Implanted devices, systems, and methods for electrical treatment of cancer

Abstract

The present application describes various implementations of devices, systems, and methods for electrical treatment of cancer in the brain. The systems can include an implanted component with a hub and two flexible electrodes, wirelessly connectable to an external retriever for transmission of power and data. The systems may provide stimulation to and / or recording from the target brain tissue. Systems and methods for implantation of one or more components are also described. Such systems can include a center stylet, a hollow insertion needle, and an outer tube for releasably retaining the implanted electrode and hub during an insertion procedure.

Description

IMPLANTED DEVICES, SYSTEMS, AND METHODS FOR ELECTRICAL TREATMENT OF CANCERINCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 636,636, filed April 19, 2024, and U.S. Provisional Patent Application No. 63 / 721 ,304, filed November 15, 2024, each of which is hereby incorporated by reference herein in its entirety.BACKGROUNDField of the Invention

[0002] The present application describes various implementations of devices, systems, and methods for electrical treatment of cancer in the brain. Systems and methods for implantation of one or more components are also described herein.Background

[0003] Cancer neuroscience is an emergent field of medicine. Electrical information within cancer is intimately involved in growth, proliferation and subtype. Implanted devices, systems, and associated methods can be used for detection of electrophysiological biomarkers in the brain that can be used to inform disease state in real time.

[0004] Neurons are known to be involved in cancer in multiple ways, such as electrochemical neural-cancer interactions, paracrine neural-cancer interactions, systemic neural-cancer interactions, neuro-immuno-oncology, cancer cell-intrinsic neuronal mechanisms, and cancer therapy effects on the nervous system. High-frequency stimulation could be applied to, for example: (i) neurons, to directly stop conduction between neurons and cancer cells, (ii) cancer cells, to directly stop them from repolarising, (iii) nerves to reduce or suppress pain; and / or (iv) nerves (e.g. vagus nerve) which innervate other organs or tissues, which indirectly or directly influences cancer growth.

[0005] Many neurological dysfunctions are accompanied by an undesirable increase of nerve activity. For example, increase in nerve activity can lead to pain or proliferation of tumor cells in humans or animals. It is therefore desirable to reduce or eliminatethis increased nerve activity. One technique for reducing increased nerve activity is by the application of high-frequency alternating currents (AC). Such high-frequency AC signals can cause a nerve conduction block, thereby reducing the associated effect (e.g., pain, tumor growth, etc.). Proper application of AC signals can produce persistent mean depolarization of the axonal membrane near the electrode contacts, causing sodium channel inactivation and a local conduction block.

[0006] As described above, neurons may be involved in cancer in a number of ways. Studies show that the nervous system plays a role in the regulation of cancers and that interactions between the nervous system and cancer can regulate oncogenesis (i.e. the process through which normal cells are transformed into cancer cells), growth, spread, treatment resistance, and stimulation of tumor-promoting inflammation.

[0007] The applicant has therefore identified the need for a technique of using the nervous system to reduce or prevent cancer development or growth.SUMMARY OF SOME EXAMPLE EMBODIMENTS

[0008] Disclosed herein are embodiments of an implantable device for acquiring electrical biomarkers associated with tumours and for delivering electrical stimulation to the nervous system of a human or animal patient and methods of using the device. For example and without limitation, some variations of the implantable device and / or methods of using same are configured to deliver electrical stimulation to a target in the central nervous system to reduce or prevent cancer development or growth. Some variations of the implanted devices, systems, and associated methods may be used for detection of electrophysiological biomarkers in the brain that can be used to inform disease state in real time. In some variations, an implanted system can provide closed-loop stimulation, leading to improvements in disease treatment by providing precision healthcare. In some variations, a system includes a retriever component, an implanted recording and / or stimulating unit, and clinician software.

[0009] In some aspects, the techniques described herein relate to a system for electrical recording from a target in a patient, the system including: an implanted component including at least two electrodes; an external retriever; a recording system coupled to the at least two electrodes; a communication system for transmitting data between the implanted component and the external retriever; and a power system for wirelessly transmitting power from the retriever to the implanted system, wherein the system can be configured to record electrical signals from the target.

[0010] In some aspects, the electrodes include a flat thin-film electrode array. In some aspects, the electrodes are arranged on a plurality of separate arrays.

[0011] In some aspects, the target is neural tissue. In some aspects, the target is malignant. In some aspects, the target is in the brain.

[0012] In some aspects, the communication system includes at least one light emitting diode and a photodiode. In some aspects, the communication system includes an infra-red or near infra-red light emitting diode and a photodiode.

[0013] In some aspects, the power system includes an RF inductive coupling system.

[0014] In some aspects, the system further includes a feedback system in the retriever.

[0015] In some aspects, the implanted component includes a hermetically sealed capsule. In some aspects, the capsule includes an optical cap, a feedthrough connected to the electrodes, and an electronics module including at least one component of the communication system. In some aspects, the at least one component of the communication system includes an infra-red or near infra-red LED or LED array.

[0016] In some aspects, the electronics module further includes a receiver coil, selective shielding, and a printed circuit board, wherein the printed circuit board includes the at least one component of the communication system. In some aspects, the selective shielding includes one or more of a coil standoff under the receiver coil, a copper shield under the coil standoff or receiver coil, or a shield standoff above the printed circuit board.

[0017] In some aspects, the system further includes a stimulation module connected to the electrodes. In some aspects, the stimulation module can be configured to apply a stimulation signal to the target.

[0018] In some aspects, the techniques described herein relate to a treatment method including: applying an electrical stimulation signal from an implanted system to a target tissue, the stimulation signal including a frequency range between 0.5 Hz to 200 kHz and an amplitude between 0.1 mA and 10 mA.

[0019] In some aspects, the frequency range can be between 0.1 kHz and 100 kHz. In some aspects, the amplitude is 0.5 mA and the frequency is selected from a range of 2.5-4 kHz. In some aspects, the stimulation signal includes a biphasic charge balanced waveform. In some aspects, the stimulation signal can be asymmetric.

[0020] In some aspects, the method further includes adjusting the stimulation signal. In some aspects, the stimulation signal has a duty cycle of 75-100%. In some aspects,the stimulation signal comprises a repeating signal comprising a negative charge amplitude delivered for 400 microseconds, then an amplitude of 0 mA for 10 microseconds, then a balanced positive amplitude delivered for 400 microseconds, wherein the repeating signal has an 80% duty cycle. In some aspects, the stimulation signal comprises a frequency selected from the range of 0.1-10kHz and a duty cycle selected from the range of 10-100%.

[0021] In some aspects, the method further includes measuring a signal from the target tissue. In some aspects, the measured signal can be used to adjust the stimulation signal. In some aspects, the measured signal can be automatically analyzed and used to adjust the stimulation signal. In some aspects, the measured signal can be an electrical signal measured by the implanted system with at least two electrodes. In some aspects, the measured signal can be transmitted from the implanted system to an external system.

[0022] In some aspects, the method further includes providing feedback to a user. In some aspects, the feedback may include audible or haptic feedback.

[0023] In some aspects, the techniques described herein relate to a system for positioning implantable components in the brain including: a center stylet, a hollow insertion needle, and an outer tube, wherein the center stylet is held within the insertion needle and the insertion needle is held within the outer tube.

[0024] In some aspects, the center stylet, insertion needle, and outer tube each include a proximal handle, wherein each handle is configured to be releasably locked to one or more of the other handles.

[0025] In some aspects, the outer tube is configured to interface with a stereotactic or robotic surgical system. In some aspects, the outer tube further comprises an insertion stop configured to limit a depth of insertion into a brain. In some aspects, the outer tube further comprises a device holder configured to releasably hold a device implantable into the skull.

[0026] In some aspects, the center stylet and insertion needle are configured to position an electrode array loaded over the center stylet and alongside the insertion needle. In some aspects, the center stylet, insertion needle, and outer tube each comprise an atraumatic distal tip.

[0027] In some aspects, the techniques described herein relate to a method of positioning implantable components in the brain including: withdrawing a center stylet from an implantable electrode array loaded over the center stylet and alongside an insertion needle; withdrawing the insertion needle to leave the electrode array in a target location in the brain; releasing an implantable hermetic capsule loaded into a device holder on an outer tube; andsecuring the hermetic capsule to the skull, wherein the center stylet is held within the insertion needle, and the insertion needle is held within the outer tube.

[0028] In some aspects, the method further includes inserting the electrode array, center stylet, and insertion needle into the target location in the brain before withdrawing the center stylet. In some aspects, a depth of insertion is controlled by an insertion stop carried by the outer tube. In some aspects, the method further includes releasing a lock between a handle of the center stylet and a handle of the insertion needle before withdrawing the center stylet.

[0029] In some aspects, the techniques described herein relate to a system for electrical treatment of cancer including one or more features of the foregoing description.

[0030] In some aspects, the techniques described herein relate to a system for recording electrical signals from the brain for treatment of cancer including one or more features of the foregoing description.

[0031] In some aspects, the techniques described herein relate to a system for electrical treatment of cancer including a retriever component and an implanted component, including one or more features of the foregoing description.

[0032] In some aspects, the techniques described herein relate to a method for electrical treatment of brain cancer including one or more features of the foregoing description.

[0033] These and other aspects and embodiments are described in greater detail below, in relation to the drawing figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0034] For purposes of summarizing some example embodiments of the disclosure, certain aspects, advantages, and novel features are discussed herein. It is to be understood that not necessarily all such aspects, advantages, or features will be embodied in any particular embodiment of the disclosure, and an artisan would recognize from the disclosure herein a myriad of combinations of such aspects, advantages, or features.

[0035] FIG. 1 illustrates an implementation of a system including implanted unit and retriever.

[0036] FIG. 2 illustrates an implementation of an implanted unit.

[0037] FIG. 3 illustrates an exploded view of the implanted unit of FIG. 2.

[0038] FIG. 4 illustrate views of the implanted unit of FIG. 2.

[0039] FIGS. 5A-5C illustrate an implementation of an electronics module of an implanted unit.

[0040] FIG. 6 illustrates an implementation of a flat thin film electrode array.

[0041] FIG. 7A illustrates a profile view of an implementation of an implanted component with a multi-lead flat thin film electrode array.

[0042] FIGS. 7B and 7C illustrate a respective side view and top view of the implanted component of FIG. 7A.

[0043] FIG. 8 illustrates an implementation of an implantation tool system.

[0044] FIGS. 9A-9C illustrate an implementation of using an implantation tool system to deliver an electrode array.

[0045] FIGS. 10A and 10B are schematic diagrams showing the impact of electrical stimulation on a target.

[0046] FIG. 11 shows effects of potential blocking stimulus signals on neural firing rates for signals with various amplitudes and frequencies.

[0047] FIG. 12 shows example neural activity without stimulation blocking.

[0048] FIG. 13 illustrates neural activity in response to application of an implementation of a stimulation block signal.

[0049] FIG. 14A illustrates an implementation of a stimulation blocking signal.

[0050] FIGS. 14B-1 and 14B-2 illustrate an implementation of a complex stimulation blocking signal.

[0051] FIG. 15 shows results of treatment by applying a stimulation blocking signal compared to control treatment.

[0052] FIG. 16 is a block diagram of an implementation of an open loop implantable device for electrical stimulation of a target in a patient.

[0053] FIG. 17 is a block diagram of an implementation of a closed loop implantable device for electrical stimulation of a target in a patient.DETAILED DESCRIPTION

[0054] In some variations, an implanted system can provide electrical stimulation to a target, leading to improvements in disease treatment by providing precision healthcare. In some variations, a system includes a retriever component, an implanted recording and / or stimulating unit, and clinician software.

[0055] Retriever Component

[0056] In some variations, a treatment system may include a retriever component 150 to interface with an implanted component 200 and / or clinician software. In some variations, a retriever component 150 can include a wireless rechargeable hand-held unit thatcontains a transmitting coil with accompanying electronics. In some variations, a retriever component 150 may comprise a wearable unit. In some variations, a retriever may include a power module and a communications module for providing power and communications to an implanted component 200. In some variations, a power module can include an inductive coil to inductively couple to an implanted unit to transfer power. In some variations, an inductive coil may provide power and communications to an implanted unit 200. For example, in some variations, an inductive coil can be used to provide steady power an intermittent communication, such as periodic instructions or software updates as described herein.

[0057] In some variations, a communications module in a retriever component 150 can include an optical receiver, for example a photodiode, to receive data from the implanted component 200. In some variations, a communications module in a retriever component 150 may cooperate with an optical data transmitter of an implanted component 200, for example an LED or LED array. In some variations, a photodiode and LED array may enable high speed data transmission for high bandwidth requirements during neural acquisition. In some variations, infra-red (IR) or near IR communication may be used.

[0058] In some variations, an optical communications system between a retriever component 150 and an implanted component 200 may be configured for bidirectional communications. In some variations, a communication system between a retriever component 150 and an implanted component 200 may use an optical system (for example the photodiode and LED array described herein) for data transmission from the implanted component 200, and an RF system (for example the inductive coil described herein) for data transmission to the implanted component 200. Accordingly, a communications module of a retriever component 150 and a corresponding communications module of an implanted component 200 may include multiple paired sub-components to transmit and receive various types of data (such as neural recordings, status information, instructions, system updates, etc.) depending on the amount of data to be transferred, desired transfer speed, expected interference, error tolerance, or other factors. In some variations, an optical communication system may include one or more of an infra-red (IR) or near infra-red component, for example an IR or near IR light emitting diode (LED). In some variations, an array of LEDs may be used, for example to allow for encoding of different information with different wavelengths and / or to transmit more data spread across multiple LEDs. In some variations, a retriever component 150 may include both a photo transmitter (e.g., an IR LED array orother I R emitter) and a photo receiver (e.g., a photodiode), each with corresponding components in a mating implanted component 200.

[0059] In some variations, a retriever component 150 may be used to provide status information, for example to a user and / or to a clinician display. In some variations, a retriever component 150 may be rechargeable and may dock to a PC or other device running the clinician software. In some variations, connecting a retriever component 150 to clinician software and to an implanted unit 200 can adjust or update internal programming of the implanted unit 200, for example by providing software and / or firmware updates. In some variations, a clinician can adjust the programming, for example to alter parameters or customize the device. In some variations, the programming can be adjusted automatically.

[0060] As shown in FIG. 1 , in some variations of the system, a retriever component 150 may inductively couple through the skull 20 to an implanted unit 200 and electrode array 250 implanted in the brain 50. In some variations, a computer display can provide a visual map to assist placement of a retriever component 150. For example, in some variations a display may assist alignment of an inductive coil in a retriever component 150 over a corresponding electronics module in an implanted unit 200. In some variations, an LED or LED array may be provided in the center of the inductive coil of the implanted component 200. The concentric geometry arrangement can facilitate proper alignment of the optical communication components (e.g., LED or LED array and photodiode) when the coil of the retriever component 150 and the implanted unit 200 are aligned to provide power and communications. In some variations, power can be transferred only when a retriever component 150 is in place for operation of an implanted unit 200, thereby enhancing safety and minimizing implanted power components.

[0061] In some variations, the retriever component 150 may include a feedback subsystem. In some variations, a feedback subsystem may be used to assist proper alignment, for example by indicating improper alignment and / or providing an indication of suggested adjustments to improve alignment. In some variations, a feedback subsystem may be used to indicate battery or power status, successful data transmission, error states, or other information. In some variations, the feedback subsystem may include visual feedback, such as a status light, to indicate when the retriever is properly aligned with the implant. In some variations, a status light may indicate the direction in which to move the retriever to improve alignment, for example via a controllable ring light or array of lights. In some variations, a status light may indicate proper alignment. In some variations, a feedback subsystem may include audible or tactile indicators, for example clicking, beeping, varying tones, vibrations, haptic, or other indicator. In some variations, the feedback subsystem may also be displayed through an app on a mobile device linked to the retriever via Bluetooth.

[0062] Implanted Component

[0063] As shown in FIGS. 2-5, in some variations, an implanted recording and / or stimulating unit 200 may include a hermetically sealed capsule 210 with at least one electrode array 250. In some variations, the at least one electrode array 250 may be a flexible thin-film component to minimize tissue damage.

[0064] As illustrated in FIG. 3, a capsule 210 of an implanted component may contain an electronics module 230 (for example as shown in FIG. 5). In some variations, a capsule 210 may be a hermetically sealed capsule to protect internal components, such as the electronics module 230. In some variations, an electronics module 230 in a hermetic capsule 210 of an implanted component 200 may include a power module for receiving power from a retriever 150, as discussed above. In some variations, a power module can include an inductive coil to inductively couple to a retriever to receive transferred power. In some variations, a power module may include a battery, rechargeable battery, capacitor, energy harvester, or other suitable power source within or connected to the electronics module.

[0065] In some variations, an electronics module 230 may contain a communications module for sending and / or receiving data to a retriever component 150 or other external device. In some variations, a communications module can include an LED or LED array to transfer data to a retriever and / or a photodiode to receive data from a retriever component 150, as discussed above. In some variations, a communications module may include a subsystem that may include a coupler and / or a wired or wireless transceiver (RF, for example Bluetooth, or other wireless protocol). In some variations, an electronics module 230 may include an RF coil and an LED or LED array that can be used together to communicate with an external system via a retriever component 150 as described above.

[0066] In some variations, an electronics module 230 may include a stimulation subsystem and / or a recording subsystem. In some variations, an implanted unit 200 may be configured to record neural data collected from an electrode array implanted near a target tissue (e.g., a tumor). In some variations, recorded neural data can be sent, for example via an LED or LED array in an implanted component 200 to a mating photodiode in a retriever component 150, to an external device for analysis. In some variations, recorded data may be further relayed to another remote device for analysis and / or storage. For example, data may be sent via wired or wireless communications to a remote server or cloud-based storage system. In some variations, an implanted unit 200 may be capable of monitoring disease progression in target tissue and may provide pre-programmed stimulation therapy to the target tissue. In some variations, disease progression may be monitored for example throughimpedance changes in target tissue, electroencephalogram analysis, or other electrical neural signal.

[0067] As further shown in FIG. 3, in some variations a hermetic capsule 210 may include one or more feedthroughs 234 and / or interconnects for an electrode array 250. Each feedthrough 234 can include a titanium case and platinum-iridium pins. In some variations, multiple feedthroughs may be used, for example to increase the number of available connections and / or to group connections. In some variations, each feedthrough 234 can include approximately 1-64 pins, for example 1 , 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 32, 48, 64 pins or any number of pins or range of pins within the foregoing range(s). A feedthrough may include one or more solder pre-forms 232B, for example an alloy mask, stencil, stamp, or template that can be used to place conductive dots for electrical connections. Non-limiting examples of appropriate conductive alloys include gold alloys, silver alloys, gold-tin alloys, gold-germanium alloys, gold-tin-copper alloys, and other conductive lead-free alloys. In some variations, multiple identical feedthroughs may be used, while in some variations one or more feedthroughs may be different in size, shape, placement, materials, and / or number of pins. In some variations, a retainer ring 204, for example a PEEK retainer ring, can be used for attachment to the skull 20.

[0068] As further illustrated in FIG. 3, in some variations, an optical data transmission component of an electronics module 230 may be covered with an optical cap 212, which can allow the optical communications component(s) to couple with a retriever component 150. In some variations, the optical cap 212 is a glass cap. In some variations, the optical cap 212 material may be a sapphire glass, a ceramic, or other suitable optically- transparent material. In some variations, the optical data transmission component may include one or more infra-red or near infra-red light emitting diodes (IR LED). In some variations, the optical transmission component may also include one or more photodiodes to receive optical data from, for example, a retriever component 150. In some variations, the optical cap 212 may be transparent to the wavelength of the optical transmitter. In some variations, the optical cap 212 surfaces may be modified to focus or disperse the infra-red light. In some variations, an optical cap 212, for example a glass cap, may allow light transmission, enhance durability, serve as a hermetic barrier, enhance MRI compatibility, and provide the ability to sinter metallic components.

[0069] With reference to FIG. 4, in some variations, an implanted unit 200 can be smaller than typical commercially available neural interfaces capable of similar recording and stimulation. In some variations, use of a thin film electrode array 250 provides multipleaddressable channels for targeted recording and / or stimulation while minimizing the size of implanted components. As described below, in some variations, an electrode array 250 may include multiple addressable channels. In some variations, an electrode array may include eight addressable channels. In some variations, high-density thin film arrays and appropriate feedthroughs may provide thousands of individually addressable channels. In some variations, size of the implanted components may be reduced via a stacked concentric layout, for example shown in FIG. 5. For example, a concentric arrangement may align an optical data transmission component, such as an LED array, in the center of a transmission coil. As noted above, this arrangement facilitates alignment of the LED array of the implanted component 200 with the photodiode of the retriever component 150 when the coils are aligned, and also allows for a small overall size. With reference to FIG. 4, in some variations, a hermetic capsule 210 of an implanted component 200 can have a height H of 9.5 mm or approximately 9.5 mm, or from 8 mm or approximately 8 mm to 11 mm or approximately 11 mm, or from 9 mm or approximately 9 mm to 10 mm or approximately 10 mm, or of any value, approximate value, or range of values in the foregoing range(s). In some variations, a hermitic capsule 210 an implanted component 200 can have a diameter D of 14.0 mm or approximately 14 mm, or from 11 mm or approximately 11 mm diameter to 17 mm or approximately 17 mm, or from 12 mm or approximately 12 mm to 16 mm or approximately 16 mm, or of any value, approximate value, or range of values in the foregoing range(s). In some variations, the overall size can be further reduced via custom ASIC and / or custom feedthrough. As described above, in some variations, an implanted component 200 receives power from a retriever component 150, removing the need for a battery in the implanted component 200 and further reducing the overall size. In some variations, the dimensions of a hermetic capsule 210 may be designed to fit in an implant location, such as an implant location in a human skull 20. In some variations, the dimensions may be designed for compatibility with known surgical techniques and implantation tools.

[0070] As illustrated in FIGS. 5A-5C, an electronics module 230 may include a printed circuit board (PCB) or flexible printed circuit board (fPCB), or rigid-flex PCB 510. In some variations, a PCB 510 may include one or more components, such as an application specific integrated circuit board (ASIC) 514 and LED or LED array 518 for communications as described herein. In some variations, a feedthrough flex circuit 522 is connected to the PCB 510, for example under the PCB 510 as shown in FIG. 5B, to provide connections to the electrode feedthrough 234 as described herein. In some variations, a radio frequency (RF) coil 526 may be provided over the PCB 510, for example to provide power and optionalcommunications as described herein. In some variations, an RF coil 526 may be provided near the top, or externally facing side of the electronics module, and therefore arranged to face the retriever component 150 when an implanted component 200 is placed in the skull 20. In some variations, an electromagnetic shield 530, for example a shield of copper, aluminum, silver, gold, tin, alloy, or other appropriate material may be provided between the RF coil 526 and the PCB 510, for example above the PCB 510 as shown in FIGS. 5A and 5C. In some variations, the electromagnetic shield 530 may be provided on a shield standoff 532 provided over the PCB 510, as shown in FIG. 5C. As illustrated in FIGS. 5A and 5C, a shield standoff 532 can help protect components on the PCB 510, for example from physical damage and / or heat. In some variations, a coil standoff 534 may be used to provide space between the RF coil 526 and the electromagnetic shield 530. In some variations, a coil standoff 534 may be used to provide a flat mounting surface for an RF coil 526.

[0071] In some variations, an electronics module 230 may be round or discshaped. In some variations, various components in an electronics module 230 may be arranged concentrically, for example as illustrated in FIG. 5C. In some variations, a concentric arrangement may include a central communications component, for example an LED 518 as shown in FIG. 5C. In some variations, a central hole may be provided in some components, for example in a shield standoff 532, electromagnetic shield 530, and / or coil standoff 534. The central hole may be aligned over the central communications component or LED 518, as illustrated in FIG. 5C, to allow the LED 518 to emit past or through the components above it. In some variations, some components, for example a shield standoff 532, electromagnetic shield 530, and / or coil standoff 534 may be provided with a central window of optically- transparent material to allow a centrally-located LED or LED array 518 to emit through the components above it. As illustrated in FIG. 5C, the electronics module 230 may be designed to be small and to minimize metallic materials and components that may react with imaging techniques, for example MRI procedures as described herein.

[0072] In some variations, an electrode array 250 of an implanted component 200 may include a thin-film probe, which can be a polyimide thin-film probe, for example as shown in FIG. 6. In some variations, an electrode array 250 may be attached to the bottom of a hermetic capsule 210 as illustrated in FIGS. 1-4. Because tumor locations can vary, in some variations an electrode array 250 is flexible to allow placement in any relevant location in the brain 50. In some variations, an electrode array 250 may be formed of metallic materials and / or metallic materials in combination with conductive polymers. In some variations, an electrode array 250 includes a flat thin-film substrate with a linear array of multiple electrodes.In some variations, electrodes may be distributed on multiple leads. For example as shown in FIGS. 7A-7C, electrodes may be arranged on three leads or arrays 752, 754, 756 connected at a single feedthrough 750 of a hermetic capsule 210. In some variations, multiple feedthroughs or a custom high-density feedthrough can be provided on the hermetic capsule 210 to allow expansion for additional electrodes and electrode arrays. In some variations, a combination of multiple feedthroughs and / or multiple arrays may be used to provide a large number of electrodes distributed around the capsule 210. In some variations, multiple electrodes located on one or more electrode arrays may be multiplexed, for example for addressability. In some variations, the hermetic capsule 210, or a portion thereof, may be used as an electrode. For example, an end cap 238 may be made of conductive material and be connected to the circuitry of electronics module 230 to function as an electrode, such as a ground or return electrode.

[0073] In some variations, the circuitry of the capsule 210 allows the system to designate a function for each electrode. For example, in some variations, each electrode is an individually addressable electrode that may be designated as a recording electrode, a stimulating electrode, a return electrode, and / or a disconnected electrode. In some variations, each electrode may be dynamically assigned a function, for example, to operate as a stimulating electrode before being re-assigned to operate as a recording electrode. In some variations, electrodes may be grouped or paired to operate together, for example as a working and return electrode, as a bipolar pair for stimulating or recording, as a block or multipoint electrode for stimulating or recording in a larger volume, and as a coordinated array to provide signal directionality. In some variations, a single electrode may be configured to operate as a sensing or recording electrode, for example as a virtual dipole or with a large return electrode or anode on the hermetic capsule 210. In some variations, a control system is configured to control connection of a stimulator and a recording system to each electrode such that only one of the stimulator and the recording system is connected to the at least two electrodes at any time. In this way, the electrodes are either in a “sense mode” during which they are being used to sense signals from the target, or in a “stimulate mode” during which they are being used to deliver the stimulation signal to the target (which in some cases, may involve stopping the delivery of the signal or not delivering the signal). In some variations, a stimulation signal can be provided by multiple electrodes, for example applied simultaneously across all electrodes or a subset of the electrodes, or applied sequentially to all electrodes or a subset of electrodes. In some variations, recordings can be taken from the same electrodes during a paused sequence.

[0074] In some variations, the implanted components 200 described herein may be distributed in multiple implants. In some variations, multiple implanted components may cooperate together as a system. For example, in some variations, a first implant may be configured as a recording implant, and a second implant may be configured as a stimulating implant. In some variations, one implanted device may include multiple electrode arrays 250, for example where a first array is configured as a stimulating array and a second array is configured as a recording array. In some variations, each implant is located in a separate location within the body, for example near a recording target or a stimulation target. In some variations, implanted components may be selected for implantation and cooperation based on tumor location, for example to target specific lesions.

[0075] Clinician Software

[0076] In some variations, a clinician software package may be a clinician-facing, benchtop unit that interfaces with a retriever to allow a clinician to interact with the retriever and / or implanted component. In some variations, clinician software may allow a clinician to enter relevant patient information, retrieve and review implanted unit information, and / or program custom operating parameters. In some variations, clinician software may be provided on a PC, tablet, smartphone, and / or other suitable devices. In some variations, a clinician software package may securely interface with a medical record of a patient.

[0077] Implantation

[0078] In some variations, an implanted unit 200 may be at least partially implanted in a subject. In some variations, an implanted unit 200 is fully implanted in a subject. In some variations, an implanted unit may be at least partially implanted on, in, or under the skull 20. In some variations, a hermetic capsule 210 of an implanted unit 200 may be implanted in the skull 20 and an electrode array 250 may be implanted in the brain 50, for example as illustrated in FIG. 1 . In some variations, fluoroscopy or other imaging techniques may be used during the implantation procedure. In some variations, one or more implanted components, such as a retainer 204, a hermetic capsule 210, and / or an electrode array 250, may include a marker, for example fluoroscopic or radio-opaque markers. In some variations, one or more markers may indicate position and / or orientation of at least a portion of an implanted component, for example an electrode array 250. In some variations, one or more markers may be used to guide and / or confirm placement of an implanted component.

[0079] In some variations, an implantation system or kit of tools may be used to facilitate placement of an implanted component 200 in the skull 20 and brain 50. FIG. 8 illustrates an example of such a tool system 800. In some variations, an implantation toolsystem 800 may include a nested set of tubes, for example three concentric stainless-steel tubes. In some variations, each tube includes an atraumatic tip, for example rounded, blunt, flexible point, or other configuration of geometry and / or materials to minimize damage and avoid coring of the brain tissue.

[0080] A center stylet 810 may be slidably housed in an insertion needle 830. In some variations, stylet 810 can include a stylet handle 812, which can allow a surgeon or other clinician to grip and control the center stylet 810. In some variations, the insertion needle 830 may be a hollow needle with a central lumen 834 holding the center stylet 810. In some variations, the insertion needle 830 may be a multi-lumen tube, with one lumen holding the center stylet 810 and one or more additional lumens for placement accessories, such as visualization devices, electrical mapping sensors, irrigation, blunt dissection, or other accessories. In some variations, the insertion needle 830 can include a needle handle 832, which can allow a surgeon or other clinician to grip and control the insertion needle 830.

[0081] The insertion needle 830 can be surrounded by an outer tube 850. Outer tube 850 can be used to guide placement of the implanted system and optionally interface with a surgical system. As illustrated in FIG. 8, the outer tube 850 may include a distal device holder 854, configured to engage with at least a portion of the implanted component 200, for example the capsule 210. The outer tube 850 may also include a surgical interface zone 858 configured to interface with a surgical system, for example a stereotactic or robotic surgical system. In some variations, the surgical interface zone is a section of tubing with a sufficient length to interface with a surgical system. In some variations, the surgical interface zone 858 includes indicia or markers, roughened surface, particular size and / or shape, notches, clamps, mating connectors, or other elements used to interface with a surgical system, for example a stereotactic or robotic surgical system. The outer tube 850 may also include an insertion stop 862 that can be used to control the depth of insertion. In some variations, the insertion stop 862 can be adjusted to customize an insertion depth of the distal end of the outer tube 850, or a length of an insertion zone 856. In some variations, outer tube 850 may include an outer tube handle 852, which can allow a surgeon or other clinician to grip and control the outer tube 850 and the attached components. The outer tube 850 can also allow implantation surgery to be performed with increased control and reduce the number of hands required in the constrained workspace. In some variations, such as system 800 illustrated in FIG. 8, when center stylet 810 is fit within insertion needle 830, which in turn is held within outer tube 850, stylet handle 812, needle handle 832, and outer tube handle 852 can cooperate to control the individual tubes together. In some variations, handles 812, 832, 852 may be fixed together,for example by releasably interlocking, to allow a surgeon to hold the tubes in fixed relative positions during phases of the implantation procedure, as described below. In some variations, handles 812, 832, and 852 may interface with a spring ball plunger 866 to assist in positioning one or more components.

[0082] In some variations, an implantation procedure may include steps of accessing the brain 50, for example by boring through the skull 20 and creating an opening in the dura mater and pia mater layers, for example by piercing or slitting the layers. Implantation tool system 800 can then be used to position the implanted components 200. Outer tube 850 can be loaded with insertion needle 830 and center stylet 810. A hermetic capsule 210 can be secured in distal device holder 854, and electrode array 250 can be loaded with insertion needle 830 and center stylet 810, inside outer tube 850, as illustrated in FIG. 9A and described further below. This allows hermetic capsule 210 and electrode array 250 to remain connected through the entire implantation procedure, thereby minimizing the time and complexity of implantation because the surgeon is not required to make hardware connections, and the system can be tested during the process, for example to verify placement.

[0083] The loaded implantation tool system 800 can be inserted into the brain by advancing the distal end. In some variations, outer tube 850 is locked into a surgical stereotactic frame or other system at surgical interface zone 858, as described above, and can be precisely advanced to a desired depth. In some variations, insertion stop 862 may be used to reduce a risk of over-penetration. In some variations, for example as illustrated in FIG. 9A, electrode array 250 is loaded alongside insertion needle 830. A distal hole 880 in electrode array 250 is arranged over the distal end of insertion needle 830 and aligned with the central lumen 834. When center stylet 810 is fully inserted in central lumen 834 of insertion needle 830, center stylet 810 also extends through distal hole 880, as shown in FIG. 9A. In this arrangement, center stylet 810, insertion needle 830, and electrode array 250 can be inserted into the brain and guided to the target location (while electrode array 250 is connected to hermetic capsule 210 as described above). In some variations, center stylet 810 is loaded into insertion needle 830, and distal hole 880 of electrode array 250 is threaded over center stylet 810.

[0084] As shown in FIG. 9B, after the electrode array 250 reaches the target location, center stylet 810 can be withdrawn, removing it from distal hole 880 and releasing electrode array 250. Insertion needle 830 can then be slowly withdrawn, leaving electrode array 250 in place as shown in FIG. 9C. Electrode array 250 may be held by friction, surface tension, and / or compressive forces to remain in the target location within the brain 50. In somevariations, the particular materials and shapes of the distal end of insertion needle 830 may be selected to facilitate sliding past electrode array 250. For example, in some variations, insertion needle 830 may be polished smooth, lubricated, or coated with low-friction material(s) to help electrode array 250 remain in place while insertion needle 830 is withdrawn. In some variations, the force required for relative sliding of insertion needle 830 and needle handle 832 may be adjustable to suit the needs and / or preferences of the surgeon. For example, in some variations, a spring ball plunger 866 may be used to adjustably control the resistance to sliding from the needle handle 832 during insertion, providing increased control to the surgeon.

[0085] After the electrode array 250 is placed at the target location, insertion needle 830 and center stylet 810 can be fully withdrawn. Distal device holder 854 can be used with outer tube 850 to position hermetic capsule 210, for example by positioning retainer ring 204 within the burr hole in the skull 20.

[0086] In some variations, the implantation tool system 800 can include marking, for example optical and / or radio-opaque markings for tracking of components or parts of components that are inserted into the body. Implantation tool system 800, for example outer tube 850 may include depth markings, notches, or other indicia to assist the surgeon and / or a surgical system (stereotactic, robotic, etc.) in accurate loading and / or placement of implantation tool system 800 and implanted components 200.

[0087] As noted above, some variations of implantation tool system 800 include releasably locking handles 812, 832, 852. In some variations, stylet handle 812 can be locked to needle handle 832 with a twist. Locking stylet handle 812 to needle handle 832 can help prevent the center stylet 810 from accidentally releasing during insertion. In some variations, the locking twist may be an angle between about 15-180 degrees, for example, approximately 15 degrees, 20 degrees, 30 degrees, 45 degrees, 60 degrees, 90 degrees, 120 degrees, 145 degrees, 160 degrees, 180 degrees, or any other angle or range of angles within 15-180 degrees. In some variations, outer tube handle 852 may be locked with needle handle 832 during transit / sh ipping and during the initial insertion to ensure the implanted components 200 remain properly loaded in implantation tool system 800. In some variations, outer tube handle 852 and needle handle 832 may be locked together with a removable clip or pin that can be released without adjusting the locations or orientations of implantation tool system 800 or implanted component 200.

[0088] In some variations, a perforator may be used to bore through the skull 20 and expose the dura mater. From there, the neurosurgeon can pierce the dura mater (forexample, via dural slit) and pia mater layer to allow insertion of an electrode array 250 into the brain 50. In some variations, the entire implanted device 200 is intact and connected throughout the installation procedure, thereby minimizing or eliminating intraoperative connections. In some variations, a bore ring and screw anchors can be used to secure the implanted unit to the skull 20.

[0089] As noted above, the system may be used in an oncology patient. The implanted components are designed to minimize artifacts during imaging, which allows patients to undergo typical frequent diagnostic imaging. For example, the materials of at least the implanted components may be selected to be used with MRI and / or other imaging techniques common in oncology patients. In some variations, the materials are selected to minimize any shadow or cast that may typically interfere with the RF signal of an MRI procedure. For example, in some variations, the implanted components include glass that is both optically transparent and MRI transparent, and the implanted components also avoid an internal battery and minimize metals (e.g., by using glass, ceramic, thin-film, and polymeric materials), as described herein, to enhance MRI compatibility. In this way, the system is designed to both protect itself from damage or interference that may be caused by an MRI procedure, and to avoid creation of artifacts, tissue damage, or other unwanted side effects of MRI procedures conducted in the region of an implanted device.

[0090] Electrical Stimulation

[0091] The system described herein may be used for methods of providing electrical stimulation to a target in a patient. In some variations, methods of providing electrical stimulation may use the implantable device, including at least two electrodes and a stimulator, and a control system for activating the stimulator to apply a signal to the target. In some variations, the stimulator may be included in the implanted component described herein, for example in an electronics module.

[0092] In some variations, an electrode array including two or more electrodes can be implanted near a target. In some variations, a target may be a neuron, an axon, a dendrite, or a cell. In some variations, a stimulator may be configured to deliver an electrical stimulation signal to a malignant tissue target via implanted electrodes.

[0093] In some variations, a stimulator may be activated by a control system. For example, a control system may generate one or more command signals for the stimulator to begin stimulation, to end stimulation, or to alter stimulation. In some variations, a command signal may be based on at least one property of the patient. For example, a command signal may be based on a property of a stimulation target tissue or of a tumour. For example,different target types may require different types of electrical stimulation. In some variations, a command signal may be at least partially based on one or more signals from the patient, such as an electrocardiogram (ECG), electroencephalogram (EEG), sleep signal, actigraph signal, temperature, accelerometer signal, position, orientation, or other appropriate recorded data. In some variations, a command signal may be at least partially based on patient information, for example medical history or demographic information, time since last treatment, etc. In some variations, a command signal may be configured to alter at least one parameter of the delivered stimulation signal, for example to change a pulse amplitude and / or duration. In some variations, multiple inputs may be used to generate a command signal. In some variations, a command signal may be provided by an external device, for example a retriever as described herein.

[0094] In some variations, a stimulator may be configured to deliver a biphasic pulse and / or a monophasic pulse. In some variations, a monophasic pulse may be cathodic or anodic in polarity. In some variations, a biphasic pulse may have any suitable pulse shape, such as, but not limited to, sinusoidal, square wave, trapezoidal, and triangular. In some variations, a pulse may be symmetric or asymmetric in amplitude and / or pulse-width. For example, in some variations the electrodes may be driven by a charge balanced cycle, which may help preserve the electrodes, and avoid tissue damage by reducing harsh electrochemical reactions.

[0095] In some variations, a wave form of the electrical stimulation signal produces sufficient charge for the intended outcome. In some variations, the desired total charge may be created by manipulating the charge frequency and amplitude, where the delivered charge is determined by integrating the area of the stimulation sequence (i.e. frequency and amplitude). In some variations, an electrical stimulation signal delivered by the stimulator may have a frequency range of between 0.5 Hz to 200 kHz. In some variations, an alternating or biphasic pulse may have a frequency between 0.1 kHz and 100 kHz. In some variations, an electrical stimulation signal may have an amplitude between 0.1 mA and 10 mA. In some variations, an electrical stimulation signal is a continuous signal.

[0096] In some variations, the electrical stimulation may vary based on a desired effect (e.g. depolarisation, hyperpolarisation, etc.) of the electrical stimulation on the target. In some variations, a stimulator may deliver different types or modes of stimulation. For example, in some variations, a stimulation signal configured to be sub-activation-threshold of a neuron may be used to induce nerve / neuronal firing (e.g., priming). In some variations, a stimulation signal may be configured to be above an activation threshold, for example to stopneuronal firing (e.g., silencing). In some variations, a stimulation signal may be configured to promote cell-specific sustained hyperpolarisation or sustained depolarisation to silence specific non-neuronal cells, for example of malignant tissue. As described herein, neuroncancer innervation causes depolarisation at the neuron-glioma synapse, and depolarisation drives proliferation (growth) of the cancer / glioblastomas. Thus, in some variations, the system may be configured to target axons with electrical stimulation to stop the continuous action potentials which trigger neuron-glioma synaptic depolarisation. In some variations, an electrical stimulation signal is a high-frequency signal.

[0097] In some variations, a stimulation signal may be configured to reduce the knock-on effect of action potentials (activation of several neurotransmitter processes), for example to cause a reduction of one or more neurotransmitters such as GABA, glutamate, and adrenaline. GABAergic interneurons are common neuron cancer interactions for pediatric gliomas in the pons. Glutamatergic neuron cancer interactions are common in adult glioblastomas. Adrenergic neurons could be associated with immune reduction in tumour regions. Selection of an appropriate stimulation signal and a neural target may reduce activity in any of these by suppressing neural activity, which in turn could each have an effect on tumour growth.

[0098] In some variations, the electrical stimulation may be configured to depolarise or hyperpolarise an axon, neuron, or cell target. Such an electrical stimulation signal may thereby be used to provide a therapy or treatment for cancer, for example. In some variations, an electrical stimulation signal may be configured to suppress or modulate a neurotransmitter. For example, in some variations an electrical stimulation signal may be configured to suppress production of a neurotransmitter, reduce uptake of a neurotransmitter, and / or alter an effect of a neurotransmitter. In some variations, an electrical stimulation signal may be configured to suppress or modulate noradrenaline; acetylcholine; glutamate; gamma- aminobutyric acid (GABA); dopamine; and / or serotonin. In some variations, an electrical stimulation signal may be configured to enhance drug / chemotherapeutic uptake through cell permeability and / or induce or increase immune recruitment. In some variations, an electrical stimulation signal may be used in combination with other neurotransmitter inhibitors, which may produce an increased response.

[0099] FIGS. 10A and 10B are schematic diagrams showing an example impact of a variation of an electrical stimulation signal, e.g., 1020A, 1020B on a target. In FIG. 10A, the target is an axon 1010 that is connected to a cancerous cell 1000. An example electrical stimulation signal 1020A may be applied to the axon 1010. The stimulation signal 1020A mayhave a broad frequency, broad pulse-width and broad amplitude, for example. The goal of applying the stimulation signal 1020A may be to cause a transmission block in one or more axons 1010 connected to the cancer cell 1000. In some variations, a stimulation signal may be configured to cause a single action potential followed by a silent neuronal state. The outcome 1030B of applying the stimulation signal 1020A to the axon 1010 is also illustrated in FIG. 10A. Specifically, the stimulation signal 1020A may cause a neurotransmitter (or other post-synaptic evoked event) to not be released, which means a growth signal is not received at the synaptic input to the cancer cell 1000. In some variations, inhibiting growth may also inhibit reciprocal engagement with the neural network by suppressing tumour neural requests for growth signals.

[0100] In FIG. 10B, the target can be a cancerous cell 1000. An example electrical stimulation signal 1020B may be applied to the cell 1000. The stimulation signal 1020B may have a broad frequency, broad pulse-width and broad amplitude, for example. The goal of applying the stimulation signal 1020B may be to cause hyperpolarisation of the cancer cell 1000, which may cause a membrane potential of the cell 1000 to be decreased. The outcome 1030B of applying the stimulation signal 1020B to the cell 1000 is also illustrated in FIG. 10B. Specifically, the stimulation signal 1020B may cause a continuous hyperpolarisation state to be induced in the cell 1000, which inhibits mitotic activity and proliferation.

[0101] FIG. 11 shows effects of potential blocking stimulus signals on neural firing rates for signals with various amplitudes and frequencies. As illustrated, effective blocking can be achieved with applied signals having amplitude between 0.50 mA and 2.00 mA, and frequency of between about 4 kHz and about 12 kHz. In some variations, the blocking signal may have a frequency of about 2.5 kHz. In some variations, the repeating signal can be applied with a duty cycle between approximately 10% and 100%, for example 10%, 20%, 25%, 30%, 33%, 40%, 45%, 50%, 60%, 66%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, or any fraction between approximately 10% and 100%. FIG. 12 shows example neural activity without a stimulation block. As illustrated, the nerve is periodically activated due to background neural inputs as the membrane potential is hyperpolarized above the spike threshold of about 0 mV. FIG. 13 illustrates example neural activity with an applied stimulation block signal 1400 having an amplitude of 0.5 mA and a frequency of 4 kHz. As seen in FIG. 13, initial application of the blocking signal 1400 creates a blocking stimulus artifact 1300 before quickly and effectively suppressing neural behavior. As shown in FIG. 14A, the applied stimulation block signal 1400 is a square wave (to create a charge balanced input current) of 0.5 mA and 4 kHz with a 100% duty cycle. In some variations, the blocking signal may be more complex. Forexample, as shown in FIG. 14B-1 and 14B-2, a blocking signal waveform 1410 may include a stepped application of amplitude delivered at a frequency F, for example at 1 kHz. An initial negative charge amplitude A can be delivered in a first phase PW, for example for 400 microseconds. This is followed by an amplitude of 0 mA for a short duration PWD, for example 10 microseconds. A balanced positive amplitude A is then delivered for another duration, for example 400 microseconds selected to create an 80% duty cycle with a final 0 mA amplitude delivered for a duration PD, for example 90 microseconds. As noted above, blocking signal waveform characteristics may be altered within the ranges discussed herein. For example, in some variations a blocking signal may have a frequency of about 2.5 kHz, or selected from a range of 2.5 kHz to 4 kHz, or an appropriate frequency from the range of 0.5 Hz to 200 kHz. In some variations, the stimulation signal comprises a frequency selected from the range of 0.1-10kHz and a duty cycle selected from the range of 10-100%.

[0102] In some variations, the applied blocking signal has a frequency of 2.5 kHz, a pulse width PW of 200 microseconds, and a charge per phase of 4 nC / ph. In some variations, the applied blocking signal has a frequency of 3.75 kHz, a pulse width PW of 130 microseconds, and a charge per phase of 3.9 nC / ph. In some variations, the applied blocking signal has a frequency of 1 kHz, a pulse width PW of 500 microseconds, and a charge per phase of 0 nC / ph. In some variations, the applied blocking signal has a frequency of 7.5 kHz, a pulse width PW of 60 microseconds, and a net charge per phase of 0 nC / ph. As noted above, in some variations, an electrical stimulation signal delivered by the stimulator may have a frequency range of between 0.5 Hz to 200 kHz. In some variations, an alternating or biphasic pulse may have a frequency between 0.1 kHz and 100 kHz. In some variations, an electrical stimulation signal may have an amplitude between approximately 0.1 mA and 10 mA, for example, 0.1 mA, 0.2 mA, 0.3 mA, 0.4 mA, 0.5 mA, 0.6 mA, 0.7 mA, 0.8 mA, 0.9 mA, 1 .0 mA, 1.1 mA, 1 .25 mA, 1 .5 mA, 2.0 mA, 2.5 mA, 3.0 mA, 3.5 mA, 4.0 mA, 4.5 mA, 5.0 mA, 6.0 mA, 7.0 mA, 8.0 mA, 9.0 mA, 10.0 mA, or any amplitude or range of amplitudes between approximately 0.1 mA and 10.0 mA.

[0103] As discussed above, increased neural activity in the brain is believed to promote tumor growth, whereas decreased neural activity promotes tumor suppression. By blocking neural activity, for example as shown in FIG. 13, tumor growth may be inhibited. As illustrated in FIG. 15, mice treated with an electrical blocking signal delivered to the brain showed lowered levels of neural activity corresponding to expected tumor suppression. This decrease in activity was significant both from pre to post stimulation treatment in stimulated mice and compared to control mice ‘treated’ with a sham implant in which no stimulation wasapplied. The stimulation signals applied to the treated mice did not invoke a motor or other observable response.

[0104] FIG. 16 is a block diagram of a variation of a suitable system 1600 with implantable components 1602 for open loop electrical stimulation of a target in a patient. The implantable device 1602 comprises: at least two electrodes 1604; a stimulator 1606 coupled to the at least two electrodes 1604, wherein the stimulator 1606 is for delivering an electrical stimulation signal to a target in a patient; and a control system 1608 for activating the stimulator 1606 to apply a signal to the target. In some variations, the implantable system described above may be suitable for providing stimulation signals to the target.

[0105] The implantable system 1602 may also include a safety subsystem 1620, which may be used to limit electrical stimulation parameters. In some variations, a safety subsystem 1620 may enforce stimulation thresholds, for example to limit pulse amplitude, pulse duration, pulse width, duty cycle, and / or charge density. In some variations, the safety subsystem 1620 may provide hard I firmware limits to enhance safety and / or avoid unwanted results of stimulation (e.g., spillover, motor activation, pain, ablation, etc.). In some variations the safety subsystem 1620 may optionally include enforcement of dynamic limits. For example, the safety subsystem 1620 may be configured to use limits that can be adjusted according to the particular patient or clinical application. For example, “hard” limits may be enforced under all conditions and “flexible” limits, within the hard limits, may be dynamically set for a particular patient or condition to optimize treatment, as discussed above.

[0106] The implantable system 1602 may also include an interface subsystem 1624. The interface subsystem 1624 can include a power receiving module, for example an inductive power coil as described herein. Interface subsystem 1624 can also include a data transmitter, receiver, or transceiver for sending and / or receiving, for example, collected data, programming, commands, status, updates, and / or other data as described herein. The implantable system 1602 may also include a power management subsystem 1628, which may be configured to manage power within or received by the implanted component 200. For example, power management subsystem 1628 may be configured to receive and optionally store power from the retriever component 150, as well as to distribute power to the various subsystems. The system 1600 may also include a power transmitter and communications transmitter, receiver, or transceiver module 1632, which may be located in a retriever component 150, as described herein.

[0107] As mentioned above, in some variations, a stimulation system 1700 may include one or more sources of feedback. In some variations, a feedback source may includeone or more sensors. As discussed above, in some variations the implantable device electrode array 1702 may include electrodes configured to be used to record electrical signals from the target tissue. In some variations, recorded electrical signals may be used, for example automatically or by a clinician, to start, stop, and / or adjust an electrical stimulation signal. In some variations, a stimulation system 1700 may be configured as a closed loop system. For example, an implantable device 1702 may receive feedback from the stimulation target and use the feedback to determine an action to take. For example, FIG. 17 is a block diagram of a closed loop implantable device 1700 for electrical stimulation of a target in a patient. In FIGS. 16 and 17, like features are represented by like reference numerals, and therefore, the description of such features is not repeated. In particular, implantable system 1602 is similar to implantable system 1702, electrodes 1704 are the same in some or all respects to electrodes 1604, stimulation subsystem 1706 is the same in some or all respects to stimulator 1606, control system 1708 shares all or some features with control system 1608 (where differences are described herein to allow for closed-loop control), safety subsystem 1720 is the same in some or all respects as safety subsystem 1620, interface subsystem 1724 is the same in some or all respects as interface subsystem 1624, power management subsystem 1728 is the same in some or all respects as power management subsystem 1628, and transceiver module 1732 is the same in some or all respects as transceiver module 1632.

[0108] Stimulation system 1700 may also include a recording subsystem 1750. In some variations, recording subsystem 1750 can be configured to obtain and optionally pre- process brain signals recorded from electrode array 250. For example, recording subsystem 1750 may record raw data, or may optionally perform signal conditioning, such as artifact identification and / or rejection, noise rejection, time-averaging, filtering, event detection, domain transforms, and the like. A feature extraction subsystem 1754 may be used to detect events, for example increases or decreases in activity that may indicate tumor growth or suppression. Stimulation system 1700 may also include a classification subsystem 1758, configured to classify the signals recorded from recording subsystem 1750. For example, classification subsystem 1758 may be configured to classify signals recorded from recording subsystem 1750 as artifacts, indicative of tumor growth, indicative of tumor suppression, indicative of seizure activity, or other features of interest. Implantable device electrode array 1702 may also include a memory 1762, configured to interface with the recording subsystem 1750, for example to store raw and / or processed signals, and to interface with control system 1708, for example to store operating parameters, provide signals for transmission, and / or other appropriate functions.

[0109] In some variations, a recording system 1700 may be configured to collect a sensed signal from a target tissue, analyse the sensed signal to determine whether the sensed signal is different to a previously sensed signal, and transmit an outcome of the analysis to the control system. In some variations, for example in a closed loop version 1700 of the system, a control system 1708 may generate a command signal for the stimulator 1706 based on the outcome of the analysis. In some variations, a control system 1708 may generate a command signal by adjusting parameters of the command signal based on the outcome of the analysis. For example, in some variations a sensed signal from a target may be used to determine if a target, such as a nerve, has been sufficiently stimulated to induce a nerve block. In some variations, a sensed signal from the target may provide information on whether a threshold has been met for silencing nerve or cell activity. In some variations, multiple electrodes from an array 250 may be used simultaneously to record and stimulate at or near the same time. In some variations, a sensed signal may provide information on disease-specific biomarkers, which may inform clinical intervention or device intervention. In some variations, a sensed signal may be used to adjust parameters for a stimulation signal or timing of a stimulation signal. For example, a sensed signal may provide information on any one or more of the following: tumour size; tumour growth rate; metastatic potential; spike rate; treatment response rate; tumour location; tumour spreading; and tumour associated seizures.

[0110] In some variations, a control system 1608 1708 may be configured to provide an alert, for example to an external device. In some variations, an alert may be provided to a retriever 150 as described herein. For example, in some variations, when the outcome of the analysis of a recorded signal indicates onset of a seizure, the control system 1608, 1708 may be configured to transmit a seizure warning alert. In this way, the patient or a third party (e.g. parent, carer, medical professional, etc.) may be alerted to the onset of a seizure and can take appropriate action. In some variations, an alert may be provided to a retriever device 150 upon detection of excessive heat, electrode breakdown, electrode migration, or other device malfunction. In some variations an implanted component 200 may include additional sensors, for example a temperature sensor, position / orientation sensor or accelerometer, piezo sensor, capacitive sensor, pressure sensor, tilt sensor, magnetic sensor, or other suitable sensor that can be used to monitor system performance and provide feedback and / or alerts. In some variations, additional sensors may be used to calibrate or adjust system performance. For example, in some implementations, an accelerometer may be used to provide additional information that can be used to inform disease patterns based on anatomical position of the patient.

[0111] Implementation 1 : An implantable device for electrical stimulation of a target in a patient, the implantable device comprising: at least two electrodes; a stimulator coupled to the at least two electrodes, wherein the stimulator is arranged for delivering an electrical stimulation signal to a target in a patient; and a control system for activating the stimulator to apply the stimulation signal to the target.

[0112] Implementation 2: The implantable device of Implementation 1 wherein the stimulator is to deliver the electrical stimulation signal to a neuron or a cell target.

[0113] Implementation 3: The implantable device of Implementations 1 or 2 wherein the stimulator is arranged to deliver the electrical stimulation signal to a malignant tissue target.

[0114] Implementation 4: The implantable device of Implementations 1 , 2 or 3 wherein the stimulator is configured to deliver any one or more of: an alternating or biphasic pulse; and a monophasic pulse.

[0115] Implementation 5: The implantable device of any preceding Implementation wherein the control system activates the stimulator by generating a command signal for the stimulator, the command signal being based on at least one property of the target.

[0116] Implementation 6: The implantable device of any preceding Implementation, further comprising a communication module coupled to the control system for communicating with an external device.

[0117] Implementation 7: The implantable device of Implementation 6 wherein the communication module receives, from the external device, instructions for the control system to do any of: generate a command signal for the stimulator to deliver an electrical stimulation signal; generate a command signal for the stimulator to stop delivering an electrical stimulation signal; and generate a command signal to alter at least one parameter of an electrical stimulation signal being delivered.

[0118] Implementation 8: The implantable device of any preceding Implementation further comprising a recording system coupled to the at least two electrodes, wherein the recording system is for sensing a signal from the target.

[0119] Implementation 9: The implantable device of Implementation 8 wherein the recording system: analyses the sensed signal to determine whether the sensed signal is different to a previously sensed signal; and transmits an outcome of the analysis to the control system.

[0120] Implementation 10: The implantable device of Implementation 9 wherein the control system: generates a command signal for the stimulator based on the outcome of the analysis.

[0121] Implementation 11 : The implantable device of Implementation 10 wherein the control system generates a command signal by adjusting parameters of the command signal based on the outcome of the analysis.

[0122] Implementation 12: The implantable device of Implementations 10 or 11 , when including the communications module of Implementation 6, wherein the outcome of the analysis indicates onset of a seizure, and wherein the control system controls the communication module to transmit a seizure warning alert to the external device.

[0123] Implementation 13: The implantable device of any of Implementations 9 to 12 wherein the control system is configured to control connection of the stimulator and the recording system to the at least two electrodes.

[0124] Implementation 14: The implantable device of Implementation 13 wherein the control system controls connection of the stimulator and the recording system to the at least two electrodes so that only one of the stimulator and the recording system is connected to the at least two electrodes at any time.

[0125] Implementation 15: The implantable device of any preceding Implementation wherein the target is in the central nervous system or peripheral nervous system.

[0126] Implementation 16: The implantable device of any preceding Implementation wherein the stimulator delivers an electrical stimulation signal to a patient to depolarise or hyperpolarise an axon, neuron or cell target.

[0127] Implementation 17: The implantable device of any preceding Implementation wherein the stimulator delivers an electrical stimulation signal that suppresses or modulates a neurotransmitter.

[0128] Implementation 18: The implantable device of Implementation 17 wherein the stimulator delivers an electrical stimulation signal that suppresses or modulates any oneor more of the following neurotransmitters: noradrenaline; acetylcholine; glutamate; gamma- aminobutyric acid; dopamine; and serotonin.

[0129] Implementation 19: The implantable device of any preceding Implementation wherein the stimulator delivers a continuous electrical stimulation signal.

[0130] Implementation 20: A system for electrical stimulation of a target in a patient, the system comprising: at least two, paired implantable electrodes; and a peripheral device comprising: a stimulator coupled to the at least two electrodes, wherein the stimulator is for delivering an electrical stimulation signal to a target in a patient; and a control system for activating the stimulator to apply a signal to the target.

[0131] Implementation 21 : The system of Implementation 20 wherein the peripheral device is coupled to the at least two implantable electrodes by a wired or wireless connection.

[0132] Implementation 22: A system for positioning implantable components in the brain, the system comprising: a center stylet; a hollow insertion needle; and an outer tube, wherein the center stylet is held within the insertion needle and the insertion needle is held within the outer tube.

[0133] Implementation 23: The system of Implementation 22 further including any of: one or more releasably locking handles, an interface with a stereotactic or robotic surgical system, an insertion stop, a device holder configured to releasably hold a device implantable into a skull, or an atraumatic distal tip.

[0134] Implementation 24: The system of Implementation 22 or 23 wherein the center stylet and insertion needle are configured to position an electrode array loaded over the center stylet and alongside the insertion needle.

[0135] Implementation 25: A method of positioning implantable components in the brain, the method comprising: withdrawing a center stylet from an implantable electrode array loaded over the center stylet and alongside an insertion needle; withdrawing the insertion needle to leave the electrode array in a target location in the brain;releasing an implantable hermetic capsule loaded into a device holder on an outer tube; and securing the hermetic capsule to the skull, wherein the center stylet is held within the insertion needle, and the insertion needle is held within the outer tube.

[0136] Implementation 26: The method of Implementation 25, further including any of: inserting the electrode array, center stylet, and insertion needle into the target location in the brain before withdrawing the center stylet; or releasing a lock between a handle of the center stylet and a handle of the insertion needle before withdrawing the center stylet.

[0137] Implementation 27: The method of Implementations 24 or 25, wherein a depth of insertion is controlled by an insertion stop carried by the outer tube.

[0138] Additional Considerations and Terminology

[0139] Features, materials, characteristics, or groups described in conjunction with a particular aspect, implementation, or example are to be understood to be applicable to any other aspect, implementation or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features or steps are mutually exclusive. The protection is not restricted to the details of any foregoing implementations. The protection extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0140] While certain implementations have been described, these implementations have been presented by way of example only and are not intended to limit the scope of protection. Indeed, the novel methods and systems described herein may be embodied in a variety of other forms. Furthermore, various omissions, substitutions and changes in the form of the methods and systems described herein may be made. Those skilled in the art will appreciate that in some implementations, the actual steps taken in the processes illustrated or disclosed may differ from those shown in the figures. Depending on the implementation, certain of the steps described above may be removed, others may be added. For example, the actual steps or order of steps taken in the disclosed processes may differ from those shown in the figure. Depending on the implementation, certain of the steps described above may be removed, others may be added. Furthermore, the features andattributes of the specific implementations disclosed above may be combined in different ways to form additional implementations, all of which fall within the scope of the present disclosure.

[0141] Although the present disclosure includes certain implementations, examples and applications, it will be understood by those skilled in the art that the present disclosure extends beyond the specifically disclosed implementations to other alternative implementations or uses and obvious modifications and equivalents thereof, including implementations which do not provide all of the features and advantages set forth herein. Accordingly, the scope of the present disclosure is not intended to be limited by the described implementations, and may be defined by claims as presented herein or as presented in the future.

[0142] Conditional language, such as “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain implementations include, while other implementations do not include, certain features, elements, or steps. Thus, such conditional language is not generally intended to imply that features, elements, or steps are in any way required for one or more implementations or that one or more implementations necessarily include logic for deciding, with or without user input or prompting, whether these features, elements, or steps are included or are to be performed in any particular implementation. The terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list. Likewise, the term “and / or” in reference to a list of two or more items, covers all of the following interpretations of the word: any one of the items in the list, all of the items in the list, and any combination of the items in the list. Further, the term “each,” as used herein, in addition to having its ordinary meaning, can mean any subset of a set of elements to which the term “each” is applied. Additionally, the words “herein,” “above,” "below," and words of similar import, when used in this application, refer to this application as a whole and not to any particular portions of this application.

[0143] Conjunctive language such as the phrase “at least one of X, Y, and Z,” unless specifically stated otherwise, is otherwise understood with the context as used in general to convey that an item, term, etc. may be either X, Y, or Z. Thus, such conjunctive language is not generally intended to imply that certain implementations require the presence of at least one of X, at least one of Y, and at least one of Z.

[0144] Language of degree used herein, such as the terms “approximately,” “about,” “generally,” and “substantially” as used herein represent a value, amount, or characteristic close to the stated value, amount, or characteristic that still performs a desired function or achieves a desired result. For example, the terms “approximately”, “about”, “generally,” and “substantially” may refer to an amount that is within less than 10% of, within less than 5% of, within less than 1 % of, within less than 0.1 % of, and within less than 0.01 % of the stated amount. As another example, in certain implementations, the terms “generally parallel” and “substantially parallel” refer to a value, amount, or characteristic that departs from exactly parallel by less than or equal to 15 degrees, 10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degree.

Claims

WHATIS CLAIMED IS:1 . A system for electrical recording from a neural tissue target in a brain of a patient with a brain tumor, the system comprising: an implanted component comprising at least two electrodes configured to be implanted in the brain of the patient; an external retriever; a recording system coupled to the at least two flexible electrodes; a communication system for transmitting data between the implanted component and the external retriever; and a power system for wirelessly transmitting power from the retriever to the implanted system, wherein the system is configured to record electrical signals from the target.

2. The system of claim 1 , wherein the electrodes comprise a flat thin-film electrode array.

3. The system of any of claims 1 -2, wherein the electrodes are arranged on a plurality of separate arrays.

4. The system of any of claims 1-3, wherein the target is malignant.

5. The system of any of claims 1 -4, wherein the communication system comprises at least one light emitting diode and a photodiode.

6. The system of any of claims 1-5, wherein the communication system comprises an infra-red or near infra-red light emitting diode and a photodiode.

7. The system of any of claims 1-6, wherein the power system comprises an RF inductive coupling system.

8. The system of any of claims 1-7, further comprising a feedback system in the retriever.

9. The system of any of claims 1-8, wherein the implanted component further comprises a hermetically sealed capsule.

10. The system of claim 9, wherein the capsule comprises an optical cap, a feedthrough connected to the electrodes, and an electronics module comprising at least one component of the communication system.11 . The system of claim 10, wherein the at least one component of the communication system comprises an infra-red or near infra-red light emitting diode or light emitting diode array.

12. The system of any of claims 10-11 , wherein the electronics module further comprises a receiver coil, selective shielding, and a printed circuit board under the receiver coil, wherein the selective shielding comprises at least one of a coil standoff, a copper shield, or a shield standoff, and wherein the printed circuit board comprises the at least one component of the communication system.

13. The system of any of claims 1 -8 further comprising a stimulation module connected to the electrodes.

14. The system of claim 13, wherein the stimulation module is configured to apply a stimulation signal to the target.

15. A treatment method comprising: applying an electrical stimulation signal from an implanted system to a target tissue in the brain of a patient with a brain tumor, the stimulation signal comprising a frequency range between 0.5 Hz to 200 kHz and an amplitude between 0.1 mA and 10 mA.

16. The treatment method of claim 15, wherein the frequency range is between 0.1 kHz and 100 kHz.

17. The treatment method of claim 15, wherein the amplitude is 0.5 mA and the frequency is selected from a range of 2.5 to 4 kHz.

18. The treatment method of any of claims 15-17, wherein the stimulation signal comprises a biphasic charge balanced waveform.

19. The treatment method of any of claims 15-18, wherein the stimulation signal is asymmetric.

20. The treatment method of any of claims 15-19, further comprising adjusting the stimulation signal.

21. The treatment method of any of claims 15-20, wherein the stimulation signal has a duty cycle of 75-100%.

22. The treatment method of claim 15, wherein the stimulation signal comprises a repeating signal comprising a negative charge amplitude delivered for 400 microseconds, then an amplitude of 0 mA for 10 microseconds, then a balanced positive amplitude delivered for 400 microseconds, wherein the repeating signal has an 80% duty cycle.

23. The treatment method of claim 15, wherein the stimulation signal comprises a frequency selected from the range of 0.1 -10kHz and a duty cycle selected from the range of 10-100%.

24. The treatment method of any of claims 15-22, further comprising measuring a signal from the target tissue.

25. The treatment method of claim 24, wherein the measured signal is used to adjust the stimulation signal.

26. The treatment method of any of claims 24-25, wherein the measured signal is automatically analyzed and used to adjust the stimulation signal.

27. The treatment method of any of claims 24-26, wherein the measured signal is an electrical signal measured by the implanted system with at least two electrodes.

28. The treatment method of any of claims 24-27, wherein the measured signal is transmitted from the implanted system to an external system.

29. The treatment method of any of claims 15-28, further comprising providing feedback to a user.

30. The treatment method of claim 29, wherein the feedback comprises audible or haptic feedback.

31. A system for positioning implantable components in the brain, the system comprising: a center stylet; a hollow insertion needle; and an outer tube, wherein: the center stylet is held within the insertion needle and the insertion needle is held within the outer tube; the center stylet and insertion needle are configured to position an electrode array loaded over the center stylet and alongside the insertion needle; and the outer tube further comprises a device holder configured to releasably hold a device implantable into the skull.

32. The system of claim 31 , wherein the center stylet, insertion needle, and outer tube each include a proximal handle, wherein each handle is configured to be releasably locked to one or more of the other handles.

33. The system of any of claims 31-32, wherein the outer tube is configured to interface with a stereotactic or robotic surgical system.

34. The system of any of claims 32-35, wherein the outer tube further comprises an insertion stop configured to limit a depth of insertion into a brain.

35. The system of any of claims 32-36, wherein the center stylet, insertion needle, and outer tube each comprise an atraumatic distal tip.

36. A method of positioning implantable components in the brain, the method comprising: inserting an implantable electrode array, a center stylet, and an insertion needle into a target location in the brain, wherein the implantable electrode array is loaded over the center stylet and alongside the insertion needle; withdrawing the center stylet from the electrode array; withdrawing the insertion needle to leave the electrode array in the target location in the brain; releasing an implantable hermetic capsule loaded into a device holder on an outer tube; and securing the hermetic capsule to the skull, wherein the center stylet is held within the insertion needle, and the insertion needle is held within the outer tube.

37. The method of claim 36, wherein a depth of insertion is controlled by an insertion stop carried by the outer tube.

38. The method of any of claims 36-37, further comprising releasing a lock between a handle of the center stylet and a handle of the insertion needle before withdrawing the center stylet.

39. A system for treating a tumor in a brain, the system comprising: an implanted system and a stimulator configured to perform a brain tumor treatment method, the method comprising: applying an electrical stimulation signal from an implanted system to a target tissue in the brain of a patient with a brain tumor, the stimulation signal comprising a frequency range between 0.5 Hz to 200 kHz and an amplitude between 0.1 mA and 10 mA.

40. The system of claim 39, wherein the frequency range is between 0.1 kHz and 100 kHz.41 . The system of claim 39, wherein the amplitude is 0.5 mA and the frequency is selected from a range of 2.5-4 kHz.

42. The system of any of claims 39-41 , wherein the stimulation signal comprises a biphasic charge balanced waveform.

43. The system of any of claims 39-42, wherein the stimulation signal is asymmetric.

44. The system of any of claims 39-43, wherein the system is further configured to adjust the stimulation signal.

45. The system of any of claims 39-44, wherein the stimulation signal has a duty cycle of 75-100%.

46. The system of claim 39, wherein the stimulation signal comprises a repeating signal comprising a negative charge amplitude delivered for 400 microseconds, then an amplitude of 0 mA for 10 microseconds, then a balanced positive amplitude delivered for 400 microseconds, wherein the repeating signal has an 80% duty cycle.

47. The system of claim 39, wherein the stimulation signal comprises a frequency selected from the range of 0.1 -10kHz and a duty cycle selected from the range of 10- 100%.

48. The system of any of claims 39-46, wherein the system is further configured to measure a signal from the target tissue.

49. The system of claim 48, wherein the system is configured to use the measured signal to adjust the stimulation signal.

50. The system of any of claims 48-49, wherein the system is configured to automatically analyze the measured signal and adjust the stimulation signal using the analyzed measured signal.51 . The system of any of claims 48-50, wherein the measured signal is an electrical signal measured by the implanted system with at least two electrodes.

52. The system of any of claims 48-51 , further comprising an external system, wherein the implanted system is configured to transmit the measured signal from the implanted system to the external system.

53. The system of any of claims 39-52, wherein the system is further configured to provide feedback to a user.

54. The system of claim 53, wherein the feedback comprises audible or haptic feedback.

55. A system for positioning implantable components in the brain, the system configured to:insert an implantable electrode array, a center stylet, and an insertion needle into a target location in the brain, wherein the implantable electrode array is loaded over the center stylet and alongside the insertion needle; withdraw the center stylet from the electrode array; withdraw the insertion needle to leave the electrode array in the target location in the brain; release an implantable hermetic capsule loaded into a device holder on an outer tube; and secure the hermetic capsule to the skull, wherein the center stylet is held within the insertion needle, and the insertion needle is held within the outer tube.

56. The system of claim 55, wherein a depth of insertion is controlled by an insertion stop carried by the outer tube.

57. The system of any of claims 55-56, further comprising a releasable lock between a handle of the center stylet and a handle of the insertion needle, the releasable lock configured to be released before withdrawing the center stylet.

58. A system for electrical treatment of cancer comprising one or more features of the foregoing description.

59. A system for recording electrical signals from the brain for treatment of cancer comprising one or more features of the foregoing description.

60. A system for electrical treatment of cancer comprising a retriever component and an implanted component, comprising one or more features of the foregoing description.

61. A method for electrical treatment of brain cancer comprising one or more features of the foregoing description.

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