Brain treatment systems and methods

Abstract

The present disclosure generally relates to nanoscale wires and nanoelectronics, to systems and methods for implanting such devices into the brain of a subject, and systems and methods of treating subjects using such devices. Certain aspects are generally directed to brain probes that are configured to determine electrical signals at mesoscale resolutions, e.g., at relatively deep depths within the brain, which may allow for determination and / or stimulation of electrical signals within the brain. The brain probes may be soft and / or mechanically flexible in some cases. In some embodiments, the devices may include a plurality of electrodes, e.g., in a mesh or an array. Some embodiments may allow for closed- loop stimulation at mesoscale resolutions, e.g., across multiple cortical and subcortical targets, and / or by targeting specific subregions of the brain. Other aspects are generally directed to systems and methods for making or using such brain probes, e.g., to treat a subject having a neurological disorder, kits involving such brain probes, or the like.

Description

[0001] BRAIN TREATMENT SYSTEMS AND METHODS

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 727,861, filed December 4, 2024, entitled “Brain Treatment Systems and Methods,” by Liu, et al., incorporated herein by reference in its entirety.

[0004] FIELD

[0005] The present disclosure generally relates to nanoscale wires and nanoelectronics, to systems and methods for implanting such devices into the brain of a subject, and systems and methods of treating subjects using such devices.

[0006] BACKGROUND

[0007] Neurological and psychiatric disorders significantly burden public health, impacting millions of individuals worldwide. These conditions encompass a broad spectrum of ailments, including epilepsy, Parkinson’s disease, depression, obsessive-compulsive disorder, and addiction, each with unique pathophysiological mechanisms within the human brain. Conventional treatments for these disorders often rely on pharmacological interventions or invasive surgical procedures, and while effective to varying degrees, they frequently entail significant side effects and limitations.

[0008] In recent years, there has been a growing interest in the development of advanced neural recording and stimulation technologies aimed at providing more precise, adaptable, and efficacious treatments for neurological and psychiatric disorders. Such technologies promise to revolutionize the field of neuromodulation by enabling real-time monitoring of neural activity and the delivery of targeted interventions to specific neural circuits. However, current implantable brain stimulation systems have suffered from limitations such as large contact size, signal drift, and rigidity. Accordingly, improvements in treatment techniques are still needed.

[0009] SUMMARY

[0010] The present disclosure generally relates to nanoscale wires and nanoelectronics, to systems and methods for implanting such devices into the brain of a subject, and systems and methods of treating subjects using such devices. The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0011] One aspect is generally directed systems and devices with the capability to perform recording and closed-loop stimulation post-implantation at the mesoscale level, e.g.,

[0012] #14412892vl simultaneous. In some cases, this may be applied simultaneously across multiple cortical and subcortical subregions, e.g., through a series of implants. In some cases, the implants may be customizable and / or modular.

[0013] For example, one set of embodiments is generally directed to systems and methods for single, chronically implanted platform for diagnostic and / or therapeutic recording, and / or stimulation. This may be useful, for example, to alleviate the need to perform intra-op recording, in the case of indications for which deep brain stimulation (DBS) could be used, and / or inpatient recoding, in the case of indications for which stereo-electroencephalography (SEEG) could be used.

[0014] In addition, certain aspects are generally drawn to systems and methods for treatment of neurological disorders, including psychiatric disorders. In some cases, this may include the use of brain probes comprising electrodes or nanoelectrodes or microelectrodes, e.g., arranged in an array. In some cases, the brain probes may be soft and / or flexible. In certain embodiments, the brain probes may include electrodes or nanoelectrodes or microelectrodes for determining or recording electrical signals from the brain, and / or applying electrical signals to the brain, e.g., to stimulate the brain. In some embodiments, such brain probes can be used in a closed-loop manner, e.g., where the electrical signals applied to stimulate to the brain are based, at least in part from electrical signals determined or recorded from the brain.

[0015] One set of embodiments is generally directed to systems and methods of restoring normal brain function with a medical device. The medical device may comprise an implantable part made from flexible or soft nanoelectrodes comprising tens or hundreds of electrodes. The method may include the application of brain recording and stimulation within the human brain, e.g., to treat brain disorders. The device may include an array of electrodes to perform brain recording and / or stimulation. The electrodes may be flexible in some embodiments. In some cases, performing stimulation from an electrode array can be beneficial in a human (or other subject) having certain medical conditions. For example, these may be used for treating symptoms of Parkinson’s disease, restoring hearing and olfaction, modulating psychiatric disorders, and inhibiting seizure occurrences, etc.

[0016] One set of embodiments is directed to systems and methods of manufacturing electrode arrays. The electrodes may include nanoelectrodes or microelectrodes. In one embodiment, the device comprises an array, e.g., comprising a plurality of electrode contacts. These electrodes may provide, in some embodiments, a neural interface, e.g., for stimulation and / or recording of neural activity.

[0017] #14412892vl Another set of embodiments is generally directed to surgical devices and methods that simultaneously target cortical and subcortical brain regions. In one implementation, the device is intended for implantation into the human cortical and subcortical regions, e.g., vertically, which may ensure accurate access to specific subregions of neural structures within the brain networks implicated in the disorders being treated.

[0018] Certain embodiments are generally directed to stimulation using an array of electrodes, e.g., including nanoelectrodes. One embodiment is generally directed to applying phased electrical signals to the brain of a subject. In some cases, individual manipulation of individual electrodes within a device may occur. This may useful, in certain embodiments, to reduce stimulation amplitude, for example, which may help to minimize unwanted side effects, enhance therapeutic outcomes, reduce the likelihood of immune reactions, or the like.

[0019] Some embodiments are generally directed to surgical devices that are compatible with surgical robotics. In one embodiment, the surgical robotics system may be a clinically approved surgical robotics system.

[0020] One set of embodiments is generally directed to systems and methods for wireless and / or wired operation. In some cases, these may include devices that are adaptable for both wireless and wired modes of operation.

[0021] One set of embodiments is generally drawn to systems and methods of performing recording and stimulation, e.g., simultaneously. In one embodiment, the system may allow for closed-loop stimulation of a brain. Simultaneously determining neural activity and applying targeted stimulation may allow real-time adjustments to therapy in certain embodiments. Some embodiments may be used for improving treatment of various neurological and psychiatric conditions.

[0022] Certain embodiments are generally directed to long-term signal stability. Some embodiments are directed to recording single-unit activity, e.g., without signal drift.

[0023] Some embodiments are generally directed to systems and methods of using a device such as those disclosed herein for diagnostic intracranial monitoring, and / or long-term therapy. In one embodiment, a device may be used as a diagnostic SEEG (stereoelectroencephalography) system and / or closed-loop brain stimulation system.

[0024] One set of embodiments is generally drawn to software for systems and methods such as those described herein. Some embodiments may include software that complements a device, facilitates execution of certain methods, and / or allowing customization of treatment parameters for individual subjects, etc. In some cases, the software may use Al functionality,

[0025] #14412892vl which may allow it to learn from recording data / or and generate optimized stimulation parameters.

[0026] One set of embodiments is directed to a medical device for closed-loop stimulation at the mesoscale level in the human brain. In some cases, the device comprises a flexible or soft nanoelectrode array with multiple electrodes, and may be designed to alleviate symptoms or treat neurological and / or psychiatric disorders. In some embodiments, the device may be able to determine and / or record brain activity or function. In some cases, the device may have capabilities to perform diagnostic monitoring and closed-loop stimulation postimplantation.

[0027] In some cases, the device may have a flexible or soft electrode array, which may be implantable into human cortical or subcortical regions, e.g., vertically. The electrodes may include nanoelectrodes. This may allow precise access to targeted neural structures.

[0028] In some cases, the device may incorporate a micro-array stimulation system resembling an Active Phased Array Radar. This may be used to facilitate manipulation of some or all of the electrodes, for example, to reduce stimulation power and / or to minimize unwanted side effects, etc. In some cases, this may enhance the accuracy of therapeutic outcomes, and / or reduce the potential for immune reactions. In one set of embodiments, an array of multiple stimulation elements may be used to direct and focus electrical signals, e.g., by controlling the direction and shape of the electrical signal by adjusting the phase and amplitude of the signals.

[0029] In some cases, the device may be designed to be compatible with clinically approved surgical robotics systems. This may allow precise and / or safe implantation into the human brain in certain embodiments.

[0030] In some cases, the device may be operable in both wireless and wired modes. This may allow for flexibility in treatment approaches and subject comfort.

[0031] In some cases, the device may include software for executing methods related to neural recording, stimulation, and / or closed-loop control. This may allow customization of treatment parameters for individual subjects at the mesoscale level in some embodiments.

[0032] In some cases, the device may exhibit the capability to record single-unit and / or local field potential activity chronically, and in some cases, without signal drifting, e.g., caused by movement of the device after implantation. This may, in some cases, ensure the stability and / or reliability of the recorded neural data.

[0033] #14412892vl In some cases, the device may work at a mesoscale level, which may include a group of neurons as an ensemble. For example, in some cases, the device may be able to determine electrical signals at a spatial resolution of between 1 micrometer and 1 mm.

[0034] Another set of embodiments is generally directed to methods for treating or alleviating symptoms of neurological or psychiatric disorders in a subject, e.g., a human subject. In some cases, the method includes the steps of implanting a medical device into a subject’s brain. The method may include utilizing associated software to execute stable neural recording and closed-loop stimulation. In some cases, this may help to optimize the treatment efficacy for the targeted medical condition.

[0035] In some cases, the method may be a method for restoring peripheral sensory function, including but not limited to hearing, vision, or olfaction in a subject, e.g., a human subject. In some cases, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop neural stimulation. This may allow the restoration of hearing and / or olfaction, for example, by selectively stimulating the auditory and / or olfactory pathways, in accordance with certain embodiments.

[0036] In some cases, the method may be a method for modulating psychiatric disorders. Non-limiting examples include, but are not limited to, obsessive-compulsive disorder, major depressive disorder, and addiction. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. This may allow the modulation of psychiatric disorders, for example, by precisely targeting specific neural circuits, in certain embodiments.

[0037] In some cases, the method may be a method for treating neurological conditions or disorders. In some cases, the method may be a method of inhibiting seizure occurrences in a subject, e.g., a human subject. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed- loop stable neural recording and / or closed-loop stimulation. In some cases, this may allow the inhibition of seizures, e.g., by real-time detection, and / or intervention within neural circuits associated with seizures.

[0038] In some cases, the method may be a method for treating a neurological condition or disease in a subject, e.g., a human subject. Non-limiting examples include Parkinson’s disease, Tourette’s syndrome, and dystonia. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In certain

[0039] #14412892vl embodiments, this may allow for effectively treating and / or alleviating symptoms of the neurological conditions. In some cases, such subjects may have the same clinical indications approved for deep brain stimulation surgery.

[0040] In some cases, the method may be a method for modulating wakefulness in a subject, e.g., one that is in a comatose state. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In some cases, the device may be configured in a manner so as to modulate neural activity in a manner conducive to promoting wakefulness, which may be useful for facilitating the modulation of wakefulness in comatose subjects.

[0041] In some cases, the method may be a method for motor and speech decoding. In some embodiments, the method may include implanting a medical device into a subject, e.g., a human subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In some cases, the device may be able to record neural activity, decode motor and / or speech-related neural signals, and / or translate them into motor commands and / or speech output. This may be useful in certain embodiments, e.g., for allowing motor and speech decoding for subjects with motor or speech impairments.

[0042] In some cases, the method may be a method for dynamic adjustment of stimulation dosage, for example, based on the evaluation of a subject’s performance or the attainment of a target neural state. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In some cases, the device may be able to record neural activity, decode motor and / or speech-related neural signals, and / or translate them into motor commands and / or speech output. In some cases, the method may include monitoring the subject’s neural activity, e.g., continuously. In some cases, the evaluation of the subject’s performance is assessed in an automated fashion. In some cases, the stimulation dosage may be adjusted in real time. This may be useful in certain embodiments, for example, to optimize the therapeutic effect and achieve the desired target neural state.

[0043] In some cases, the method may be a method for sensing the behavior of a subject, e.g., a human subject. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. The method may also include using sensors such as accelerometers, thermometers, etc., for monitoring the subject. For example, such sensors can be used to monitor a subject’s behavior and / or physiological parameters,

[0044] #14412892vl e.g., in real time. This may be useful in certain embodiments, e.g., for facilitating the adaptation of neural stimulation parameters to the subject’s current state.

[0045] In some cases, the method may be a method for assessing the attainment of a target neural state of a subject, e.g., a human subject. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. The method may also include using sensors such as accelerometers, thermometers, etc. The method may also include using assessment methods such as, but not limited to, EMG (Electromyography), EEG (Electroencephalography), ECoG (Electrocorticography), singleunit recording, and fMRI (functional Magnetic Resonance Imaging), etc. This may be useful, for example, for precise evaluation and confirmation of a subject’s neural state. This may allow dynamic adjustment of neural stimulation parameters in some embodiments.

[0046] In some cases, the method may be a method for enhancing the performance of neural stimulation. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In some embodiments, machine learning techniques may be used to control stimulation parameters. This may be useful, in some embodiments, for improving the precision and / or effectiveness of neural stimulation, e.g., for the treatment of neurological and psychiatric disorders.

[0047] In some cases, the method may be a method for personalized neural stimulation in the treatment of neurological and psychiatric disorders in a subject, e.g., a human subject. In some embodiments, the method may include implanting a medical device into a subject. The method may include utilizing software to execute closed-loop stable neural recording and / or closed-loop stimulation. In some cases, the stimulation parameters or ranges may be customized to specific subject requirements. In some cases, clinical indications may be used to optimize the efficacy of neural stimulation therapy.

[0048] In one set of embodiments, the method comprises inserting, into an organ of a subject, an insertion portion of a probe, wherein the insertion portion is inserted to a depth of at least 10 cm; and determining electrical signals within the organ of the subject using the probe at a spatial resolution of between 1 micrometer and 1 mm.

[0049] In another set of embodiments, the method comprises inserting, into the brain of a subject, an insertion portion of a probe, wherein the insertion portion is inserted to a depth of at least 10 cm, and determining electrical signals within the brain of the subject using the probe at a spatial resolution of between 1 micrometer and 1 mm.

[0050] #14412892vl In still another set of embodiments, the method comprises inserting, into the brain of a subject, an insertion portion of a probe, wherein the insertion portion is inserted to a depth of at least 10 cm; determining electrical signals within the brain using the probe; and applying electrical signals to the brain using the probe based on the determined electrical signals.

[0051] The method, in yet another set of embodiments, comprises inserting, into the brain of a subject, an insertion portion of a probe, wherein the insertion portion is inserted to a depth of at least 10 cm, and wherein the probe comprises a conductive region defining the insertion portion, a passivation region surrounding the conductive region, and a biocompatible region surrounding the conductive region.

[0052] According to still another set of embodiments, the method comprises determining electrical signals within the brain of a subject using a probe inserted at a depth of at least 10 cm, and applying electrical signals to the brain using the probe based on the determined electrical signals.

[0053] In yet another set of embodiments, the method comprises determining electrical signals at a spatial resolution of between 1 micrometer and 1 mm and a depth of at least 10 cm within the brain of a subject using a probe inserted into the brain of the subject, and applying electrical signals to the brain using the probe based on the determined electrical signals.

[0054] In another set of embodiments, the method comprises inserting, into the brain of the subject, an insertion portion of a brain probe, wherein the insertion portion has a Young’s modulus of less than 1 MPa and a bending stiffness of 10’4nN m to 101nN m; and applying electrical signals to the brain of the subject using the brain probe to treat the neurological disorder.

[0055] Another aspect is generally directed to a method of treating a subject having a neurological disorder. In one set of embodiments, the method comprises inserting, into the brain of the subject, an insertion portion of a brain probe, wherein the insertion portion is inserted to a depth of at least 10 cm; and applying electrical signals to the brain of the subject using the brain probe to treat the neurological disorder.

[0056] Another aspect is generally directed to a method of treating a subject having a neurological or psychiatric disorder. The method, according to one set of embodiments, comprises inserting, into the brain of the subject, an insertion portion of a brain probe, wherein the insertion portion is inserted to a depth of at least 10 cm; and applying electrical signals to the brain of the subject using the brain probe to treat the neurological or psychiatric disorder.

[0057] #14412892vl Yet another set of embodiments is generally directed to a medical device for neural recording and stimulation. In some cases, the device may be used to alleviate symptoms of neurological and psychiatric disorders in a subject, e.g., a human subject. In some cases, the device may be used to perform closed-loop stimulation.

[0058] In one set of embodiments, the device comprises a probe having an insertion portion having a length of at least 10 cm and a bending stiffness of 10’4nN m to 101nN m. In some cases, the insertion portion is configured to determine electrical signals at a spatial resolution of between 1 micrometer and 1 mm.

[0059] In some cases, the device may include one or more electrodes. The electrodes may include nanoelectrodes. The electrode configuration may be compatible with recording electrochemistry function, e.g., for determining and / or recording the chemical status within the brain of a subject, e.g., a human subject. This may, in some embodiments, allow the assessment of changes in neural and / or chemical activity, e.g., in real time. In some cases, this may be useful to optimize neural stimulation therapy.

[0060] In some cases, the device may include one or more flexible or soft materials. Nonlimiting examples include, but are not limited to, flexible dielectric materials. Specific nonlimiting examples of flexible dielectric materials include polyimide, Parylene N, Parylene C, SU8 epoxy, perylene, hydrogel, etc. Specific non-limiting examples of soft dielectrics include SEBS, PDMS, etc. In some cases, such materials may be flexible and / or biocompatible. These may be useful, for example, for safe and / or effective neural recording and / or stimulation within the brain of a subject, e.g., a human subject.

[0061] In some cases, the device may include one or more conductive interconnects, e.g., for a nanoelectrode array. In some embodiments, the conductive interconnects materials include, but are not limited to, gold, platinum, titanium, etc. In some cases, such materials may be biocompatible and / or conductive. These may be useful, for example, for efficient neural recording and / or stimulation within the brain of a subject, e.g., a human subject.

[0062] In some cases, the device may include one or more electrode contact materials. Nonlimiting examples of such materials include, but are not limited to, platinum, iridium oxide, etc. Such materials may, in some embodiments, be conductive, biocompatible, and / or corrosion-resistant, etc. In some cases, these may be useful, for example, for neural recording and / or stimulation within the brain of a subject, e.g., a human subject.

[0063] In some cases, the device may be compatible with existing neural recording and stimulation rigs. Non-limiting examples include TDT (Tucker Davis Technologies), BlackRock, Ripple, Neuropixel, and other established recording systems. In some

[0064] #14412892vl embodiments, this may allow for integration with established research and clinical equipment.

[0065] In some cases, the device may be suitable for use, for example, in research involving animal models and / or humans. In some cases, the device may be suitable for use for the treatment of medical conditions, for example, in animal and / or human subjects.

[0066] In some cases, the device may include a connector part that can be used to establish a connection, e.g., between the electrode array and a backend. This may be useful, in some embodiments, to allow transmission of neural signals, e.g., for efficient device operation.

[0067] In some cases, the backend may include components such as an analog-to-digital processor, preprocessing processor, signal transmission equipment, a battery, etc. In some cases, the backend may allow for signal acquisition, processing, transmission, and power supply within the device.

[0068] In some cases, the device may be in communication with an external device that communicates with the implanted device. This may be useful, for example, to allow the exchange of data, downloading of information, control of the device, etc. For example, this may be useful to allow for remote monitoring, adjustments of the device as needed, etc.

[0069] In some cases, the device may include or be in communication with an external device designed for recharging a battery. This may be useful, for example, to allow for continuous and / or efficient operation of the device, for example, through wireless power transfer, recharging capabilities, or the like.

[0070] In some cases, the device may induce a reduced immune reaction due to the construction of the device, for example, when compared to existing deep brain stimulation (DBS) devices. This may be useful, for example, to enhance the biocompatibility of the device, and / or minimize immune-related complications in neural stimulation therapy.

[0071] In some cases, the device is capable of recording local field potential, multi-unit activity, and / or single-unit activity within the brain. In some cases, this may be useful, for example, to provide neural recording capabilities, e.g., for a more thorough and precise assessment of neural activity.

[0072] In some cases, the device can be used to assess and / or diagnose the brain state of a subject, e.g., a human subject. This may be useful, for example, to provide enhanced information for clinical assessment, and / or calibration of clinical needs in subjects, for example, having neurological disorders. In some cases, by monitoring and evaluating the subject’s brain state, e.g., continuously, including neural activity patterns and / or responses to stimulation. The device may, in some cases, allow for the tailoring of treatment strategies to

[0073] #14412892vl individual subject requirements, improve therapeutic outcomes for neurological disorder management, or the like.

[0074] In some cases, the device is capable of modulating the brain state of a subject, e.g., a human subject, for example, to enhance brain function. In some cases, by dynamically adjusting neural stimulation parameters, for example, based on assessments of the subject’s brain state, e.g., in real time, the device may be used to improve cognitive, sensory, and / or motor function, e.g., in individuals with neurological disorders. This may be useful, for example, to enhance quality of life or neurological health.

[0075] In some cases, the device is capable of modulating the brain state of a subject, e.g., a human subject, for example, to improve cognitive and executive function in the subject. In some embodiments, the subject may have a pre-existing cognitive deficit or impairment, or not. In some cases, through real-time adjustments of neural stimulation parameters, the device may be used to enhance cognitive and / or executive abilities, including memory, attention, problem- solving, decision-making, etc. In some cases, this may allow for improved cognitive performance and / or overall brain function, e.g., in a subject across various neurological states.

[0076] In some cases, the device is capable of modulating the brain state of a subject, e.g., a human subject, for example, to enhance cognitive and executive function in the subject. In some embodiments, the subject may have a pre-existing cognitive deficit or impairment, or not. In some cases, the subject may have a neurological condition or disorder. Examples include, but are not limited to, surgical trauma, traumatic brain injury, neurodegeneration, brain cancer, epilepsy, ischemia, etc. In some cases, the subject may not have a pre-existing neurological condition. This may allow, in some embodiments, a spectrum of clinical needs for example, for cognitive and executive function enhancement.

[0077] In some cases, the device is capable of augmenting brain function by modulating neural activity and / or optimizing neural circuits in a subject, e.g., a human subject. In some embodiments, by using adjustments of neural stimulation parameters, e.g., in real time, the device may be used to enhance various aspects of brain function. Examples include, but are not limited to, cognitive, sensory, motor, and / or emotional functions. In some cases, this may contribute to improved overall brain performance or neurological well-being in a subject.

[0078] In some cases, the device is capable of augmenting brain function in a subject, e.g., a human subject. This may allow, in various embodiments, a range of improvements. These include, but are not limited to, enhanced vision, olfaction, audition, or sensation, etc.

[0079] Through modulation of neural activity, the device in certain embodiments facilitates sensory

[0080] #14412892vl perception and / or processing improvements. This may in certain cases lead to heightened sensory experiences, enhanced brain function, etc.

[0081] In some cases, the device is capable of augmenting brain function in a subject, e.g., a human subject. This may be used, in some cases, in subjects with or without pre-existing sensory deficits or impairment. In some cases, this may be used in subjects with intact sensory function, subjects with sensory deficits, etc. In some cases, the device may enhance sensory perception and / or processing. In some embodiments, this may be used to promote heightened sensory experiences, and / or improved brain function across various neurological states, etc.

[0082] In another aspect, the present disclosure encompasses methods of making one or more of the embodiments described herein, for example, a brain probe such as disclosed herein. In still another aspect, the present disclosure encompasses methods of using one or more of the embodiments described herein, for example, a brain probe such as disclosed herein.

[0083] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures.

[0084] BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0086] Figs. 1A-1G illustrate a flexible mesh nanoelectrode array in accordance with one embodiment;

[0087] Figs. 2A-2G illustrate surgical implantation of a nanoelectrode array, in another embodiment;

[0088] Figs. 3A-3D illustrate implantation of a nanoelectrode array, in another embodiment; and

[0089] Fig. 4 is a block diagram of an example special purpose computer system improved by the functions and / or processes disclosed herein, in certain embodiments.

[0090] #14412892vl DETAILED DESCRIPTION

[0091] The present disclosure generally relates to nanoscale wires and nanoelectronics, to systems and methods for implanting such devices into the brain of a subject, and systems and methods of treating subjects using such devices. Certain aspects are generally directed to brain probes that are configured to determine electrical signals at mesoscale resolutions, e.g., at relatively deep depths within the brain, which may allow for determination and / or stimulation of electrical signals within the brain. The brain probes may be soft and / or mechanically flexible in some cases. In some embodiments, the devices may include a plurality of electrodes, e.g., in a mesh or an array. Some embodiments may allow for closed- loop stimulation at mesoscale resolutions, e.g., across multiple cortical and subcortical targets, and / or by targeting specific subregions of the brain. Other aspects are generally directed to systems and methods for making or using such brain probes, e.g., to treat a subject having a neurological disorder, kits involving such brain probes, or the like.

[0092] Some aspects are generally drawn to a medical device that may be designed for neural determination and / or stimulation within a brain of a subject, for example, to treat and / or alleviate symptoms of neurological or psychiatric disorders. In some embodiments, the device may include an array of electrodes, which may be flexible in some cases. The electrodes may include nanoelectrodes in some cases. Such devices, according to some embodiments, may allow access to targeted neural structures within the brain of a subject. For example, the device may include an array of electrodes that may allow relatively finetuned control over determination and / or stimulation of the brain. In some cases, such devices may be compatible with surgical robotics systems, e.g., that are commercially available. The devices may be operable wirelessly or wired in various embodiments. In some embodiments, the device may allow for relatively high resolutions of electrical signals, e.g., spatially and / or temporally. For example, in some embodiments, the device may allow long-term stable, single-unit activity recording, and / or high-density, precise, local electrical stimulation, etc. Certain embodiments are also directed to the treatment of different medical conditions, for example, sensory function restoration, psychiatric disorder modulation, dynamic stimulation adjustment, or the like. These may be applied for clinical and / or research use, e.g., in animal models, disease treatment, or the like. In some cases, the device may be flexible and / or biocompatible. In some embodiments, the device may be compatible with established neural recording and stimulation systems.

[0093] Another aspect is generally drawn to systems and methods for diagnostic and / or therapeutic neural determination and / or stimulation, e.g., by determining electrical signals

[0094] #14412892vl from the brain, and / or applying electrical signals to the brain. Some aspects, for example, are generally drawn to brain probes comprising soft and / or mechanically flexible arrays of nanoelectrodes, e.g., with multiple electrode contacts. In some cases, this may allow for implantation into cortical or subcortical regions, e.g., vertically, which in some embodiments may facilitate direct access to neural structures responsible for the manifestation of various disorders.

[0095] In one set of embodiments, the device may be able to perform simultaneous recording and stimulation (e.g., forming a closed loop), for example, at the mesoscale level, e.g., at a spatial resolution of between 1 micrometer and 1 mm. In some cases, this may be achieved simultaneously across multiple cortical and subcortical targets within the brain.

[0096] In some embodiments, the device may comprise a plurality of electrodes, e.g., nanoelectrodes, which may be arranged in an array. In some cases, the size of the electrodes may allow the brain probe to be implanted in a brain of a subject such that the electrodes are able to functionally access specific subregions of the brain. In some embodiments, the system may be a closed-loop system, e.g., one that can assess neural activity and / or adapt stimulation parameters, for example, on a continuous basis, which may result in optimized treatment outcomes. In some cases, side effects may be reduced by providing dynamic control over such stimulation. For example, a stimulation electrode may be able to receive signals in different directions, e.g., downward and upward. Based on its structure, in some cases, the stimulation direction can be adjusted to minimize side effects.

[0097] In certain embodiments, the device may be compatible with surgical robotics systems, e.g., including clinically approved robotics systems, which may allow for improved implantation procedures. The device may be operated, for example, by wireless and / or by wired systems. In some embodiments, the device may determine and / or record single-unit activity chronically, e.g., of a cell or a cluster of cells.

[0098] The device may be used for a variety of applications. For example, in some embodiments, the device may be used for the treatment of neurological and psychiatric disorders. As other examples, the device may be used to restore sensory functions, decode motor and / or speech for subjects with motor or speech impairments, or other applications such as any of those described herein.

[0099] The above discussion is a non-limiting example of one embodiment of the present disclosure. However, other embodiments are also possible. Accordingly, more generally, various aspects are directed to various systems and methods for systems and methods for

[0100] #14412892vl implanting such devices into the brain of a subject, and systems and methods of treating subjects using such devices.

[0101] For example, certain aspects encompass systems and methods for neural recording and stimulation within a brain (e.g., a human brain) to alleviate neurological disorders, or symptoms of neurological disorders (including psychiatric disorders). In some cases, the system may include an array of electrodes that in some cases can be individually modulated. Some or all of the electrodes may include nanoelectrodes. The system may include flexible and / or soft materials. In some cases, the device may include a closed-loop brain stimulation system, for example, with simultaneous recording and / or stimulating multiple regions of the brain, for example, as discussed below.

[0102] Certain embodiments also encompass systems and methods of restoring sensory function, e.g., in a subject. In some cases, the surrounding environment of a subject may be determined and used to stimulate a brain region, e.g., to restore perception when the original sensory function is impaired. Other applications are possible in other embodiments, e.g., as discussed herein.

[0103] In some cases, the subject is a human subject. In one set of embodiments, the subject may be a subject having a neurological disorder, including but not limited to Parkinson’s disease, Tourette’s syndrome, epilepsy, addiction, depression, and dystonia. Other examples of neurological disorders are described herein. In some embodiments, the subject may be a non-human animal. For example, the subject may be a non-human primate (e.g., a monkey, a chimpanzee, etc.). The subject may be a non-human mammal such as rodents, canines, felines, bovines, equines, or the like. In some cases, the subject is a non-mammal such as a bird or a reptile. In some cases, the non-human subjects may include test animals, animal models of disease or aging, livestock, veterinary subjects, or pets.

[0104] In some embodiments, a machine learning algorithm may be used to analyze a subject’s neural activity patterns and initial response to stimulation. This can be used to establish a baseline and tailor stimulation parameters to the individual subject. In some cases, real-time data from the device may be fed into a machine learning model that evaluates the efficacy of ongoing stimulation. These models may have the capability to detect subtle shifts in neural states and predict potential issues, and then adjust stimulation parameters, e.g., in real time. For example, parameters such as stimulation amplitude, frequency, and / or waveform may be adjusting using the model. In some cases, this may be used to ensure that the device is able to maintain or restore a subject’s desired target neural state.

[0105] #14412892vl In some embodiments, the device may be used with surgical robotics, e.g., including those that are clinically approved. In some cases, the device may be integrated with robotic systems using adaptors , many of which are commercially available. The adaptor may interface with an electrode array of the device and the robotic surgical instruments, which in some embodiments can be used to accurately position the device within targeted brain regions. In addition, in some embodiments, the device may provide real-time feedback from one or more sensors to aids in the placement of the device, e.g., within the brain of a subject. In some embodiments, the adaptor may facilitate device integration with surgical robotics, for example, to ensure controlled manipulation.

[0106] As mentioned, in certain embodiments, the device may allow for closed-loop stimulation. In some cases, the device, once implanted, may be able to record a subject’s neural activity within the targeted brain regions, e.g., to capture data about a subject’s neural state, responses to stimulation, etc. The data may be analyzed, e.g., by machine learning models such as those discussed herein. For example, in some cases, the device may be able to detect deviations from the desired neural state, signs of neural dysfunction, or the like. Based on this analysis, in some embodiments, the device may dynamically adjust its stimulation parameters. This may, in some cases, improve treatment efficacy, minimize side effects, maintain a desired neural state, etc. The device, in certain embodiments, may allow for data storage, transmission, analysis protocols, etc., e.g., based on acquired data from the subject.

[0107] In some cases, the closed-loop system may allow for adjusting electrical pulses, e.g., for neural stimulation. In some embodiments, a subject’s neural activity may be monitored, e.g., continuously, in response to an electrical stimulation, and used to determine subsequent electrical stimulation. In certain cases, these may be analyzed in real time, e.g., using machine learning models such as those discussed herein. When deviations from a desired neural state, signs of potential side effects, etc. are detected, the device may adjust the stimulation applied to the subject. These adjustments can include, for example, modifications to stimulation amplitude, frequency, or waveform.

[0108] The device may be a wired or a wireless device, in various embodiments. In some cases, the device may be able to function in both wired and wireless modes.

[0109] In some embodiments, the device may be used with existing surgical techniques, such as stereoelectroencephalography (sEEG) implantation procedures. For example, during sEEG implantation, a device may allow for simultaneous neural recording and stimulation, e.g., as discussed herein. The device also may be used with other techniques, such as CT

[0110] #14412892vl (Computed Tomography), MRI (Magnetic Resonance Imaging), or the like. In some cases, the device may include a multi-layered structure made of materials with distinct impedances. The transitions in electrical properties at the interfaces may disrupt radiofrequency-induced currents, which may reduce distal electrode heating, specific absorption rate, and MRI / or artifacts.

[0111] Certain embodiments are generally directed to software for operating the device. For example, the software may allow real-time data collection, analysis, or visualization of neural activity. The software may include closed-loop or machine learning capabilities, e.g., as discussed herein. In some cases, the software may use Al-enabled functionality, which may allow it to learn from recording data / or and generate optimized stimulation parameters.

[0112] Thus, certain aspects such as described herein are generally directed to systems and methods for implanting certain types of devices into the brain of a subject. The subject may be human, or non-human, e.g., as discussed herein. The device may be implanted into any portion of the brain. For example, the device may be implanted into the cerebrum, the cerebellum, or the brainstem. The device may be implanted into the frontal lobe, parietal lobe, temporal lobe, or the occipital lobe. In some cases, the device is implanted into the brain such that at least a portion of the device is implanted into a cortical region or a subcortical region of the subject. In some cases, the device is implanted such that it is inserted into both a cortical region and a subcortical region of the subject. In some embodiments, the device is implanted into the brain such that a portion of the device reaches at least 5 cm, at least 10 cm, at least 15 cm, etc. below the surface of the brain, e.g., using an insertion portion such as is described herein.

[0113] In some embodiments, the subject may have or be at risk of a neurological disorder, which may include psychiatric disorders. Those of ordinary skill in the art will be aware that neurological disorders include a broad spectrum of disorders, including psychiatric disorders, and the difference between a psychiatric disorder and a more conventional neurological disorder is often one of degree or severity, and the boundary can be fuzzy or subjective. Non-limiting examples of neurological disorders (which may include psychiatric disorders) include epilepsy, Parkinson’s disease, autism, schizophrenia, depression (e.g., major or clinical depression), obsessive-compulsive disorder, addiction (e.g., drug addiction), seizures (e.g., repeated seizures), essential tremor, Tourette’s syndrome, dystonia, etc. Other neurological disorders that may be treated in certain embodiments include reduced or impaired hearing and / or olfaction, reduced or impaired sensory function (e.g., peripheral sensory function), reduced or impaired motor function (e.g., muscle tremors), reduced or

[0114] #14412892vl impaired wakefulness (e.g., in a partially or fully comatose state), reduced or impaired speech, or the like. Still other neurological disorders include any of those described herein.

[0115] In some cases, certain aspects are generally directed to a device comprising a probe that can be implanted into a brain (e.g., a brain probe), or other suitable locations in a subject (for example, the spinal cord, or another organ such as the heart, kidney, or the stomach, etc.).

[0116] In some cases, the probe may include an insertion portion that may be inserted into the brian. In some cases, the insertion portion may have a length of at least 5 cm, at least 10 cm, or at least 15 cm, which can be inserted into the brain of the subject, e.g., to reach deeper regions within the brain. In contrast, many prior art devices are applied to the surface of the brain, rather than are inserted into the brain. In some embodiments, the insertion portion may have at least one cross-sectional dimension that has a maximum of less than 5 cm, less than 4 cm, less than 3 cm, less than 2 cm, or less than 1 cm. In some cases, the insertion portion may have two cross-sectional dimensions that each independently have a maximum of less than 5 cm, less than 4 cm, less than 3 cm, less than 2 cm, or less than 1 cm. The insertion portion may in some cases be substantially planar, or in some cases the insertion portion may be substantially cylindrical. Other shapes are also possible in other embodiments.

[0117] In some cases, the insertion portion may include a plurality of electrodes, e.g., in an array. Such electrodes are described in more detail herein. The array on the insertion portion may include at least 10, at least 20, at least 30, at least 50, at least 100, at least 200, at least 300, at least 500, at least 1000, at least 2000, or at least 4000 electrodes. In some cases, some or all of the electrodes may be independently addressable. The electrodes may have any suitable arrangement in the insertion portion, e.g., in a rectangular or square grid, in a triangular or hexagonal grid, or the like. The electrodes may also be regularly or irregularly distributed in the insertion portion. Additional examples of electrodes are described in more detail herein. In some cases, an electrode may be a nanoelectrode, i.e., the electrode may have a maximum dimension of less than 1 micrometer, e.g., such that the electrode dimensions are measured on the order of nanometers.

[0118] In one set of embodiments, the electrodes may be configured and arranged to be able to determine and / or apply electrical signals at mesoscale spatial resolutions, i.e., having spatial resolutions of between 1 micrometer and 1 mm. For example, the electrodes may be spaced at a repeat unit of at least 1 micrometer, at least 2 micrometers, at least 3 micrometers, at least 5 micrometers, at least 10 micrometers, at least 20 micrometers, at least 30

[0119] #14412892vl micrometers, at least 50 micrometers, at least 100 micrometers, at least 200 micrometers, at least 300 micrometers, at least 500 micrometers. In addition, in some embodiments, the electrodes may be spaced at a repeat unit of no more than 1 mm, no more than 500 micrometers, no more than 300 micrometers, no more than 200 micrometers, no more than 100 micrometers, no more than 50 micrometers, no more than 30 micrometers, no more than 20 micrometers, no more than 10 micrometers, no more than 5 micrometers, no more than 3 micrometers, or no more than 2 micrometers. Combinations of any of these are also possible, e.g., the electrodes may be spaced at a repeat unit of between 1 micrometer and 1 mm, between 20 micrometers and 50 micrometers, between 1 micrometer and 100 micrometers, between 30 micrometers and 200 micrometers, between 1 micrometer and 10 micrometers, or the like.

[0120] In some embodiments, the insertion portion may be flexible. In some embodiments, the insertion portion may be soft. In some cases, the insertion portion may have a shape and / or may be formed from one or more materials that allow it to be flexible or soft. For example, the insertion portion may include shapes, such as serpentine shapes, that can be extended, thereby allowing the material to be soft or flexible. In some cases, the insertion portion can be formed of components that are not straight, and can be extended, e.g., when pulled on. For instance, the insertion portion may comprise one or more nodes that are connected by various interconnects, for example, forming a mesh or a network, e.g., of electrodes. The nodes may be evenly or nonevenly distributed within the insertion portion, and the interconnects may connect them in a regular pattern (for example, in rectangular or triangular arrays of nodes), or in an irregular pattern. The nodes may represent points of connectivity, or there may be one or more electronic components at some or all of the nodes, such as conductive pathways, nanoscale wires, electrodes, sensors, or the like. The same or different electronic components may independently be present at different nodes within a mesh or network.

[0121] In some cases, the insertion portion may have a soft portion or include a soft material. The soft material or portion may have a Young’s modulus of less than 10 MPa, less than 5 MPa, less than 3 MPa, less than 1 MPa, less than 0.5 MPa, less than 0.3 MPa, or less than 0.1 MPa. In addition, in some cases, a soft material may have a glass transition temperature of less than 50 °C, less than 40 °C, less than 30 °C, less than 25 °C, less than 20 °C, or less than 10 °C.

[0122] In certain embodiments, the insertion portion may have a flexible portion or include a flexible material. The material or portion may be relatively flexible, for example, have a

[0123] #14412892vl flexibility or a bending stiffness comparable to the tissue. The flexibility or bending stiffness may be determined, for example, by multiplying the Young’s modulus of the material times the cube of the thickness of the material. In some cases, a flexible material may be one that is formed from a relatively flexible material, e.g., the Young’s modulus may be low. A flexible material may also be one that is relatively thin, e.g., the Young’s modulus may be relatively higher, but the thickness of the material may be low. In some cases, a flexible material may have a bending stiffness of at least IxlO-5nN m, at least 3xl0-5nN m, at least 5xl0-5nN m, at least 1x1 O’4nN m, at least 3x1 O’4nN m, at least 5x1 O’4nN m, at least 1x1 O’3nN m, at least 3x1 O’3nN m, at least 5x1 O’3nN m, at least 1x1 O’2nN m, at least 3x1 O’2nN m, at least 5x1 O’2nN m, or at least IxlO-2nN m. In some cases, the bending stiffness may be no more than 1x1 O’2nN m, no more than 5x1 O’3nN m, no more than 3x1 O’3nN m, no more than IxlO-3nN m, no more than 5x1 O’4nN m, no more than 3x1 O’4nN m, no more than IxlO-4nN m, no more than 5x1 O’5nN m, no more than 3x1 O’5nN m, or no more than IxlO-5nN m. Combinations of any of these are also possible, e.g., the bending stiffness may be between IxlO-4nN m and IxlO1nN m, between 3xl0-4nN m and IxlO-5nN m, between IxlO-3nN m and IxlO-2nN m, etc. In one aspect, the insertion portion may have a structure that includes a rigid polymer and a soft polymer. The soft polymer may be in interior of the insertion portion, partially or completely surrounded by an outer portion. In some cases, the outer portion may include a rigid polymer.

[0124] In some cases, the insertion portion may include a soft polymer, optionally including one or more conductive materials (e.g., gold, platinum, silver, copper, etc.) patterned thereon, for example, which can be used as interconnects. The soft polymer may be contained within another polymer, for example, a rigid or not soft polymer. In some cases, this polymer may be useful for protecting the soft polymer, e.g., as an outer coating or layer.

[0125] The soft polymer may be an elastomer in some cases. The softness of the polymer may be determined by determining its Young’s modulus and / or its glass transition temperature. For example, a soft polymer may have a Young’s modulus of less than 10 MPa, and / or a glass transition temperature of less than 50 °C. Other potential values for the Young’s modulus and / or the glass transition temperature are discussed in more detail herein. One non-limiting example of a soft polymer is hydrogenated styrene-ethylene-butylene- styrene (H-SEBS). Other examples include PDMS (polydimethylsiloxane), PFPE (perfluoropolyether), etc.

[0126] In certain cases, the soft polymer may be partially or complexly contained within another polymer, e.g., forming an outer portion. Other materials may also be present in some

[0127] #14412892vl embodiments, e.g., partially or completely surrounding the outer portion. In some embodiments, the polymer may be a photoresist, or other material that can be deposited on the soft polymer and / or the interconnects, e.g., as discussed herein. For example, the polymer may be SU-8. Other non-limiting examples of photoresist polymers include SI 805, LOR 3A, poly(methyl methacrylate), poly(methyl glutarimide), phenol formaldehyde resin (diazonaphthoquinone / novolac), diazonaphthoquinone (DNQ), Hoechst AZ 4620, Hoechst AZ 4562, Shipley 1400-17, Shipley 1400-27, Shipley 1400-37, or the like. These and many other photoresists are available commercially. Still other examples of photoresist polymers include, but are not limited to, those described herein, and those described in Int. Pat. Apl. Pub. No. WO 2019 / 084498, incorporated herein by reference.

[0128] The interconnects connecting two (or more) nodes together may have the same or different shapes or structure within a mesh or network, and different interconnects within the mesh may independently have the same or different shapes. In some cases, an interconnect may have a shape that is extendible. For example, an interconnect may have a straight-line or linear shape, or have shapes that are non-linear, such as S shapes, serpentine shapes (e.g., having two, three, four, or more bends or inflection points), zigzag shapes (e.g., having two, three, four, or more vertices), coiled shapes, or the like. Such interconnect shapes may allow various manipulations to occur without disrupting the connection of the interconnect to the nodes, e.g., during stretching, compression, folding, etc. Thus, such interconnects may provide soft or flexible electrodes to the insertion portion.

[0129] In one set of embodiments, an interconnect may comprise one or metal leads and one or more polymers, such as those discussed below. The polymers can include photoresist polymers (such as SU-8), and / or biocompatible polymers (such as Matrigel™). Examples of metals that can be used for such interconnects or pathways include, but are not limited to platinum, aluminum, gold, silver, copper, molybdenum, tantalum, titanium, nickel, tungsten, chromium, palladium, or the like, as well as any combinations of these and / or other metals. Other examples include conductive polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT), poly acetylene, polyphenylene vinylene, polypyrrole, polythiophene (for example poly(3,4-ethylenedioxythiophene)), polyphenylene sulfide, etc. Still other examples of photoresist polymers include, but are not limited to, those described below.

[0130] In one set of embodiments, one or more materials within the device are soft and / or flexible. For example, in some cases, a device may comprise a mesh or portions thereof (e.g., interconnects) that can be stretchable or flexible, or can be manipulated or distorted in some fashion, thereby allowing it to be soft. It should be understood that the flexibility of a

[0131] #14412892vl material is not purely an intrinsic material propriety; a thinner piece of material may offer more flexibility than a comparably thicker piece of the same material. In addition, in some cases, the flexibility of the material may also be a function of its shape, e.g., as discussed above. In addition, in some cases, the device may be non-flexible, or contain non-flexible components.

[0132] In certain instances, a device may have components, such as interconnects, that are sufficiently flexible or stretchable such that the device (or a component thereof, such as an insertion portion) may be stretchable in a linear direction by at least 10%, at least 20%, at least 30%, at least 50%, at least 75%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 350%, at least 400%, at least 450%, at least 500%, etc., for example, before catastrophic failure of the device, breakage, disruption of the connection of the interconnect to the nodes, loss of electrical connections, or the like.

[0133] In addition, in certain cases, the device may also be soft, i.e., such that it exhibits some degree of elasticity, e.g., such that the device may return (at least partially) to its original structure prior to stretching or distortion. For instance, the device (or a component thereof, such as an insertion portion) may return at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% (perfectly elastic) back to its original structure, measured from when stretching of the material is stopped. Thus, for example, a 1 cm material stretched to 2 cm experiences a 100% stretch in a linear direction, and if it afterwards contracts to 1.5 cm, it exhibits a 50% recovery to its original structure (returning 0.5 cm from its stretch of 1 cm). However, it should be understood that in some embodiments, the device is not elastic or soft.

[0134] In some embodiments, the device may have components that are sufficiently flexible or soft such that the device (or a component thereof, such as an insertion portion) may have an effective bending stiffness of at least 0.01 n-Nm, at least 0.02 n-Nm, at least 0.03 n-Nm, at least 0.04 n-Nm, at least 0.05 n-Nm, at least 0.06 n-Nm, at least 0.07 n-Nm, at least 0.08 n-Nm, at least 0.09 n-Nm, at least 0.1 n-Nm, at least 0.2 n-Nm, at least 0.3 n-Nm, at least 0.4 n-Nm, at least 0.5 n-Nm, at least 0.7 n-Nm, at least 1 n-Nm, at least 1.5 n-Nm, at least 2 n-Nm, at least 2.5 n-Nm, at least 3 n-Nm, at least 3.5 n-Nm, at least 4 n-Nm, at least 4.5 n-Nm, at least 5 n-Nm, etc. In some embodiments, the device may have an effective bending stiffness of less than 5 n-Nm, less than 4.5 n-Nm, less than 4 n-Nm, less than 3.5 n-Nm, less than 3 n-Nm, less than 2.5 n-Nm, less than 2 n-Nm, less than 1.9 n-Nm, less than 1.8 n-Nm, less than 1.5 n-Nm, less than 1.3 n-Nm, less than 1 n-Nm, less than 0.9 n-Nm, less than 0.8 n-Nm, less than 0.5 n-Nm, less than 0.3 n-Nm, etc. Combinations of any of these are also

[0135] #14412892vl possible; for example, the device or insertion portion may exhibit an effective bending stiffness of between 0.090 n-Nm and 1.9 n-Nm.

[0136] In certain embodiments, the device may have components, such as an insertion portion, that is sufficiently flexible or soft such that the device (or a component thereof, such as an insertion portion) can be compressed in a linear direction by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, etc., without catastrophic failure of the device, breakage, disruption of the connection of the interconnects or electrodes, loss of electrical connections, or the like.

[0137] In addition, in certain embodiments, the device may have components, such as an insertion portion, that are sufficiently flexible or soft such that the device (or a component thereof, such as an insertion portion) is foldable by at least 30°, at least 45°, at least 90°, at least 135°, at least 150°, at least 180°, etc. from an initial planar structure.

[0138] In one set of embodiments, the insertion portion comprises a conductive region, a passivation region surrounding the conductive region, and a biocompatible region surrounding the conductive region. The conductive region, in certain embodiments, may include a metal, for example, gold, platinum, titanium, or the like. In some cases, the conductive region may comprise a polymer, an elastomer, SiC, or the like. In some cases, the passivation region partially or completely surrounds the conductive region. In some embodiments, the passivation region may include a dielectric, an oxide, an inorganic oxide, or the like. Non-limiting examples of oxides include titanium oxide, silicon oxide, etc. In some cases, the biocompatible region partially or completely surrounds the conductive region. In some embodiments, the biocompatible region comprises a polyimide, parylene N, parylene C, SU8, styrene ethylene butylene styrene, poly(dimethylsiloxane), or the like.

[0139] In some embodiments, the device may comprise one or more electrodes (e.g., a nanoelectrode), for example, positioned on or in an insertion portion. For example, the device may include at least 10, at least 20, at least 30, at least 50, at least 100, at least 200, at least 300, at least 500, or at least 1000 electrodes, etc. The electrode may comprise any suitable material, for example, carbon, or metals such as gold, platinum, silver, or the like.

[0140] In some cases, the electrode may be used to determine a property of the brain of the subject (e.g., an electrical property, a chemical property, a mechanical property, etc.), and / or to apply a stimulus (e.g., an electrical stimulus) to the brain of the subject. In some cases, a conductive polymer may also be used with the electrode. Non-limiting examples of conductive polymers include poly(3,4-ethylenedioxythiophene) (PEDOT), polyacetylene, polyphenylene vinylene, polypyrrole, polythiophene (for example poly (3, 4-

[0141] #14412892vl ethylenedioxythiophene)), polyphenylene sulfide, or other conductive polymers such as those described herein.

[0142] In some embodiments, a device comprises one or more components such as nanowires, nanoelectrodes and / or interconnects of the nanoscale, e.g., used as an electrode. In some embodiments, a component used as a nanoelectrode has a dimension (e.g., a length, a width, a diameter) of less than or equal to 1,000 nm, less than or equal to 500 nm, less than or equal to 250 nm, less than or equal to 100 nm, less than or equal to 75 nm, less than or equal to 50 nm, less than or equal to 25 nm, or less than or equal to 10 nm. In some embodiments, a component has a dimension of greater than or equal to 10 nm, greater than or equal to 25 nm, greater than or equal to 50 nm, greater than or equal to 75 nm, greater than or equal to 100 nm, greater than or equal to 250 nm, greater than or equal to 500 nm, or greater than or equal to 1,000 nm. Combinations of the above-referenced ranges are also possible (e.g., greater than or equal to 10 nm and less than or equal to 1,000 nm). Other ranges are possible.

[0143] In some embodiments, a nanowire or nanoelectrode may be used to assist in determining a property of a biological system, e.g., when it is implanted in the brain of a subject. For example, one or more locations within the brain (for example, an electrode or a nanoscale wire, etc.) may be determined to determine a property, such as a chemical property, an electrical property, a mechanical property, or the like. Other examples include sensing Ca2+spikes, voltage changes, cell signaling pathways, ion concentrations, pH changes, sensing of biomolecules or reaction entities, etc. In some cases, the locations are defined as one or more nodes within the brain of a subject, some or all of which may be individually addressable. For example, an electrode within a device may comprise a nanoscale wire, such as those described in more detail elsewhere herein.

[0144] Devices (e.g., meshes, nanowire arrays, etc.) described herein may be implanted into the brain of a subject. In some cases, devices described herein may have a degree of softness, flexibility, and / or stretchability to be implanted into a brain while not damaging components of the device (e.g., nanowires, interconnects, etc.).

[0145] As mentioned, certain embodiments are generally directed to systems and methods for determining a property of the brain of the subject (e.g., an electrical property, a chemical property, a mechanical property, etc.), and / or applying a stimulus (e.g., an electrical stimulus) to the brain of the subject based on the determined property. For example, one or more electrical signals within the brain of the subject may be determined using a device as discussed herein, e.g., with one or more electrodes, and then one or more electrical signals may be applied to stimulate the brain of the subject based on the determined electrical

[0146] #14412892vl signals, e.g., as in a feedback loop or a closed-loop system. These may be applied, for example, using the same device or a different device, or using the same electrode(s) or different electrodes. In some cases, a plurality of electrical signals may be determined from the brain of a subject, and / or a plurality of electrical signals may be applied to the brain of a subject.

[0147] In addition, in some cases, more than probe may may be applied to the subject. For example, a device may contain more than one probe, e.g., 2, 3, 4, 5, or more probes. In some cases, one or more of the probes may introduced through a burr hole drilled in the skull of the subject, or through than more than one burr hole in some embodiments. In some embodiments, the probes may be inserted at a density of at least 3, at least 5, or at least 10 probes per 100 mm3of tissue. In some cases, the probe may include a cap portion physically connected to an insertion portion.

[0148] In some cases, the electrical signals applied to the subject may be applied at a charge density of at least 0.01 microcoulombs / cm2, at least 0.02 microcoulombs / cm2, at least 0.03 microcoulombs / cm2, at least 0.05 microcoulombs / cm2, at least 0.1 microcoulombs / cm2, at least 0.2 microcoulombs / cm2, at least 0.3 microcoulombs / cm2, at least 0.5 microcoulombs / cm2, at least 1 microcoulombs / cm2, at least 2 microcoulombs / cm2, at least 3 microcoulombs / cm2, at least 5 microcoulombs / cm2, at least 10 microcoulombs / cm2, etc. In some cases, the charge density may be no more than 10 microcoulombs / cm2, no more than 5 microcoulombs / cm2, no more than 3 microcoulombs / cm2, no more than 2 microcoulombs / cm2, no more than 1 microcoulombs / cm2, no more than 0.5 microcoulombs / cm2, no more than 0.3 microcoulombs / cm2, no more than 0.2 microcoulombs / cm2, no more than 0.1 microcoulombs / cm2, no more than 0.05 microcoulombs / cm2, no more than 0.03 microcoulombs / cm2, no more than 0.02 microcoulombs / cm2, or no more than 0.01 microcoulombs / cm2. Combinations of any of these are also possible, e.g., the charge density may be between 0.05 microcoulombs / cm2and 5 microcoulombs / cm2, between 0.1 microcoulombs / cm2and 3 microcoulombs / cm2, between 0.05 microcoulombs / cm2and 0.03 microcoulombs / cm2, etc.

[0149] In certain cases, the electrical signals applied to the brain of the subject may be determined using machine learning techniques, for example, an Al model. The machine learning technique, for example, may accept one or more electrical signals (e.g., obtained as discussed above), and optionally, other inputs from other sensors, such as accelerometers, thermometers, etc. Other inputs may include inputs from other assessment methods such as, but not limited to, EMG (Electromyography), EEG (Electroencephalography), ECoG

[0150] #14412892vl (Electrocorticography), single-unit recording, and fMRI (functional Magnetic Resonance Imaging), etc.

[0151] In some cases, the machine learning systems may comprise a computer-readable medium configured to process data transmitted and / or received (e.g., electrical signals, etc.), for example, using Gaussian and / or Bayesian processes, and / or other machine learning processes. For example, in some embodiments, a computer-readable medium comprises executable instructions to determine input and / or output signals using a Gaussian and / or Bayesian process. In some embodiments, a computer-readable medium comprises a predictive model comprising a reinforcement learning model. Based, at least in part, on the data transmitted and / or received, the computer-readable medium can adjust an input or output (e.g., a subsequent electrical output), for example, by modifying electrical signals applied to the subject.

[0152] For example, as discussed herein, the device may be implanted to determine and / or stimulate various regions within the brain, e.g., cortical and / or subcortical targets, specific subregions of the brain, etc. In some cases, a feedback loop or a closed-loop system may be used in conjunction with a predictive model to provide electrical signals stimulate the brain. By monitoring electrical inputs and outputs from the brain, the brain may be at least partially controlled.

[0153] In some cases, this may be used to treat a subject having or at risk of a neurological disorder, e.g., as discussed herein. Non-limiting examples include Parkinson’s disease, Tourette’s syndrome, epilepsy, addiction, depression, and dystonia. As another example, such systems may be used to restore peripheral sensory function, for example impaired hearing, vision, or olfaction. Still other applications include inhibiting seizure occurrences, modulating wakefulness, motor and speech decoding, sensing the behavior of a subject, or the like.

[0154] In some cases, the device may be connected to a computer system, e.g., a general or a special purpose computer system. The system may be used in some embodiments to apply electrical stimulation to one or more portions of the device, e.g., to be applied to the brain of a subject. For instance, one or more portions of the device may be individually addressable, e.g., via the computer system. In addition, in some embodiments, the system may be used to determine a property of the device, e.g., when it is implanted within a brain of a subject, such as described elsewhere herein. For instance, a property, such as a chemical property, an electrical property, a mechanical property, or the like may be determined and recorded by the computer system. In some cases, one or more electrodes may be used. In certain

[0155] #14412892vl embodiments, the computer system may be used to apply electrical stimulation to the brain, determine one or more properties of the brain, and predict electrical stimulation to be applied based on properties of the brain.

[0156] A non-limiting illustrative implementation of a special purpose computer system 300 that may be specially programmed to be used in connection with any of the embodiments of the disclosure provided herein is shown in Fig. 4. The computer system 300 may include one or more processors 310 and one or more articles of manufacture that comprise non-transitory computer-readable storage media (e.g., memory 320 and one or more non-volatile storage media 330). The processor 310 may control writing data to and reading data from the memory 320 and the non-volatile storage device 330 in any suitable manner. To perform any of the functionality described herein (e.g., build predictive models, provide inputs to the predictive models, apply electrical stimuli to one or more portions of the brain, etc.), the processor 310 may execute one or more processor-executable instructions stored in one or more non-transitory computer-readable storage media (e.g., the memory 320), which may serve as non-transitory computer-readable storage media storing processor-executable instructions for execution by the processor 310.

[0157] The terms “program” or “software” or “app” are used herein in a generic sense to refer to any type of computer code or set of processor-executable instructions that can be employed to program a computer or other processor to implement various aspects of embodiments as discussed above. Additionally, it should be appreciated that according to one aspect, one or more computer programs that when executed perform methods of the disclosure provided herein need not reside on a single computer or processor, but may be distributed in a modular fashion among different computers or processors to implement various aspects of the disclosure provided herein.

[0158] Processor-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically, the functionality of the program modules may be combined or distributed as desired in various embodiments.

[0159] Also, data structures may be stored in one or more non-transitory computer-readable storage media in any suitable form. For simplicity of illustration, data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a non-transitory computer-readable medium that convey relationships between the fields. However, any

[0160] #14412892vl suitable mechanism may be used to establish relationships among information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationships among data elements.

[0161] Also, various concepts may be embodied as one or more processes, of which examples have been provided herein. The acts performed as part of each process may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.

[0162] As noted above and elsewhere herein, a computer-readable medium may be associated with a device to receive and / or transmit electrical signals. In some such embodiments, the computer-readable medium is configured to process a first signal based on a first current having a first peak shape to determine a second current having a second peak shape, different from the first peak shape, to apply to the biological system.

[0163] In some embodiments, the computer-readable medium is configured to use machine learning to determine a set of subsequent outputs. For example, a biological system may provide a series of inputs (e.g., electrical impedance measurements), and the computer- readable medium is configured to determine a set of subsequent outputs. In some embodiments, the computer-readable medium is configured to train using a predictive model and at least one of a voltage supplied during electrical stimulation, a duration of electrical stimulation, a volume or density of the portions of the brain undergoing electrical stimulation, type of cells undergoing electrical stimulation, an intensity or pattern of electrical stimulation, a frequency of electrical stimulation, periodicity of electrical stimulation, and, optionally, further trained on a resulting brain response.

[0164] Certain aspects are generally directed to systems and methods for preparing devices such as those described herein. The devices can be fabricated, for example, using well- known lithographic techniques such as those discussed below.

[0165] In various embodiments, a device is constructed by assembling various polymers, metals, and other components (for example, nanoscale wires) together on a substrate. For example, lithographic techniques such as e-beam lithography, photolithography, X-ray lithography, extreme ultraviolet lithography, ion projection lithography, etc. may be used to pattern polymers, metals, etc. on the substrate. After assembly, at least a portion of the substrate (e.g., a sacrificial material) may be removed, allowing the device to be partially or completely removed from the substrate. Other materials may also be added to the device,

[0166] #14412892vl e.g., to help stabilize the structure, to add additional agents to enhance its biocompatibility, etc. The device can be used in vivo, e.g., by implanting it in a subject.

[0167] For example, in one set of embodiments, a device may be constructed by providing a substrate, depositing a sacrificial layer on the substrate, then patterning a first photoresist on the sacrificial layer, a conductive pathway on the first photoresist, and a second photoresist on the conductive pathway, and removing the sacrificial layer to produce the device. The first and second photoresists may comprise the same or different materials. Optionally, other components can also be added to the device, before or during formation, such as electrode components, nanoscale wires, connectors such as cables, or the like.

[0168] The substrate may be chosen to be one that can be used for lithographic techniques such as e-beam lithography or photolithography, or other lithographic techniques including those discussed herein. For example, the substrate may comprise or consist essentially of a semiconductor material such as silicon, although other substrate materials (e.g., a metal) can also be used. Typically, the substrate is one that is substantially planar, e.g., so that polymers, metals, and the like can be patterned on the substrate. In some cases, a portion of the substrate can be oxidized, e.g., forming SiCF and / or Si?N4 on a portion of the substrate, which may facilitate subsequent addition of materials (metals, polymers, etc.) to the substrate.

[0169] In certain embodiments, one or more polymers can also be deposited or otherwise formed prior to depositing the sacrificial material. In some cases, the polymers may be deposited or otherwise formed as a layer of material on the substrate. Deposition may be performed using any suitable technique, e.g., using lithographic techniques such as e-beam lithography, photolithography, X-ray lithography, extreme ultraviolet lithography, ion projection lithography, etc. In some cases, some or all of the polymers may be biocompatible and / or biodegradable. The polymers that are deposited may also comprise methyl methacrylate and / or poly(methyl methacrylate), in some embodiments.

[0170] Next, a sacrificial material may be deposited. The sacrificial material can be chosen to be one that can be removed without substantially altering other materials (e.g., polymers, other metals, nanoscale wires, etc.) deposited thereon. For example, in one embodiment, the sacrificial material may be a metal, e.g., one that is easily etchable. For instance, the sacrificial material can comprise germanium or nickel, which can be etched or otherwise removed, for example, using a peroxide (e.g., H2O2) or a nickel etchant (many of which are readily available commercially). In some cases, the sacrificial material may be deposited on oxidized portions or polymers previously deposited on the substrate. In some cases, the sacrificial material is deposited as a layer. The layer can have a thickness of less than about 5

[0171] #14412892vl micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1 micrometer, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, etc.

[0172] In some embodiments, a first photoresist can be deposited, e.g., on the sacrificial material. The photoresist may include one or more polymers, which may be deposited as one or more layers. Examples of photoresist include, but are not limited to, SU-8, SI 805, LOR 3A, poly(methyl methacrylate), poly(methyl glutarimide), phenol formaldehyde resin (diazonaphthoquinone / novolac), diazonaphthoquinone (DNQ), Hoechst AZ 4620, Hoechst AZ 4562, Shipley 1400-17, Shipley 1400-27, Shipley 1400-37, etc., as well as any others discussed herein.

[0173] The photoresist can be used to at least partially define a device. In one set of embodiments, the photoresist may be deposited as a layer of material, such that portions of the photoresist may be subsequently removed. For example, the photoresist can be deposited using lithographic techniques such as e-beam lithography, photolithography, X-ray lithography, extreme ultraviolet lithography, ion projection lithography, etc., or using other techniques for removing polymer that are known to those of ordinary skill in the art. In some cases, more than one photoresist is used, e.g., deposited as more than one layer (e.g., sequentially), and each layer may independently have a thickness of less than about 5 micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1 micrometer, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, etc. For example, in some embodiments, portions of the photoresist may be exposed to light (visible, UV, etc.), electrons, ions, X-rays, etc. (e.g., projected onto the photoresist), and the exposed portions can be etched away (e.g., using suitable etchants, plasma, etc.) to produce the pattern.

[0174] Accordingly, the photoresist may be formed into a particular pattern, e.g., in a grid or a mesh, e.g., as discussed herein. For instance, the pattern may include a mesh and interconnects that have a shape that allow the interconnects to be manipulated or distorted without disrupting their connections, e.g., during stretching, compression, folding, or the like. The pattern can be regular or irregular.

[0175] Next, a metal or other conductive material can be deposited e.g., on one of the previous materials, to form conductive pathways within the device. More than one metal can

[0176] #14412892vl be used, which may be deposited as one or more layers. For example, a first metal may be deposited, and a second metal may be deposited on at least a portion of the first metal. Optionally, more metals can be used, e.g., a third metal may be deposited on at least a portion of the second metal, and the third metal may be the same or different from the first metal. In some cases, each metal may independently have a thickness of less than about 5 micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1 micrometer, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, less than about 80 nm, less than about 60 nm, less than about 40 nm, less than about 30 nm, less than about 20 nm, less than about 10 nm, less than about 8 nm, less than about 6 nm, less than about 4 nm, or less than about 2 nm, etc., and the layers may be of the same or different thicknesses.

[0177] Any suitable technique can be used for depositing metals, and if more than one metal is used, the techniques for depositing each of the metals may independently be the same or different. For example, in one set of embodiments, deposition techniques such as sputtering can be used. Other examples include, but are not limited to, physical vapor deposition, vacuum deposition, chemical vapor deposition, cathodic arc deposition, evaporative deposition, e-beam PVD, pulsed laser deposition, ion-beam sputtering, reactive sputtering, ion-assisted deposition, high-target-utilization sputtering, high-power impulse magnetron sputtering, gas flow sputtering, or the like.

[0178] The metals can be chosen in some cases such that the deposition process yields a prestressed arrangement, e.g., due to atomic lattice mismatch, which causes the subsequent metal leads to warp or bend, for example, once released from the substrate. Although such processes were typically undesired in the prior art, in certain embodiments of the present invention, such pre- stressed arrangements may be used to cause the resulting device to form a 3-dimensional structure, in some cases spontaneously, upon release from the substrate. See, e.g., U.S. Pat. Apl. Pub. Nos. 2014 / 0073063, 2014 / 0074253, 2017 / 0069858, 2017 / 0072109, each of which is incorporated herein by reference in its entirety. However, it should be understood that in other embodiments, the metals may not necessary be deposited in a prestressed arrangement.

[0179] Examples of metals that can be deposited (stressed or unstressed) include, but are not limited to, aluminum, gold, silver, copper, molybdenum, tantalum, titanium, nickel, tungsten, chromium, palladium, as well as any combinations of these and / or other metals. For example, a chromium / gold / chromium deposition process can be used.

[0180] #14412892vl In certain embodiments, a second photoresist can be deposited on the previous materials. The second photoresist may be the same or different from the first photoresist, and may include any of the photoresist materials discussed herein, including any of those described with reference to the first photoresist. The second photoresist may include one or more polymers, which may be deposited as one or more layers. In some embodiments, the second photoresist may be deposited on one or more portions of a substrate, e.g., as a layer of material such that portions of the second photoresist can be subsequently removed, e.g., using lithographic techniques such as e-beam lithography, photolithography, X-ray lithography, extreme ultraviolet lithography, ion projection lithography, etc., or using other techniques for removing photoresist that are known to those of ordinary skill in the art. In some cases, more than one photoresist may be used, e.g., deposited as more than one layer (e.g., sequentially), and each layer may independently have a thickness of less than about 5 micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1 micrometer, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, less than about 100 nm, etc.

[0181] After formation of the device, some or all of the sacrificial material may then be removed in some cases. In one set of embodiments, for example, at least a portion of the sacrificial material is exposed to an etchant able to remove the sacrificial material. For example, if the sacrificial material is a metal such as nickel, a suitable etchant (for example, a metal etchant such as a nickel etchant, acetone, etc.) can be used to remove the sacrificial metal. Many such etchants may be readily obtained commercially. In addition, in some embodiments, the device can also be dried, e.g., in air (e.g., passively), by using a heat source, by using a critical point dryer, etc.

[0182] Thus, as mentioned, in some aspects, the device can comprise one or more nanoscale wires. For instance, one or more nodes may contain nanoscale wires, and / or nanoscale wires may be contained within interconnects, or the like. In some cases, the device within the organoids, organs, or organisms may include one or more sensors or stimulators, interconnected with stretchable mesh interconnects, to form a network. The sensors or stimulators may, in some embodiments, comprise nanoscale wires, such as those described herein. Such sensors may be monitored, e.g., individually or collectively.

[0183] Non-limiting examples of suitable nanoscale wires include carbon nanotubes, nanorods, nanowires, organic and inorganic conductive and semiconducting polymers, metal nanoscale wires, semiconductor nanoscale wires (for example, formed from silicon), and the

[0184] #14412892vl like. If carbon nanotubes are used, they may be single- walled and / or multi-walled, and may be metallic and / or semiconducting in nature. Other conductive or semiconducting elements that may not be nanoscale wires, but are of various small nanoscopic-scale dimension, also can be used within the device.

[0185] In general, a “nanoscale wire” (also known herein as a “nanoscopic-scale wire” or “nanoscopic wire”) generally is a wire or other nanoscale object, that at any point along its length, has at least one cross-sectional dimension and, in some embodiments, two orthogonal cross-sectional dimensions (e.g., a diameter) of less than 1 micrometer, less than about 500 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 70, less than about 50 nm, less than about 20 nm, less than about 10 nm, less than about 5 nm, than about 2 nm, or less than about 1 nm. In some embodiments, the nanoscale wire is generally cylindrical. In other embodiments, however, other shapes are possible; for example, the nanoscale wire can be faceted, i.e., the nanoscale wire may have a polygonal cross-section. The cross-section of a nanoscale wire can be of any arbitrary shape, including, but not limited to, circular, square, rectangular, annular, polygonal, or elliptical, and may be a regular or an irregular shape. The nanoscale wire can also be solid or hollow.

[0186] In some cases, the nanoscale wire has one dimension that is substantially longer than the other dimensions of the nanoscale wire. For example, the nanoscale wire may have a longest dimension that is at least about 1 micrometer, at least about 3 micrometers, at least about 5 micrometers, or at least about 10 micrometers or about 20 micrometers in length, and / or the nanoscale wire may have an aspect ratio (longest dimension to shortest orthogonal dimension) of greater than about 2:1, greater than about 3:1, greater than about 4:1, greater than about 5:1, greater than about 10:1, greater than about 25:1, greater than about 50:1, greater than about 75:1, greater than about 100:1, greater than about 150:1, greater than about 250:1, greater than about 500:1, greater than about 750:1, or greater than about 1000:1 or more in some cases.

[0187] In some embodiments, a nanoscale wire is substantially uniform, or the nanowire may have a variation in average diameter of the nanoscale wire of less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%. For example, the nanoscale wires may be grown from substantially uniform nanoclusters or particles, e.g., colloid particles. See, e.g., U.S. Patent No. 7,301,199, issued November 27, 2007, entitled “Nanoscale Wires and Related Devices,” by Lieber, et al., incorporated herein by reference in its entirety. In some cases, the nanoscale wire may be one of a population of nanoscale wires having an average variation in diameter, of the

[0188] #14412892vl population of nanowires, of less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5%.

[0189] In some embodiments, a nanoscale wire has a conductivity of or of similar magnitude to any semiconductor or any metal. The nanoscale wire can be formed of suitable materials, e.g., semiconductors, metals, etc., as well as any suitable combinations thereof. In some cases, the nanoscale wire will have the ability to pass electrical charge, for example, being electrically conductive. For example, the nanoscale wire may have a relatively low resistivity, e.g., less than about 10’3Ohm m, less than about 10’4Ohm m, less than about 10’6Ohm m, or less than about 10’7Ohm m. The nanoscale wire can, in some embodiments, have a conductance of at least about 1 microsiemens, at least about 3 microsiemens, at least about 10 microsiemens, at least about 30 microsiemens, or at least about 100 microsiemens.

[0190] The nanoscale wire can be solid or hollow, in various embodiments. As used herein, a “nanotube” is a nanoscale wire that is hollow, or that has a hollowed-out core, including those nanotubes known to those of ordinary skill in the art. As another example, a nanotube may be created by creating a core / shell nanowire, then etching away at least a portion of the core to leave behind a hollow shell. Accordingly, in one set of embodiments, the nanoscale wire is a non-carbon nanotube. In contrast, a “nanowire” is a nanoscale wire that is typically solid (i.e., not hollow). Thus, in one set of embodiments, the nanoscale wire may be a semiconductor nanowire, such as a silicon nanowire.

[0191] For example, in one embodiment, a nanoscale wire may comprise or consist essentially of a metal. Non-limiting examples of potentially suitable metals include aluminum, gold, silver, copper, molybdenum, tantalum, titanium, nickel, tungsten, chromium, or palladium. In another set of embodiments, a nanoscale wire comprises or consists essentially of a semiconductor. Typically, a semiconductor is an element having semiconductive or semi-metallic properties (i.e., between metallic and non-metallic properties). An example of a semiconductor is silicon. Other non-limiting examples include elemental semiconductors, such as gallium, germanium, diamond (carbon), tin, selenium, tellurium, boron, or phosphorous. In other embodiments, more than one element may be present in the nanoscale wire as the semiconductor, for example, gallium arsenide, gallium nitride, indium phosphide, cadmium selenide, etc. Still other examples include a Group II- VI material (which includes at least one member from Group II of the Periodic Table and at least one member from Group VI, for example, ZnS, ZnSe, ZnSSe, ZnCdS, CdS, or CdSe), or a Group III-V material (which includes at least one member from Group III and at least one member from Group V, for example GaAs, GaP, GaAsP, InAs, InP, AlGaAs, or InAsP).

[0192] #14412892vl In certain embodiments, the semiconductor can be undoped or doped (e.g., / ?-type or n-type). For example, in one set of embodiments, a nanoscale wire may be a / ?-type semiconductor nanoscale wire or an 77-type semiconductor nanoscale wire, and can be used as a component of a transistor such as a field effect transistor (“FET”). For instance, the nanoscale wire may act as the “gate” of a source-gate-drain arrangement of a FET, while metal leads or other conductive pathways (as discussed herein) are used as the source and drain electrodes.

[0193] In some embodiments, a dopant or a semiconductor may include mixtures of Group IV elements, for example, a mixture of silicon and carbon, or a mixture of silicon and germanium. In other embodiments, the dopant or the semiconductor may include a mixture of a Group III and a Group V element, for example, BN, BP, BAs, AIN, A1P, AlAs, AlSb, GaN, GaP, GaAs, GaSb, InN, InP, InAs, or InSb. Mixtures of these may also be used, for example, a mixture of BN / BP / BAs, or BN / A1P. In other embodiments, the dopants may include alloys of Group III and Group V elements. For example, the alloys may include a mixture of AlGaN, GaPAs, InPAs, GalnN, AlGalnN, GalnAsP, or the like. In other embodiments, the dopants may also include a mixture of Group II and Group VI semiconductors. For example, the semiconductor may include ZnO, ZnS, ZnSe, ZnTe, CdS, CdSe, CdTe, HgS, HgSe, HgTe, BeS, BeSe, BeTe, MgS, MgSe, or the like. Alloys or mixtures of these dopants are also be possible, for example, (ZnCd)Se, or Zn(SSe), or the like. Additionally, alloys of different groups of semiconductors may also be possible, for example, a combination of a Group II-Group VI and a Group III-Group V semiconductor, for example, (GaAs)x(ZnS)i-x. Other examples of dopants may include combinations of Group IV and Group VI elemnts, such as GeS, GeSe, GeTe, SnS, SnSe, SnTe, PbO, PbS, PbSe, or PbTe. Other semiconductor mixtures may include a combination of a Group I and a Group VII, such as CuF, CuCl, CuBr, Cui, AgF, AgCl, AgBr, Agl, or the like. Other dopant compounds may include different mixtures of these elements, such as BeSiN2, CaCN2, ZnGeP2, CdSnAs2, ZnSnSb2, CuGeP3, CuSi2P3, Si3N4, Ge3N4, A12O3, (Al, Ga, In)2(S, Se, Te)3, A12CO, (Cu, Ag)(Al, Ga, In, Tl, Fe)(S, Se, Te)2and the like.

[0194] The doping of the semiconductor to produce a -type or n-type semiconductor may be achieved via bulk-doping in certain embodiments, although in other embodiments, other doping techniques (such as ion implantation) can be used. Many such doping techniques that can be used will be familiar to those of ordinary skill in the art, including both bulk doping and surface doping techniques. A bulk-doped article (e.g. an article, or a section or region of an article) is an article for which a dopant is incorporated substantially throughout the

[0195] #14412892vl crystalline lattice of the article, as opposed to an article in which a dopant is only incorporated in particular regions of the crystal lattice at the atomic scale, for example, only on the surface or exterior. For example, some articles are typically doped after the base material is grown, and thus the dopant only extends a finite distance from the surface or exterior into the interior of the crystalline lattice. It should be understood that “bulk-doped” does not define or reflect a concentration or amount of doping in a semiconductor, nor does it necessarily indicate that the doping is uniform. “Heavily doped” and “lightly doped” are terms the meanings of which are clearly understood by those of ordinary skill in the art. In some embodiments, one or more regions comprise a single monolayer of atoms (“deltadoping”). In certain cases, the region may be less than a single monolayer thick (for example, if some of the atoms within the monolayer are absent). As a specific example, the regions may be arranged in a layered structure within the nanoscale wire, and one or more of the regions can be delta-doped or partially delta-doped.

[0196] Accordingly, in one set of embodiments, the nanoscale wires may include a heterojunction, e.g., of two regions with dissimilar materials or elements, and / or the same materials or elements but at different ratios or concentrations. The regions of the nanoscale wire may be distinct from each other with minimal cross-contamination, or the composition of the nanoscale wire can vary gradually from one region to the next. The regions may be both longitudinally arranged relative to each other, or radially arranged (e.g., as in a core / shell arrangement) on the nanoscale wire. Each region may be of any size or shape within the wire. The junctions may be, for example, a p / n junction, a p / p junction, an n / n junction, a p / i junction (where i refers to an intrinsic semiconductor), an n / i junction, an i / i junction, or the like. The junction can also be a Schottky junction in some embodiments. The junction may also be, for example, a semiconductor / semiconductor junction, a semiconductor / metal junction, a semiconductor / insulator junction, a metal / metal junction, a metal / insulator junction, an insulator / insulator junction, or the like. The junction may also be a junction of two materials, a doped semiconductor to a doped or an undoped semiconductor, or a junction between regions having different dopant concentrations. The junction can also be a defected region to a perfect single crystal, an amorphous region to a crystal, a crystal to another crystal, an amorphous region to another amorphous region, a defected region to another defected region, an amorphous region to a defected region, or the like. More than two regions may be present, and these regions may have unique compositions or may comprise the same compositions. As one example, a wire can have a first region having a first composition, a second region having a second composition, and a third region having a

[0197] #14412892vl third composition or the same composition as the first composition. Non-limiting examples of nanoscale wires comprising heterojunctions (including core / shell heterojunctions, longitudinal heterojunctions, etc., as well as combinations thereof) are discussed in U.S. Patent No. 7,301,199, issued November 27, 2007, entitled “Nanoscale Wires and Related Devices,” by Lieber, et al., incorporated herein by reference in its entirety.

[0198] In some embodiments, a nanoscale wire is a bent or a kinked nanoscale wire. A kink is typically a relatively sharp transition or turning between a first substantially straight portion of a wire and a second substantially straight portion of a wire. For example, a nanoscale wire may have 1, 2, 3, 4, or 5 or more kinks. In some cases, the nanoscale wire is formed from a single crystal and / or comprises or consists essentially of a single crystallographic orientation, for example, a <110> crystallographic orientation, a <112> crystallographic orientation, or a < 1 120> crystallographic orientation. It should be noted that the kinked region need not have the same crystallographic orientation as the rest of the semiconductor nanoscale wire. In some embodiments, a kink in the semiconductor nanoscale wire may be at an angle of about 120° or a multiple thereof. The kinks can be intentionally positioned along the nanoscale wire in some cases. For example, a nanoscale wire may be grown from a catalyst particle by exposing the catalyst particle to various gaseous reactants to cause the formation of one or more kinks within the nanoscale wire. Non-limiting examples of kinked nanoscale wires, and suitable techniques for making such wires, are disclosed in International Patent Application No. PCT / US2010 / 050199, filed September 24, 2010, entitled “Bent Nanowires and Related Probing of Species,” by Tian, et al., published as WO 2011 / 038228 on March 31, 2011, incorporated herein by reference in its entirety.

[0199] In one set of embodiments, the nanoscale wire is formed from a single crystal, for example, a single crystal nanoscale wire comprising a semiconductor. A single crystal item may be formed via covalent bonding, ionic bonding, or the like, and / or combinations thereof. While such a single crystal item may include defects in the crystal in some cases, the single crystal item is distinguished from an item that includes one or more crystals, not ionically or covalently bonded, but merely in close proximity to one another.

[0200] In some embodiments, the nanoscale wires used herein are individual or free-standing nanoscale wires. For example, an “individual” or a “free-standing” nanoscale wire may, at some point in its life, not be attached to another article, for example, with another nanoscale wire, or the free-standing nanoscale wire may be in solution. This is in contrast to nanoscale features etched onto the surface of a substrate, e.g., a silicon wafer, in which the nanoscale features are never removed from the surface of the substrate as a free-standing article. This is

[0201] #14412892vl also in contrast to conductive portions of articles which differ from surrounding material only by having been altered chemically or physically, in situ, i.e., where a portion of a uniform article is made different from its surroundings by selective doping, etching, etc. An “individual” or a “free-standing” nanoscale wire is one that can be (but need not be) removed from the location where it is made, as an individual article, and transported to a different location and combined with different components to make a functional device such as those described herein and those that would be contemplated by those of ordinary skill in the art upon reading this disclosure.

[0202] In various embodiments, more than one nanoscale wire may be present within the device. The nanoscale wires may each independently be the same or different. For example, the device can comprise at least 5 nanoscale wires, at least about 10 nanoscale wires, at least about 30 nanoscale wires, at least about 50 nanoscale wires, at least about 100 nanoscale wires, at least about 300 nanoscale wires, at least about 1000 nanoscale wires, etc. The nanoscale wires may be distributed uniformly or non-uniformly throughout the device. In some cases, the nanoscale wires may be distributed at an average density of at least about 10 nanoscale wires / mm3, at least about 30 nanoscale wires / mm3, at least about 50 nanoscale wires / mm3, at least about 75 nanoscale wires / mm3, or at least about 100 nanoscale wires / mm3. In certain embodiments, the nanoscale wires are distributed within the device such that the average separation between a nanoscale wire and its nearest neighboring nanoscale wire is less than about 2 mm, less than about 1 mm, less than about 500 micrometers, less than about 300 micrometers, less than about 100 micrometers, less than about 50 micrometers, less than about 30 micrometers, or less than about 10 micrometers.

[0203] Within the device, some or all of the nanoscale wires may be individually electronically addressable. For instance, in some cases, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or substantially all of the nanoscale wires within the device may be individually electronically addressable. In some embodiments, an electrical property of a nanoscale wire can be individually determinable (e.g., being partially or fully resolvable without also including the electrical properties of other nanoscale wires), and / or such that the electrical property of a nanoscale wire may be individually controlled (e.g., by applying a desired voltage or current to the nanoscale wire, for instance, without simultaneously applying the voltage or current to other nanoscale wires). In other embodiments, however, at least some of the nano scale wires can be controlled within the

[0204] #14412892vl same electronic circuit (e.g., by incorporating the nanoscale wires in series and / or in parallel), such that the nanoscale wires can still be electronically controlled and / or determined.

[0205] The nanoscale wire, in some embodiments, may be responsive to a property external of the nanoscale wire, e.g., a chemical property, an electrical property, a physical property, etc. Such determination may be qualitative and / or quantitative. For example, in one set of embodiments, the nanoscale wire may be responsive to voltage. For instance, the nanoscale wire may exhibits a voltage sensitivity of at least about 5 microsiemens / V; by determining the conductivity of a nanoscale wire, the voltage surrounding the nanoscale wire may thus be determined. In other embodiments, the voltage sensitivity can be at least about 10 microsiemens / V, at least about 30 microsiemens / V, at least about 50 microsiemens / V, or at least about 100 microsiemens / V. Other examples of electrical properties that can be determined include resistance, resistivity, conductance, conductivity, impendence, or the like.

[0206] As another example, a nanoscale wire may be responsive to a chemical property of the environment surrounding the nanoscale wire. For example, an electrical property of the nanoscale wire can be affected by a chemical environment surrounding the nanoscale wire, and the electrical property can be thereby determined to determine the chemical environment surrounding the nanoscale wire. As a specific non-limiting example, the nanoscale wires may be sensitive to pH or hydrogen ions. Further non-limiting examples of such nanoscale wires are discussed in U.S. Patent No. 7,129,554, filed October 31, 2006, entitled “Nanosensors,” by Lieber, et al., incorporated herein by reference in its entirety.

[0207] As an example, the nano scale wire may have the ability to bind to an analyte indicative of a chemical property of the environment surrounding the nanoscale wire (e.g., hydrogen ions for pH, or concentration for an analyte of interest), and / or the nanoscale wire may be partially or fully functionalized, i.e. comprising surface functional moieties, to which an analyte is able to bind, thereby causing a determinable property change to the nanoscale wire, e.g., a change to the resistivity or impedance of the nanoscale wire. The binding of the analyte can be specific or non-specific. Functional moieties may include simple groups, selected from the groups including, but not limited to, -OH, -CHO, -COOH, -SO3H, -CN, - NH2, -SH, -COSH, -COOR, halide; biomolecular entities including, but not limited to, amino acids, proteins, sugars, DNA, antibodies, antigens, and enzymes; grafted polymer chains with chain length less than the diameter of the nanowire core, selected from a group of polymers including, but not limited to, polyamide, polyester, polyimide, polyacrylic; a shell of material comprising, for example, metals, semiconductors, and insulators, which may be a metallic element, an oxide, an sulfide, a nitride, a selenide, a polymer and a polymer gel.

[0208] #14412892vl In some embodiments, a reaction entity may be bound to a surface of the nanoscale wire, and / or positioned in relation to the nanoscale wire such that the analyte can be determined by determining a change in a property of the nanoscale wire. The “determination” may be quantitative and / or qualitative, depending on the application. The term “reaction entity” refers to any entity that can interact with an analyte in such a manner to cause a detectable change in a property (such as an electrical property) of a nanoscale wire. The reaction entity may enhance the interaction between the nanowire and the analyte, or generate a new chemical species that has a higher affinity to the nanowire, or to enrich the analyte around the nanowire. The reaction entity can comprise a binding partner to which the analyte binds. The reaction entity, when a binding partner, can comprise a specific binding partner of the analyte. For example, the reaction entity may be a nucleic acid, an antibody, a sugar, a carbohydrate or a protein. Alternatively, the reaction entity may be a polymer, catalyst, or a quantum dot. A reaction entity that is a catalyst can catalyze a reaction involving the analyte, resulting in a product that causes a detectable change in the nanowire, e.g. via binding to an auxiliary binding partner of the product electrically coupled to the nanowire. Another exemplary reaction entity is a reactant that reacts with the analyte, producing a product that can cause a detectable change in the nanowire. The reaction entity can comprise a shell on the nanowire, e.g. a shell of a polymer that recognizes molecules in, e.g., a gaseous sample, causing a change in conductivity of the polymer which, in turn, causes a detectable change in the nanowire.

[0209] The term “binding partner” refers to a molecule that can undergo binding with a particular analyte, or “binding partner” thereof, and includes specific, semi- specific, and nonspecific binding partners as known to those of ordinary skill in the art. The term “specifically binds,” when referring to a binding partner (e.g., protein, nucleic acid, antibody, etc.), refers to a reaction that is determinative of the presence and / or identity of one or other member of the binding pair in a mixture of heterogeneous molecules (e.g., proteins and other biologies). Thus, for example, in the case of a receptor / ligand binding pair the ligand would specifically and / or preferentially select its receptor from a complex mixture of molecules, or vice versa. An enzyme would specifically bind to its substrate, a nucleic acid would specifically bind to its complement, an antibody would specifically bind to its antigen. Other examples include, nucleic acids that specifically bind (hybridize) to their complement, antibodies specifically bind to their antigen, and the like. The binding may be by one or more of a variety of mechanisms including, but not limited to ionic interactions, and / or covalent interactions, and / or hydrophobic interactions, and / or van der Waals interactions, etc.

[0210] #14412892vl Int. Pat. Apl. Pub. Nos. WO 2022 / 192319 and WO 2020 / 263772 are each incorporated herein by reference in their entireties. In addition, the following are each also incorporated herein by reference in their entireties: U.S. Pat. Apl. Ser. Nos. 18 / 455,535, 63 / 567,332, 63 / 567,834, 63 / 681,224, and 63 / 681,627. Furthermore, a U.S. Patent Application Serial No. 63 / 727,825, entitled “Flexible Nanoelectrode Systems and Methods,” by Liu, et al. , filed on December 4, 2024, is also incorporated herein by reference in its entirety. In addition, U.S. Patent Application Serial No. 63 / 727,861, filed December 4, 2024, entitled “Brain Treatment Systems and Methods,” by Liu, et al., is incorporated herein by reference in its entirety

[0211] The following examples are intended to illustrate certain embodiments of the present disclosure, but do not exemplify the full scope of the disclosure.

[0212] EXAMPLE 1

[0213] This example illustrates free-standing, flexible deep brain probes in accordance with certain embodiments. This example uses a flexible nanoelectrode array which can interface with the brain for both stable recording and stimulation purposes. This example device, as depicted in FIGs. 1A-1F, show a flexible mesh nanoelectrode array for the treatment of neurological and psychiatric disorders. The array’s design facilitates long-term stable electrical recording and closed-loop stimulation.

[0214] FIG. 1A illustrates schematics showing implantation of a flexible mesh nanoelectrode array into a human brain for long-term stable electrical recording and closed-loop stimulation. FIG. IB illustrates representative images of a free-standing flexible mesh nanoelectrode array with 64 individual recording and stimulation sensors at (i) front view; (ii) tilted view. FIG. 1C illustrates an overview of an unreleased flexible mesh nanoelectrode array with 64 individual recording and stimulation sensors with two 32-channel flexible flat cables (FFC). FIG. ID illustrates representative bright-field microscope images of (i) electrodes, (ii) an implantation guide ring, (iii) I / O for connection with an FFC and (iv) interconnects of unreleased flexible mesh nanoelectrode array. FIG. IE illustrates representative bright-field microscope images of a released flexible mesh nanoelectrode array in water with different flexible statuses in (i), (ii), (iii) and (iv). FIG. IF illustrates electrochemical impedance of electrodes before and after Pt black electroplating at a frequency of 1 kHz. FIG. 1G illustrates electrochemical impedance spectroscopy of impedance and phase of the electrode before and after Pt black electroplating from a frequency of 10 Hz to 10 kHz.

[0215] EXAMPLE 2

[0216] #14412892vl This non-limiting example illustrates a flexible nanoelectrode array for chronic implantation and single unit recordings. Chronic implantation is important to ensure the long-term efficacy of this device. As illustrated in FIGs. 2A-2G, the array can be surgically implanted into the brain, ensuring long-term stable recordings. The surgical procedure, and post-operative images of a mouse and the recording traces, are shown in this figure. This demonstrates the ability to capture single-unit spikes with local field potentials, especially over extended periods.

[0217] FIG. 2A illustrates a surgical procedure for the implantation of a flexible nanoelectrode array for long-term stable recording, including the steps of: (i) opening the skull and apply the implantation guide ring of a flexible nanoelectrode array at the opening of the skull; (ii) applying the reference electrode; (iii) aligning the surgical probe with the implantation guide ring of the flexible nanoelectrode array; (iv) lowering the surgical probe;

[0218] (v) further lowering the surgical probe to the implantation location into the deep brain region;

[0219] (vi) extracting the surgical probe. FIG. 2B is a photograph of a representative mouse after implantation surgery of the flexible nanoelectrode array. FIG. 2C is a photograph showing recording traces of 32-channel electrodes during the recording procedure. FIG. 2D is a photograph of zoomed-in recording traces of 2 channels of the electrodes, showing singleunit spikes during the recording procedure. FIG. 2E are examples of overlaid waveforms showing 12 single-unit spikes recorded of mouse brain after 2 weeks post- implantation. FIG. 2F shows examples of average waveforms of the overlaid waveforms in FIG. 2E. FIG. 2G illustrate representative interspike interval (ISI) plots of 12 single-unit spikes in FIG. 2E recorded of mouse brain after 2 weeks post-implantation.

[0220] EXAMPLE 3

[0221] This example illustrates a flexible nanoelectrode array for acute implantation with local field potential and single unit spike recordings. The device can also be used for acute implantation. FIGs. 3A-3D show the device’s capability for acute implantation, e.g., for recordings in an operating room setting. The surgical procedure and recording traces are shown in this figure.

[0222] FIG. 3A illustrates representative flexible nanoelectrode array floating on sterile saline in a container. FIG. 3B illustrates a surgical procedure of implantation of flexible nanoelectrode array for acute recording in an operating room, including the steps of: (i) opening the skull, (ii) applying the flexible nanoelectrode array to the brain region, (iii) aligning the flexible nanoelectrode array with a surgical probe, and (iv) applying a FCB on the surgical stage, (v) connecting a flexible flat cable with the FCB. (vi) shows a side view

[0223] #14412892vl of the setup. FIG. 3C illustrates recording traces of 64-channels of the flexible nanoelectrode array, showing the local field potentials. FIG. 3D illustrates examples of average waveforms of single unit spikes from a human brain.

[0224] While several embodiments of the present disclosure have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present disclosure is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

[0225] In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, then the document having the later effective date shall control.

[0226] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0227] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0228] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are

[0229] #14412892vl conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0230] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.”

[0231] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0232] #14412892vl When the word “about” is used herein in reference to a number, it should be understood that still another embodiment of the disclosure includes that number not modified by the presence of the word “about.”

[0233] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0234] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0235] What is claimed is:

[0236] #14412892vl

Claims

CLAIMS1. A device, comprising: a probe having an insertion portion having a length of at least 10 cm and a bending stiffness of 10’4nN m to 101nN m, wherein the insertion portion is configured to determine electrical signals at a spatial resolution of between 1 micrometer and 1 mm.

2. The device of claim 1, further comprising a charge source able to cause the insertion portion to produce an electric charge.

3. The device of any one of claims 1 or 2, wherein the electric charge has a charge density of at least 0.05 microcoulombs / cm2.

4. The device of any one of claims 1-3, wherein the electric charge has a charge density of no more than 5 microcoulombs / cm2.

5. The device of any one of claims 1-4, wherein the probe further comprising a cap portion physically connected to the insertion portion.

6. The device of any one of claims 1-5, wherein the cap portion further contains electronics for determining the electrical signals.

7. The device of any one of claims 1-6, wherein the insertion portion comprising a conductive region defining the insertion portion, a passivation region surrounding the conductive region, and a biocompatible region surrounding the conductive region.

8. The device of any one of claims 1-7, wherein the probe is soft.

9. The device of any one of claims 1-8, wherein the probe has a Young’s modulus of less than 1 MPa.

10. The device of any one of claims 1-9, wherein the probe has a glass transition temperature of less than 25 °C.#14412892vl11. The device of any one of claims 1-10, wherein the spatial resolution is between 1 micrometer and 100 micrometers.

12. The device of any one of claims 1-11, wherein the spatial resolution is between 1 micrometer and 10 micrometers.

13. The device of any one of claims 1-12, wherein the insertion portion comprises an array of electrodes.

14. The device of claim 13, wherein the array of electrodes comprises at least 10 electrodes.

15. The device of any one of claims 13 or 14, wherein the array of electrodes comprises at least 100 electrodes.

16. A method, comprising: inserting, into an organ of a subject, an insertion portion of a probe, wherein the insertion portion is inserted to a depth of at least 10 cm; and determining electrical signals within the organ of the subject using the probe at a spatial resolution of between 1 micrometer and 1 mm.

17. The method of claim 16, wherein the organ is a brain.

18. The method of claim 17, comprising inserting the insertion portion of the probe through a burr hole of the subject’s skull into the brain of the subject.

19. The method of claim 18, comprising inserting a plurality of insertion portions through the burr hole into the brain of the subject.

20. The method of claim 19, comprising inserting the plurality of insertion portions at a density of at least 5 probes per 100 mm3of brain.#14412892vl21. The method of any one of claims 17-20, comprising inserting the insertion probe into the cortical region of the brain of the subject.

22. The method of any one of claims 17-21, comprising inserting the insertion probe into the subcortical region of the brain of the subject.

23. The method of any one of claims 17-22, comprising inserting the insertion probe into both the cortical region and the subcortical region of the brain of the subject, and determining electrical signals within both the cortical region and the subcortical region.

24. The method of any one of claims 16-23, wherein the probe is flexible.

25. The method of any one of claims 16-24, wherein the insertion portion comprising a conductive region defining the insertion portion, a passivation region surrounding the conductive region, and a biocompatible region surrounding the conductive region.

26. The method of any one of claims 16-25, wherein the insertion portion comprises an array of electrodes.

27. The method of any one of claims 16-26, comprising inserting the insertion portion using a surgical robot.

28. A method of treating a subject having a neurological or psychiatric disorder, comprising: inserting, into the brain of the subject, an insertion portion of a brain probe, wherein the insertion portion is inserted to a depth of at least 10 cm; and applying electrical signals to the brain of the subject using the brain probe to treat the neurological or psychiatric disorder.

29. The method of claim 28, wherein the brain probe is flexible.#14412892vl30. The method of any one of claims 28 or 29, wherein the insertion portion is configured to determine electrical signals at a spatial resolution of between 1 micrometer and 1 mm.

31. The method of any one of claims 28-30, wherein the insertion portion comprising a conductive region defining the insertion portion, a passivation region surrounding the conductive region, and a biocompatible region surrounding the conductive region.

32. The method of any one of claims 28-31, wherein the insertion portion comprises an array of electrodes.

33. The method of any one of claims 28-32, comprising inserting the insertion probe into the cortical region of the brain of the subject.

34. The method of any one of claims 28-33, comprising inserting the insertion probe into the subcortical region of the brain of the subject.

35. The method of any one of claims 28-34, wherein the neurological disorder is Parkinson’s disease.

36. The method of any one of claims 28-34, wherein the neurological disorder is schizophrenia.

37. The method of any one of claims 28-34, wherein the neurological disorder is autism.

38. The method of any one of claims 28-34, wherein the neurological disorder is clinical depression.

39. The method of any one of claims 28-34, wherein the neurological disorder is addiction.

40. The method of any one of claims 28-34, wherein the neurological disorder is drug addiction.#14412892vl41. The method of any one of claims 28-34, wherein the neurological disorder is epilepsy.

42. The method of any one of claims 28-34, wherein the neurological disorder is obsessive-compulsive disorder.

43. The method of any one of claims 28-34, wherein the neurological disorder is impaired sensory function.

44. The method of any one of claims 28-34, wherein the neurological disorder is impaired motor function.

45. The method of any one of claims 28-34, wherein the neurological disorder is muscle tremor.

46. The method of any one of claims 28-34, wherein the neurological disorder is impaired speech.

47. The method of any one of claims 28-34, wherein the neurological disorder is repeated seizures.

48. The method of any one of claims 28-34, wherein the neurological disorder is essential tremor.

49. The method of any one of claims 28-34, wherein the neurological disorder is dystonia.#14412892vl

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