. 6 is a flowchart illustrating an example technique for delivering AEF therapy to a patient. The technique of FIG. 6 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 6 in other examples. The technique of FIG. 6 may apply to therapies other than AEF therapy in a similar manner.

[0150] As shown in the example of FIG. 6, processing circuitry 210 receives a request to deliver alternating electric field (AEF) therapy (600), such as from external programmer 104 or a pre-programmed delivery schedule. Processing circuitry 210 then determines therapy parameter values for AEF therapy (602). This determination may be retrieval of parameter values from memory or determining one or more parameter values based on a delivery schedule, sensed data, or any other information.

[0151] Processing circuitry 210 then delivers the AEF therapy by delivering a first electric field from a first electrode combination (604) alternating with delivery of a second electric field from a second electrode combination different than the first electrode combination (606). In some examples, the first and second electrical fields may be phase shifted so as to not overlap. In other examples, the first and second electrical fields may be phase shifted so as to partially overlap in time. In some examples, the first and second electrical fields may be temporally interleaved to be fully non-overlapping or partially overlapping. Although the first and second electrical fields may be delivered with the same amplitude and frequency, the first and second electrical fields may be defined by different amplitudes and/or different frequencies (e.g., 150 kHz and 200 kHz). The first and second electrode combinations may use completely different electrodes or partially different electrodes, for example. The first and second electrode combinations may be selected to generate respective electrical fields that are orthogonal to each other or oblique, in some examples. Although all electrodes of the first and second electrode combinations may be implanted in some examples, one or more of the electrodes may be external electrodes in other examples. In general, processing circuitry 210 may determine the frequency of electrical field alternation based on the number of electrical combinations used to alternate the electrical fields for therapy. No interphase period may be required between the delivery of each electric field, although processing circuitry 210 may provide an interphase period in some examples.

[0152] Processing circuitry 210 then determines whether to terminate the AEF therapy (608). If processing circuitry 210 determines that AEF therapy is not to be terminated, processing circuitry 210 continues to deliver the first and second electric fields (604 and 606). If processing circuitry 210 determines that AEF therapy is to be terminated or otherwise paused, processing circuitry 210 stops delivering the AEF therapy to the patient (610).

[0153] FIG. 7 is a flowchart illustrating an example technique for generating a model of anatomy for a patient for AEF therapy planning. The technique of FIG. 7 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 7 in other examples.

[0154] In the example of FIG. 7, processing circuitry 310 receives imaging data of anatomy for a patient (700). This imaging data may include at least one of data obtained by at least one of magnetic resonance imaging (MRI), computed tomography, or magnetoencephalography

(MEG), or any other imaging modality. Processing circuitry 310 then receives sensing data from one or more implanted sensors in the patient (702). This sensed data may include LFPs, impedance tomography, voltage gradients or electric field strengths, or any other type of sensed information. Processing circuitry 310 may then identify, based on the imaging data and the sensing data, locations of cerebral spinal fluid, a resection cavity, and a possible residual tumor (704). In this manner, external and internal imaging techniques can be used to identify various tissue locations. These locations of anatomical structures and fluids may play a role in the propagation of electrical fields within the anatomy for a brain of a patient. Locations of other types of tissues may also be determined from the imaging data and/or sensing data. Different locations may be applicable to other types of target tissue. Based on the identified locations, processing circuitry 310 then generates a model of the anatomy for the patient (706). In some examples, the model of the anatomy may indicate locations of high electric field strength, high field gradients, or other electrical properties that may affect the AEF therapy. These high gradients may occur at edges or interfaces between different types of tissues such as between CSF and the resection bed.

[0155] Processing circuitry 310 can then output, for display, the model (708). For example, user interface 302 may generate a visual representation of the model to a user. In other examples, the model may be of a brain of the patient and identify various locations, target tissues, or other aspects of the anatomy for delivery of AEF therapy. A user, such as a surgeon, may utilize the model to plan implant locations for leads or electrodes and/or determine various stimulation parameters that will define AEF therapy. The model may indicate the tumor that needs to be removed and/or the expected resection region that will result from surgical removal of the tumor. Therefore, lead position and/or electrode configuration may be planned to treat the tumor and/or treat the remaining tissue around the resection region after the tumor is removed. In some examples, different types of leads may be selected for implantation based on the model. [0156] For sensing data, the system may utilize an electrode array for electrical impedance tomography by injecting a current in a pair of electrodes and then recording the resulting voltage at other electrodes. The system can then generate a resulting reconstructed image using electrical impedance tomography. In some examples, additional electrodes may be utilized as floating ground during sensing in order to “soak” extra current delivered to the patient. These floating grounds may enable improved signal to noise ratio of the reconstructed image. [0157] FIG. 8 is a flowchart illustrating an example technique for predicting electrical field strength for AEF therapy. The technique of FIG. 8 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 8 in other examples.

[0158] As shown in the example of FIG. 8, processing circuitry 310 is configured to control stimulation circuitry 208 of IMD 106 to deliver AEF therapy to patient 112 (800) and control sensing circuitry 204 to generate sensed data representative of a sensed electric signal resulting from delivery of the AEF therapy (802). Processing circuitry 310 then receives the sensed data and determines one or more electrical physics parameters indicative of the sensed electric field (e.g., the sensed electrical signal) (804) and predicts an electrical field strength for anatomy of the patient based on the electrical physics parameter, such as an electrical field strength (806). Then, processing circuitry 310 generates, based on an electrical field strength (or other electrical physics parameter), a metric of the AEF therapy and displays the metric of the AEF therapy (808).

[0159] In some examples, stimulation circuitry 208 is configured to deliver the AEF therapy via a first set of electrodes, and sensing circuitry 204 is configured to generate the sensed data from the sensed electrical signal obtained from a second set of electrodes different than the first set of electrodes. The sensing data may include at least one of evoked signals, local field potentials (LFPs), or impedance tomography, or measures of voltage gradient or electric field generated by the therapy. In some examples, processing circuitry 310 may predict the electric field strength over a volume of the anatomy. The metric may include a singular value indicative of the AEF therapy efficacy for a target tissue within the anatomy. In other examples, the metric may provide location specific information related to the predicted electrical field strength, such as gradients with respect to respective locations of the anatomy of the patient,

[0160] In this manner, a system can model electric field strength magnitude and/or direction across surrounding tissue and tumor volume. Multiple factors can impact this calculation, including: tissue conductivity for each tissue type, tissue relative permittivity for each tissue type, electrode selection, inter-electrode spacing, intra-electrode contact spacing, electrode contact size, proximity and distribution of fluid collections relative to the tissue of interest (i.e. CSF within sulci, ventricles, lesional cyst, or resection cavity), some of which may change over time with disease progress, recovery after surgery, or normal lifestyle and ageing effects. Therefore one, some, or all of these factors can be sensed and used to calculate the electric field strength. For example, data recording from stimulating parameters and resulting electric field reported by measurement electrodes can be used by the system to derive values for intrinsic electrical physics parameters (i.e. conductivity and relative permittivity). Following the derivation and/or assumption of one or more electrical physics parameters, the system can utilize a model of the patient anatomy to predict electrical field dispersion within the target organ environment (e.g., the brain). Programmer 104 or another device may display the metric indicative of alternating electrical field over tissue (as opposed to a static electric field of one polarity).

[0161] FIG. 9 is a flowchart illustrating an example technique for determining stimulation parameters for AEF therapy based on user input identifying target tissue. The technique of FIG.

9 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3.

However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 9 in other examples.

[0162] As shown in the example of FIG. 9, processing circuitry 310 receives first user input defining target tissue to receive AEF therapy (900) and receives second user input defining tissue to avoid receiving AEF therapy (902). User interface 302 may receive the first and second user input. Then, processing circuitry 310 determines, based on at least one of the first user input or the second user input, one or more stimulation parameters that at least partially defines the AEF therapy (904). In other examples, processing circuitry 310 may only receive user input that defines the target tissue or only user input that identifies tissue to avoid.

[0163] Processing circuitry 310 can then control a medical device (e.g., IMD 106) to deliver the AEF therapy according to the one or more stimulation parameters. For example, programmer 104 can transmit the stimulation parameters to IMD 106. The one or more stimulation parameters may include one or more electrode combinations that at least partially define the AEF therapy. In addition, or alternatively, the one or more stimulation parameters comprises one or more implant locations for one or more leads that carry electrodes for delivering the AEF therapy. [0164] In this manner, a user can define a desired target tissue and compare, or the system can automatically compare, predictions of electrical field to desired values for the anatomy. For treatment of glioblastoma, boundaries of the resection tumor bed (e.g., the region around surgically resected tumor) is the most likely target tissue for AEF therapy. In some examples, it may be beneficial for the user or system to define regions of tissue to avoid delivering alternating electric fields during therapy. These avoidance regions may be appropriate for regions with high conductivity in which current would be pulled and “wasted” within this tissue types (i.e. within the brain paths that go through CSF, such as the ventricle).

[0165] One possible approach for treating the patient with AEF is to provide weak electric fields spread over large area (in contrast to deep brain stimulation (DBS), which generally uses a more concentrated electrical signal). This relatively weaker electrical stimulation may avoid neural activation from electrical fields, enable the system to track levels of field strength as a function of activation threshold (e.g., sub- or supra-threshold stimulation), and track electrical fields. In some examples, programmer 104 can display a metric of this weaker electric field for real-time monitoring of AEF therapy by programmer 104 and/or the clinician. The metric may include dosimetry and/or may be used by IMD 106 in a closed-loop manner to maintain a minimum electrical field strength and/or prevent exceeding a maximum electrical field strength. [0166] Despite a presumed minimal impact of thermal heating from implanted electrodes during AEF therapy, some tissue regions will be eloquent or particularly sensitive to the alternating electrical fields. Therefore, planning software provided by programmer 104 may include options for regional distinctions that identify acceptable level of risk. One example would be for cerebral implantation where the system can present eloquent regions of the brain to consider in avoiding neurological morbidity within the planning environment.

[0167] In some examples, predictive modeling may by employed by the system to update predictions of AEF magnitude and/or direction based on a new imaging evaluation of the patient’s target organ of interest, such as the brain. The system may utilize predictive modeling to provide computer generated optimization of implantation strategy, such as the locations at which electrodes or leads should be implanted, to improve the ability of the sy stem to treat a target region of interest (e.g., a tumor or resection bed) within the target organ and/or increase the coverage of therapy to the entire target organ. The sy stem may generate predictions for initial implantation to aid in surgical planning and/or for updated or revised implantation configurations. Generally, predictions can accommodate or select different electrode styles (e.g., electrode grids, depth electrodes, etc.), different electrode pairing combinations, and different phase shifting pairs within different pairing combinations for various possible alternating electrode field options. In some example, each pair of electrodes (or electrode combination) maybe phase shifted in order to deliver the alternating electric fields. Therefore, the system may utilize the magnitude of the phase shifting as part of predicting the AEF magnitude delivered to tissue.

[0168] These predictions can be leveraged by the system to determine appropriate wavelength and amplitude of the electrical signals applied. In some examples, the system may adjust options for reducing the number of leads, utilization of only certain types of leads, application of certain types of pairing combinations, and/or customization of all parameters within the dosimetry principles for AEF therapy. In some examples, the system may generate a target zone for standard treatment planning based on the target AEF dosimetry. This target zone may include the region of interest and some additional tissue width, such as 3 mm around resection cavity.

[0169] The system may perform modeling of tissue and predictions of AEF therapy at different times with respect to planning and delivery of therapy. In one example, the system may operate to provide preoperative modeling with predictive mapping of electrical fields anatomy to facilitate treatment planning. In some examples, the system may provide postoperative modeling with predictive mapping to guide treatment initial parameter selections for AEF therapy, such as frequencies, electrode combinations, amplitudes, and other parameter values. In addition, or alternatively, the system may generate progress update mapping following the acquisition of new imaging of the patient including the region of the previous implant. This process can enable the system and/or clinician to monitor for changes in residual tumor and the surrounding tissue, and account for remodeling of tissue that might occur post-surgery and/or normal changes with ageing or growth. User interface 302 of programmer 104 may display possible implant configuration and AEF dispersion predictions during treatment parameter programming. These user interface options may be different for clinicians and patients, such as providing more detailed parameter selection for clinicians and a simpler interface and selections for patients (e.g., on/off and/or amplitude adjustments. [0170] FIG. 10 is a conceptual diagram of an example three-dimensional user interface for programming AEF therapy. As shown in FIG. 10, user interface 1002 may be displayed as a three-dimensional representation (on a two-dimensional screen or a three-dimensional interface) of various elements associated with AEF therapy. User interface 1002 provides three- dimensional environment 1004 that includes brain 1006, leads 1020 A, 1020B, 1020C, and 1020D (collectively “leads 1020”). Affected tissue 1008 indicates the tissue region that receives AEF therapy to a level that can treat the cells within, target tissue 1010 is the tissue area defined by user input that is desired to be treated, and avoidance regions 1012 and 1014 are those tissue areas that the user input has defined for avoiding AEF therapy.

[0171] User interface 1002 can be used as an AEF therapy planning tool (e.g., for lead implantation locations and other stimulation parameters that define AEF therapy) and as a tool for updating stimulation parameters after therapy has begun. For example, a user may initially provide user input defining target tissue 1010 and/or avoidance regions 1012 and 1014 (or more). Brain 1006 may include imaging data that represents various locations of different tissues and structures within the anatomy so that the user can identify which regions of interest for AEF therapy. The user input may be input outlining each tissue region, dragging outlines to desired locations, moving regions to a desired location, or any other input method. In some examples, the system may automatically suggest target tissue 1010, but the user can move or adjust that region as desired.

[0172] Based on the target tissue 1010 and/or avoidance regions 1012 and 1014, the system may recommend a certain number of leads 1020, implant locations for leads 1020, types of leads 1020, any other hardware recommendations. The system may also, or alternatively, recommend stimulation parameter values that will result in affected tissue 1008 that may be similar to target tissue 1010 while reducing the overlap with any of avoidance regions 1012 and 1014. User interface 1002 may receive user input moving one or more of leads 1020, adjusting one or more stimulation parameters, and/or adjusting one or more of target tissue 1010 or any of avoidance regions 1012 and 1014. In some examples, user interface 1002 may also show additional features related to AEF therapy, such as electrical field gradients. As described herein, the system may include a therapy planning module that generates recommendations for one or more aspects of AEF therapy (or other therapy) based on user input and/or sensed signals associated with the patient. The system may generate recommendations for lead placement, electrode selection, or other stimulation parameters based on any available information for the patient and predictions generated using the patient model or other characteristics. In some examples, the therapy planning module may provide guidance that may reduce electric field spread into unwanted or avoided regions which can increase energy efficiency for therapy and/or reduce unwanted side effects from the delivered electric field therapy. For example, since AEF therapy may reduce growth of cancerous tissue, electric field spread into healthy tissue may also reduce the growth or other function of cells in the healthy tissue.

[0173] FIG. 11 is a flowchart illustrating an example technique for determining stimulation parameters for AEF therapy based on histological data from tumor tissue. The technique of FIG. 11 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 11 in other examples.

[0174] In the example of FIG. 11, processing circuitry 310 can receive histological data for tissue associated with a glioblastoma tumor (1100). For example, a clinician may take a sample of tissue from the patient and perform one or more histological analyses on the sample. Then, processing circuitry 310 or a user can determine one or more characteristics of tissue from the histological data (1102). Based on these one or more characteristics, processing circuitry 310 can determine stimulation parameters for AEF therapy (1104). For example, processing circuitry 310 can make an adjustment to one or more parameters to refine the AEF therapy, either retrospectively using stored data or in real-time as sensed data is received. Processing circuitry 310 can then store the new stimulation parameters for subsequent AEF therapy delivery (1106) and, in some cases, control IMD 106 to deliver the updated AEF therapy.

[0175] Given that cells respond differently to AEF therapy largely due to differences in the physical size and orientation of different tumor cells, these personalized stimulation parameters can be more accurately assigned following histological analysis of a given patient’s tumor biopsy. Cell size can be an important physical parameter because the cell size impacts the dispersion of electric field across the cell in a predictable pattern. In some examples, the system may select lower frequency of AEF therapy for larger cells than smaller cells. In this manner, a patient-specific therapy plan can include customized stimulation parameters such as AEF magnitude or strength, frequency, vectoral field direction, phase shift, etc. In some examples, the system or user can utilize a patient-specific tumor cell culture to establish patient-specific treatment parameters that increase the cells inhibition of mitotic activity. For example, an amplitude of 2.25V/cm or a frequency of 187.3 kHz may be used as an AEF configuration to cease cell division in target tissue. This magnitude is likely variable dependent on the tumor type, patient-specific tumor subtype, and other treatment parameters (e.g., AEF frequency). Other parameters that may be adjusted based on patient-specific cell status may include duty cycle, frequency, amplitude, and duration of exposure to the AEF therapy.

[0176] FIG. 12 is a flowchart illustrating an example technique for identifying target tissue for AEF therapy based on water content determined from imaging data. The technique of FIG. 12 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 12 in other examples.

[0177] In the example of FIG. 12, processing circuitry 310 can receive MR! data for target anatomy associated with a glioblastoma tumor (1200). Then, processing circuitry 310 or a user can determine water content variations in the target anatomy based on the MRI or diffusion tensor imaging (DTI) data (1202). Based on the water content variations, processing circuitry 310 can determine different tissue types for the target anatomy (1204). The water content variations may be indicative of conductivity estimates for the tissue. In some examples, water content variations may be indicative of tissue boundaries. Then processing circuitry 310 can identify target tissue for delivery of AEF therapy based on the locations of the tissue types (1206). In some examples, processing circuitry 310 can determine stimulation parameters for AEF therapy in order to deliver the AEF therapy to the target tissue. Processing circuitry 310 can then store the stimulation parameters for subsequent AEF therapy delivery (1106) and, in some cases, control IMD 106 to deliver the updated AEF therapy.

[0178] In this manner, modeling of AEF therapy can be informed by assumptions regarding the electrophysical parameters of tissue types. The system can then utilize MRI data to determine one or more physical parameters based on the water content (and/or boundaries between different tissue types) quantified by the imaging, e.g. ,MR electrical properties tomography (MREPT). The water content data can serve as a baseline for model generation which can be enhanced further utilizing real-time patient data from implanted recording, which may leverage machine learning techniques. Existing efforts to perform modeling of body tissues (particularly the brain) are challenged by the anatomical complexity and person-to-person variability. Therefore, assumptions regarding electrophysical parameters can reduce modeling accuracy considerably. Measuring water content and other aspects can increase the modeling accuracy. In some examples, the water content data can improve conductivity estimates for known tissue structures within the brain of the patient. In addition, or alternatively, the system may segment the anatomy based on the water content to indicate regions with different electrical conductivity.

[0179] FIG. 13 is a flowchart illustrating an example technique for identifying target tissue based on impedance tomography data. The technique of FIG. 13 will be described with respect to processing circuitry 310 of programmer 104 in FIG 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 13 in other examples.

[0180] In the example of FIG. 13, processing circuitry 310 controls IMD 106 to deliver electrical signals via different electrode combinations (1300). IMD 106 then senses electrical potentials from one or more respective electrode combinations for electrical signals delivered from each electrode combination (1302). Then, processing circuitry 310 can receive the sensed electrical potentials and generate impedance tomography data for the patient anatomy based on the sensed electrical potentials (1304). Based on the impedance tomography data, processing circuitry 310 can identify target tissue for delivery of AEF therapy (1306). In other examples, IMD 106 may perform some or all of these steps in order to identify target tissue based on the impedance tomography data.

[0181] As discussed herein, the impedance tomography data can characterize types of tissue within the treatment planning environment for AEF therapy. The electrical potentials sensed from the anatomy can be used to determine impedance measures to localize the area of the glioblastoma progression or likelihood of progression. Impedance tomography can characterize the heterogeneity of the cells in the anatomy, which can improve understanding of the tissue subject to the AEF therapy. For example, the system or user can utilize the impedance tomography data in order to identify the greatest density of tumor cells, which may be identified as at least part of the target tissue for AEF therapy, which can inform lead placement. [0182] FIG. 14 is a flowchart illustrating an example technique for generating a map of AEF dosimetry for a patient. The technique of FIG. 14 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 14 in other examples.

[0183] In the example of FIG. 14, processing circuitry 310 can receive a model of the anatomy of the patient (1400). This model may be generated based on one or more imaging modalities as described herein. Then, processing circuitry 310 can generate an AEF dosimetry metric based on the model (1402). This dosimetry metric may represent the effective therapy dose of the AEF received by cells during therapy. Processing circuitry 310 can then map the AEF dosimetry across the target tissue of the anatomy in order to indicate which areas of tissue are receiving different doses of AEF therapy (1404). In order to visualize the map, processing circuitry 310 may control user interface 302 to display the map of the AEF dosimetry with respect to the anatomy (1406). For example, the user can identify which regions of tissue may be receiving a too high dose, or a dose that is insufficient for therapy.

[0184] As discussed herein, characteristics of the AEF therapy that may influence effectiveness include frequency, magnitude, and vectoral direction of the electrical fields. One dosimetry metric may be an average field intensity. The average field intensity may instead be referred to as a local minimum field intensity (LMiFI). For example, this metric may be equivalent to a lower of the 2-field intensities from 2 orthogonal directions used during AEF treatment. In situations in which the electrode combinations provide more than 2 orthogonal directions, this metric may represent an average of all AEF magnitudes experienced by a single point in space over a period of time, such as a one second interval.

[0185] Another dosimetry metric may be referred to as the power loss density. The power loss density may be referred to as the energy per unit of time deposited by AEF therapy, which may be P = 1/2σE ² . P is the power loss density (e.g., Watt/volume), σ is the tissue conductivity (Siemens/meter), and E is the magnitude of the electric field (Volts/cm). In some examples, the average field intensity metric could be used in place of the magnitude of the electric field to provide a combination of information that may indicate the power dispersion over the tissue. Another dosimetry metric may be a dose density which can be referred to as local minimum dose density. The dose density metric may be equivalent to the local minimum pow'er density (LMiPD) multiplied by the average patient compliance with treatment. In other words, if the patient does not comply with the treatment schedule, the dose density metric decreases. AEF therapy using IMD 106 may increase patient compliance to, or close to, 100% because the patient can receive therapy during most times of the day. However, less compliance may be relevant and used to identify reduced dosages that may affect therapy efficacy.

[0186] Any of the AEF dosimetry metrics can be display ed by the user interface of the modeling predictions for mapping AEF across a target tissue of interest. For a treatment planning system, the dosimetry metric can be used to specify the desired region of effect. For example, the user interface may present the dosimetry metric at various stages of planning in order to inform stimulation parameter selection, lead implant locations, durations of therapy, amplitudes, frequencies, or any other parameters. In some examples, the system may display a target dosimetry that the user, or system, may attempt to achieve for the target tissue during therapy planning. In some examples, mapping the AEF therapy may utilize the power loss density metric in order to distinguish between various electrode locations, electrode combinations, or other stimulation parameters during treatment planning. In some examples, dosimetry metrics may account for phase shifting if not already addressed in the metric. In some examples, the user will be configured to receive one or more of user selection of a defined target tissue 1010, user selection of one or more lead style(s), user selection of lead locations, user selection of lead stimulation amplitudes, or user selection of lead stimulation frequencies. For any of these parameters that the system does not receive user input, the system may automatically select parameter values that would be appropriate to satisfy the given user input received. In some examples, the system can then output appropriate AEF dosimetry metrics resulting within the 1010 target tissue environment. Example user input fields that can be used to receive user input may include text boxes, magnitude or location sliders, numerical input, drop down selection menus, (e.g., lead styles or lead location), or any other type of input mechanism.

[0187] FIG. 15 A is a flowchart illustrating an example technique for sweeping through different frequencies for AEF therapy . The technique of FIG. 15 A will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 15A in other examples. [0188] In the example of FIG. 15A, processing circuitry 210 initiates AEF therapy using a frequency sweep (1500). First, processing circuitry 210 controls IMD 106 to deliver the AEF therapy according to a selected frequency and amplitude (1502) for a predetermined period of time. This selected frequency may be one of several frequencies part of the sweep. If processing circuitry 210 determines there are no other frequencies to deliver (“NO” branch of block 1504), processing circuitry 210 stops delivery of the AEF therapy (1506). If processing circuitry 210 determines that there is another frequency to use (“YES” branch of block 1504), processing circuitry 210 determines the new frequency and the new amplitude for that frequency of AEF therapy based on AEF modeling (1508). Since the electrical field propagation through tissue changes with frequency, processing circuitry 210 may adjust the amplitude of stimulation for different frequencies. Processing circuitry 210 then sets the new amplitude for the next frequency of AEF therapy (1510). In some examples, the amplitude selections for respective frequencies may be performed prior to therapy and stored for later retrieval as different sets of parameters for each frequency.

[0189] As discussed above, each AEF frequency permeates tissue types differently. Therefore this modeling variable can be informed by real-time clinical application data recording to estimate the electrical physics parameters (e.g., impedance and/or permeability) relevant to the tissue type at a given AEF frequency. In use, the system can ensure constant field strength from AEF therapy as IMD 106 changes frequency by changing voltage amplitudes to account for changing tissue permeabilities during the frequency sweep. In some examples, the amplitude selections may be based on generalized tissue data or patient populations. In other examples, the patient specific model of tissue may be used to select amplitudes for respective frequencies. The utilization of measurement electrodes can enable data acquisition during real-time clinical delivery of AEF from implanted electrodes. The system can then utilize the measurements for improving the model of tissue under AEF therapy. This improved model can then be leveraged by the system to improve modeling predictions during implant planning and or delivery of therapy.

[0190] As described above, processing circuitry, such as processing circuitry 210, can receive a request to deliver alternating electric field (AEF) therapy, wherein the AEF therapy comprises delivery of a first electric field and a second electric field. Processing circuitry 210 can also control an IMD 106 to deliver the AEF therapy by iteratively sweeping through each selected frequency of a plurality of frequencies, where, for each selected frequency of the plurality of frequencies, processing circuitry 210 controls IMD 106 to deliver the first electric field from a first electrode combination of implanted electrodes at the selected frequency in alternating fashion with the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination and at the selected frequency. In addition, processing circuitry 210 or other device can determine respective amplitudes for each selected frequency of the plurality of frequencies based on a model of AEF therapy.

[0191] In some examples, the system can predict progression zones, which may be areas of tissue where disease progression may occur, such as progression within the brain (for glioblastoma). Therefore, this prediction of progression can be combined with the AEF treatment modeling environment to further establish target tissue or other parameters via the user interface for the clinician during procedural planning and treatment parameter evaluations. In some examples, clinical data research can be conducted utilizing data acquisition of regional recurrence relative to the AEF treatment dosimetry map in populations in order to refine AEF therapy over time.

[0192] FIGS. 15B and 15C include graphs of example relationships between certain cell characteristics. As shown in FIG. 15B, graph 1540 provides a relationship between a force applied to a cell at different frequencies of electrical field. Graph 1542 provides a relationship between the frequency of maximal force to a cell and the cell radius, or cell size. As shown, the relationship between frequency and cell size to achieve the maximal force is an inverse relationship. Smaller frequencies are effective for larger cell size. As described herein, determining the cell size of a tumor or possible tumor cells can enable a system to adjust the frequency of the electric field therapy to achieve the maximal force for disrupting cell mitosis and/or other functions. As shown in FIG. 15C, graph 1544 is a graph of the relationship between the maximum force (as frequency to cytoplasm conductivity. Graph 1546 is a graph of the relationship between the maximum force (as frequency) to the membrane thickness. Therefore, the system may adjust frequency of electric field therapy according to any one or all of these cell characteristics in order to improve effectiveness of the therapy in disrupting cell function such as mitosis.

[0193] FIG. 16 is a conceptual diagram of an example three-dimensional user interface 1602 for planning implantation of electrodes for AEF therapy. As shown in FIG. 16, user interface 1600 may be displayed as a three-dimensional representation (on a two-dimensional screen or a three-dimensional interface) of various elements associated with AEF therapy. User interface 1600 provides three-dimensional environment 1602 that includes brain 1604, leads 1610A, 1610B, 1610C, and I610D (collectively “leads 1610”). Resection bed 1606 indicates the location of the area from which a glioblastoma tumor was removed. The resection bed generally refers to the tissue that is exposed after the tumor is removed, such that the resection bed would be the inner surfaces of the remaining tissue. Initially, imaging data may be used to identify the location, size, and shape of resection bed 1606 with respect to other tissues or structures (not shown) identified within brain 1604.

[0194] Then, the system may automatically place one or more leads 1610 in spatial relation to resection bed 1606 in order to treat that area, such as at the boundary of resection bed 1606 and adjacent unremoved tissue. User interface 1600 may receive user input moving any of leads 1610 to a different location. The locations of leads 1610 may be used to plan implant locations for the patient. The electrodes of leads 1610 may be used to deliver AEF therapy and/or sense signals. For example, sensing electrodes at this boundary of resection bed 1606 may enable the system to measure AEF dosimetry metrics.

[0195] FIG. 17 is a flowchart illustrating an example technique for adjusting stimulation parameters for AEF therapy based on sensed electrical signals. The technique of FIG. 17 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 17 in other examples.

[0196] In the example of FIG. 17, processing circuitry 210 delivers AEF therapy (1700). Processing circuitry 210 then controls IMD 106 to sense electrical signals via one or more electrodes disposed at a boundary of a tumor resection bed (1702), such as shown in FIG. 16. Then, processing circuitry 210 compares the sensed electrical signals to target signal characteristics (1704). This process may enable the system to adjust AEF therapy based on one or more feedback variables to increase therapy efficacy.

[0197] If processing circuitry 210 determines therapy should not be adjusted (“NO” branch of block 1706), processing circuitry 210 continues to deliver AEF therapy (1700). If processing circuitry 210 determines that adjustments should be made (“YES” branch of block 1706), processing circuitry 210 adjusts one or more stimulation parameters that define AEF therapybased on the comparison. The process then continues to deliver AEF therapy with the adjusted parameters. In some examples, processing circuitry 210 may adjust the parameters within (e.g., limited by) one or more safety ranges, minimum levels, or energy budgets. In this manner, the adjustment may be limited in one or more respects. For example, processing circuitry 210 may deliver as much energy as possible until a recharge interval hits a low patient tolerated value. [0198] In this manner, IMD 106 may operate such that stimulation circuitry 202 is configured to deliver AEF therapy to a patient and sensing circuitry 204 is configured to generate sensed data representative of a sensed electric signal(s) via one or more electrodes disposed at a boundary of a tumor resection. Processing circuitry 210 can then receive the sensed data, compare the sensed data to one or more target signal characteristics, adjust, based on the comparison, one or more stimulation parameters from a first value to a second value, and control the stimulation circuitry to deliver the AEF therapy according to the second value of the one or more stimulation parameters. In some examples, processing circuitry 210 is configured to compare the sensed data to one or more target signal characteristics at a predetermined interval. The stimulation parameters may include one or more electrode combinations, a frequency, or a cycling duration for the AEF therapy.

[0199] In some examples, processing circuitry 210 or other device may modulate AEF dosimetry parameters to maintain therapeutic effect based on the measured electrode feedback (e.g., signals sensed at the sensing electrodes). The sensed parameters may include amplitude (Vpp), electrode pairing (e.g., electrode combination and/or polarity), and AEF frequency. Processing circuitry 210 may initiate sensing of electrical signals are various times, such as following implantation to establish tissue baseline for initial treatment parameter selection or on continuous or interval based schedules over time to account for changes in target tissue (e.g., scarring, tumor progression) or lead migration.

[0200] In some examples, the system may utilize different stimulating and measuring electrodes to determine electrical field at target region around or within the tumor or resection bed. Processing circuitry 210 may time interleave stimulating and sensing functions. Further, one or more extra electrodes may be configured to “soak” up stimulation (like floating ground to work with stimulating and sensing electrodes) during sensing functionality. These current sink electrodes may be selected based on where the sensing electrodes are and/or where the target tissue is located with respect to the electrodes.

[0201] FIG. 18A is a flowchart illustrating an example technique for switching polarity of electrodes for AEF therapy. The technique of FIG. 18A will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 18 in other examples.

[0202] In the example of FIG. 18 A, processing circuitry 210 delivers AEF therapy with a first electrode configuration having alternating polarities between adjacent electrodes (1800). Processing circuitry 210 then controls IMD 106 to switch polarity of all electrodes to determine second electrode configuration having alternating polarities between adjacent electrodes (1802). In some examples, this switching may be between more than two electrode configurations. The number of electrode configurations may only be limited by the possible electrode combinations available to IMD 106. This switching scheme is shown in FIG. 18B. Then, processing circuitry 210 delivers AEF therapy with the second electrode configuration (1804). If processing circuitry 210 determines therapy should not be terminated (“NO” branch of block 1806), processing circuitry 210 continues to deli ver AEF therapy (1800). If processing circuitry 210 determines that therapy is to be terminated (“YES” branch of block 1806), processing circuitry 210 terminates or stops AEF therapy (1808).

[0203] FIG. 18B is a conceptual drawing illustrating an example progression of polarity switching for AEF therapy. As shown in FIG. 18B, the vectoral direction of the electric field is ideally parallel to the axis of cell division designed to hinder the mitotic process of cells. The arrow heads represent anodes of voltage sources and the arrow tails indicate cathodes of voltage sources.

[0204] The chain strategy for electrode contact pairing shown in FIGS. 18A and 18B illustrate that pairing is defined as a state of inverse waveform state comparing one contact to the other. Within the chain adjacent electrode contacts are 180 degrees (Iπ) out of phase between electrodes resulting in increased change in voltage between the tissue separating the two given electrode contacts. This may result in the strongest electric field magnitude. Pairing of electrode contacts with separate adjacent electrodes can permit greater control of the electric field vectoral direction. Therefore a vast number of potential directional options can be dependent on the selected pairing, phase shifting, and inter-lead 3-dimensional configuration.

[0205] FIG. 19A is a flowchart illustrating an example technique for switching polarity between electrode pairs of a cube configuration for AEF therapy. The technique of FIG. I9A wall be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 19A in other examples.

[0206] In the example of FIG. 19A, processing circuitry 210 delivers AEF therapy with a first electrode configuration having paired electrodes selected from cube configurations (1900). Processing circuitry 210 then controls IMD 106 to select second electrode combinations having paired electrodes selected from the cube configurations (1902). This switching scheme is shown in FIG. 19B. Then, processing circuitry 210 delivers AEF therapy- with the second electrode configuration (1904). If processing circuitry 210 determines therapy should not be terminated (“NO” branch of block 1906), processing circuitry 210 continues to deliver AEF therapy (1900). If processing circuitry 210 determines that therapy is to be terminated (“YES” branch of block 1906), processing circuitry 210 terminates or stops AEF therapy (1908).

[0207] FIG. 19B is a conceptual drawing illustrating an example progression of paired electrode selection using cube configurations for AEF therapy. As shown in FIG. 19B, the cube strategy for electrode contact pairing includes pairing defined as a state of inverse waveform state comparing one contact to the other. Within the cube configuration, pairing is performed between contacts along the 8 apices of the cube. This provides for 28 possible electrode pairing combinations and therefore numerous potential methods of achieving vectoral electric field control within the region of the cube. In one examples, IMD 106 may include independent voltage or current sources to enable IMD 106 to incrementally sweep the field vector from an apex on one cube to another (e.g., from one electrode to another electrode in an electrode array). In this manner, IMD 106 may provide more intermediate field orientations that can impact cells. [0208] Over time, the system can vary between different electrodes at different times to sweep polarity and field strength over the entire volume of target tissue. This method may result in complex steering with changing direction, phase, and field strength to achieve greater control of electric field vectoral direction and strength for AEF therapy. [0209] FIG. 20 is a flowchart illustrating an example technique for displaying user selectable electrode configurations for AEF therapy. The technique of FIG. 20 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 20 in other examples.

[0210] In the example of FIG. 20, processing circuitry 310 determines possible electrode combinations for delivering AEF therapy (2000). These electrode combinations may be used for sweeping AEF therapy between different electrode combinations which may reach additional tissue. Then, processing circuitry 310 displays the possible electrode configurations for AEF therapy (2002). User input may also select a desired order in which the electrode combinations may be used to deliver AEF therapy. In some examples, processing circuitry 310 may preselect a subset of recommended electrode combinations based on already collected data such as target tissue locations. If processing circuitry 210 determines that user input was not received (“NO” branch of block 2004), processing circuitry 210 continues to present the possible electrode combinations (2002). If processing circuitry 210 determines that user input was received (“YES” branch of block 2004), processing circuitry 210 stores the selected electrode combinations and sweep selections for delivery of AEF therapy (2006).

[0211] In some examples, the system may map different stimulation channels (e.g., electrode configurations) using multiple contacts can be more complex than 1 : 1 mapping. This may enable greater control of AEF dosimetry with a given implantation configuration. Since different electrode configurations can provide different orientation phasing when everything changes, the system may provide a disruptive environment within the tissue between the two paired stimulating electrode contacts. Configurations of stimulation channels can be wired for different directional pairing (i.e. diagonal vs. inline). The system may sweep through configurations to get many different permutations to cover the field. In some examples, the system may provide many independently controlled electrodes (e.g., 128 or more electrodes) to enable any pairing configurations an option at any point in time to cover target tissue and/or avoid other tissue.

[0212] FIG. 21 is a conceptual diagram illustrating an example implantable medical device for delivering AEF therapy. As shown in FIG. 21 , system 2100 includes IMD 2106 connected to leads 114A and 114B carrying respective electrodes. IMD 2106 may be referred to as a cranioplasty implant. Following craniotomy for tumor resection from brain 120 of patient 112, bone flap 2102 is still flipped out from the rest of cranium 122. Then, IMD 2106 could be installed within the bone defect (i.e. craniotomy/ craniectomy) 2104 (or burr hole or craniostomy in cranium 122) or within in the bone flap 2102 itself.

[0213] The benefit of this implantation approach is the ability to get an implant within the intracranial space without impinging on the cerebrum. Although IMD 2106 may be further from the target zone (e.g., the resection bed), leads 114A and 114B coupled to IMD 2106 may be inserted to the target tissue. In some examples, leaving the dura open may enable the implant at the level of the cranioplasty to act within the subdural space without impedance. In some examples, leads 114A and 114B may provide an option to remain within the resection cavity or penetrate the cerebral surface, to serve as a surveillance method for the resection bed. In other examples, if the resection bed is closer to the surface of brain 122, electrodes may be carried on IMD 2106 housing itself instead or addition to leads 114A and 114B. Fewer or more leads may be used in other examples, inclusive examples in which multiple cranioplasty implants 2106 are inserted within the same cranium 122.

[0214] FIG. 22 is a conceptual diagram illustrating example implantable medical devices disposed within burr holes for delivering AEF therapy. As shown in the example of FIG. 22, system 2200 includes IMDs 2206 and 2208 connected to leads 114 A and 114B, respectively, carrying respective electrodes. Each of IMDs 2206 and 2208 are sized and configured to be disposed within respective burr holes 2202 and 2204 within cranium 122, IMDs 2206 and 2208 may be referred to as a burr hole sized implants. IMDs 2206 and 2208 may be in wireless communication to synchronize stimulation delivery for AEF therapy. In some examples, IMDs 2206 and 2208 may be coupled via a wire to increase the possible electrode configurations when the electrode array can function as a singular array. In other examples, only one, or three or more, burr hole sized implants may be provided.

[0215] Burr hole sized implants may require the surgeon to make a small skin incision overlying the anticipated electrode placement site an using a drill bit (such as a perforator drill bit). A channel will be made within the skull that is a preset diameter (based on the drill bit). Then the surgeon creates an opening within the dura to expose the burr hole to the pial surface of the brain. Then a custom designed implant the size of the burr hole can be inserted. The distal end of the electrode can be tunneled to a connector which permits tunneling of an extension and connection to the stimulator/waveform generator within the implant. In some examples, a burr hole implant electrode may be paired with a large surface area contact in the brain, subdural location, or external location.

[0216] The configuration of the burr hole implant would require a number of electrodes to be placed to accommodate cerebral stimulation that may be dependent on the target tumor of interest. For example, the implantation strategy might include unilateral or bilateral placement of frontal, occipital, and temporal electrodes. Existing procedures such as pial synangiosis techniques in vascular neurosurgery implement numerous burr holes performed during a single surgery. However, this technique would require multiple incisions or a single very large incision. The distance between electrodes could be between 2 and 15 cm, but smaller or larger distances may also be appropriate for AEF therapy. The position of the burr hole implant(s) would be determined based on patient specific target location 1010 and other stimulating electrodes (e.g., electrodes disposed in the brain, a subdural location, or an external location). [0217] Stimulation voltage for AEF from burr hole implants could be as large as is feasible for an implantable generator of the allowable size that would still avoid thermal injury to tissue. This is because the larger the input voltage the stronger the resulting electric field values within the target tissue to provide greater therapy efficacy. In other examples, one or more electrodes may be coupled to an IMD and placed within a respective burr hole to reach the brain.

Stereotactic EEG or other sensing or stimulation configurations may be used. In some examples, one or more burr hole implant devices (e.g., IMDs 2206 and 2208) could be combined with a cranioplasty implant device (e.g., IMD 2106) to provide a non-cerebral implanted application of AEF therapy to the brain. Such configurations may be particularly useful for superficial tumors. [0218] In some examples, bone-screw electrode implants may be used in addition to, or instead of, the other implanted electrodes described herein. For example, one or more bone- screw electrodes may be coupled to an IMD in order to improve wide range electrical fields and/or increase sensing capabilities to superficial areas of the brain. The dimensions of the bone- screw electrodes may be dependent on the cranium thickness within the target region of the patient. This minimally invasive approach to lead implantation may include either multiple incisions or a single very large incision to expose the cranium and permit distal lead connection. [ 0219] FIG. 23 is a conceptual diagram of an example three-dimensional user interface for planning implantation of electrode arrays for AEF therapy. As shown in FIG. 23, user interface 2300 may be displayed as a three-dimensional representation (on a two-dimensional screen or a three-dimensional interface) of various elements associated with AEF therapy. User interface 2300 provides three-dimensional environment 2302 that includes brain 2304, leads 2308A, 2308B, 2308C, and 2308D (collectively “leads 2308”). Resection bed 2306 indicates the location of the area from which a glioblastoma tumor was removed. Initially, imaging data may be used to identify the location, size, and shape of resection bed 2306 with respect to other tissues or structures (not shown) identified within brain 2304.

[0220] As described herein, depth electrodes (e.g., electrodes carried by leads 2308) may be placed around periphery of resection bed 2306 paired to create a “force field” surrounding resection bed 2306 thereby hindering inward progression of any cancerous cells. Planning of AEF therapy may include determining the number of electrodes, the distance from electrodes to resection bed 2306, and the distance between electrodes. In some examples, the size of electrodes may also be determined. Small electrodes typically create a more focal electrical field close to the electrodes and have trouble reaching deeper tissue. Therefore, when placed within a tumor, small electrodes may be beneficial. For implantation strategies that involve electrode placements farther away from the target tissue, larger electrodes may be advantageous. Various thermal considerations for electrode sizes and shapes may also be considered, as well as electrode materials. Certain electrode characteristics may also be selected to be MRI comparable where appropriate. In this manner, the system may be configured to provide a “tool box” of electrode options that are compatible with implantation for AEF therapy delivery and planning software. Combinations from the tool box may be more appropriate for certain lesions dependent on the target anatomy of interest. In addition to electrodes, any implanted devices or systems described herein may be configured to be compatible with MRI, computed tomography imaging, radiation therapy, or any other imaging modalities. Such compatibility may include selection of compatible materials, compatible structure shapes and/or sizes, or the ability to turn device functionality on or off as needed to reduce interference with imaging systems.

[0221] As shown in FIG. 23, leads 2308 may be disposed around the periphery of resection bed 2306 and combined with one or more paddle lead 2310 disposed a surface of resection bed 2306. Paddle lead 2310 may be any array of electrodes that can be placed near the boundary of the tumor resection. This close placement of paddle lead 2310 may reduce complexity during or after resection of the tumor and may provide a larger surface area to cover the tissue within and/or near resection bed 2306. Instead of paddle lead 2301, any electrode strips or electrode coils may be used to provide a similar coverage effect.

[0222] In any effect, it may be desirable to deliver AEF therapy near resection bed 2306 because the resection bed 2306 is generally a place for tumor regrowth. In one example, one or more balloon or expandable elements can be combined with electrodes or conductive surface within resection bed 2306 to permit appropriate positioning of the electrodes along the irregular interior of the resection bed. In one example, a balloon placement vehicle may be used to place one or more electrodes around resection bed 2306 before removing the balloon placement vehicle. In some examples, the clinician may use a bio-compatible adhesive agent (such as DuraSeal) to affix electrodes at desired locations along the surface of the target organ or resection bed 2306. Additional electrodes or leads may include 3D printable electrode structures configured to match patient-specific resection bed 2306, other tissues, or optimize therapy placement for the specific patient.

[0223] Example types of leads 2308 may include paddle leads for spreading electrical fields or cylindrical leads (as shown in FIG. 23). Electrodes with acute edges or shapes can deliver higher voltage density at those surfaces, and may include star shape electrodes, zig-zag electrodes, many curved and/or angled portions, or other shapes. In some examples, electrode shapes may be configured for patient anatomy and/or resection bed 2306 following surgical resection. In some examples, patient specific sizes of electrodes or leads may be used or modular electrode designs can be configured, assembled, or cut to size in the operating room for a specific target geometry. For example, patient specific dimensions, size of electrodes, electrode spacing, or number of electrodes can be specified for any custom array for a patient. In other examples, a patient-specific three-dimensional form of electrode or array of electrodes may be used to fit the cavity.

[0224] FIG. 24 is a conceptual diagram illustrating example subcutaneous electrodes for use in delivering AEF therapy. As shown in FIG. 24, system 2400 includes IMD 106 connected to leads 114A and 114B carrying respective electrodes 116, 118. In addition, subcutaneous electrodes 2402 and 2404 are controlled by IMD 106 implanted beneath the skin and external of cranium 122 of patient 112, In this manner, processing circuitry 210 of IMD 106 can be configured to control an IMD 106 to deliver a first electric field from a first electrode combination of implanted electrodes and control IMD 106 to deliver, alternating with the first electric field, a second electric field from a second electrode combination of implanted electrodes different than the first electrode combination. The first electric field and the second electric field include AEF therapy deliverable to patient 112, and at least one of the first electrode combination or the second electrode combination comprises one or more subcutaneous electrodes 2402 and/or 2404. In this manner, IMD 106 may be configured to provide wide volume electrical fields while also providing smaller electrical fields from leads 114.

[0225] In some examples, the first electrode combination or the second electrode combination comprises one or more electrodes carried by one or more implantable leads. Put another way, two or more electric fields of the AEF therapy may all include at least one electrode from leads 114. In other examples, one electric field may be provided by only some or all of subcutaneous electrodes 2402 and 2404 and another electric field may be provided by only some or all of electrodes 166, 118. In some examples, subcutaneous electrodes 2402 and 2404 may enable IMD 106 to deliver bihemispherical wide volume AEF therapy.

[0226] FIG. 25 is a conceptual diagram illustrating example cutaneous electrodes and external medical device for use in delivering AEF therapy. As shown in FIG. 25, system 2500 includes IMD 106 connected to leads 114A and 114B carrying respective electrodes 116, 118.

In addition, external cutaneous electrodes 2504 and 2506 are controlled by external medical device 2502. In this manner, processing circuitry 210 of IMD 106 can be configured to control IMD 106 to deliver a first electric field from a first electrode combination of electrodes carried by one or more implanted leads and control external medical device 2502 to deliver, alternating with the first electric field, a second electric field from a second electrode combination of external cutaneous electrodes 2504 and 2406, where the first electric field and the second electric field comprise AEF therapy deliverable to patient 112. In other examples, external electrodes 2504 and 2406 may be directly coupled to IMD 106 such that IMD 106 controls electric fields produced by implanted and external electrodes.

[0227] In some examples, IMD 106 includes the processing circuitry configured to control external medical device 2502 to deliver the second electric field. In other examples, external medical device 2502 comprises processing circuitry configured to control IMD 106 to deliver the first electric field. In this manner, external medical device 2502 and IMD 106 may be configured to directly wirelessly communicate with each other in order to synchronize the delivery of the AEF therapy. In other example, an external programmer (e.g., programmer 104) may be configured to wirelessly communicate with IMD 106 and external medical device 2502 to coordinate delivery of the AEF therapy.

[0228] In some examples, the first electrode combination or the second electrode combination comprises one or more electrodes carried by one or more implantable leads 114. Put another way, two or more electric fields of the AEF therapy may all include at least one electrode from leads 114. In other examples, one electric field may be provided by only some or all of cutaneous electrodes 2504 and 2406 and another electric field may be provided by only some or all of electrodes 116, 118. In some examples, cutaneous electrodes 2504 and 2506 may enable IMD 106 to deliver bihemispherical wide volume AEF therapy.

[0229] External cutaneous electrodes may enable system 2500 to improve efficacy of therapy or adjust AEF therapy as a tumor evolves. For example, external electrodes may be used to deliver AEF therapy on a regular basis or to enhance therapy at select times (e.g., provide increased electrical field coverage while patient 112 is sleeping). In some examples, external electrodes may enable adjustments to new locations of target tissue without additional surgery. In some examples, system 2500 may be configured to pass current between implanted electrodes and external electrodes. System 2500 may be configured to provide electrical fields between external electrodes and then activate various electrodes 116, 118 in order to steer these electrical fields to target tissues. Although cutaneous electrodes 2504 and 2506 are described as example external electrodes, other external electrodes may be used. For example, penetrating transcutaneous needles could serve as “external” electrodes and used in these techniques.

[0230] FIG. 26 is a flowchart illustrating an example technique for scheduling electrical field sensing based on patient activity. The technique of FIG. 26 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 26 in other examples.

[0231] In the example of FIG. 26, processing circuitry 210 can control one or more sensors, such as sensor 212, to sense patient activity (2600). Processing circuitry 210 then can schedule, based on the sensed patient activity, electrical signal sensing using sensing circuitry 204 (2606). Since muscle activity, cardiac cycles, breathing, or patient movement may introduce noise in electrical signals that can be sensed, processing circuitry 210 may schedule electrical signal sensing during relatively quiet period. In some examples, processing circuitry 210 may gate electrical sensing during periodic activity such as cardiac cycles or breathing. Then, processing circuitry 210 can control sensing circuitry 204 to sense electrical signals from one or more electrodes at the schedule time(s) (2604).

[0232] In this manner, a system may include an activity sensor (e.g., sensor 212) configured to generate activity data indicative of patient activity and sensing circuity configured to sense an electrical signal through at least a portion of target tissue configured to receive alternating electric field (AEF) therapy. Processing circuitry 210 can also be configured to receive the activity data from the activity sensor, control, based on the activity data, sensing circuitry 204 to sense the electrical signal, and control, based on the electrical signal, IMD 106 to deliver AEF therapy. The sensed electrical signals may be any electrical signal or electrical field described herein that may be used as feedback to inform AEF therapy efficacy. For example, processing circuitry 210 may be configured to control sensing circuitry 204 by at least scheduling sensing circuitry 204 to sense the electrical signal during a period of reduced patient activity. Sensing circuitry 204 may be configured to sense the electrical signal by sensing an electrical field via two or more implanted electrodes.

[0233] FIG. 27 is a conceptual diagram illustrating example implantable coils for delivering alternating magnetic field ( AMF) therapy. As shown in the example of FIG 27, system 2700 includes IMD 106 couped to leads 2702 and 2706 via lead extension 110. Leads 2702 and 2706 include coils 2704 and 2708, respectively. Coils 2704 and 2708 may be configured to produce a magnetic field in response to IMD 106 driving electrical current through each coil. The magnetic fields from each coil may be alternating in time in order to produce an effect similar to AEF therapy described herein in order to provide various treatments, such as reducing or preventing cell division for treating glioblastoma. The range of magnitude for delivered AMF therapy may be generally between 0.1 millitesla (mT) and 1mT, but smaller or larger magnitudes may be used in other examples.

[0234] Although coils 2704 and 2708 are shown with large and spaced out turns, each coil may be much smaller and closely packed turns in other examples. In any example, coils 2704 and 2708 may be configured to generate respective magnetic fields may alternate in time as controlled by IMD 106. Coils 2704 and 2708 are shown positioned with the coil axes parallel to each other, but the coil axes may be orthogonal or oblique to each other or disposed in other positions. Three or more coils may be implanted in other examples. Moreover, in some examples, IMD 106 may be coupled to one or more implantable coils and two or more electrodes to produce alternating fields of an electric field and a magnetic field, respectively. The delivery of these two modalities can be temporally simultaneous or temporally interleaved dependent on which combination provides highest efficacy within the tissue type of interest. Therefore, in some examples, the system may utilize one or more feedback variables (e.g., user input and/or sensed signals) to adjust parameters that define electrical field and/or magnetic field delivery over time to titrate therapy towards clinically efficacious results.

[0235] In this manner, system 2700 can include IMD 106 which includes processing circuitry configured to receive a request to deliver AMF therapy and determine therapy parameter values that define the AMF therapy, where the AMF therapy comprises delivery of a first magnetic field and a second magnetic field. The processing circuitry can then control an IMD 106 to deliver the first magnetic field from at least implantable coil 2704 and control IMD 106 to deliver, alternating with the first magnetic field, the second magnetic field from implantable coil 2708.

[0236] Extremely low' frequency electromagnetic fields (ELF -EMF) can be capable of impacting cell division, as the magnetic field lines alternating between magnetic fields may provide a similar mechanism of cell division disruption as caused by AEF therapy. Such AMF therapy may be able to inhibit any types of cell division, which may include glioblastoma cancers, breast cancer, or other types of cancer cells. Although the mechanism of AEF may be similar to AMF, AMF therapy may require different lead designs, different placements, different amplitudes, different period of time, or other changes. In some examples, AMF therapy may be used to reduce neuroplasticity. Given the defined role of transcranial magnetic stimulation (TMS) for impacting neuroplasticity, system 2700 or other similar AMF system may deliver post-debulking to enhance recovery (magnetic or electric) or reduce inflammation.

[0237] FIG. 28 is a flowchart illustrating an example technique for delivering AMF therapy using multiple implantable coils. The technique of FIG. 28 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 28 in other examples. [0238] As shown in the example of FIG. 28, processing circuitry 210 receives a request to deliver alternating magnetic field (AMF) therapy (2800), such as from external programmer 104 or a pre-programmed delivery schedule. Processing circuitry 210 then determines therapy parameter values for AMF therapy (2802). This determination may be retrieval of parameter values from memory or determining one or more parameter values based on a delivery schedule, sensed data, or any other information.

[ 0239] Processing circuitry 210 then delivers the AMF therapy by delivering a first magnetic field from a first coil (2804) alternating with delivery of a second magnetic field from a second coil different than the first coil (2806). In some examples, the first and second magnetic fields may be interleaved such that they do not overlap. In other examples, the first and second magnetic fields may be partially overlapping in time. Although the first and second magnetic fields may be delivered with the same amplitude and frequency, the first and second electrical fields may be defined by different amplitudes and/or different.

[0240] Processing circuitry 210 then determines whether to terminate the AMF therapy (2808). If processing circuitry 210 determines that AMF therapy is not to be terminated (“NO” branch of block 2808), processing circuitry 210 continues to deliver the first and second magnetic fields (2804 and 2806). If processing circuitry 210 determines that AMF therapy is to be terminated or otherwise paused (“YES” branch of block 2808), processing circuitry 210 stops delivering the AMF therapy to the patient (2810).

[0241] FIG. 29 is a flowchart illustrating an example technique for cycling AEF therapy based on sensed temperatures of patient tissue. The technique of FIG. 29 will be described with respect to processing circuitry 210 of IMD 106 in FIG, 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 29 in other examples.

[0242] In the example of FIG. 29, processing circuitry 210 delivers AEF therapy (2900). Processing circuitry 210 then receives temperate data representative of tissue temperature (2902). In some examples, processing circuitry 210 controls a temperate sensor to generate temperature data at a predetermined schedule or on demand. In other examples, the temperature sensor continually or periodically transmits the temperature data which can be sampled or otherwise detected by processing circuitry 210. Then, processing circuitry 210 compares the temperature data to a threshold temperature (2904). This process may enable the system to monitor tissue for elevated temperatures caused by AEF therapy that could damage tissue if exceeding safe temperature levels. For example, the threshold temperature may be 43 degrees Celsius. In other examples, processing circuitry 210 may track a cumulative thermal dose that tracks a given heat for a certain period of time and compare that cumulative therapy dose to a threshold thermal dose above which may cause tissue damage.

[0243] If processing circuitry 210 determines that the temperature of tissue is not greater than the threshold temperature (“NO” branch of block 2906), processing circuitry 210 continues to deliver AEF therapy (2900). If processing circuitry 210 determines that the temperature of tissue is greater than the threshold temperature (“YES” branch of block 2906), processing circuitry 210 pauses or cancels delivery of AEF therapy (2908). Then, processing circuitry 210 may continue to monitor the temperature data and withhold AEF therapy until the temperature drops back down below the threshold temperature.

[0244] In this manner, processing circuitry 210 may be configured to receive temperature data generated by a temperature sensor, the temperature data indicative of temperature at a tissue region of a patient, and control, based on the temperature, IMD 106 to deliver alternating electric field (AEF) therapy via a plurality of implantable electrodes. In some examples, processing circuitry 210 is configured to determine, based on the temperature data, that the temperature exceeds a threshold temperature and, responsive to the temperature exceeding the threshold temperature, control IMD 106 to terminate AEF therapy. In addition, processing circuitry 210 may be configured to determine, based on the temperature data, that the temperature drops below an acceptable temperature and, responsive to the temperature dropping below the acceptable temperature, control IMD 106 to redeliver the AEF therapy,

[0245] In some examples, AEF devices may utilize high voltage (50V peak or 100Vpp) which can cause electrodes to reach critical temperature that can damage tissue. For example, AEF device can increase tissue temperatures may several degrees in some cases. This tissue temperature may be a specific temperature, such as 41 degrees Celsius, or may be defined by a quantify of heat received over a period of time. Exceeding such temperatures may trigger IMD 106 to terminate AEF therapy to allow the tissue to cool. For example, IMD 106 may cycle AEF therapy on or off, spread out alternating electrical field switching, or otherwise reduce delivered heat to the tissue. In some examples, instead of turning off stimulation, IMD 106 may reduce the amplitude of the electrical fields which can reduce tissue heating. In any event, the smaller voltages used for implanted AEF therapy may cause less heating than external electrode based AEF therapy.

[ 0246] In some examples, AEF therapy may cause certain changes to tissue. For example, AEF therapy may breakdown the blood brain barrier. AEF within the cranium has been demonstrated to impact the integrity of the blood brain barrier. This has been suggested as a potential reason for why some chemotherapy treatments have been suggested to be augmented with concurrent AEF treatment. In this manner, AEF therapy can be delivered as a standalone treatment or as an augmentation strategy to facilitate the efficacy of other treatment methods. In some examples, the timing of adjuvant treatments, such as chemotherapy, should be concurrent to the application of AEF to the tumoral environment. Implanted AEF therapy may provide an improvement over external systems because the patient could receive AEF therapy at any time necessary to augment the other treatment modality.

[0247] Different AEF parameter values may increase the blood brain barrier breakdown effect. For example, certain frequencies of the electrical fields may improve blood barrier breakdown. In one case, 100 kHz (or some similar frequency) may be the frequency value for blood brain barrier disruption, following a test of the range from 100 kHz - 300kHz. In some examples, the timing of chemotherapy agents or other drugs may be set based on when AEF therapy is delivered, or AEF therapy triggered according to the dosing schedule of the agents. [0248] FIG. 30 is a flowchart illustrating an example technique for synchronizing AEF therapy to cell cycle phases. The technique of FIG. 30 will be described with respect to processing circuitry 310 of programmer 104 in FIG. 3. However, other processors, devices, or combinations thereof, such as processing circuitry 210 of IMD 106 or some combination of devices or processors (e.g,, server 130), may perform the techniques of FIG. 30 in other examples.

[0249] In the example of FIG. 30, processing circuitry 310 controls IMD 106 to deliver AEF therapy to a target tissue (3000). A clinician later extracts a cell sample from the tumor or resection bed from the patient (3002). The clinician or other professional may perform histological analysis on the cell sample (3004). The clinician or other professional may then determine the types and duration (timing within and between) of phases of cell cycle from the histological analysis (3006). The phases of the analyzed cells may inform the clinician as to how the AEF therapy is affecting the cell cycle. The clinician or processing circuitry 310 can then adjust one or more stimulation parameter values, such as cycling time, for subsequent AEF therapy based on the phases of the cell cycle determine in the histological analysis (3008). [0250] Given that AEF therapy has been shown to increase the number of cells that are within the G2 state of the mitotic cell cycle (and also translates to enlarged physical cell size), AEF therapy can be utilized as a synchronizer of the cell cycle within a population of cells. Synchronization of the cell cycle phase within a population of cells has numerous applications throughout practically all ceil types within the body. For oncology, a clinician or system may improve chemotherapeutic or radiation therapy efficacy using AEF therapy because different chemotherapy agents can impart cellular effects within certain phases of the cycle. For non- oncological use cases, a clinician may enhance or select for the output of bone marrow or synchronize cells to increase the number of cells at a stage where a given drug is most effective. In addition, the AEF therapy may be used to synchronize cell division state at a prior stage (so the cells all transition to target stage together with the appropriately timed drug exposure). In some examples, the cells may benefit from staying in a phase, e.g., G2, longer than other phases of the cycle. In addition, vitamin benefits may be realized from AEF therapy by nutritionally synchronizing for cell division. AEF can serve as a trigger for a secondary agent at or after the optimal phase of the cell cycle, such as after the cells have been exposed to AEF to have been synchronized. In one example, the system may deliver a first regime of AEF (e.g., at a first frequency) to phase synchronize cells of a certain size. Then, the system may deliver a second regime of AEF (e.g., at the first frequency or a different frequency) to selectively impact cells in that phase (by altered size, etc.) to increase the impact of the delivered AEF therapy.

[0251] In some examples, certain treatment parameters of AEF therapy can select for certain phases of the cell cycle to become selected for, and therefore synchronized within, the cell population receiving therapy. Following the synchronization of the mitotic state of a cell population, a parameter dependent application of AEF can permit the system to control how the cells progress through the phases of the cell cycle (i.e. rate of individual phases, overall time for mitotic division, etc.).

[0252] In some examples, tumor cell histological analysis following tumor cell exposure to AEF therapy of a given frequency can permit determination of the population of cells within a given phase of the cell cycle (Gl, S, G2/M) through FACS analysis, or immunofluorescent staining. In some examples, the system or clinician can distinguish G2 and M phase cell populations utilizing an M-phase marker (i.e. anti-phospho-histone H3 antibody). This would permit an assessment for the percentage of synchronization within the tumor cell population regarding the cell cycle when using AEF therapy. This would also permit analysis for increasing cell cycle synchronization following modulation of the stimulating frequency for AEF therapy. [0253] FIG. 31 is a flowchart illustrating an example technique for cycling through different frequencies for AEF therapy. The technique of FIG. 31 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors (e.g., server 130), may perform the techniques of FIG. 31 in other examples.

[0254] In the example of FIG. 31, processing circuitry 210 receives a request to deliver AEF therapy (3100). Processing circuitry 210 then delivers the first electric field from a first electrode combination at a selected frequency (3102) and then delivers the second electric field from a second electrode combination at the selected frequency (3104). If processing circuitry 210 determines the frequency is not to be adjusted (“NO” branch of block 3106), processing circuitry 210 continues to deliver AEF therapy at the selected frequency (3102). If processing circuitry 210 determines that adjustments should be made to the frequency as part of cycling (“YES” branch of block 3106), processing circuitry 210 selects a different frequency for AEF therapy according to the frequency cycling schedule (3108) and again delivers AEF therapy using the new selected frequency (3102). In this manner, IMD 106 may cycle through different frequencies to affect different cells that may be affected by different therapies.

[0255] As described above, IMD 106 may provide “cyclic” AEF frequency sweeping. In one example, the frequency may be alternating between 150 kHz and 200 kHz for glioblastoma cells continuously. In other examples, the frequency sweep may include additional frequencies between those values. However, other frequencies may be used in other examples.

[0256] The distribution of AEF across a membrane is different dependent upon the physical size of the cells. Through the application of AEF therapy, the system impacts cell size by inhibiting cell division and enhancing the G2 state. Therefore, a sweeping frequency range can capture both larger cells (potentially those enhanced in size by the AEF treatment and increased G2 state of the population) and smaller cells. In some examples, IMD 106 may continuously sweep from top to botom frequency (or vice versa) repeatedly to capture the majority of cells regardless of the current cell size. In other examples, IMD 106 may deliver AEF therapy using multiple frequencies at the same time. For example, IMD 106 may interleave the frequencies, deliver simultaneous fields at different frequencies, dwell time at each frequency, or adjust the frequencies based on sensed patient data.

[0257] For a given tumor cell type there may be a target AEF frequency to generate an inhibitory response in cell growth. Therefore, a stimulation plan could include beginning treatment at the target frequency and maintaining the treatment at that frequency for the majority of the time but perform “sweeps” to lower frequencies to “pick up” those cells that would have experienced G2 state physical cell enlargement or to accommodate the tumor cells that were innately a smaller size than the majority of the other cells within the tumor. Sweeping could also be performed to the higher frequencies such that tumor cells that are innately smaller than the majority of the remaining tumor cells could experience a more optimized inhibitor field for a portion of the stimulation interval.

[0258] In some examples, stimulation parameters defining the AEF therapy could utilize phase shifting combined with frequency sweeping. Histological analysis of tumor cells can permit personalization of the “tuneable” treatment parameters such that the clinician can use waveforms with frequencies selected for that type (or sub-population within tumor based on cell marker analysis) or size of cell based on the histological analysis. Tunable treatment parameters could be adjusted at any time during the therapy delivery process.

[0259] FIG. 32 is a flowchart illustrating an example technique for delivering AEF therapy that includes different frequencies from different electrode combinations. The technique of FIG. 32 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG 32 in other examples.

[0260] As shown in the example of FIG. 32, processing circuitry 210 receives a request to deliver alternating electric field (AEF) therapy (3200), such as from external programmer 104 or a pre-programmed delivery schedule. Processing circuitry 210 then determines therapy parameter values for AEF therapy (3202). This determination may be retrieval of parameter values from memory or determining one or more parameter values based on a delivery schedule, sensed data, or any other information.

[0261] Processing circuitry 210 then delivers the AEF therapy by delivering a first electric field from a first electrode combination at a first frequency (3204) alternating with delivery of a second electric field from a second electrode combination different than the first electrode combination and at a second frequency different than the first frequency (3206). In some examples, the first and second electrical fields may be interleaved such that they do not overlap. In other examples, the first and second electrical fields may be partially overlapping in time. Although the first and second electrical fields may be delivered with the same amplitude and frequency, the first and second electrical fields may be defined by different amplitudes and/or different frequencies (e.g., 150 kHz and 200 kHz or other frequencies or frequency ranges). The first and second electrode combinations may use completely different electrodes or partially different electrodes, for example. The first and second electrode combinations may be selected to generate respective electrical fields that are orthogonal to each other or oblique, in some examples. Although all electrodes of the first and second electrode combinations may be implanted in some examples, one or more of the electrodes may be external electrodes in other examples.

[0262] Processing circuitry 210 then determines whether to determinate the AEF therapy (3208). If processing circuitry 210 determines that AEF therapy is not to be terminated (“NO” branch of block 3208), processing circuitry 210 continues to deliver the first and second electric fields (3204 and 3206). If processing circuitry 210 determines that AEF therapy is to be terminated or otherwise paused (“YES” branch of block 3208), processing circuitry 210 stops delivering the AEF therapy to the patient (3210). In some examples, the concept of interleaving electric fields can be utilized within the stimulation parameters, wherein different electrodes are utilized at different frequencies to permit spatially separated mixing of waveforms.

[0263] FIG. 33 is a flowchart illustrating an example technique for adjusting the frequency of AEF therapy in response to detecting a trigger event. The technique of FIG. 33 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 33 in other examples. [0264] As shown in the example of FIG. 33, processing circuitry 210 receives a request to deliver alternating electric field (AEF) therapy (3300), such as from external programmer 104 or a pre-programmed delivery schedule. Processing circuitry 210 then delivers the first and second electric fields alternating from first and second electrode combinations at a primary frequency (3202). The primary frequency may be selected to generally treat tissue at certain cell sizes or under certain physiological conditions. If no trigger event is detected (“NO” branch of block 3204), processing circuitry 210 continues to deliver AEF therapy at the primary frequency.

[0265] If processing circuitry 210 detects a trigger event (“YES” branch of block 3204), processing circuitry selects a secondary frequency for the trigger event (3206). Example trigger events may be MRI indicated tumor progression, increases or decreases in cell size, tumor resection, or any other event that may change how cells react to AEF therapy. Surgical resection biopsy-based events could include an increase or decrease in cell size. The preceding trigger events would be human-operator dependent based on interaction with a UI. Measurement of cell size or tumor size, for example, may be performed using tissue impedance measurements, strain gauges, imaging, or any other sensor technique. An exemplary triggered event that can be conducted in an automated (or human- operator dependent) manner is the achievement of certain threshold values of electrical physics parameters as calculated by differential in input from sensed electric field. Further exemplary trigger events may be a certain duration of stimulation pursued at the preceding frequency (i.e. primary or secondary). Processing circuitry 210 then delivers third and fourth electric fields alternating from first and second electrode combinations, respectively, at the secondary frequency. If the trigger event has not ended (“NO” branch of block 3210), processing circuitry 210 continues to deliver AEF therapy at the secondary frequency (3208). If processing circuitry 210 determines that the trigger event ended (“YES” branch of block 3210), processing circuitry 210 selects the primary frequency for subsequent AEF therapy once more (3202).

[0266] FIG. 34 is a flowchart illustrating an example technique for adjusting the frequency of AEF therapy in response to tissue changes indicated by image data. The technique of FIG. 34 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 34 in other examples. [0267] As shown in the example of FIG. 34, processing circuitry 210 receives a request to deliver alternating electric field (AEF) therapy (3400), such as from external programmer 104 or a pre-programmed delivery schedule. Processing circuitry 210 then delivers the AEF therapy by delivering a first electric field from a first electrode combination at a selected frequency (3404) alternating with delivery of a second electric field from a second electrode combination different than the first electrode combination and at the selected frequency (3406). If processing circuitry 210 or other device or user determines that there is no change in cells from imaging data (“NO” branch of block 3408), processing circuitry 210 continues to deliver AEF therapy (3402). If processing circuitry 210 or other device or user determines that imaging data indicates a change to cells (“YES” branch of block 3408), processing circuitry 210 selects a different frequency for subsequent AEF therapy based on the imaging data (3410).

[0268] In some examples, imaging data may be obtained after a certain amount of time of AEF therapy, such as after 24 hours at a certain frequency. A change in the size of cells may be indictive of effective AEF therapy, but a change in frequency may continue to affect the cells. A broad cytokine, growth factor, and circulating biomarker panel for cell death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor burden can be utilized to monitor for evidence of response to treatment or tumor progression.

[0269] In some examples, ultrasound can be used to visualize tumor necrosis for the purposes of feedback on the sweeping or modification of the treatment frequency. Stem cell differentiation can be impacted by exposure to electric fields; therefore, implantable delivery of AEF can be used for inducing stem cell differentiation.

[0270] FIG. 35 is a flowchart illustrating an example technique for delivering AEF therapy to activate an exogenous agent injected into the patient. The technique of FIG. 35 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2, However, other processors, devices, or combinations thereof, such as processing circuitry/ 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 35 in other examples. [0271] As shown in the example of FIG. 35, a clinician can deliver an exogenous agent to the patient (3500). In other examples, an implantable pump or other device may automatically deliver the exogenous agent. Processing circuitry 210 monitors whether or not to deliver the AEF that may activate the exogenous agent (3502). If AEF is not to be delivered (“NO” branch of block 3502), processing circuitry 210 withholds AEF therapy. If processing circuitry/ 210 determines that AEF therapy is to be delivered (“YES” branch of block 3502), processing circuitry 210 controls IMD 106 to deliver AEF to the patient according to stimulation parameters selected to activate the exogenous agent that treats the target tissue (3504). In some examples, processing circuitry 210 controls IMD 106 to deliver AEF therapy as needed, but adjusts one or more parameters of the AEF in order to activate the exogenous agent when needed.

[0272] AEF can thus be applied to a tissue in combination with an exogenous agent (e.g., a pharmaceutical) that is modified to a more pharmacokinetically active state following exposure to the AEF. Therefore, the AEF delivered within the region of the tumor via an implant would permit selective activation of the exogenous agent. In one example, high frequency AEF can disrupt a lipid-polymer nano-/micro-particle containing a regionally significant exogenous agent such as a chemotherapy drug a chemotherapy drug. In other words, the AEF can dissolve the agent or a coating that contains the agent. Without exposure to the AEF, the lipid-polymer is inert and the nano-micro-particles do not get exposed to the body. The system can control the electrical field strength, frequency, etc., as needed to activate any substance.

[0273] AEF may generically impact the cellular transcriptom ics for protein synthesis. Therefore, this is a selective impact within the tumor cells (compared to no impact in normal cells). This difference in the transcriptomic profile of a cell could serve as a method to trigger therapeutic activity of an exogenous agent.

[0274] FIG. 36 is a flowchart illustrating an example technique for delivering a voltage bolus configured to cause irreversible or reversible electroporation of cell membranes in a target tissue. The technique of FIG. 36 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 36 in other examples.

[0275] AEF delivery can induce irreversible electroporation within tumor cells and thereby permit a single dose-based cell death triggering event, IMD 106 or other AEF delivery system can be utilized to give a one-time bolus of voltage to cause AEF with parameters sufficient to achieve irreversible electroporation in cells. Therefore, this may be described as a method of permissive electrode heating. In some examples, this bolus of voltage may be utilized following radiographic confirmation of tumor progression or recurrence. In other words, the electroporation may be used to halt further tumor progress and destroy existing region tumor. [0276] As shown in the example of FIG. 36, processing circuitry 210 delivers the AEF therapy by delivering a first electric field from a first electrode combination at a selected frequency (3600). Processing circuitry 210 then determines from imaging data that a voltage bolus is required (3602). Processing circuitry 210 than controls IMD 106 to deliver the voltage bolus from the AEF electrodes sufficient to cause electroporation in the cells of the target tissue (3604). For example, the voltage bolus may create electric fields with a strength much greater than normal AEF therapy. This voltage bolus may be created by the implanted device alone, or facilitated by the addition of a temporarily applied external power source (via induction or other energy transfer means) to enhance the strength of the electric field levels.

[0277] If processing circuitry 210 determines to continue delivering AEF therapy (“YES” branch of block 3606), processing circuitry 210 continues to deliver AEF therapy (3600). If processing circuitry 210 or other device or user determines that AEF therapy is no longer required (“NO” branch of block 3606), processing circuitry 210 discontinues AEF therapy (3608).

[0278] For a less disruptive electroporation technique, the application of nanosecond pulsed electric fields could be adopted by IMD 106 to generate nanoscale pores along the cell membrane. This modality could be adopted in an interleaved manner with an additional modulated therapy described herein, such as AEF therapy. The therapy could utilize DC frequencies of approximately 1Hz or AC frequencies of 60Hz to generate electric fields of approximately 15kV/cm to initiate the nanoporation event within the treated bodily region.

[0279] In some examples, IMD 106 could adopt both AC circuitry for AEF therapy delivery and DC circuitry for application of direct current electric stimulation (DCS). DCS could be utilized for enhancement of native tissue function (such as cognitive enhancement for multitasking capability or numerical cognition) or enhanced tissue recovery. DCS can permit tailorable control over cellular behaviors, such as rescue of cells from genetic dysfunctions such as Rett Syndrome. This therapy could be interleaved with the application of AEF therapy, or be utilized independent of AEF therapy.

[0280] In some examples, IMD 106 could adopt an electro-capacitive capability to generate an electrostatic wave from one capacitive electrode through the tumor to another electrode. This would adopt a low-intensity, approximately 18V peak-to-peak, intermediate frequency (e.g., 100 kHz to 200kHz) parameter to inhibit cell division with clinical application in cancer treatment for example.

[0281] In some examples, IMD 106 may not be configured to provide the sufficient voltage bolus with the contained power supply. Therefore, IMD 106 may utilize a transcutaneous pathway that enables IMD 106 to receive additional energy delivered from an external source. For example, IMD 106 may include a primary battery “bypass” mode that enables external energy into the implant system and through the electrodes to deliver the desired large voltage bolus. In some examples, this process may be performed under the oversight of a clinician during an office visit. In other examples, IMD 106 or another device may include the use of external cutaneous electrodes to augment the voltage bolus treatment either with additional energy delivery or field steering by selective current source and sinks using the external electrodes.

[0282] FIG. 37 is a flowchart illustrating an example technique for adjusting a parameter of AEF therapy based on migration state of one or more cell types. Electrical field therapy, such as AEF, can impact microtubule and actin dynamics within a cell, which are important for cell motility. Therefore, certain markers, such as a serological marker, can be correlated to cytoskeletal aberrations and monitored to determine cellular responsiveness to the electrical field therapy. In addition, since electrical field therapy can impact cell motility, a system may utilize electrical field therapy to direct and/or restrict migration of one or more types of cells within a region of a patient.

[0283] In this manner, electrical field therapy may be configured and employed by a system to control where cells go, which include tumor cells and/or normal cells. One or more different markers may be detected in order to determine whether or not electrical field therapy is affecting cell motility and, in some examples, to what extent (direction, location, and/or speed) cells are migrating within a region of tissue. Example markers may include blood markers, such as the release of vesicles or other chemicals from a cell. For example, if actin and microtubles are modulated by the electrical field therapy, the ability of cells to secrete compounds such as hormones into the blood stream. Other markers may include byproducts of cell damage as a result of apoptosis or other process. In other examples, markers may include one or more chromosomes from cells to determine if electrical field therapy is changing cell mitosis. [0284] The technique of FIG. 37 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 37 in other examples. As shown in the example of FIG. 37, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy (3700). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy.

Processing circuitry 210 may then receive one or more markers associated with one or more cell types, such as from user input or from another computing device.

[0285] Processing circuitry 210 may then determine, based on the one or more markers, a migration state of the one or more cell types (3702). For example, if the markers indicate that microtubule and/or actin dynamics have been impaired, processing circuitry 210 may determine that the AEF therapy is effective. Conversely, processing circuitry 210 may determine that AEF therapy needs to be adjusted if cell motility has not been impaired. In other examples, the markers obtained from various tissues may indicate how the one or more cell types subject to AEF therapy have moved within the patient.

[0286] Therefore, based on the one or more markers, processing circuitry 210 may adjust one or more parameters that at least partially define the electric field therapy (3604). In some examples, processing circuitry 210 may continuously or periodically perform this marker determination in order to adjust electric field therapy as needed over time. In some examples, processing circuitry 210 may track changes to cell motility and/or marker characteristics over time. Processing circuitry 210 may correlate the cell motility and/or marker characteristics with one or more parameters of the electric field therapy in order to determine how electric field therapy affects one or more cell types. In this manner, processing circuitry 210 may adjust electric field therapy based on one or more markers indicative of cell motility and associated with one or more cell types.

[0287] FIG. 38 is a flowchart illustrating an example technique for determining a change in geometry of response to electrical stimulus that indicates a change in target tissue. In some examples, single pulse electrical stimulation (e.g., an electrical stimulus) may induce or elicit a neurological response within certain tissues, such as the brain, spinal cord, or other nerve tissues. For example, this neurological response may be characterized as having a “shape” or “geometry” between two or more regions of tissue. A change to the geometry of the neurological response may be indicative of a change to the types of cells in those regions of tissues, such as an invasion or increase in tumor cells or other changes to the cells in those regions. In some examples, a system may identify such changes to the geometry of a response to electrical stimulus and determine a change to the physiology of a patient or the condition of a disease (e.g., cancer or tumor progression) based on the change to the geometry of the response.

[0288] The technique of FIG. 38 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 38 in other examples. As shown in the example of FIG. 38, processing circuitry 210 may be configured to control IMD 106 to deliver electric field therapy, such as AEF therapy (3800). The electric field therapy may include delivery of a first electric field and a second electric field. Processing circuitry 210 may then control IMD 106 to deliver an electrical stimulus at a scheduled time (3802). This electrical stimulus may be delivered between two electrodes associated with delivery of the electrical field therapy or two electrodes separate from the delivery of the electrical field therapy.

[0289] In response to the delivery of the electrical stimulus, IMD 106 may sense one or more signals indicative of the neurological response to the electrical stimulus. Then, processing circuitry’ 210 may determine a geometry of the response to the electrical stimulus (3804). This geometry may indicate one or more circuits involved in the response, a volume of tissue associated with the response, a strength of the neurological response (e.g., a magnitude or area under the curve of the sensed signal and/or amplitude of one or more frequency bands), or any other indication of which tissues have responded to the electrical stimulus. Processing circuitry- 210 can then determine that the geometry of the response is different from a baseline geometry (e.g., a geometry determined from a previous response, average of previous responses, etc.). If the geometry of the response has not changed from the baseline geometry (“NO” branch of block 3806), processing circuitry 210 may continue to control IMD 106 to deliver electrical field therapy (3800). If the geometry of the response has changed from the baseline response (“YES” branch of block 3806), processing circuitry 210 then can control a user interface to present an indication of a change in the geometry from the baseline geometry (3808). In this manner, the patient and/or clinician may be informed of a physiological change to the patient that may indicate improvement of the condition or possibly progression of the disease.

[0290] In some examples, processing circuitry 210 may be configured to generate a map of the response to the electrical stimulus. For example, the map may indicate which locations of anatomy were active in response to the electrical stimulus, and programmer 104 may present a visual representation of the map to enable the physician to view the map. In other examples, processing circuitry 210 may determine volumes or areas of response from the map and determine the geometry of the response according to the map. In some examples, processing circuitry 210 may track multiple geometries of the responses over time in order to determine longitudinal data indicative of the changes to the geometry over time. In this manner, processing circuitry 210 or programmer 104 may be configured to track therapy improvements or disease progression over time based on the incremental changes to the geometry over that time. In some examples, various patient or physiological changes may be correlated to the changes in the geometry and/or map over time. For example, processing circuitry 210 may receive user input (negative or positive changes to symptoms), functional changes, metabolism effects in one or more neural networks, or other data indicative of patient changes to determine whether the geometry changes correspond to disease progression or symptom improvement.

[0291] FIG. 39 is a conceptual diagram illustrating an example lead 3904 configured to deliver electrical energy and a drug to a target tissue 3912 within region 3902. As shown in the example of FIG. 39, brain 3900 may have a target region 3902 into which a distal tip of lead 3800 is inserted. Lead 3904 may include a lead housing 3906 defining a channel (not shown) configured to transmit a fluid (e.g., a drug) from a proximal end of lead housing 3906 to a distal end (e.g., one or more ports 3910) of lead housing 3906. In addition, lead 3904 may include one or more electrodes 3908 carried by an electrode housing (e.g., a part, of lead housing 3906 or a different structure coupled to lead housing 3906) and configured to deliver electric field therapy. The electrode housing may include a plurality of ports (e.g,, such as port 3910) defined by the electrode housing, where the plurality of ports are in fluid communication with the channel. [0292] In some examples, the electrode being utilized for delivery of AEF therapy could be designed in such a way as to permit continuous or intermittent infusion of pharmaceutical agents or other liquid agents such as fluorescent tumor markers. The design could include a reservoir for the pharmaceutical agent at the location of an IMD (e.g., IMD 106), or could simply resemble a port to permit infusion via direct injection. The depth electrode design could implore a hollow central channel which permits delivery of the liquid agent through the tip of the electrode or through small holes placed along the body of the electrode. In some examples, a grid electrode design could include one or more arrays of tubing defining holes of predetermined one or more diameters configured to permit egress of liquid agent from within the tubing to outside of the tubing at a selected rate, which may be a homogenous rate across each array or differing rates based on the adjacent anatomy.

[0293] As shown in the example of FIG. 39, a system, such as IMD 106, may include processing circuitry 210 configured to control IMD 106 to deliver electric field therapy (e.g., AEF therapy) via lead 3904, wherein the electric field therapy comprises delivery of a first electric field and a second electric field. Processing circuitry 210 may also be configured to control the implantable medical device to deliver a drug through lead and out of a plurality of ports defined by the lead.

[0294] The delivered fluid, which may include a drug, may enhance or otherwise facilitate the effectiveness of the delivered electric field therapy. In this manner, the fluid may be delivered in coordination with the electric field therapy in order to enhance the effectiveness of fluid entry into one or more types of cells (e.g., open cell membranes). Alternatively, the electric field therapy may open the blood brain barrier in order to introduce drugs into the desired region of tissue.

[0295] FIG. 40 is a conceptual diagram illustrating an example lead 4000 with ports configured to deliver a drug to a target tissue. Lead 4000 may be similar to lead 3904 of FIG. 39 and configured to deliver a drug (e.g., a fluid) and electrical field therapy. Lead 4000 includes lead housing 4002 which defines a channel 4004 through which fluids (e.g., a drug or other agent) can flow from a proximal end of lead housing 4002 to the distal end of lead housing 4002. Channel 4004 may continue through a least a portion of electrode housing 4006. Electrode housing 4006 may be shaped as a paddle or any other shape. Electrode housing 4006 carries a plurality of electrodes 4008 and defines a plurality of ports 4010 provided at different locations than electrodes 4008. The example of FIG. 40 illustrates eight electrodes 4008 and four ports 4010, but fewer or greater number of electrodes and/or fewer or great number of ports may be used in other examples. In some examples, the cross-sectional area of channel 4004 and/or the cross-sectional area of ports 4010 may vary in order to achieve a desired fluid flow out of ports 4010. For example, ports 4010 may have increasing cross-sectional areas towards the distal end of electrode housing 4006 in order to achieve a more even flow of fluid from each port 4010. The pattern of ports 4010 may be a grid, line, curve, or randomly pattern in different examples. Ports 4010 may be located on one or more sides of electrode housing 4006.

[0296] In some examples, electrode housing 4006 may also include one more sensors configured to detect various characteristics such as drug concentration, flow, impedance changes, pressure changes, or any other changes that may be indicative of target fluid flow, effective electric field therapy, and/or effective drug delivery to tissue. In some examples, the system may modulate the electric field therapy in order to drive progressive permeability of desired membranes to force drugs into desired tissues and/or cells. Although the fluid is described as a drug in some examples, the fluid may instead be selected to enhance the effectiveness or intensity of the electric field therapy at desired regions of the tissue. The fluid may otherwise be inert. In other examples, the fluid may be delivered to increase conductivity and the volume of tissue affected by the delivered electric field therapy.

[0297] FIG. 41 is a flowchart illustrating an example technique for delivering AEF therapy and a drug from a lead. The technique of FIG. 41 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 41 in other examples. In addition, lead 4000 will be described as an example, but lead 3902 or other leads may be used in other examples. [0298] As shown in the example of FIG. 41 , processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via an electrode combination that includes at least one electrode of lead 4000 and/or another one or more leads (4100). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy. Processing circuitry 210 may then determine whether or not to deliver a drug or other fluid via lead 4000 (4102). If no drug is to be delivered (“NO” branch of block 4102), processing circuitry 210 continues to control IMD 106 to deli ver electric field therapy (4100). If processing circuitry 210 determines that drug is to be delivered (“YES” branch of block 4102), processing circuitry 210 controls IMD 106 to deliver drug from a reservoir within IMD 106 and out of one or more ports 4010 of lead 4000 (4104). [0299] In other examples, processing circuitry 210 may determine to deliver drug or other fluid prior to and/or during delivery of the electric field therapy. In this manner, IMD 106 and lead 4000 may be configured to deliver fluid out of one or more ports 4010 at different times or at the same time current is delivered from one or more electrodes of lead 4000. Fluid or drug delivered prior to electric field therapy may enable the drug or fluid to prime tissues or cells for the electric field therapy. In other examples, a drug or fluid may be delivered after electric field delivery (or interleaved with electric field therapy) in order to provide post-electric field therapy or conditions to the cells affected by the electric field therapy.

[0300] FIG. 42 is a flowchart illustrating an example technique for delivering an electrical stimulus configured to increase drug uptake by a target tissue. The technique of FIG. 42 may be similar to the technique of FIG. 41, and will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 41 in other examples. In addition, lead 4000 will be described as an example, but lead 3902 or other leads may be used in other examples. For example, the lead carrying electrodes may be different than a catheter that delivers the drug to the patient.

[0301] Single pulse delivery of moderate voltage may induce reversible electroporation of cells. This reversible electroporation may temporarily open pores of cells, but allow those pores to close after some period of time. During this time that the pores of the cells are open, the cells may be more likely to uptake drug present near the cell. For the example of tumor cells, reversible electroporation may enable a drug that includes certain genes or other agents that mayincrease the susceptibility of the tumor cells to a chemotherapy agent or other drug. Although the below example includes delivering AEF therapy and single electrical stimulus for reversible electroporation, some example techniques may include single electrical stimulus delivery without delivery of electrical field therapy such as AEF therapy.

[0302] As shown in the example of FIG. 42, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via an electrode combination that includes at least one electrode of lead 4000 and/or another one or more leads (4200). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy. Processing circuitry 210 may then determine whether or not to deliver a drug or other fluid via lead 4000 (4202). The drug may be an agent that the clinician desires to place within cells. If no drug is to be delivered (“NO” branch of block 4202), processing circuitry 210 continues to control IMD 106 to deliver electric field therapy (4200).

[0303] If processing circuitry 210 determines that drug is to be delivered (“YES” branch of block 4202), processing circuitry 210 controls IMD 106 to deliver a single electrical stimulus configured to increase drug uptake, such as inducing reversible electroporation (4204). This single electrical stimulus may have a greater voltage and/or current amplitude than other electrical field therapy or other therapies. In one example, the single electrical stimulus may have a pulse width from approximately 20 milliseconds (ms) to 100 ms and a voltage density of approximately 5 volts per centimeter (V/m) to 20 V/m. In one example, the single electrical stimulus may have a pulse width of approximately 50 ms, a voltage density of approximately 10 V/m, and an alternating current frequency of approximately 60 Hz. The electrical stimulus may have parameters designed to enable reversible electroporation while not killing the cells. After IMD 106 delivers the single electrical stimulus, processing circuitry 210 may control IMD 106 or other device to deliver the drug to tissue including cells that have been subject to the electroporation (4206). This delivery of drug would occur prior to the cells being able to re- close the pores after the electrical stimulus. In some examples, the delivery of the drug may happen prior to delivery of the electrical stimulus m order for the drug to be present around the cells at the time the single electrical stimulus is delivered.

[0304] FIG. 43 is a flowchart illustrating an example technique for creating liquid metal electrodes on target tissue for AEF therapy. In some examples, implantation of electrodes configured prior to implantation may limit how the electrodes can conform to a target tissue surface. Instead of attempting to conform an array of rigid electrodes to a tissue surface, a system can spray or otherwise apply a conductive material (e.g., a liquid metal material) directly on the target tissue to form one or more electrodes at precisely the desired locations. In this manner, the system can generate electrical field therapy in any configuration desired. Moreover, inserting an electrode array may require invasive surgery, but a relatively small nozzle may be inserted into any desired tissue in order to create an electrode or electrode array of any larger size without a mechanism required to expand the electrode or array after insertion.

[0305] The system may use one or more nozzles to spray a conductive material on one or more tissues. The conductive material may be a liquid metal (e.g., that maintains a shape as a liquid or solidifies into one or more unitary solid structures), electrically conductive polymer, or any other conductive material that may be sprayed into a desired tissue. These materials may also be configured to adhere to all tissue or just the type of tissue that is targeted. For example, if the material is configured to adhere to brain tissue instead of fluids, the conductive material may selectively adhere to the targeted tissue for creation of the electrodes. In some examples, the conductive material may be modified to form thicker or thinner structures. Thicker structures may be more appropriate for rigid applications where the electrodes do not need to be flexible, and thinner structures may be more appropriate for movable tissues and flexibility of the electrodes.

[0306] Although the conductive material may be sprayed from a nozzle in some examples, the system may dispose the materials using other techniques. For example, the system may include an brush applicator, a rolling applicator, one or more ports to flow material more slowly, or any other structure that is configured to deposit the conductive material at the target tissue. In some examples, the conductive material may be non-degradable such that the material does not degrade in the body over time. In other examples, the conductive material may be configured to biodegrade over time for a temporary type of electrode.

[0307] As show in the example of FIG. 43, a clinician may insert a insert a spray nozzle to a target tissue of a patient, such as a spray nozzle configured to spray a liquid metal onto the target tissue (4300). Once in position, the clinician may operate the delivery system to dispense or spray a liquid metal from the spray nozzle and onto a target tissue, wherein the liquid metal is configured to form an electrode on the target tissue (4302). If there is another target tissue to receive the liquid metal (“YES” branch of block 4304), the clinician can move the nozzle to the next target tissue (4306) and spray the liquid metal another time (4302). If there are no other target tissues (“NO” branch of block 4304), the clinician can electrically couple the one or more electrodes formed by the liquid metal to an implantable medical device (e.g., IMD 106) via one or more conductors (4308). The one or more conductors may be formed by liquid metal traces disposed m a path back to the IMD, or preformed conductors. Then, the clinician can remove the spray nozzle from the patient (4310). .After these electrodes are placed in the patient, IMD 106 can deliver electrical field therapy, such as AEF therapy, to the target tissue via the disposed electrode(s). [0308] FIG. 44 is a flowchart illustrating an example technique for delivering AEF therapy and direct current stimulation. The technique of FIG. 44 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 44 in other examples.

[0309] Direct current stimulation can provide various therapies, such as enhancing bone repair, treating neurological ailments, improve mental skills, improve cell function, enhance recovery, and produce other benefits. In some examples, direct current stimulation may be configured to correct genetic dysfunctions or even control cellular behavior. In this manner, electrical field therapy (e.g., AEF therapy) can be delivered in additional direct current stimulation in order to provide benefits of both types of stimulation.

[0310] As shown in the example of FIG. 44, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy (4400). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy. Processing circuitry 210 may then determine whether or not to deliver direct current stimulation (4402). For example, processing circuitry 210 may interleave, or alternate between, delivery of AEF therapy and direct current stimulation. In another examples, processing circuitry 210 may schedule the direct current stimulation at certain times that may not interfere with the delivery of the AEF therapy. The electrode combinations used to deliver AEF therapy and direct current stimulation may be the same, partially overlapping, or include completely different electrodes. If direct current stimulation is not to be delivered (“NO” branch of block 4402), processing circuitry 210 continues to control IMD 106 to deliver electric field therapy (4400).

[0311] If processing circuitry 210 determines that direct current stimulation is to be delivered (“YES” branch of block 4402), processing circuitry 210 controls IMD 106 to deliver the direct current stimulation interleaved with the electric field therapy for a predetermined period of time (4404). In other examples, processing circuitry 210 may continue to deliver direct current stimulation until an input or data indicate to stop the delivery of the direct current stimulation. IMD 106 may deliver the electric field therapy on a continuous basis, with a portion of time during which direct current stimulation is interleaved with the electric field therapy, or IMD 106 may pause electric field therapy for a period of time in which direct current stimulation can be delivered. In any examples, the periods of time for electric field therapy and direct current stimulation may be asymmetrical or symmetrical.

[0312] FIG. 45 is a flowchart illustrating an example technique for delivering AEF therapy and a single electrical stimulus to elicit T cell response. Generally, a patient’s immune system can atempt to dispose of cancer cells. However, a stimulus may improve the patient’s immune response. For example, electroporation stimulus may generate a robust cytotoxic T lymphocyte expansion. In this way, certain electrical stimulus may activate T cells that can attack tumor cells or other undesired cells. Although a system may use different electrodes to deliver AEF therapy (or other electrical field therapy) and the single electrical stimulus for activating T cells, the same electrodes may be used in other examples. It is noted that electrical field therapy, such as AEF therapy, may provide immunotherapy against a tumor or other cancer cells. In other words, electrical field therapy may be configured to promote the immune response of the patient. [0313] The technique of FIG. 45 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 45 in other examples.

[0314] As shown in the example of FIG. 45, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via a first electrode configuration (4500). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy. Processing circuitry 210 may then determine whether or not to deliver a single electrical stimulus configured to stimulate an immune response (4502). If direct the single electrical stimulus is not to be delivered (“NO” branch of block 4502), processing circuitry 210 continues to control IMD 106 to deliver electric field therapy (4500).

[0315] If processing circuitry 210 determines that single electrical stimulus is to be delivered (“YES” branch of block 4502), processing circuitry 210 controls IMD 106 to deliver the single electrical stimulus configured to elicit T cell response from a second electrode configuration different than the first electrode configuration (4504). The system may repeat this process periodically on a scheduled basis or in response to some trigger event (e.g., sensor triggered event or user input request). In some examples, the single electrical stimulus may be of higher voltage than typical stimulation, such as from 1250 V/m to 2500 V/m and from approximately 15 kHz to 25 kHz (e.g., 20 kHz). This intensity of electrical stimulus may elicit T cell response and, m some examples, also cause irreversible electroporation. In some examples, this electrical stimulus may be configured solely for the immune response function. In other examples, this electrical stimulus may be configured to provide both the immune response and electroporation functions. In any event, the immune response may involve activating more T cells and a more pronounced T cell response to a tumor than the body would otherwise provide naturally.

[0316] FIG. 46 is a flowchart illustrating an example technique for delivering AEF therapy and nanopulse electrical stimuli. In some examples, short and high intensity electrical pulses may create many nanoscale pores in a plasma membrane of a cell, which may be termed nanoporation. Such nanoporation may cause cell death, and it may be beneficial when an affected cell is a tumor cell, for example. The duration of each electrical pulse may be on the nanosecond scale (e.g., less than one microsecond), and the intensity may have a voltage density larger than 1,000 V/m. Example voltage intensities may be at 15kV/m or higher, and the pulses may be delivered for a short duration and/or on a repeated basis (e.g., pulses repeated at a 1 Hz interval). These electrical pulses may also exert effects on mitrochondria, endoplasmic reticulum, nucleus, or other components.

[0317] The technique of FIG. 46 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 46 in other examples.

[0318] As shown in the example of FIG. 46, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via a first electrode configuration (4600). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy. Processing circuitry 210 may then determine whether or not to deliver nanopulse electrical stimulation configured to cause nanoporation and/or ablation (4602). If direct the nanopulse electrical stimulation is not to be delivered (“NO” branch of block 4602), processing circuitry 210 continues to control IMD 106 to deliver electric field therapy (4600).

[0319] If processing circuitry 210 determines that nanopulse electrical stimulation is to be delivered (“YES” branch of block 4602), processing circuitry 210 controls IMD 106 to deliver the nanopulse electrical stimulation interleaved with the AEF therapy and for a predetermined amount of time (4604). The system may repeat this process periodically on a scheduled basis or in response to some trigger event (e.g., sensor triggered event or user input request).

[0320] FIG. 47 is a flowchart illustrating an example technique for delivering AEF therapy and stimulation via a capacitive electrode. A capacitive electrode may be used to transmit electrical signals through tissue and to another electrode that is non-capacitive. Such signals may inhibit tumor growth.

[0321] The technique of FIG. 47 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 47 in other examples.

[0322] As shown in the example of FIG. 47, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via a first electrode configuration to target tissue (4700). As described herein, the electric field therapy may include delivery of a first electric field and a second electric field, such would be the case for AEF therapy.

Processing circuitry 210 may then determine whether or not to deliver electro-capacitive stimulation (4702). If direct the electro-capacitive stimulation is not to be delivered (“NO” branch of block 4702), processing circuitry 210 continues to control IMD 106 to deliver electric field therapy (4700).

[0323] If processing circuitry 210 determines that electro-capacitive stimulation is to be delivered (“YES” branch of block 4702), processing circuitry 210 controls IMD 106 to deliver the electro-capacitive stimulation via a second electrode combination that includes one or more capacitive electrodes to target tissue (4704). In this manner, the system can interleave or alternate between electro-capacitive stimulation and AEF therapy in order to reduce or prevent tumor growth. The system may repeat this process periodically on a scheduled basis or in response to some trigger event (e.g., sensor triggered event or user input request).

[0324] FIG. 48 is a flowchart illustrating an example technique for updating parameter values that define AEF therapy using machine learning. Various feedback for AEF therapy (or other electrical field therapy), may be collected and leveraged by a system to adjust AEF therapy parameters over time and improve efficacy for the patient. These parameters may include frequency, delivery patterns, cycling on and off times, amplitude, or other parameters. In some examples, feedback data may include impedance values collected between various electrodes, batery usage or capacity, or other data. For example, as discussed herein, frequency of electrical field therapy may affect different size cells. This data may be sent to an application running on a mobile device or programmer, and the application may apply a machine learning algorithm to the patient feedback data to obtain suggested adjustments to one or more parameters that define the AEF therapy. The suggested adjustments may then be directly transmitted to IMD 106, for example, for subsequent therapy or first presented to a user for approval. In this manner, the machine learning algorithm may modify the AEF therapy over time in order to manage changes to the patient physiology and/or achieve more efficacious therapy.

[0325] The technique of FIG. 48 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 48 in other examples.

[0326] As shown in the example of FIG. 48, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via a first electrode configuration to target tissue (4800). Processing circuitry 210 may then receive sensed data and user input data (e.g., an example of manual data) associated with the electric field therapy (4802). The sensed data may be data, such as impedance data, sensed from the patient, and the user input data may include patient feedback provided via a user interface, as one example. Then, processing circuitry 210 applies a machine learning algorithm to the sensed data and user input data (4804). Based on the application of the machine learning algorithm, processing circuitry 210 then can update one or more parameter values that define the electric field therapy (4806) and store the updated parameter values in IMD 106 to at least partially define subsequent electric field therapydeliverable by IMD 106 (4808).

[0327] FIG. 49 is a flowchart illustrating an example technique for updating parameter values that define AEF therapy using machine learning. The example technique of FIG. 49 may be similar to the technique of FIG. 48 in that a machine learning algorithm may be trained and used to adjust parameter values that define subsequent AEF therapy. For example, the system may tram the machine learning algorithm using a variety of data from various sources, such as tissue impedance data, strain gauge information, chemical markers, imaging data, patient input, etc. Any of these data may be indicative of tumor size, changes to tumor size, tissue changes, or any other physiological indication of disease progression and/or electrical field therapy efficacy. [0328] The technique of FIG. 49 will be described with respect to processing circuitry 210 of IMD 106 in FIG. 2. However, other processors, devices, or combinations thereof, such as processing circuitry 310 of programmer 104 or some combination of devices or processors, may perform the techniques of FIG. 49 in other examples.

[0329] As shown in the example of FIG. 49, processing circuitry 210 receives initial impedance measurements for one or more leads implanted within a patient and generates a baseline impedance (4900). This baseline impedance may be used to track any subsequent changes to the impedance. The impedance may be representative of changes to tissue impedance that may be due to changes in tumor size, for example. When starting therapy, processing circuitry 210 is configured to control IMD 106 to deliver electric field therapy, such as AEF therapy via a first electrode configuration to target tissue (4902). If processing circuitry 210 does not obtain updated data, such as updated impedance measurements and/or updated patient input (“NO” branch of block 4904), processing circuitry 210 continues to control IMD 106 to deliver AEF therapy (4902).

[0330] If processing circuitry 210 has updated data to obtain (“YES” branch of block 4904), processing circuitry 210), processing circuitry 210 may then obtain sensed data (e.g., impedance measurements) and patient feedback data (e.g., an example of manual data) associated with the electric field therapy (4906). The sensed data may be data, such as impedance data, sensed from the patient, and the user input data may include patient feedback provided via a user interface, as one example. If the impedance measurements and the patient feedback are acceptable (“YES” branch of block 4908), processing circuitry 210 then performs an action to improve system function, such as reduce the usage of the device (e.g., increase a cycle off time to reduce battery consumption (4910). Acceptable impedance measurements may be impedance values below a threshold, where above threshold impedance may indicate increased tumor size and unacceptable patient feedback may be feedback indicative of unacceptable symptoms from the therapy.

[0331] If at least one of the impedance measurements or patient feedback are not acceptable

(“NO” branch of block 4908), processing circuitry 210 then checks the battery status of IMD 106 (4912). The battery status may indicate remaining voltage or charge available for IMD 106 to operate. If processing circuitry 210 determines that the battery level is below a threshold (“No” branch of block 4912), then processing circuitry 210 controls programmer 104 to deliver an alert to the clinician indicating that the battery level is below threshold (4914). If the battery level is above threshold (“YES” branch of block 4912), then processing circuitry 210 checks to determine if a machine learning algorithm has determined updates to one or more parameter values of the AEF therapy are greater than a threshold change (4916). Processing circuitry 210 may execute the machine learning algorithm or receive the output from the machine learning algorithm executed by another device. The threshold change may be an absolute change in a parameter value magnitude, which may be a specific value for each respective parameter, or a percentage change, which may also be the same for all parameters or different for respective parameters. If the machine learning adjustment to one or more parameters is greater than the threshold change (“YES” branch of block 4916), processing circuitry 210 controls programmer 104 to deliver an alert to the clinician indicating that the suggested parameter changes exceed a threshold (4914). These above threshold changes may indicate that the changes to AEF therapy are substantial and may be noticed by the patient or outside of clinician set ranges. Programmer 104 may request user acceptance or approval of the suggested changes, and then receive user input accepting or approving the suggested changes, or if the machine learning adjustment to one or more parameters is less than the threshold change (“NO” branch of block 4916), processing circuitry 210 then adjusts the one or more parameter values according to the machine learning algorithm suggested adjustments (4918). IMD 106 may then store the adjusted parameter values and deliver subsequent AEF therapy according to the suggested adjusted parameter values. If the user declines the suggested changes to the parameter values, then processing circuitry 210 can control IMD 106 to continue delivering AEF therapy according to previous parameter values or patient requested changes.

[0332] The machine learning algorithm described in FIG. 49 may enable processing circuitry 210 or other device to initially set up AEF therapy that is at least partially customized for the patient. Over time, the machine learning algorithm may also provide continuous updates to one or more parameters of the AEF therapy based on data indicative of physiological changes, tumor size change and/or tumor migration, or other changes. Batery saving features such as adjustments to duty cycle or other parameters based on therapy efficacy and battery status may also increase operational life of IMD 106 and/or decrease charging frequency. Although the system may incorporate patient feedback in the machine learning algorithm, processing circuitry 210 may disable this feedback in some examples in response to clinician input. In some examples, the machine learning algorithm may output suggested parameter values. In other examples, the machine learning algorithm may output tumor size and/or estimated patient comfort. Processing circuitry 210 may then determine adjusted parameter values based on this output.

[ 0333] FIGS. 50-61 are conceptual screenshots of an example user interface 5000 that facilitates interaction with a system configured to deliver of AEF therapy to a patient. In some examples, user interface 5000 may incorporate the techniques described herein, such as the techniques of FIGS. 48 and 49. In the screen of FIG. 50, user interface 5000 provides a home page at which the user can select the patient icon 5002 to enter the patient interface or the physician icon 5004 to enter the physician interface. In the screen of FIG. 51, the patient interface of user interface 5000 provides user name entry 5102, password entry 514, and biometric entry 5104 as inputs to access the patient interface.

[0334] After entering the patient interface, user interface 5000 may show the screen of FIG. 52 includes a check battery icon 5202, a record symptoms icon 5204, a comfort level icon 5206, and message provider icon 5208. Selection of check battery icon 5202 brings the user to the screen of FIG. 53 of user interface 5000 at which the battery level is indicated in battery level field 5302. The battery level can be shown using one or more of a graphical battery level, numerical percentage, numerical voltage capacity remaining, approximate operational time remaining, or any other presentation of the battery level. Selection of record symptoms icon 5204 in FIG. 52 brings the user to the screen of FIG. 54 of user interface 5000 which includes symptom selection field 5402 and text field 5404. Symptom selection field 5402 may provide a list of common symptoms that can be checked by the user if any symptoms are experienced. Alternatively, or additionally, the user may enter the symptoms using text field 5404. Selection of the submit button enters the provided symptoms. In some examples, the screen of FIG. 54 may include a slider that is movable by the patient to indicate a spectrum of how the patient feels (e.g., bad through good), a numerical input field indicative of patient symptoms, or any other type of feedback mechanism to obtain patient input regarding the disease status and/or therapy efficacy. Selection of message provider icon 5208 brings the user to the screen of FIG. 55 of user interface 5000 which provides message text field 5502 configured to receive text from the user that will be delivered to the physician. An example message may include information such as side effects from therapy, inadequate therapeutic efficacy, charging issues, or any other issues that need to be relayed to the physician. Selection of submit button 5504 submits the message for transmission to the physician.

[0335] In response to selecting physician icon 5004 in the screen of FIG. 50, user interface 5000 displays the screen of FIG. 56. user interface 5000 then provides machine learning icon 5602, message icon 5604, diagnostic icon 5606, and configuration icon 5608. Selection of machine learning icon 5602 causes user interface 5000 to present the screen of FIG. 57 which includes machine learning algorithm status 5702 which indicates the status of the machine learning algorithm executed by programmer 104. Once the machine learning algorithm has completed executing, user interface 5000 displays the screen of FIG. 58. Suggested parameter values 5802 are displayed for confirmation by the user. If the user desires to edit the suggested parameter values 5802, selection of edit button 5804 may enable the user to change some or all of the parameter values. Selection of program button 5806 causes programmer 104 to transmit the suggested parameter values 5802 to IMD 106 to define subsequent AEF therapy. Selection of message icon 5604 causes programmer 104 to display the screen of FIG. 59 in which user interface 5000 presents message field 5902. Message field 5902 enables the physician to read patient messages and input text responding to the message. Selection of diagnostic icon 5606 causes user interface 5000 to present the screen of FIG. 60 which includes battery life icon 6002 and diagnostic data 6004 for the patient. Example diagnostic data may include stimulation on- time (e.g., amount of time per day or percentage of time), measured voltage (Vpp), measured electric field magnitude (V/cm), electric field orientation, pairing frequency (percentage for one or more leads or electrode combinations), stimulation frequency (e.g., a specific frequency or range of frequencies), input voltage (Vpp), impedance values, impedance variance (e.g., percentage of variance of the impedance), and any other relevant information.

[0336] Selection of configuration icon 5608 causes user interface 5000 to present information that may include optimization field 6102, therapy selector 6104, and interleaving settings 6106 in FIG. 61. Optimization field 6102 may enable the user to select whether or not programmer 104 should optimize lead pairing strategies using various automated algorithms. Therapy selector 6104 enables the user to provide selection of one or more available therapies, such as Tumor Treating Field Therapy (e.g., AEF therapy), pulse electric fields (which may include irreversible electroporation and/or reversible electroporation, magnetic field therapy, or direct current stimulation. Interleaving settings 6106 may enable the user to select a type of interleaving modality which may include the percentage of interleaving for each therapy being interleaved. The screens of user interface 5000 in the examples of FIGS. 50-61 are just some examples, as fewer or more screens with less or other information, such as any information discussed herein, may be provided in other examples.

[0337] FIG. 62-69 are conceptual screenshots of an example user interface configured to plan and set up AEF therapy. In the example of FIG. 62, the user can select a desired region of interest (ROI) that may include using a generic image set or importing patient-specific DICOM image set (6200). For the patient-specific images, the user can request that the system, such as programmer 104 or other device, autodetect the lesion or tumor (6202). If the user requests autodetecting the lesion (“YES” branch of block 6202), the system automatically determines the lesional region corresponding to the cancer region, or resection region, for the patient (6206). If the user requests manual lesion selection (“NO” branch of block 6202), the user can manually annotate the lesional region for the patient (6204). For any image set, the user may manually annotate the images to identify the lesion or tumor. The annotations may be provided in a three- dimensional space or in one or more two-dimensional views 6220, such as the coronal, axial, and sagittal views of the skull as shown. The user may also select the region of interest features utilized to define the therapeutic region of interest. The system may determine the variables of interest for the lesional region (6208) such as the T2 FLAIR volume, the T1 enhancing volume, and the definition for the peritumoral margin (e.g., a margin of a particular dimension or size such as 1 mm, 2 mm, 3 mm, etc. around the T1 volume). Once these variables are determined, the system may store the determined variables defining the determined lesion(s) (6210).

[0338] FIG. 63 provides example user input fields that the user can use to specify the implant strategy. For example, the system may receive inputs such as whether to optimize the implant strategy in window 6302, Window 6302 may be part of user interface 6300. If the “No” box of window 6302 is selected, the system may retain the determined parameters for stimulation and/or implantation to be performed. Put another way, the system may skip the other windows in FIG. 63 or close those windows if already open. The system may then select options that optimally treat lesions based on an assumption, such as to complete T1 enhancing volume removal and peritumoral margin remaining as a high risk zone. If the “Yes” box of window 6302 is selected, the sy stem may enter a screen of user interface 6300 that includes additional selectable details. User interface 6300 may provide input fields that enable the user to specify which types of leads are desired or already implanted, the frequency of desired electrical field therapy, whether or not the system should optimize for maximal field orientations, or the minimal field strength for one or more types of volume or tumor margin.

[ 0339] For example, user interface 6300 may include lead options window 6304 that includes different selectable lead style options that may be used for therapy, such as depth electrodes, grid electrodes, grid electrodes with projections, or even “all” of these lead style options. Frequency window 6308 may include input fields to specify a specific frequency for therapy or a frequency range for therapy. Field strength window 6310 enables the user to enter various minimal field strengths for various aspects of tissue, such as the T1 enhancing volume, T2 FLAIR volume, and/or the peritumor margin. Field orientation window 6306 may enable the user to select “No” which retains preset or default field orientations. Selection of “Yes” may cause the system to enter a different screen of user interface 6300 that enables the user to optimize or select the field orientations for the implanted electrode combinations or leads.

[0340] FIG. 64 provides example images and input fields for viewing the estimated electric fields produced for the patient and/or optimizing the field orientations for one or more target regions. In some examples, this screen of user interface 6300 may be entered via selection of “Yes” from field orientation window' 6306. Programmer 104 may provide different two- dimensional views of planes crossing the tumor or resection bed, such as a coronal, axial, and sagital planes in views 6402. Programmer 104 may also present a three-dimensional view 6404. The system may enable the user to select which types of views to show, such as the electric field magnitude, the electric field orientation, or both via selections in metric window 6406. In addition, the system may enable the user to select, for viewing, a time-lapse view 6408 of the simulated deliver of the electric field therapy. In some examples, the system may set up three- dimensional view 6404 based in previous inputs to place leads within the volume of tissue to demonstrate an implant strategy with a illustrated resulting electric field map.

[0341] As shown in FIG. 65, user interface 6300 may enable the user to edit the system configuration that is part of the system plan. User interface 6300 may include three-dimensional view 6404, metric window 6406, time-lapse view' 6408, and tools window' 6502. Example editing capabilities include the system receiving user input adding one or more leads 6508 from tools window 6502 and moving the lead(s) to the desired region of the brain in three-dimensional view 6404. User interface 6300 may also enable the user to move one or more leads with respect to a representation of tissue (e.g., the brain or a region of the brain), changing the size of one or more regions of the brain, moving the tissue with movement tool 6504, rotating the tissue with rotation tool 6506, or any other editing features.

[ 0342] As shown in FIG. 66, user interface 6300 may also display a summary of the hardware to be implanted, or already implanted, in the patient. This user interface may specific status of IMD 106 in status window 6604, such as battery level and/or condition, battery recharge cycle count, waveform generator condition, lead pairing configuration optimization, or other characteristics. The system may present an editing window to change any IMD 106 details in response to receiving user selection of an “edit” button. The user interface may also display the leads that are implanted in the patient in leads window 6606. If four leads are implanted, or to be implanted as part of the plan, each of depth leads 1-4 may be displayed. Selection of a specific lead in lead window 6606 may cause the system to present details on that selected lead. In some examples, the user interface may receive selection of the patient icon 6602 and display, responsive to the selection or tapping on patient icon 6602, a preview of the map of therapy for the patient.

[0343] FIG. 67 illustrates example stimulator settings that the user interface may display and associated input fields configured to receive user input for user interface 6300, which may be entered m response to the edit button of status window 6604 of FIG. 66. Example input fi elds that configure IMD 106 may include fields that enable the user to select whether or not programmer 104 should optimize lead pairing strategies using various automated algorithms in optimize window 6702. Stimulation statistics window 6704 may show various information about stimulation therapy, such as the stimulation on-time as a percentage or amount of hours and overall stimulation frequency of therapy. Modalities window 6706 may enable the user to provide selection of one or more available therapies, such as Tumor Treating Field Therapy (e.g., AEF therapy), pulse electric fields (which may include irreversible electroporation and/or reversible electroporation, magnetic field therapy, or direct current stimulation. Multiple therapy field 6708 may enable the user to select a type of interleaving modality which may include the percentage of interleaving for each therapy being interleaved.

[0344] FIG. 68 illustrates example lead details associated with the delivery of therapy and options in a different screen of user interface 6300. This screen is shown for lead Depth 1 which may be shown at the specific implant location in tissue view 6802. For example, input field 6804 may be configured to receive input selecting whether or not the system should optimize the lead pairing strategy for available implanted electrodes or leads. In pairing field 6806, the system can receive user input selecting which leads, or electrodes, to use for generating the electric field therapy. For example, the user may select additional leads to use with Depth 1, such as Depth 2, Depth 3, Depth 4, Paddle 1, and/or Paddle 2. The user may also to select a phase shift for the stimulation from the different paired lead. In addition, stimulation statistics field 6808 may be displayed in user interface 6300, such as stimulation on-time, measured voltage (which may also illustrate an associated graph of the measured voltage), measured electric field magnitude, electric field orientation (which may include a graph of the field vectors for the generated electric field), pairing frequency, stimulation frequency, input voltage, impedance values, impedance variance, and any other relevant information. User interface 6300 may also provide a representation of the one or more leads with respect to a tissue region (e.g., a brain or portion of the brain).

[0345] FIG. 69 illustrates an example screen of user interface 6300 that can display a preview of therapy to the user. This screen may be similar to the electric field map shown in FIG. 64. However, in the screen of FIG. 69, the user can view the estimated therapy preview and make adjustments as desired. For example, the coronal, axial, and sagittal planes may be presented in views 6402. Three-dimensional view 6404 may also be provided to illustrate where the electric field(s) may be delivered to the target tissue. When the adjustments are completed, the user interface can receive user input requesting that the treatment plan be updated with the adjusted settings using the “Yes” or “No” selection in update field 6902, These are example screens of user interface 6300 that may facilitate planning the delivery of electrical field therapy as described herein, but more or fewer user input may be collected in other examples.

[0346] A variety of different therapies are described herein that are related to each other, but some are slightly different. Generally, electric and magnetic stimulation therapy covers all of the therapies described herein. This includes, for example, direct current stimulation (DCS).

Electric field therapy includes alternating current stimulation, which also includes alternating electric field (AEF) therapy, which includes tumor treating field (TTF) therapy (e.g., AEF therapy within a range of 100kHz to 500kHz). Electric field therapy also includes pulse electric fields, which includes nanosecond pulsed electric fields (or nanopulse stimulation), which includes both irreversible electroporation and reversible electroporation. Electric and magnetic stimulation therapy also includes magnetic field therapy, which includes examples such as alternating magnetic field (AMF) therapy, oscillating magnetic field (OMF) therapy, and extremely low frequency electromagnetic field (ELF-EMF) therapy. Other types of therapy may also be included within any of these example categories of therapies.

[0347] The following examples are described herein.

[0348] Example 1. A system comprising: processing circuitry configured to: receive a request to deliver electric field therapy; determine therapy parameter values that define the electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; control an implantable medical device to deliver the first electric field from a first electrode combination of implanted electrodes; and control the implantable medical device to deliver, alternating with the first electric field, the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination. [0349] Example 2. The system of example 1, wherein: the first electrode combination comprises a first set of anodes carried by a first lead; the second electrode combination comprises a first set of cathodes carried by a second lead different than the first lead; the third electrode combination comprises a second set of anodes carried by a third lead different than the first lead and the second lead; and the fourth electrode combination comprises a second set of cathodes carried by a fourth lead different than the first lead, the second lead, and the third lead. [0350] Example 3. The system of any of examples 1 and 2, wherein: the first electrode combination comprises a first set of anodes carried by a first lead; the second electrode combination comprises a first set of cathodes carried by a second lead different than the first lead; the third electrode combination comprises a second set of anodes carried by the second lead; and the fourth electrode combination comprises a second set of cathodes carried by the first lead.

[0351] Example 4. The system of any of examples 1 through 3, wherein the processing circuitry is configured to cycle the electric field therapy on and off according to a predetermined schedule.

[ 0352] Example 5. The system of any of examples 1 through 4, wherein the processing circuity is configured to: receive temperature data indicative of a temperature of tissue that receives the electric field therapy; determine that the temperature exceeds a threshold temperature; and responsive to determining that the temperature exceeds the threshold temperature, terminate delivery of the electric field therapy.

[0353] Example 6. The system of any of examples 1 through 5, wherein the processing circuitry is configured to adjust a frequency of the first electric field and the second electric field according to a predetermined schedule.

[0354] Example 7. The system of any of examples 1 through 6, wherein the processing circuitry is configured to: receive an indication that a trigger event occurred; and responsive to receiving the indication that the trigger event occurred, adjust a frequency of the first electric field and the second electric field.

[0355] Example 8. The system of any of examples 1 through 7, wherein the first electric field is defined by a first frequency, and wherein the second electric field is defined by a second frequency different than the first frequency.

[0356] Example 9. The system of any of examples 1 through 8, further comprising a user interface configured to receive user input indicative of target tissue to receive electric field therapy, and wherein the processing circuitry is configured to determine, based on the user input, the first electrode combination and the second electrode combination.

[0357] Example 10. The system of any of examples 1 through 9, further comprising a user interface configured to receive user input indicative of tissue to avoid receiving electric field therapy, and wherein the processing circuitry is configured to determine, based on the user input, the first electrode combination and the second electrode combination.

[0358] Example 11. The system of any of examples 1 through 10, wherein the processing circuitry is configured to adjust one or more stimulation parameters that at least partially defines the electric field therapy based on histological data obtained from a sample of tissue affected by the electric field therapy.

[0359] Example 12. The system of any of examples 1 through 11, wherein the processing circuitry is configured to: determine target tissue for electric field therapy based on water content data obtained from magnetic resonance imaging (MRI) data; and determine, based on the target tissue, the first electrode combination and the second electrode combination for delivery of the electric field therapy.

[ 0360] Example 13. The system of any of examples 1 through 12, wherein the processing circuitry is configured to: determine target tissue for electric field therapy based on impedance tomography data obtained from sensed electrical potentials sensed from two or more of the implanted electrodes; and determine, based on the target tissue, the first electrode combination and the second electrode combination to deliver the electric field therapy.

[ 0361 ] Example 14. The system of any of examples 1 through 13, wherein the processing circuitry is configured to: generate an electric field dosimetry metric for anatomy that receives the electric field therapy; map the electric field dosimetry across target tissue of the anatomy; and output, for display, the map of the electric field dosimetry with respect to the anatomy. [0362] Example 15. The system of any of examples 1 through 14, wherein the first electrode combination comprises a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes, and wherein the second electrode combination comprises the first set of electrodes defined as anodes and the second set of electrodes defined as cathodes.

[0363] Example 16. The system of any of examples 1 through 15, wherein: the first electrode combination comprises a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes; the second electrode combination comprises a third set of electrodes defined as anodes and a fourth set of electrodes defined as cathodes; the third set of electrodes are adjacent to the first set of electrodes m one direction on a first lead; and the fourth set of electrodes are adjacent to the second set of electrodes in the one direction on a second lead. [0364] Example 17. The system of any of examples 1 through 16, wherein the first electrode combination comprises a first set of electrodes defined as cathodes and a second set of electrodes defined as anodes in a first paired configuration from a cube configuration, and wherein the second electrode combination comprises the first set of electrodes defined as anodes and the second set of electrodes defined as cathodes in a second paired configuration from the cube configuration.

[0365] Example 18. The system of any of examples 1 through 17, wherein the implanted electrodes are carried by two or more implanted leads.

[0366] Example 19. The system of any of examples 1 through 18, wherein at least two electrodes of the implanted electrodes are carried by an electrode array positioned adjacent a resection bed of tissue.

[0367] Example 20. The system of any of examples 1 through 19, wherein at least two electrodes of the implanted electrodes are subcutaneous electrodes. [0368] Example 21. The system of any of examples 1 through 20, further comprising a plurality of external cutaneous electrodes, and wherein at least one of the first electrode combination or the second electrode combination comprises one or more electrodes of the plurality of external cutaneous electrodes.

[ 0369] Example 22. The system of any of examples 1 through 21, further comprising the implantable medical device.

[ 0370] Example 23. A computer-readable storage medium comprising instructions that, when executed, cause processing circuitry to: receive a request to deliver electric field therapy; determine therapy parameter values that define the electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; control an implantable medical device to deliver the first electric field from a first electrode combination of implanted electrodes; and control the implantable medical device to deliver, alternating with the first electric field, the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination.

[0371] Example 101. A system comprising: processing circuitry- configured to: receive imaging data of anatomy for a patient; receive sensing data from one or more implanted sensors in the patient; identify, based on the imaging data and the sensing data, locations of cerebral spinal fluid, a resection cavity, and a possible residual tumor; generate, based on the locations identified, a model of the anatomy for the patient; and output, for display, the model.

[0372] Example 102. The system of example 101 , wherein the imaging data comprises at least one of data obtained by at least one of magnetic resonance imaging (MRI), computed tomography, or magnetoencephalography (MEG).

[0373] Example 103. The system of any of examples 101 and 102, wherein the sensing data, comprises at least one of local field potentials (LFPs) or impedance tomography.

[0374] Example 104. The system of any of examples 101 through 103, wherein the processing circuitry is configured to generate, as part of the model, locations of high electric field strength.

[0375] Example 105. The system of any of examples 101 through 104, wherein the anatomy of the patient comprises at least a portion of a brain of the patient. [0376] Example 106. The system of any of examples 101 through 105, wherein the processing circuitry is configured to generate, as part of the model, anatomical locations within a brain of the patient.

[0377] Example 107. The system of any of examples 101 through 106, further comprising a user interface configured to display the model.

[0378] Example 108. The system of any of examples 101 through 107, wherein the processing circuitry is configured to determine a value of one or more stimulation parameters that at least partially define alternating electric field therapy.

[0379] Example 109. The system of example 108, wherein the processing circuitry is configured to output, for display, the value of the one or more stimulation parameters as a recommendation for alternating electric field therapy as part of a therapy planning user interface. [0380] Example 110. The system of example 109, wherein the value is a first value, and wherein the processing circuitry is configured to: receive user input adjusting the first value of the one or more stimulation parameters to a second value different than the first value; and storing the second value of the one or more stimulation parameters for subsequent delivery of alternating electric field therapy to the patient.

[0381] Example 201. A system comprising: stimulation circuitry configured to deliver electric field therapy to a patient; sensing circuitry configured to generate sensed data representati ve of a sensed electri c signal resulting from delivery of the electric field therapy; and processing circuitry configured to: receive the sensed data; determine one or more electrical physics parameters indicative of the sensed electric signal; predict an electrical field strength for anatomy of the patient; generate, based on an electrical field strength, a metric of the electric field therapy; and output, for display, the metric of the electric field therapy.

[0382] Example 202. The system of example 201 , wherein the stimulation circuitry is configured to deliver the electric field therapy via a first set of electrodes, and wherein the sensing circuitry is configured to generate the sensed data from the sensed electrical signal obtained from a second set of electrodes different than the first set of electrodes.

[0383] Example 203. The system of any of examples 201 and 202, wherein the sensing data comprises at least one of evoked signals, local field potentials (LFPs), or impedance tomography. [0384] Example 204. The system of any of examples 201 through 203, wherein the processing circuitry is configured to predict the electric field strength over a volume of the anatomy.

[0385] Example 205. The system of any of examples 201 through 204, wherein the anatomy of the patient comprises at least a portion of a brain of the patient.

[0386] Example 206. The system of any of examples 201 through 205, wherein the metric comprises a singular value indicative of the electric field therapy efficacy for a target tissue within the anatomy.

[0387] Example 207. The system of any of examples 201 through 206, wherein the metric comprises gradients with respect to respective locations of the anatomy of the patient.

[0388] Example 208. The system of any of examples 201 through 207, further comprising a user interface configured to display the metric of the electric field therapy.

[0389] Example 301. A system comprising: processing circuitry configured to: receive first user input defining target tissue to receive electric field therapy; receive second user input defining tissue to avoid receiving electric field therapy; determine, based on at least one of the first user input or the second user input, one or more stimulation parameters that at least partially defines the electric field therapy; and control a medical device to deliver the electric field therapy according to the one or more stimulation parameters.

[0390] Example 302. The system of example 301, w'herein the one or more stimulation parameters comprises one or more electrode combinations that at least partially define the electric field therapy.

[0391] Example 303. The system of any of examples 301 and 302, wherein the one or more stimulation parameters comprises one or more implant locations for one or more leads that carry electrodes for delivering the electric field therapy.

[0392] Example 304. The system of any of examples 301 through 303, further comprising a user interface configured to receive at least one of the first user input or the second user input.

[0393] Example 401. A system comprising: processing circuitry configured to: receive a request to deliver electric field therapy, w'herein the electric field therapy comprises delivery of a first electric field and a second electric field; and control an implantable medical device to deliver the electric field therapy by iteratively sweeping through each selected frequency of a plurality of frequencies, wherein, for each selected frequency of the plurality of frequencies, the implantable medical device is controlled to deliver the first electric field from a first electrode combination of implanted electrodes at the selected frequency in alternating fashion with the second electric field from a second electrode combination of implanted electrodes different than the first electrode combination and at the selected frequency.

[0394] Example 402. The system of example 401 , further comprising the implantable medical device configured to deliver the electric field therapy.

[ 0395] Example 403. The system of any of examples 401 and 402, wherein the processing circuitry is configured to determine respective amplitudes for each selected frequency of the plurality of frequencies based on a model of electric field therapy.

[0396] Example 501. A system comprising: stimulation circuitry configured to deliver electric field therapy to a patient; sensing circuitry configured to generate sensed data representative of a sensed electric signals via one or more electrodes disposed at a boundary of a tumor resection; and processing circuitry configured to: receive the sensed data; compare the sensed data to one or more target signal characteristics; adjust, based on the comparison, one or more stimulation parameters from a first value to a second value; and control the stimulation circuitry to deliver the electric field therapy according to the second value of the one or more stimulation parameters.

[0397] Example 502. The system of example 501, wherein the processing circuitry is configured to compare the sensed data to one or more target signal characteristics at a predetermined interval.

[0398] Example 503. The system of any of examples 501 and 502, wherein the one or more stimulation parameters comprises one or more electrode combinations.

[0399] Example 504. The system of any of examples 501 through 503, wherein the one or more stimulation parameters comprises a frequency.

[0400] Example 505. The system of any of examples 501 through 504, wherein the one or more stimulation parameters comprises a cycling duration for the electric field therapy.

[0401] Example 601. A system comprising: processing circuitry configured to: control an implantable medical device to deliver a first electric field from a first electrode combination of implanted electrodes; and control the implantable medical device to deliver, alternating with the first electric field, a second electric field from a second electrode combination of implanted electrodes different than the first electrode combination, wherein the first electric field and the second electric field comprise electric field therapy deliverable to a patient, and wherein at least one of the first electrode combination or the second electrode combination comprises one or more subcutaneous electrodes.

[0402] Example 602. The system of example 601, wherein at least one of the first electrode combination or the second electrode combination comprises one or more electrodes carried by one or more implantable leads.

[0403] Example 603. The system of any of examples 601 and 602, wherein the implantable medical device is configured to be electrically coupled to electrodes of the first electrode combination and the second electrode combination.

[0404] Example 604. The system of any of examples 601 through 603, further comprising the implantable medical device.

[0405] Example 605. The system of any of examples 601 through 604, wherein the implantable medical device comprises the processing circuitry.

[0406] Example 606. The system of any of examples 601 through 605, further comprising the implanted electrodes that include the one or more subcutaneous electrodes.

[0407] Example 701. A system comprising: processing circuitry configured to: control an implantable medical device to deliver a first electric field from a first electrode combination of electrodes carried by one or more implanted leads; and control an external medical device to deliver, alternating with the first electric field, a second electric field from a second electrode combination of external cutaneous electrodes, wherein the first electric field and the second electric field comprise electric field therapy deliverable to a patient.

[0408] Example 702. The system of example 701 , further comprising the implantable medical device, wherein the implantable medical device comprises the processing circuitry configured to control the external medical device to deliver the second electric field.

[0409] Example 703. The system of any of examples 701 and 702, further comprising the external medical device, wherein the external medical device comprises the processing circuitry configured to control the implantable medical device to deliver the first electric field.

[ 0410] Example 704. The system of any of examples 701 through 703, further comprising an external programmer comprising the processing circuitry, wherein the external programmer is configured to wirelessly communicate with the implantable medical device and the external medical device to coordinate delivery of the AEF therapy. [0411] Example 705. The system of any of examples 701 through 704, wherein the implantable medical device comprises the processing circuitry.

[0412] Example 706. The system of any of examples 701 through 705, further comprising the implanted leads and the external cutaneous electrodes.

[0413] Example 801. A system comprising: an activity sensor configured to generate activity data indicative of patient activity ; sensing circuity configured to sense an electrical signal through at least a portion of target tissue configured to receive electric field therapy; and processing circuitry configured to: receive the activity data; control, based on the activity data, the sensing circuitry to sense the electrical signal; and control, based on the electrical signal, an implantable medical device to deliver electric field therapy.

[0414] Example 802. The system of example 801, wherein the processing circuitry is configured to control the sensing circuitry by at least scheduling the sensing circuitry to sense the electrical signal during a period of reduced patient activity.

[0415] Example 803. The system of any of examples 801 and 802, wherein the sensing circuitry is configured to sense the electrical signal by sensing an electrical field via two or more implanted electrodes.

[0416] Example 804. The system of any of examples 801 through 803, further comprising the implantable medical device.

[0417] Example 901. A system comprising: processing circuitry configured to: receive a request to deliver alternating magnetic field (AMF) therapy; determine therapy parameter values that define the AMF therapy, wherein the AMF therapy comprises delivery of a first magnetic field and a second magnetic field; control an implantable medical device to deliver the first magnetic field from at least a first implantable coil; and control the implantable medical device to deliver, alternating with the first magnetic field, the second magnetic field from a second implantable coil different than the first implantable coil.

[0418] Example 902. The system of example 901 , further comprising the first implanted coil and the second implantable coil.

[0419] Example 903. The system of any of examples 901 and 902, further comprising the implantable medical device.

[0420] Example 1001. A system comprising: processing circuitry configured to: receive temperature data generated by a temperature sensor, the temperature data indicative of temperature at a tissue region of a patient; control, based on the temperature, an implantable medical device to deliver electric field therapy via a plurality of implantable electrodes.

[0421] Example 1002. The system of example 1001, wherein the processing circuitry is configured to: determine, based on the temperature data, that the temperature exceeds a threshold temperature; and responsive to the temperature exceeding the threshold temperature, control the implantable medical device to terminate electric field therapy.

[0422] Example 1003. The system of any of examples 1002 and 1003, wherein the processing circuitry is configured to: determine, based on the temperature data, that the temperature drops below an acceptable temperature; and responsive to the temperature dropping below the acceptable temperature, control the implantable medical device to redeliver the electric field therapy.

[0423] Example 1004. The system of any of examples 1001 through 1003, further comprising the temperature sensor.

[0424] Example 1005. The system of any of examples 1001 through 1004, further comprising the implantable medical device.

[0425] Example 1006. The system of any of examples 1001 through 1005, wherein the implantable medical device comprises the processing circuitry.

[0426] Example 1 100. Any device, system, method, or computer-readable medium described or otherwise supported in the specification herein.

[0427] Example 1201. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; receive one or more markers associated with one or more cell types; determine, based on the one or more markers, a migration state of the one or more cell types; and adjust, based on the migration state, one or more parameters at least partially defining the electric field therapy.

[0428] Example 1301. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; control the implantable medical device to delivery an electrical stimulus at a scheduled time; determine a geometry of a response to the electrical stimulus; determine that the geometry of the response is different from a baseline geometry; and control a user interface to present an indication of a change in the geometry from the baseline geometry.

[0429] Example 1401. A medical lead comprising: a lead housing defining a channel configured to transmit a fluid from a proximal end of the lead housing to a distal end of the lead housing; one or more electrodes carried by an electrode housing and configured to deliver electric field therapy; and a plurality of ports defined by the electrode housing, wherein the plurality of ports are in fluid communication with the channel.

[0430] Example 1402. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy via a lead, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; and control the implantable medical device to deliver a drug through lead and out of a plurality of ports defined by the lead.

[0431] Example 1501. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; control the implantable medical device to deliver a single electrical stimulus to a tissue, wherein the single electrical stimulus is configured to increase drug uptake by one or more cells of the tissue; and control the implantable medical device to deliver the drug to the tissue.

[0432] Example 1601. A method comprising: inserting a spray nozzle to a target tissue of a patient; dispensing a liquid metal from the spray nozzle and onto a target tissue, wherein the liquid metal is configured to form an electrode on the target tissue; and electrically coupling the electrode to an implantable medical device.

[0433] Example 1602. The method of example 1601 , further comprising controlling the implantable medical device to deliver electrical field therapy to the target tissue via the electrode.

[0434] Example 1603. The method of example 1601 , wherein the electrode is a first electrode and the target tissue is a first target tissue, and wherein the method further comprises: moving the spray nozzle to a second target tissue; dispensing the liquid metal from the spray nozzle and onto the second target tissue, wherein the liquid metal is configured to form a second electrode on the second target tissue; and electrically coupling the second electrode to the implantable medical device. [0435] Example 1701. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; and control the implantable medical device to deliver direct electrical stimulus interleaved with the electric field therapy for a predetermine period of time.

[0436] Example 1801. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy via a first electrode combination, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; and control the implantable medical device to deliver a single electrical stimulus configured to elicit T cell response via a second electrode combination different from the first electrode configuration.

[0437] Example 1901. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy via a first electrode combination, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; and control the implantable medical device to deliver nanopulse electrical stimuli interleaved with the electric field therapy for a predetermined period of time.

[0438] Example 2001. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy via a first electrode combination to a target tissue, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; and control the implantable medical device to deliver electro-capacitive stimulation via a second electrode combination comprising one or more capacitive electrodes to the target tissue.

[0439] Example 2101. A system comprising: processing circuitry configured to: control an implantable medical device to deliver electric field therapy via a first electrode combination to a target tissue, wherein the electric field therapy comprises delivery of a first electric field and a second electric field; receive sensed data and user input data associated with the electric field therapy; apply a machine learning algorithm to the sensed data and user input data; determine, based on the application of the machine learning algorithm, updated parameter values that define the electric field therapy; and store the updated parameter values in the implantable medical device to at least partially define subsequent electric field therapy deliverable by the implantable medical device. [0440] Example 2102. The system of example 2102, wherein the processing circuitry is configured to: compare the updated parameter values to prior parameter values; determine that the updated parameter values exceed a threshold parameter difference; responsive to determining that the updated parameter values exceed the threshold parameter difference, control a user interface to request user approval of the updated parameter values; and responsive to receiving user approval via the user interface, storing the updated parameter values in the implantable medical device.

[0441] The techniques described in this disclosure may be implemented, at least in part, in hardware, software, firmware or any combination thereof. For example, various aspects of the described techniques may be implemented within one or more processors, such as fixed function processing circuitry and/or programmable processing circuitry, including one or more microprocessors, digital signal processors (DSPs), application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), or any other equivalent integrated or discrete logic circuitry, as well as any combinations of such components. The term “processor” or “processing circuitry” may generally refer to any of the foregoing logic circuitry, alone or in combination with other logic circuitry, or any other equivalent circuitry. A control unit comprising hardware may also perform one or more of the techniques of this disclosure.

[0442] Such hardware, software, and firmware may be implemented within the same device or within separate devices to support the various operations and functions described in this disclosure. In addition, any of the described units, modules or components may be implemented together or separately as discrete but interoperable logic devices. Depiction of different features as modules or units is intended to highlight different functional aspects and does not necessarily imply that such modules or units must be realized by separate hardware or software components. Rather, functionality associated with one or more modules or units may be performed by separate hardware or software components, or integrated within common or separate hardware or software components,

[0443] The techniques described in this disclosure may also be embodied or encoded in a computer-readable medium, such as a computer-readable storage medium, containing instructions. Instructions embedded or encoded in a computer-readable storage medium may cause a programmable processor, or other processor, to perform the method, e.g., when the instructions are executed. Computer readable storage media may include random access memory (RAM), read only memory (ROM), programmable read only memory (PROM), erasable programmable read only memory (EPROM), electronically erasable programmable read only memory (EEPROM), flash memory, a hard disk, a CD-ROM, a floppy disk, a cassette, magnetic media, optical media, or other computer readable media.

[0444] Various examples have been described. These and other examples are within the scope of the following claims.