Neuromodulation leads for chemical analyte sensing

Abstract

Provided herein are neuromodulation leads and systems including the leads that can be used to both detect chemical analytes in the brain and stimulate the brain. The neuromodulation leads described herein can detect chemical analytes by measuring an electrochemical signal, for example, in response to an applied energy waveform. The systems described herein can utilize a two-electrode and / or three-electrode sensing electrode arrangement to measure electrochemical signals. Moreover, various measuring modalities, such as impedance, amperometry, potentiometry, and / or cyclic voltammetry can be used to measure electrochemical signals. Based on the measured electrochemical signal, the concentration of the chemical analytes in the brain can be determined. The determination of the chemical analytes present in the tissue, including the concentration of the chemical analytes, can be used to inform stimulation parameters of the neuromodulation therapy, exogenous drug dosing, and / or diagnosis chronic diseases.

Description

NEUROMODULATION LEADS FOR CHEMICAL ANALYTE SENSINGCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 574,151, filed April 3, 2024, the contents of which are incorporated herein in its entirety.FIELD

[0002] This disclosure relates generally to neuromodulation leads, and more specifically to neuromodulation leads that stimulate the brain and / or detect chemical analytes in the brain.BACKGROUND

[0003] Many chemical analytes in the human brain serve as biomarkers for chronic neurological diseases. For example, dopamine and serotonin are implicated in major depressive and movement disorders. Thus, monitoring such analytes is crucial for the early diagnosis and effective treatment of diseases. Typical chemical analyte sensors are standalone devices, often made from unconventional materials. Furthermore, the chemical analyte sensors are implanted separately from neuromodulation leads, which exposes patients to an increased risk of complications due to the number and / or length of the surgical procedure(s). Accordingly, there is a need for neuromodulation leads that can both stimulate and sense chemical analytes in the brain.SUMMARY

[0004] Described herein are neuromodulation leads that include both sensing and stimulation electrodes, implantable neuromodulation systems including the neuromodulation leads described herein, and methods of use thereof. The sensing electrodes can measure electrochemical signals generated by chemical analytes in the brain, for example, based on the chemical analytes interacting with the sensing electrodes. The chemical analytes can interact with a working electrode of the sensing electrodes. Different measuring modalities can be employed at the sensing electrodes, such as impedance, amperometry, potentiometry, and voltammetry, to measure the electrochemical signal generated by the chemical analyte. Based on the measured electrochemical signals, the neuromodulation systems described herein can determine the presence and / or concentration of the chemical analytes. By detecting chemical analytes that are present in the brain and the concentrations of thesechemical analytes, neuromodulation therapy can be refined to be more targeted, adaptive, and utilize lower energy. Detecting chemical analytes can also inform exogenous drug therapy and has the potential to enable earlier diagnosis of chronic diseases.

[0005] In some aspects, a neuromodulation lead is provided, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode and at least one counter-reference electrode or (b) at least one working electrode, at least one counter electrode, and at least one reference electrode, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in a brain interacting with at least one of the plurality of sensing electrodes. In some aspects, the lead comprises one or more of stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0006] In some aspects, a neuromodulation lead is provided, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode that is a microelectrode and at least one counter-reference electrode, or (b) at least one working electrode that is a microelectrode, at least one counter electrode, and at least one reference electrode, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes. In some aspects, the lead comprises one or more of stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0007] In some aspects, a neuromodulation lead is provided, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain, wherein one or more sensing electrodes of the plurality of sensing electrodes comprises a chemical-analyte-selective coating that interacts with at least one specific chemical analyte at the one or more sensing electrodes. In some aspects, the lead comprises one or more of stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0008] In some aspects, an implantable neuromodulation system is provided, comprising: the lead of any one of the above aspects; and a pulse generator configured to receive a portion of the lead to electrically couple the lead to a control circuit of the pulse generator, wherein the control circuit is configured to receive the measured electrochemical signal from the plurality of sensing electrodes and determine the one or more chemical analytes present in thebrain based on the measured electrochemical signal. In some aspects, the control circuit is configured to generate and transmit electrical energy to the one or more stimulating electrodes and one or more of the plurality of sensing electrodes.

[0009] In some aspects, a neuromodulation system is provided, comprising: a neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain; and a control circuit electrically coupled to the plurality of sensing electrodes and configured to determine a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

[0010] In some aspects, a method for determining concentration of a chemical analyte in a brain is provided, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; and determining, at a control circuit electrically coupled to the plurality of sensing electrodes, a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

[0011] In some aspects, a method of controlling electrochemical signal detection is provided, comprising: measuring, at one or more sensing electrodes of a plurality of sensing electrodes of a neuromodulation lead, a first electrochemical signal generated by one or more chemical analytes present in a brain; and based on a determination that the first electrochemical signal reaches a threshold, measuring, at the one or more sensing electrodes of the neuromodulation lead, a second electrochemical signal generated by the one or more chemical analytes present in the brain, the second electrochemical signal different from the first electrochemical signal.

[0012] In some aspects, a neuromodulation system is provided, comprising: a neuromodulation lead, comprising: a lead body; one or more stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to a brain; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in the brain; and a control circuit electrically coupled to the one or more stimulating electrodes and the plurality of sensing electrodes, the control circuit configured to: receive the electrochemical signal measured by the plurality of sensing electrodes; based on the measured electrochemical signal, determine one or more stimulation parameters for the electrical stimulation; and generate and transmit the electrical stimulation in accordance with the one or more stimulation parameters to the one or more stimulating electrodes.

[0013] In some aspects, a method for stimulating a brain based on electrochemical signals is provided, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; determining, at a control circuit electrically coupled to the plurality of sensing electrodes, one or more stimulation parameters for electrical stimulation of the brain based on the measured electrochemical signal; and delivering, at one or more stimulating electrodes disposed on the lead body and electrically coupled to the control circuit, the electrical stimulation in accordance with the one or more stimulation parameters to the brain.BRIEF DESCRIPTION OF THE FIGURES

[0014] Various aspects of the disclosed systems and methods are set forth with particularity in the appended claims. A better understanding of the features and advantages of the disclosed systems and methods will be obtained by reference to the detailed description of illustrative embodiments and the accompanying drawings.

[0015] FIG. 1 illustrates an implantable neuromodulation system including a neuromodulation lead and a pulse generator, in accordance with some embodiments.

[0016] FIG. 2 illustrates a neuromodulation lead including sensing electrodes and stimulating electrodes, in accordance with some embodiments.

[0017] FIG. 3A illustrates sensing electrodes on a neuromodulation lead that include working electrodes and counter-reference electrodes, in accordance with some embodiments.

[0018] FIG. 3B illustrates sensing electrodes on a neuromodulation lead that include working electrodes, reference electrodes, and counter electrodes, in accordance with some embodiments.

[0019] FIG. 3C illustrates an arrangement of sensing electrodes on a neuromodulation lead that include working electrodes and counter-reference electrodes separated by an insulation gap, in accordance with some embodiments.

[0020] FIG. 3D illustrates an arrangement of sensing electrodes on a neuromodulation lead that include working electrodes, reference electrodes, and counter electrodes separated by insulation gaps, in accordance with some embodiments.

[0021] FIG. 3E illustrates an arrangement of sensing electrodes on a neuromodulation lead that includes a microelectrode, counter electrode, and a reference electrode, in accordance with some embodiments.

[0022] FIG. 3F illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a working electrode surrounded by a counter-reference electrode, in accordance with some embodiments.

[0023] FIG. 3G illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a working electrode and a counter electrode surrounded by a reference electrode, in accordance with some embodiments.

[0024] FIG. 3H illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a microelectrode surrounded by a counter electrode and a reference electrode, in accordance with some embodiments.

[0025] FIG. 31 illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a plurality of working electrodes and a counter-reference electrode, in accordance with some embodiments.

[0026] FIG. 3J illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a plurality of working electrodes, a reference electrode, and a counter electrode, in accordance with some embodiments.

[0027] FIG. 3K illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a plurality of microelectrodes and a counter-reference electrode, in accordance with some embodiments.

[0028] FIG. 3L illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a plurality of microelectrodes, a reference electrode, and a counter electrode, in accordance with some embodiments.

[0029] FIG. 3M illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a microelectrode and a counter-reference electrode, in accordance with some embodiments.

[0030] FIG. 3N illustrates another arrangement of sensing electrodes on a neuromodulation lead that includes a working electrode and a reference electrode, in accordance with some embodiments.

[0031] FIG. 4A illustrates a redox reaction that occurs between a chemical analyte and sensing electrode on a neuromodulation lead in which the chemical analyte transfers electrons to the sensing electrode, in accordance with some embodiments.

[0032] FIG. 4B illustrates the redox reaction that occurs between the chemical analyte and sensing electrode on the neuromodulation lead in which the chemical analyte transfers electrons to the sensing electrode, in accordance with some embodiments.

[0033] FIG. 4C illustrates another redox reaction, that occurs between a chemical analyte and sensing electrode on a neuromodulation lead in which the sensing electrode transfers electrons to the chemical analyte, in accordance with some embodiments.

[0034] FIG. 4D illustrates the redox reaction that occurs between the chemical analyte and sensing electrode on the neuromodulation lead in which the sensing electrode transfers electrons to the chemical analyte, in accordance with some embodiments.

[0035] FIG. 5 illustrates redox reactions that occur between more than one chemical analyte and sensing electrode on a neuromodulation lead, in accordance with some embodiments.

[0036] FIG. 6 illustrates a method diagram for determining concentration of a chemical analyte based on a measured electrochemical signal, in accordance with some embodiments.

[0037] FIG. 7 illustrates a method diagram for measuring different electrochemical signals based on a first measured electrochemical signal reaching a threshold, in accordance with some embodiments.

[0038] FIG. 8 illustrates a method diagram for dynamically adjusting stimulation parameters based on a measured electrochemical signal, in accordance with some embodiments.

[0039] FIG. 9 illustrates a neuromodulation system including a neuromodulation lead, a pulse generator, and an external device that communicates with the control circuit of the pulse generator, in accordance with some embodiments.

[0040] FIG. 10A illustrates a graph of a potential signal generated by a chemical analyte when no current is applied against time, in accordance with some embodiments.

[0041] FIG. 10B illustrates a graph of the potential signal generated by the chemical analyte in the brain when no current is applied against concentration, in accordance with some embodiments.

[0042] FIG. 11 illustrates potential signals generated by exemplary chemical analytes in the brain when a constant current waveform is applied, in accordance with some embodiments.

[0043] FIG. 12 illustrates potential signals generated by exemplary chemical analytes in the brain when a pulsed current waveform is applied, in accordance with some embodiments.

[0044] FIG. 13A illustrates a current signal generated by a chemical analyte when a constant potential is applied, in accordance with some embodiments.

[0045] FIG. 13B illustrates current signals generated by exemplary chemical analytes in the brain when a constant potential is applied, in accordance with some embodiments.

[0046] FIG. 14A illustrates a current signal generated by a chemical analyte when a triangular potential is applied, in accordance with some embodiments.

[0047] FIG. 14B illustrates current signals generated by an exemplary chemical analyte at different concentrations when a triangular potential is applied, in accordance with some embodiments.

[0048] FIG. 14C illustrates repeatability of voltammetry despite fouling of the sensing electrodes, in accordance with some embodiments.

[0049] FIG. 14D illustrates bilinearity of measured current signals across a range of physiological concentrations of chemical analytes, in accordance with some embodiments.

[0050] FIG. 14E illustrates low hysteresis of carbon-based microelectrodes in measuring chemical analytes, in accordance with some embodiments.

[0051] FIG. 15A illustrates measured current signals generated by an exemplary chemical analyte over time when a triangular potential is applied, in accordance with some embodiments.

[0052] FIG. 15B illustrates measured current signals generated by an exemplary chemical analyte at different time intervals when a triangular potential is applied, in accordance with some embodiments.

[0053] FIG. 15C illustrates a relationship between a measured current signal generated by an exemplary chemical analyte and pulse width of the applied pulsed potential, in accordance with some embodiments.

[0054] FIG. 15D illustrates a relationship between a measured current signal generated by an exemplary chemical analyte and amplitude of the applied pulse potential, in accordance with some embodiments.DETAILED DESCRIPTION

[0055] Described herein are neuromodulation leads, neuromodulation systems including the leads, and methods of use thereof. The neuromodulation leads can be used to detect chemical analytes in the brain by measuring an electrochemical signal generated by the chemical analytes at sensing electrodes on the lead. The neuromodulation leads can also be used to stimulate the brain, for example, to treat neurological disorders. The sensing electrodes can be disposed on the lead in several different configurations and can be configured to measure an electrochemical signal in accordance with various measuring modalities. Measuring modalities can include impedance, potentiometry, amperometry, and voltammetry, all of which can include the use of a microelectrode disposed on the lead.Voltammetry can enable selective measuring of a target chemical analyte. Additionally or alternatively, one or more of the sensing leads on the electrode can be coated for selective detection of a target chemical analyte. Based on the measured electrochemical signals, the neuromodulation therapy can be refined and adapted, lending to a more individualized, lower-energy, and more efficacious therapy. Detecting chemical analytes can also inform proper dosing of exogenous drugs and / or enable earlier diagnosis of chronic diseases.

[0056] The neuromodulation leads described herein may integrate sensing electrodes to existing neuromodulation lead profiles. In turn, a single neuromodulation lead made from standard lead materials is maintained. Further, safe sensing methodologies can be coupled with known applied energy methods. In combination, a low risk profile is achieved by the neuromodulation lead and methods of use thereof. Additionally, the electrochemical signals measured by the sensing electrodes during neuromodulation therapy can guide therapy parameters, inform stimulation onset, and / or inform stimulation electrode usage on the lead, thereby improving efficacy of the therapy and reducing any potential negative side effects associated with the therapy. Furthermore, the neuromodulation systems described herein can use the measured electrochemical signals to automatically adjust neuromodulation therapy parameters without clinician intervention, individualizing the therapy for each subject, reducing the time spent with non-optimal therapeutic parameters, and reducing patient and healthcare provider burden. Finally, the neuromodulation systems described herein have the potential to advance clinical research by enabling users to monitor disease progression and response to drugs taken concomitantly with neuromodulation therapy, as well as to identify new therapies based on the measured electrochemical signals.

[0057] The following disclosure describes an exemplary implantable neuromodulation system (FIG. 1) followed by an exemplary neuromodulation lead of the system (FIG. 2). Various arrangements of sensing electrodes on exemplary neuromodulation leads are then described with reference to FIGS. 3A-3N. The reactions that can occur between the sensing electrodes and chemical analytes are illustrated in and described with respect to FIGS. 4A-4D and 5. Measurement modalities for measuring an electrochemical signal generated by the reactions are described, including impedance, potentiometry, amperometry, and voltammetry. Methods of using the neuromodulation leads (and systems including the lead) are described with respect to FIGS. 6, 7, and 8. Another exemplary neuromodulation system that includes a neuromodulation lead, a pulse generator, and an external device is described in greater detail with reference to FIG. 9. Finally, experimental data for measuring chemical analytes anddetermining characteristics thereof are described with respect to FIGS. 10A-10B, 11, 12, 13A-13B, 14A-14E, and 15A-15D.

[0058] Neuromodulation (e.g., deep brain stimulation, or DBS) can be used to treat neurodegenerative disorders such as epilepsy, Parkinson’s disease (PD), dystonia, and obsessive-compulsive disorder (OCD). Neuromodulation includes delivering an artificial electrical current to specific parts of the brain to stimulate neurons, which in turn eases the symptoms experienced in these different brain disorders. For example, in patients with PD, high-frequency stimulation is provided to regions of the basal ganglia (e.g., the subthalamic nucleus (STN) or internal globus pallidus (GPi)) to correct imbalances in the basal ganglia circuit. Neuromodulation can ease motor symptoms experienced in PD and decrease the need for pharmacological treatment.

[0059] Neuromodulation systems commonly include one or more stimulation leads implanted in the brain and a pulse generator connected to the lead(s). The pulse generator can be implanted in the chest, or in recent developments, in the skull of the patient. FIG. 1 illustrates an example neuromodulation system 150 that includes a lead 100 and pulse generator 102. The pulse generator 102 (i.e., a control circuit of the pulse generator 102) can generate and deliver energy to electrodes of the lead 100. For example, the lead 100 includes one or more sensing electrodes 104 and one or more stimulation electrodes 106. The one or more sensing electrodes 104 can detect chemical analytes in the brain. The one or more stimulation electrodes 106 can deliver electrical energy (i.e., stimulation) to the brain.

[0060] The stimulation electrode(s) 106 can be disposed distal to the sensing electrode(s) 104 on the body of the lead 100. In this manner, the sensing electrodes 104 can be implanted to one region of the brain 108, and the stimulation electrode(s) 106 can be implanted to another region of the brain 110. The sensing electrodes 104 and / or the stimulation electrodes 106 may be implanted to an intercranial space, such as the brain tissue and / or the cerebral spinal fluid (CSF). In some examples, the sensing electrode(s) 104 can be implanted to the basal ganglia (e.g., the subthalamic nucleus (STN), internal globus pallidus (GPi)), cortex, and / or another brain region that is viable for sensing. Similarly, the stimulating electrode(s) can be implanted to the basal ganglia (e.g., the STN, GPi), cortex, and / or another brain region that is a therapeutic target for stimulation. In one example, the region of the brain 108 that the sensing electrode(s) 104 are implanted to can be the striatum, and the region of the brain 110 that the stimulating electrode(s) 106 are implanted to can be the subthalamic nucleus (STN). In some examples, one or more of the sensing electrodes 104 can be configured to operate asa stimulating electrode. Similarly, in some examples, one or more of the stimulating electrodes 106 can be configured to operate as a sensing electrode.Neuromodulation Leads

[0061] FIG. 2 illustrates an exemplary neuromodulation lead 200 that can be used for the lead 100 in the neuromodulation system 150. The lead 200 includes a lead body 202 and sensing electrodes 204, stimulating electrodes 206, and electrical contacts 208 disposed along the lead body 202. The electrical contacts 208 can be disposed at a proximal end of the lead body for electrically connecting the lead 200 to a pulse generator (e.g., pulse generator 102 of neuromodulation system 150). Although the lead 200 includes two pairs of each of the sensing electrodes 204 and the stimulating electrodes 206, it is to be understood that the neuromodulation leads described herein are not limited to this electrode arrangement. For example, an exemplary neuromodulation lead may include a plurality (e.g., two or more) sensing electrodes 204 that are configured to both detect chemical analytes and stimulate the brain. In another example, an exemplary neuromodulation lead can include more than two (e.g., 3, 4, 5, etc.) sensing electrodes 204 and / or stimulating electrodes 206.

[0062] The lead body 202 can be sized and be made from materials that are commonly used for neuromodulation leads. For example, the lead body 202 can be 1-2 mm in diameter. The lead body 202 can include materials such as ethylene tetrafluoroethylene copolymer (ETFE) conductive wire insulation material, silicone, and / or 55D urethane lead body material.

[0063] The electrodes (e.g., sensing electrodes 204 and stimulating electrodes 206) can include an electrically conducting element (typically made of metal) that receives electrical energy and subsequently releases the electrical energy to another electrically conducting element. The electrodes can include at least one of platinum, iridium, gold, silver, titanium, carbon, silicon, and nickel. The electrodes can include combinations of the aforementioned elements and / or a combination of one or more of the aforementioned elements with another known element (e.g., nitrogen, oxygen, phosphorous, arsenic, boron, chlorine, etc.) in various ratios. For example, the electrodes can include one or more platinum-iridium (Pt-Ir) electrodes, silicon carbide (Si-C) electrodes, silicon nitride, silicon oxide, titanium nitride, silicon oxynitride, iridium oxide, titanium oxide, silver chloride, etc. In some examples, an end of a conductive wire extending from the pulse generator within the lead body 202 can terminate at a wall of the lead body to form an electrode. In some examples, an electrode may include an annular band (or ring) of conductive material that wraps around at least a portionof the lead body 202, as illustrated in lead 200 in FIG. 2. In some examples, the electrodes can include one or more microelectrodes composed of at least one of the aforementioned materials. A microelectrode is a type of electrode that can be used for sensing or stimulation and has a smaller surface area than a typical electrode. Microelectrodes can enable additional measuring modalities, such as fast-scan cyclic voltammetry (FSCV, discussed in greater detail below), that are selective and sensitive to desired chemical analytes.

[0064] The sensing electrodes 204 and / or stimulating electrodes 206 can be individually addressable to allow energy (e.g., current, potential) to be applied to the sensing electrodes 204 and / or stimulating electrodes 206 in an arbitrary manner. Stated another way, in an exemplary neuromodulation lead 200 having several sensing electrodes 204 and / or stimulating electrodes 206, an individual current (or potential) can be applied to each of the different sensing electrodes 204 and / or stimulating electrodes 206. For example, a lead may include two stimulating electrodes 206, and a pulse generator coupled to the lead 200 may deliver a first magnitude of energy to the first stimulating electrode, and a second magnitude of energy (different from the first) to the second stimulating electrode. In this manner, the energy applied to the various sensing electrodes 204 and stimulating electrodes 206 can be individualized to, for example, target different regions of the brain based on the position of the electrodes on the lead 200.

[0065] The electrodes (e.g., sensing electrodes 204 and stimulating electrodes 206) can be positioned on the lead body 202 in pairs or sets (e.g., 2 or more electrodes can constitute a “set”). FIG. 3A illustrates a portion of a neuromodulation lead 300a that includes two pairs of sensing electrodes 302 and can be used for neuromodulation lead 200. A pair of sensing electrodes 302 in lead 300a includes a working electrode 304 and a counter-reference electrode 306. Energy (e.g., potential, current) can be applied at the working electrode 304, at the counter-reference electrode 306, or between the working electrode 304 and the counterreference electrode 306. A counter-reference electrode can serve the purpose of both a reference electrode and a counter electrode. As a counter electrode, the counter-reference electrode 306 completes the electrical circuit with the working electrode 304 by enabling the flow of energy between itself and the working electrode 304. As a reference electrode, the counter-reference electrode 306 maintains a stable and known potential (or current) against which the potential (or current) at the working electrode 304 is measured.

[0066] In some examples, the working electrode 304 can include a platinum-iridium electrode or a carbon microelectrode. In some examples, the counter-reference electrode 306 can be a silver chloride (Ag-AgCl) electrode.

[0067] The surface area of the working electrode 304 may be between about 78x1 O’6mm2to 3 mm2(accounting for the possible size of a microelectrode-type working electrode). The surface area of the counter-reference electrode may be between about 2x1 O’3mm2to 12 mm2. As illustrated in FIG. 3A, the counter-reference electrode 306 may have a greater surface area than the working electrode 304. For example, the surface area of the counter-reference electrode 306 may be about 1.25, 1.5, 2, 2.5, 3, 4, 5, or 10 times larger than the surface area of the working electrode 304. The working electrode 304 and the counter-reference electrode 306 can be arranged side-by-side with an insulation gap 308 separating the electrodes. In some examples, the insulation gap 308 can be between about 0.1-10 mm.

[0068] In some examples, the housing of the pulse generator can include a conductive material and thus can serve as the counter-reference electrode. In this example, the surface area of the counter-reference electrode can be as large as, e.g., about 2890 mm2.

[0069] In some examples, rather than including a counter-reference electrode 306, the sensing electrodes 302 can include a separate reference electrode 307 and counter electrode 312 (in addition to the working electrode 304). FIG. 3B illustrates a portion of a neuromodulation lead 300b that includes 3 electrodes in a set of sensing electrodes 310 and can be used for the neuromodulation lead 200. The sensing electrodes 310 includes a working electrode 304, a reference electrode 307, and a counter electrode 312. In some examples, the counter electrode 312 can include a platinum-iridium (Pt-Ir) electrode.

[0070] The surface area of the counter electrode 312 may be between about 2xl0"3mm2to 12 mm2' The surface area of the counter electrode 312 may be greater than or equal to the working electrode 304 and / or reference electrode 307. The counter electrode 312 may be separated from the reference electrode 307 by an insulation gap 314. For example, the insulation gap 314 may be about 0.1-10 mm. In some examples, the housing of the pulse generator can include a conductive material and thus can serve as the counter electrode. As noted above with respect to the pulse generator housing serving as the counter-reference electrode, in this example, the surface area of the counter electrode can be as large as about 2890 mm2.

[0071] FIGS. 3C-3N illustrate additional exemplary 2-electrode and 3-electrode arrangements of sensing electrodes that can be used for the neuromodulation lead 200. The neuromodulation lead 300c illustrated in FIG. 3C includes several pairs of sensing electrodes, each of which include a working electrode 304 and a counter-reference electrode 306. The pair of sensing electrodes 316 is separated from another pair of sensing electrodes 318 by an insulation gap 320. The insulation gap 320 can be less than or equal to the insulation gap 308.For example, the insulation gap 320 may be about 0.5 pm-0.05 mm. The neuromodulation lead 300d illustrated in FIG. 3D is similar to lead 300c except that the sets of sensing electrodes 322, 324 that are separated by the insulation gap 320 include a working electrode 304, reference electrode 307, and a counter electrode 312.

[0072] The neuromodulation lead 300e illustrated in FIG. 3E demonstrates a particular arrangement of sensing electrodes on a neuromodulation lead that includes a microelectrode 326. The microelectrode 326 can be composed of carbon or another material described herein with respect to sensing electrodes 204 and stimulating electrodes 206. The microelectrode 326 can be disposed in the insulation gap 320 between electrodes 328, 330. As described in greater detail below, the microelectrode 326 may enable voltammetric sensing with the neuromodulation lead 300e.

[0073] In some examples, the sensing electrodes 302 can be arranged such that an outer electrode surrounds an inner electrode. FIG. 3F illustrates a neuromodulation lead 300f with pairs of sensing electrodes 332 in which the counter-reference electrode 306 surrounds the working electrode 304. The working electrode 304 and the counter-reference electrode 306 are separated by an insulation gap 334. The insulation gap 334 may be between about 0.05-1 mm. In the arrangement of sensing electrodes 332 illustrated in FIG. 3F, the counterreference electrode 306 wraps around at least a portion of the lead body, and the working electrode 304 is a circular electrode disposed within the band of the counter-reference electrode 306 (separated by the insulation gap 334). In an alternative arrangement, the counter-reference electrode 306 may have an annular or semi-annular shape that surrounds the circular-shaped working electrode 304. In some examples, the working electrode 304 may be a platinum-iridium electrode or a carbon microelectrode.

[0074] The neuromodulation lead 300g illustrated in FIG. 3G is similar to lead 300f except that the set of sensing electrodes 336 includes a counter electrode 312 surrounding both of a working electrode 304 and a reference electrode 307. In this example, as explained above with respect to the counter-reference electrode 306 in the lead 300f, the counter electrode 312 can assume a different shape, such as an annular or semi-annular shape surrounding at least a portion of the working electrode 304 and the reference electrode 307. The working electrode 304, reference electrode 307, and counter electrode 312 of a given set of sensing electrodes 336 can be separated by an insulation gap 338 that may be substantially the same as insulation gap 334 of lead 300f.

[0075] The neuromodulation lead 300h illustrated in FIG. 3H is similar to lead 300g except that reference electrode 307 may surround the working electrode (e.g., microelectrode326 in this example). Each of the reference electrode 307 and the microelectrode 326 may be surrounded by a counter electrode 312. The microelectrode 326 and the reference electrode 307 of a given set of electrodes 340 may be separated by an insulation gap 342. The insulation gap may be between about 0.05-0.3 mm. The counter electrode 312 and the reference electrode 307 may be separated by an insulation gap that may be substantially the same as the insulation gap 338 of lead 300g.

[0076] In some examples, a neuromodulation lead may include several (e.g., 2, 3, 4, 5, or “n”) working electrodes, each working electrode coupled to a single counter-reference electrode (or alternatively, a counter electrode and reference electrode). FIGS. 3I-3J illustrate sensing electrode arrangements having n-working electrodes that can be used for neuromodulation lead 200. FIG. 31 illustrates a portion of an exemplary neuromodulation lead 300i that includes a plurality of working electrodes 304 and a counter-reference electrode 306. FIG. 3J illustrates a portion of an exemplary neuromodulation lead 300j that includes a plurality of working electrodes 304, a reference electrode 307, and a counter electrode 312. As discussed in greater detail below, these electrode arrangements illustrated in FIGS. 31-3 J may enhance sensitivity and / or selectivity via redox cycling between the working electrodes 304 and the counter-reference electrode 306 (FIG. 31) or counter electrode 312 (FIG. 3J). The working electrodes 304 in FIGS. 3I-3J may be used as generator or collector electrodes, and may be individually addressable, such that any one or more of the working electrodes 304 may be independently programmed to carry arbitrary values of energy (e.g., potential and / or current). In some examples, the spacing between adjacent working electrodes 304 may range from about 1 pm to about 100 pm. Such interelectrode distances may be achieved using laser machining, ion milling, chemical etching, etc.

[0077] In some examples, a neuromodulation lead may include several (e.g., 2, 3, 4, 5, or “n”) microelectrodes that serve as working electrodes. FIGS. 3K-3E illustrate sensing electrode arrangements having n-microelectrodes 326 that can be used for neuromodulation lead 200. FIG. 3K illustrates a portion of an exemplary neuromodulation lead 300k that includes a plurality of microelectrodes 326 and a counter-reference electrode 306. FIG. 3E illustrates a portion of an exemplary neuromodulation lead 3001 that includes a plurality of microelectrodes 326, a reference electrode 307, and a counter electrode 312. Similar to as noted above, the electrode arrangements illustrated in FIGS. 3K-3E can enhance sensitivity and / or selectivity via redox cycling between the microelectrodes 326 and the counterreference electrode 306 (FIG. 3K) or counter electrode 312 (FIG. 3E). Similar to the working electrodes 304 described with respect to FIGS. 3I-3J, the microelectrodes 326 may be used asgenerator or collector electrodes, and may be individually addressable, such that any one or more of the microelectrodes 326 may be independently programmed to carry arbitrary values of energy (e.g., potential and / or current). In some examples, the spacing between adjacent microelectrodes 326 may range from about 1 pm to about 100 pm. The interelectrode distances may be achieved as noted above.

[0078] In some examples, a two -electrode sensing electrode arrangement on a neuromodulation lead may in its simplest form include one or more working electrodes and one or more counter-reference electrodes (e.g., as illustrated in FIG. 3A). As noted above, the working electrode in this arrangement may be a microelectrode. FIG. 3M illustrates a sensing electrode arrangement similar to that which is described with respect to FIG. 3A, except that the working electrodes are microelectrodes 326. The neuromodulation lead 300m can be used for neuromodulation lead 200. The neuromodulation lead 300m includes a plurality of microelectrodes 326 and a plurality of counter-reference electrodes 306 distributed in pairs.

[0079] In some examples, using a three-electrode sensing electrode arrangement with particular measurement modalities may not utilize all three of a working electrode 304, reference electrode 307, and counter electrode 312 on the neuromodulation lead. FIG. 3N illustrates a neuromodulation lead 300n that can be used for neuromodulation lead 200 and includes a plurality of working electrodes 304 and a plurality of reference electrodes 307. The neuromodulation lead 300n may be capable of detecting the presence of chemical analytes via passive potentiometry, as described in greater detail below.Chemical Analyte Detection

[0080] As noted above, the sensing electrodes of a neuromodulation lead can be configured to detect chemical analytes in the brain. For example, the working electrode 304 can measure electrochemical signals generated by one or more chemical analytes present in the brain. FIGS. 4A-4B illustrate a portion of a lead 400 that includes sensing electrodes (i.e., working electrode 402 and counter-reference electrode 404) and is implanted to an intercranial space in the brain (e.g., brain tissue, cerebral spinal fluid (CSF), etc.). Although the arrangement of the working electrode 402 and counter-reference electrode 404 in the lead 400 most closely resembles that which is illustrated in leads 200, 300a, and 300b, it is understood that the following interactions that are described between the sensing electrodes and the chemical analyte can be applicable to any of the sensing electrode arrangements described with respect to FIGS. 2 and 3A-3N.

[0081] The brain in FIGS. 4A-4B includes chemical analytes 406 (“A”) and 407 (“B”). In some examples, the chemical analytes 406, 407 can include one or more of dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, hydrogen peroxide, oxygen, uric acid, ascorbic acid, lactate, and pyruvate. The chemical analytes 406, 407 can be charged, as demonstrated by the two pairs of electrons 408, 409. The working electrode 402 can be configured to detect the chemical analyte of interest, i.e., chemical analyte 406 in FIGS. 4A-4D. To do so, energy can be applied at the working electrode 402 (or between the working electrode 402 and the counter-reference electrode 404, dependent on the measurement modality) to oxidize the chemical analyte 406 by attracting the electrons 408 to the working electrode 402. Applying energy at the working electrode 402 (or between the working electrode 402 and the counter-reference electrode 404) to measure an electrochemical signal can be defined as operating the working electrode 402 and the counter-reference electrode 404 in an active mode (or actively). The working electrode 402 can react with the chemical analyte 406 in a redox reaction where the electrons 408 are transferred from the chemical analyte 406 to the working electrode 402. This transfer of electrons 408 generates an electrochemical signal that can be measured at the working electrode 402 and / or at the counter-reference electrode 404 (or between the working electrode 402 and the counter-reference electrode 404).

[0082] The magnitude of the electrochemical signal can be dependent on the number of electrons 408 that are transferred between the chemical analyte 406 and the working electrode 402, characteristics of the working electrode 402 and / or the counter-reference electrode 404 (e.g., surface area, material, etc.), and / or the amount of time needed to complete this transfer of charge. This is because current “I” is defined as the number of charges “Q” (e.g., ions or electrons) flowing across an interface in a given duration of time “t”, i.e., I=Q / t. In most cases, t is determined by the speed of the transfer of charges between the chemical analyte and the working electrode. This speed of charge transfer can vary depending on characteristics of the working electrode (e.g., material, surface area, etc.). Thus, electrodes that facilitate a fast transfer of electrons can support a higher current flow and can likely yield larger magnitudes of electrochemical signal.

[0083] As illustrated in FIGS. 4A-4D, when the working electrode 402 interacts with the chemical analyte of interest 406, the counter-reference electrode 404 interacts with another chemical analyte 407 (“B”) present in the brain. This is to complete the electrical circuit including the working electrode 402 and the counter-reference electrode 404. The counterreference electrode 404 transfers electrons 409 to and from the chemical analyte 407. Asshown in FIGS. 4A-4B, when the chemical analyte 406 is oxidized by the working electrode 402, the chemical analyte 407 is reduced by the counter-reference electrode 404. The opposite scenario can also occur (depicted in FIGS. 4C-4D) in which the chemical analyte 406 is reduced by the working electrode 402, and the chemical analyte 407 is oxidized by the counter-reference electrode 404. The chemical analytes 406, 407 can be the same type of chemical analyte or a different type of chemical analyte. In some examples, while the chemical analyte of interest 406 reacts with the working electrode 402, the counter-reference electrode 404 may react (i.e., transfer electrons to / from) more than one chemical analyte.

[0084] The opposite situation to that which is described above with respect to FIGS. 4A- 4B can also exist and is demonstrated by FIGS. 4C-4D. FIGS. 4C-4D illustrate a redox reaction between the chemical analyte 406 and the working electrode 402 in which the working electrode 402 is charged with the electrons 408. The working electrode 402 can be charged with the electrons 408 because energy can be applied at the working electrode 402 (or between the working electrode 402 and the counter-reference electrode 404). The electrons 408 can be transferred from the working electrode 402 to the chemical analyte 406 to generate an electrochemical signal that is measured at the working electrode 402 and / or the counter-reference electrode 404 (or between the working electrode 402 and the counterreference electrode 404). As noted above, when the chemical analyte of interest 406 is reduced by the working electrode 402, the counter-reference electrode 404 can oxidize another chemical analyte 407 in the brain. The counter-reference electrode 404 does so by receiving electrons 409 from the chemical analyte 407.

[0085] Although illustrated with a negative charge in FIGS. 4A-4D, it is to be understood that the chemical analytes 406, 407 can be neutral or charged (e.g., positively or negatively) before and / or after chemical reactions with the working electrode 402 and / or counterreference electrode 404. Thus, the charges depicted on the chemical analytes 406, 407, the working electrode 402, and the counter-reference electrode 404 in FIGS. 4A-4D (as well as the working electrodes 502, 504, counter-reference electrodes 503, 505, and chemical analytes 506, 508 illustrated in FIG. 5) are merely illustrative and do not cover all possibilities. Similarly, the two electrons 408, 409 illustrated in FIGS. 4A-4D are intended to be exemplary; one of ordinary skill in the art will recognize that any reasonable number of electrons can be transferred between the chemical analyte 406 and the working electrode 402, and the chemical analyte 407 and the counter-reference electrode 404. Furthermore, the electrons 408, 409 are depicted on the surface of the working electrode 402 and the counterreference electrode 404 merely for illustrative purposes; it is to be understood that in practice,the charge transferred to the working electrode 402 and the counter-reference electrode 404 flow through the neuromodulation lead 400 and into the pulse generator coupled to it.

[0086] Electrons can be exchanged between the working electrode 402 and the chemical analyte 406 in a repeated, cyclic manner, otherwise referred to as cyclic voltammetry. Cyclic voltammetry can be illustrated by the sequence of FIGS. 4A-4D together, in which electrons 408 are transferred from the chemical analyte 406 and to the working electrode 402, and then from the working electrode 402 back to the chemical analyte 406. The reverse situation could occur in which electrons 408 are transferred from the working electrode 402 and to the chemical analyte 406, and then from the chemical analyte 406 back to the working electrode 402. As noted above, the cyclic transfer of electrons can also take place between the chemical analyte 407 and the counter-reference electrode 404. Cyclic voltammetry can create multiple measured electrochemical signals from a given chemical analyte of interest 406. For example, the electrochemical signal from the oxidation or reduction reaction between the working electrode 402 and the chemical analyte 406 can be measured at the working electrode 402 (or between the working electrode 402 and the counter-reference electrode 404), and then another subsequent electrochemical signal from the oxidation or reduction reaction between the working electrode 402 and the chemical analyte 406 can be measured at the working electrode 402 (or between the working electrode 402 and the counter-reference electrode 404).

[0087] In some examples, an electrochemical signal generated by the chemical analyte 406 can be measured at the working electrode 402, at the counter-reference electrode 404, or between the working electrode 402 and the counter-reference electrode 404 in response to stimulation of the brain by the stimulating electrodes on the same lead as the working electrode 402 and the counter-reference electrode 404 (e.g., stimulating electrodes 206 of lead 200). As noted above, in some examples, one or more of the sensing electrodes (e.g., the working electrode 402 and / or the counter-reference electrode 404) can additionally or alternatively be used to stimulate the brain. In some examples, an electrochemical signal generated by the chemical analyte 406 can be measured at the working electrode 402, at the counter-reference electrode 404, or between the working electrode 402 and the counterreference electrode 404 without any stimulation applied to the brain by stimulating electrodes on the neuromodulation lead. Similarly, in some examples, an electrochemical signal can be measured at the working electrode 402, at the counter-reference electrode, or between the working electrode 402 and the counter-reference electrode 404 without applying energy at theworking electrode 402 or the counter-reference electrode 404 (i.e., passively, or in a passive mode).

[0088] The transfer of electrons demonstrated in FIGS. 4A-4D using a two-electrode sensing electrode arrangement is also applicable to a three-electrode sensing electrode arrangement. Electrons may be transferred between a chemical analyte (e.g., chemical analyte 406, 407) and one or more of the sensing electrodes (e.g., the working electrode, counter electrode) in this electrode arrangement to generate an electrochemical signal by the chemical analyte. For example, the electrochemical signal generated from the transfer of electrons may be measured at the working electrode or between the working electrode and the reference electrode. In some examples, energy (e.g., voltage or current) may be applied at the working electrode or at the working electrode relative to the reference electrode, and the electrochemical signal generated by the transfer of electrons between the chemical analyte 406 and the working electrode may be measured between the working electrode and the reference electrode or at the working electrode. While the chemical analyte reacts with the working electrode, another chemical analyte present in the brain can react (i.e., transfer electrons) with the counter electrode.

[0089] Although FIGS. 4A-4D illustrate only a single chemical analyte of interest 406, it is to be understood that the sensing electrodes described herein can be configured to measure electrochemical signals generated by several different chemical analytes. For example, one working electrode 402 and / or counter-reference electrode 404 can be configured to measure electrochemical signals generated by several different chemical analytes. In another example, a neuromodulation lead can include several working electrodes and / or counter-reference electrodes 404, and each working electrode (or counter-reference electrode 404) can be configured to measure electrochemical signals generated by a target chemical analyte. FIG. 5 illustrates a portion of a neuromodulation lead 500 that is implanted to the brain and includes two working electrodes 502, 504 that can be configured to measure electrochemical signals generated by different chemical analytes.

[0090] For example, the working electrode 502 can be configured to detect chemical analyte (“A”) 506, whereas the working electrode 504 can be configured to detect chemical analyte (“C”) 508. The working electrode 502 can measure electrochemical signals generated by chemical analyte 506 by transferring electrons 510 from the chemical analyte 506. Similarly, the working electrode 504 can measure electrochemical signals generated by chemical analyte 508 by transferring electron 512 from the chemical analyte 508. Other combinations of transferring electrons between chemical analytes and working electrodes canalso exist. For example, the working electrode 502 may transfer electrons 510 to the chemical analyte 506 while the working electrode 504 receives electrons 512 from the chemical analyte 508. In some examples, the working electrode 502 may receive electrons 510 from the chemical analyte 506 while the working electrode 504 transfers electrons 512 to the chemical analyte 508. In some examples, both the working electrode 502 and the working electrode 504 may transfer electrons 510, 512 to the chemical analytes 506, 508 (respectively).

[0091] While the working electrodes 502, 504 react with the chemical analytes of interest 506, 508 (respectively), the counter-reference electrodes 503, 505 can also react with chemical analytes in the brain. The counter-reference electrode 503 can transfer electrons 511 to the chemical analyte (“B”) 507. The counter-reference electrode 505 can transfer electron(s) 513 to the chemical analyte (“D”) 509. Thus, while the chemical analyte 506 is oxidized (or reduced), the chemical analyte 507 is reduced (or oxidized). Similarly, while the chemical analyte 508 is oxidized (or reduced), the chemical analyte 509 is reduced (or oxidized). In some examples, the counter-reference electrodes 503, 505, like counterreference electrode 404, may receive or transfer electrons to more than one chemical analyte. As described above with respect to FIGS. 4A-4D, electrons can be transferred from the chemical analytes and to the working electrodes and / or counter-reference electrodes (or vice versa) via redox reactions. The chemical analytes 506, 507, 508, 509 can be any of the chemical analytes described above with respect to chemical analytes 406, 407. Further, as noted above with respect to FIGS. 4A-4D, the chemical analytes 507, 509 may be the same or a different chemical analyte as chemical analytes 506, 508. The working electrodes 502, 504 and / or the counter-reference electrodes 503, 505 may measure the electrochemical signals generated by the different chemical analytes 506, 508 present in the brain simultaneously or near-simultaneously.

[0092] In some examples, one or more sensing electrodes of an exemplary neuromodulation lead may be coated with a chemical-analyte-selective coating to interact with specific (i.e., target) chemical analytes. For example, with reference to FIG. 5, one or more of the working electrodes 502, 504 and / or the counter-reference electrodes 503, 505 can be coated for selective and sensitive measurement of electrochemical signals generated by chemical analytes 506, 508 (respectively). Coatings of the sensing electrodes can include ion- selective coatings (e.g., Nafion™), size-selective coatings (e.g., porous gold or porous alumina), enzymes (e.g., tyrosine hydroxylase, glutamate oxidase), redox mediators (e.g., methylene blue), anti-fouling coatings (e.g., zwitterionic sulfobetaine methacrylate),aptamers, and / or molecularly implanted polymers (MIPs). If the working electrodes 502, 504 are configured to measure different electrochemical signals, as is the case in the example described above with respect to FIG. 5, the coatings of the working electrodes 502, 504 can be different. The different coatings in FIG. 5 are illustrated using different shading textures on the working electrodes 502, 504. As noted above, in some examples, other sensing electrodes in a given set of sensing electrodes (e.g., the counter-reference electrode 503, 505 in FIG. 5, or a reference electrode and / or counter electrode in a three-electrode sensing electrode arrangement) can be coated in addition to or instead of the working electrode.

[0093] Coated sensing electrodes may operate in a few different ways. In some examples, when the target chemical analyte is detected, the coating of a given sensing electrode can generate an electrochemical signal that can be detected by the sensing electrode. In these examples, when the target chemical analyte is absent, and / or when other (non-target) chemical analyte(s) are detected, the coating of the sensing electrode may not generate an electrochemical signal. In some examples, the coating of the sensing electrode may facilitate and / or enable the transfer of electrons between the target chemical analyte and the sensing electrode. The coating may allow the sensing electrode to transfer electrons to / from the target chemical analyte but may block the sensing electrode from transferring electrons to / from a non-target chemical analyte.

[0094] In some examples, in addition to or instead of coating the sensing electrodes, exemplary neuromodulation leads described herein may achieve chemical analyte selectivity using specific compositions of the sensing electrode. For example, specific compositions of platinum-iridium (Pt-Ir) may be sensitive to specific types of chemical analytes. Varying the amount of iridium in the Pt-Ir electrode composition may enhance sensitivity of the sensing electrode to glucose, hydrogen ions (H+), and / or other chemical analytes. For example, the amount of iridium may be varied between about 0-100%, 0-50%, 25-100%, 25-75%, 25-50%, 50-100%, 50-75%, or 75-100%. For example, the amount of iridium in the Pt-Ir composition may be about 0%, 5%, 10%, 15%, 20%, 22%, 25%, 30%, 35%, 38%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, or another value therebetween. In a similar nature, electrodes composed from carbon (e.g., microelectrode 326) or other organic conductive materials, or coated with said materials, may selectively react with specific chemical analytes, which will be described in greater detail below. The organic composition and / or coating of the electrodes may also improve their sensitivity to target analytes. In some examples, selectivity may be achieved through the analysis of electrochemical signals obtained from a plurality of electrodes having different compositions (e.g., a plurality of Pt-IR electrodes having a range of Pt-IR compositions). In general, the measured electrochemical signal can increase or decrease with analyte concentration depending on the analyte chemistry, material composition of sensing electrodes, and the fluid environment surrounding them.

[0095] Implanting neuromodulation leads to the brain can cause a strong immune response (i.e., a foreign body response) in the brain that subjects the lead to oxidative and highly fouling environments that cause damage to the electrodes on the lead. Furthermore, the brain contains several active chemicals that could exchange electrons with the working electrode and contribute to the overall signal. Both the chemical interference and the foreign body response can interfere with the ability of the sensing electrodes to measure electrochemical signals if not addressed properly.

[0096] The neuromodulation leads described herein are configured to address these challenges. For example, the neuromodulation leads can be pre-calibrated in a solution representative of the in vivo environment. The solution can include oxidative and chemically active biomolecules in physiological saline. In addition to or instead of pre-calibration, as noted above, the sensing electrode can be coated with a chemical-analyte-selective coating. Another strategy to counter the chemical interference and foreign body response can be to modify the applied energy waveforms (e.g., electric potential and / or current) in accordance with the target analyte. For example, a given applied energy may amplify the response of a target chemical analyte in comparison to another chemical analyte, so the applied energy can be selected to amplify the signal of the target chemical analyte. Finally, the spacing between electrodes (e.g., working, counter, reference, and / or counter-reference electrodes) can be used to facilitate electrochemical redox cycling with target chemical analytes. In redox cycling, the oxidized or reduced form of the target chemical analyte can interact with the working or counter-reference electrode(s) to regenerate the target analyte, which can enhance the electrochemical signal generated by the target analyte. Multiple counter-reference electrodes disposed at different distances from a working electrode, or multiple working electrodes disposed at different distances from a counter-reference electrode, may be used to selectively detect the target chemical analyte via redox cycling (see, e.g., neuromodulation leads 300i, 300j, 300k, and 3001 illustrated in FIGS. 3I-3L).

[0097] If fouling occurs at the surface of the electrodes, the neuromodulation leads described herein may utilize subthreshold energy waveforms (i.e., energy waveforms that do not stimulate the tissue and / or cause generation of an electrochemical signal) to condition and replenish the surface of the electrodes. The subthreshold energy waveforms can also improvethe permeability of the biofouling layers and / or prevent or delay protein coverage of the electrodes, thereby reducing biofouling and maintaining signal quality for a longer period of time.Electrochemical Measuring Modalities

[0098] The sensing electrodes of the neuromodulation leads described herein can measure electrochemical signals generated by chemical analytes using different electrochemical measuring modalities. The measuring modalities include impedance, potentiometry (e.g., active potentiometry and passive potentiometry), amperometry, and voltammetry, each of which are described below. With respect to a single set (e.g., a pair) of sensing electrodes on a neuromodulation lead (e.g., lead 100, 200, etc.) that can include several sensing electrodes, each of the electrochemical measuring modalities can be utilized in a two-electrode arrangement (i.e., a working electrode and a counter-reference electrode) and a three- electrode arrangement (i.e., a working electrode, reference electrode, and counter electrode). As noted above, in some examples, the counter-reference (in a two-electrode arrangement) or counter electrode (in a three-electrode arrangement) may be embodied by the pulse generator (i.e., a conductive housing of the pulse generator).

[0099] Impedance can be used for calibration of the neuromodulation lead, as well as for sensing chemical analytes. For example, impedance can be used to monitor electrode fouling and provide a correction factor for the fouling. Impedance includes measuring a time- varying electrochemical signal (e.g., electrical potential signal or current signal) based on applied frequency-varying energy. The frequency-varying energy can begin at a low initial frequency and be increased over time, or vice versa. Impedance can be potentiostatic (measure the timevarying current) or galvanostatic (measure the time-varying potential).

[0100] Potentiostatic impedance with a two-electrode sensing electrode arrangement can include applying a frequency-varying alternating current (AC) electric potential between the working electrode and the counter-reference electrode and measuring the time-varying current passing through the working electrode and / or the counter-reference electrode. Potentiostatic impedance with a three-electrode sensing electrode arrangement can include applying a frequency-varying AC electric potential at the working electrode, relative to the reference electrode, and measuring the time-varying current passing through the working electrode or the counter electrode. In each arrangement, the AC electric potential can be applied with or without finite direct current (DC) bias.

[0101] Galvanostatic impedance with a two-electrode sensing electrode arrangement can include applying a frequency-varying AC electric current at the working electrode or the counter-reference electrode and measuring the time-varying potential between working electrode and the counter-reference electrode. Galvanostatic impedance with a three-electrode sensing electrode arrangement can include applying a frequency-varying AC current at the working electrode or the counter electrode and measuring the time-varying potential between the working electrode and the reference electrode. In each arrangement, the AC electric current can be of varying frequencies, with or without finite DC bias. The DC offset can be chosen, for example, based on the oxidation / reduction potential of the chemical analyte.

[0102] Potentiometry includes measuring an electrochemical signal that is an electric potential signal. In measuring an electric potential signal with a neuromodulation lead having a two-electrode arrangement, a current waveform may be applied at the working electrode or the counter-reference electrode, and an electric potential signal generated by the chemical analyte(s) in response to the applied current waveform can be measured between the working electrode and the counter-reference electrode. In a three-electrode arrangement, the current waveform can be applied at the working electrode or the counter electrode, and the electric potential signal generated by the chemical analyte(s) in response to the applied current waveform can be measured between the working electrode and the reference electrode.

[0103] Passive potentiometry can include measuring an electric potential signal without applying any energy, or current, between the sensing electrodes. Passive potentiometry can offer high temporal resolution, low limit of detection, high level of safety, and a wide range of operation. Passive potentiometry can occur in either a two-electrode or three-electrode sensing electrode arrangement. In a three-electrode arrangement, the potential between the reference electrode and the working electrode is measured (i.e., the counter electrode is not used). In a two-electrode arrangement, the potential between the counter-reference electrode and the working electrode is measured.

[0104] Active potentiometry can include measuring an electric potential signal in response to an applied constant or pulsed current waveform. Both constant and pulsed current potentiometry can offer high temporal resolution and a low limit of detection. In some examples, pulsed current potentiometry may be preferable to constant current potentiometry because it may offer safer operation as compared to constant current potentiometry. As noted above, active potentiometry can occur in either a two-electrode or three-electrode sensing electrode arrangement. In a three-electrode arrangement, current is applied at the working electrode or the counter electrode, and the potential between the reference electrode and theworking electrode is measured based on the presence of chemical analytes. In a two-electrode arrangement, current is applied at the working electrode or the counter-reference electrode, and the potential between the counter-reference electrode and the working electrode is measured based on the presence of chemical analytes. The amplitude of the current (e.g., constant current or pulsed current) may be between about 10 nA and 1 mA. The pulse train duration of the pulsed current may be between about 1 millisecond (ms) and 600 seconds (s). The pulse width of the pulsed current can be between about 10 ps and 200 s (DC).

[0105] Amperometry includes measuring an electrochemical signal, a current signal, in response to an applied electric potential waveform. Amperometry can offer high temporal resolution. In measuring a current signal with a neuromodulation lead having a two-electrode arrangement, the electric potential waveform can be applied between the working electrode and the counter-reference electrode, and the working electrode or the counter-reference electrode can measure a current signal passing through it that has been generated by chemical analytes in the brain in response to the applied electric potential waveform. In a three- electrode arrangement, the electric potential waveform can be applied to the working electrode relative to the electric potential of the reference electrode, and the working electrode or counter electrode can measure a current signal passing through the working electrode or counter electrode that has been generated by the chemical analytes in the brain in response to the applied electric potential waveform.

[0106] The electric potential waveform can be a constant electric potential waveform or a pulsed electric potential waveform. The amplitude of the electric potential (constant or pulsed waveform) may be between about -2.5 and 2.5 volts (V). The pulse train duration of a pulsed electric potential waveform may be between about 1 ms-600 seconds (s). The pulse width of the pulsed electric potential waveform can be between about 10 ps-200 s (DC).

[0107] Voltammetry includes measuring an electrochemical signal, a time- varying current signal, passing through a working electrode (e.g., microelectrode 326) in response to a time-varying electric potential waveform applied between the sensing electrodes. At least a portion of the time-varying current signal may be generated by the exchange of electrons between the working electrode and the chemical analyte(s) as part of oxidation and / or reduction reactions at the working electrode. Voltammetry can offer high temporal resolution, high specificity, and a low limit of detection. In measuring a current signal with a neuromodulation lead having a two-electrode arrangement, the electric potential waveform can be applied at the working electrode relative to the counter-reference electrode, and the working electrode or the counter-reference electrode can measure a current signal generatedby chemical analytes in response to the applied electric potential waveform. In a three- electrode arrangement, the electric potential waveform can be applied at the working electrode relative to a reference electrode, and the working electrode or the counter-electrode can measure a current signal generated by chemical analytes in response to the applied electric potential waveform.

[0108] Fast scan fast scan cyclic voltammetry (FSCV) is a type of voltammetric measurement where the applied electric potential waveform is swept rapidly across a range of voltages. The shape and voltage range of the applied electric potential waveform may be customized based on the sensing electrodes and the redox characteristics (i.e., reduction and oxidation potentials, adsorptive properties) of the target analyte. For example, the detection of dopamine on carbon-based sensing electrodes utilizes a waveform comprising a holding phase where the electrode is held at a constant potential, followed by a scanning phase where a triangular electric potential waveform is applied to the electrode. The switching potential of the triangular electric potential waveform may be between -1.5 and 2 volts (V). The holding potential may be between -1.5 and 2 V. The scan rate of the triangular electric potential waveform may be between about 100-3000 V / s. The frequency of the triangular electric potential waveform may be between about 0.01-500 Hz.

[0109] Performing FSCV measurements at high scan rates may enable lower detection limits and higher temporal resolution for specific combinations of chemical analytes and sensing electrodes. The shape of FSCV waveform may be adjusted to achieve high selectivity to target analytes. The measured current signal can include contributions from a reduction reaction between the chemical analyte and the microelectrode, and a subsequent oxidation reaction between the reduced form of the chemical analyte and the microelectrode. The opposite scenario can also occur in which the measured current signal includes contributions from an oxidation reaction between the chemical analyte and the microelectrode, and a subsequent reduction reaction between the oxidized form of the chemical analyte and the microelectrode.

[0110] Voltammetry has additional characteristics that may enable its use in the detection of chemical analytes in the brain. For example, voltammetry may enable a wide range of concentrations of chemical analytes to be detected.

[0111] In some examples, the neuromodulation leads described herein can employ a combination of measuring modalities. For example, an exemplary neuromodulation lead may include one or more sets of sensing electrodes, each set of sensing electrodes configured to measure an electric potential signal and / or a current signal. In a non-limiting example, aneuromodulation lead may include at least one set of sensing electrodes that can measure a current signal, and at least one set of sensing electrodes that can measure an electric potential signal. The current signal may be measured using amperometry or voltammetry (e.g., fast scan cyclic voltammetry) modalities, as described above. In another example, a neuromodulation lead may include at least one set of sensing electrodes that can measure a current signal using voltammetry, and at least one set of sensing electrodes that can measure a current signal using amperometry. As noted above, the different measurement modalities can be used in combination with coatings on the sensing electrodes (e.g., chemical-analyte- selective coatings) and / or specific electrode compositions (e.g., Pt-Ir) to specifically measure the electrochemical signal generated by a target analyte.Methods for Using Neuromodulation Leads

[0112] The neuromodulation leads described herein can be used to both measure electrochemical signals generated by chemical analytes in the brain and stimulate the brain (e.g., to treat or otherwise alleviate symptoms of a neurological disorder). In some examples, the electrochemical signal(s) measured at the sensing electrodes of a neuromodulation lead can be used to inform the stimulation parameters by the stimulating electrodes of the lead. For example, one or more sensing electrodes of an exemplary neuromodulation lead can measure electrochemical signal generated by a chemical analyte that interacts with the sensing electrode(s) and can transmit the measured signal to a control circuit (e.g., of a pulse generator). Based on the measured electrochemical signal, the control circuit can generate and transmit electrical energy to one or more stimulation electrodes of the neuromodulation lead to stimulate the brain. The electrochemical signals measured by the neuromodulation lead can additionally or alternatively be used to inform dosing of exogenous drugs, and / or early diagnosis of chronic diseases.

[0113] In some examples, e.g., in passive potentiometry, an electrochemical signal can be measured without any electrical energy first being applied to the brain. In some examples, e.g., impedance, active potentiometry, amperometry, or voltammetry, the at least one working electrode may deliver electrical energy (e.g., an electric potential waveform or current waveform) to the brain and then may subsequently measure an electrochemical signal generated in response to the delivered electrical energy.

[0114] In some examples, sensing electrode(s) of the neuromodulation lead can be configured to measure electrochemical signals generated by a target chemical analyte. The above methods are applicable to sensing electrodes including microelectrodes (e.g., for fastscan cyclic voltammetry) and sensing electrodes coated with chemical-analyte-selective coatings (e.g., enzymes, aptamers, MIPs, etc.), each of which can enable selective chemical analyte detection.

[0115] In some examples, an exemplary neuromodulation system (e.g., system 150) can be configured to determine characteristics of detected chemical analytes based on electrochemical signals generated by the chemical analytes. The characteristics of the detected chemical analytes may include, but are not limited to, temporal concentration profiles, spatial concentration profiles, and characteristics of chemical reactions, such as reduction and / or oxidation potentials and impedance to charge transfer. FIG. 6 illustrates an exemplary method 600 for determining concentration of a chemical analyte in the brain.

[0116] At block 610, the method 600 can (optionally) include delivering an energy waveform to the brain at sensing electrode(s) of the neuromodulation lead. As noted above, some measuring modalities (e.g., passive potentiometry) may not necessitate an initial electrical energy to be delivered to the brain to enable measurements, whereas others may (e.g., impedance, active potentiometry, amperometry, voltammetry). The energy waveform can be an electric potential waveform or a current waveform, corresponding to the desired measuring modality. In some examples, the energy waveform may be a predetermined electric potential waveform or predetermined current waveform that elicits a known response by a given chemical analyte when that chemical analyte is present in the brain.

[0117] At block 620, the method 600 includes measuring an electrochemical signal generated by a chemical analyte in the brain at sensing electrode(s) of the neuromodulation lead. The electrochemical signal can be an electric potential signal, or a current signal based on the measurement modality employed. Electrochemical signals generated by several different chemical analytes can be detected using one lead simultaneously or near- simultaneously. For example, different sensing electrodes of a single neuromodulation lead can be configured to detect different chemical analytes.

[0118] At block 630, the method 600 includes determining a concentration of the chemical analyte based on the electrochemical signal. For example, the sensing electrodes of the neuromodulation lead may transmit the measured electrochemical signal to a control circuit of the neuromodulation system that is configured to determine the concentration of the chemical analyte which generated the electrochemical signal. The control circuit can be of the pulse generator implanted to the patient, or of an external device that is communicably coupled to the pulse generator. The chemical analyte concentration may be determined based on calibration curve data accessible to the control circuit. The calibration curve data mayinclude experimentally determined data that describes a relationship between stimulation parameters, measured response, and concentration of the chemical analyte. The calibration curve data can be used to differentiate between detected chemical analytes and determine the individual concentrations of the different chemical analytes. Additional or alternative characteristics of the chemical analyte that may be determined include characteristics of chemical reactions, such as reduction and / or oxidation potentials and impedance to charge transfer.

[0119] As noted above, a given chemical analyte may generate a particular electrochemical signal based on a particular applied energy waveform. The calibration curve data may describe the relationship between applied energy and the evoked response to the applied energy for different chemical analytes that can be present in the brain so that the chemical analyte that generates an electrochemical signal can be identified. Further to this, the calibration curve data can describe a relationship between the aforementioned applied energy and evoked response at various concentrations of a given chemical analyte so that concentration of the chemical analyte detected in the brain can be determined.

[0120] At block 640, the method 600 can (optionally) include delivering electrical stimulation to the brain by one or more stimulating electrodes on the neuromodulation lead based on the determined concentration of the chemical analyte. One or more parameters of the electrical stimulation, such as stimulation onset (e.g., when stimulation should be delivered), amplitude, pulse train duration, pulse width, and / or frequency of the electrical stimulation may be determined based on the concentration of the detected chemical analyte. In some examples, the determined concentration of chemical analytes may be used to inform which stimulating electrodes on the neuromodulation lead to use for stimulation. For example, the determined chemical analyte concentration may inform stimulation using a single stimulating electrode (i.e., monopolar stimulation therapy), stimulation using a pair of stimulation electrodes (e.g., bipolar stimulation therapy), etc. In some examples, based on the concentration of the chemical analyte, a diagnosis of a chronic disease may be achieved. Additionally or alternatively, drug therapy of an exogenous drug may be informed by the determined concentration of the chemical analyte(s) in the brain. For example, a response to the exogenous drug by chemical analytes that are native to the brain can be detected and measured by the neuromodulation lead., which can be used to inform dosage (e.g., dosage amount, frequency, etc.) of a drug.

[0121] In some embodiments, additionally or alternatively to delivering electrical stimulation based on determined concentration(s) of the chemical analyte, stimulation may bedelivered based on relative changes in the electrochemical signal measured by the sensing electrodes. More generally, one or more stimulation parameters (e.g., stimulation onset, amplitude, frequency, pulse width, pulse train duration, etc.), stimulating electrode selection, etc. may be informed by relative changes in the measured electrochemical signal. In this manner, conversion from the measured electrochemical signal generated by the chemical analyte to a concentration of the chemical analyte (e.g., using calibration curve data) to be able to inform stimulation and its related parameters may, in some cases, not be necessary. In some examples, method 600 may be used to measure the concentration of an exogenous drug in the brain. The drug can be introduced to the brain, and method 600 can be executed to detect and determine the concentration of the drug in the brain.

[0122] In some examples, an exemplary neuromodulation system (e.g., system 150) can be configured to passively monitor an electrochemical signal in the brain. The neuromodulation system can be configured such that when a characteristic of the monitored electrochemical signal reaches a predetermined threshold, the system may begin measuring another (different) electrochemical signal. FIG. 7 illustrates an exemplary method 700 for monitoring different electrochemical signals at different times in a measurement session.

[0123] At block 710, the method 700 includes measuring a (first) electrochemical signal generated by a chemical analyte present in the brain at sensing electrode(s) of the neuromodulation lead. The first electrochemical signal can be a tonic, or baseline, signal. In some examples, the electrochemical signal is an electric potential signal. Measuring the electric potential signal can occur passively, i.e., without any energy applied to the brain. In this manner, the electrochemical signal can be measured continuously. In another example, measuring the electrochemical signal can occur subsequent to applying energy in the form of a current waveform or potential waveform to the brain. The electrochemical signal can be measured intermittently, i.e., for a duration of time following the applied energy.

[0124] The electrochemical signal can be measured (continuously or intermittently) until, at block 720, the electrochemical signal reaches a threshold. The control circuit of the neuromodulation system can receive the measured electrochemical signal and can be configured to determine when the electrochemical signal reaches the threshold. When the (first) electrochemical signal reaches the threshold, the control circuit can cause (or trigger) the sensing electrode(s) to start measuring another (second) electrochemical signal. In some examples, the threshold may be a predetermined threshold that is based on an increase or a decrease in the measured electrochemical signal. For example, when the control circuit determines that the electrochemical signal has increased (or decreased) by at least 10%, thecontrol circuit may send a signal to the sensing electrode(s) to cause the sensing electrodes to start measuring the second electrochemical signal. Other thresholds may alternatively be employed, such as 1%, 2%, 5%, 8%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or another value therebetween.

[0125] Once the first electrochemical signal reaches the trigger threshold, at block 730, the method 700 includes measuring another (second) electrochemical signal generated by a chemical analyte present in the brain at the sensing electrode(s) of the neuromodulation lead. The second electrochemical signal can be a phasic, or stimulation-evoked, signal. The second electrochemical signal can be different from the first electrochemical signal. For example, the electrochemical signal can be a current signal evoked from voltammetry. In another example, the electrochemical signal is a current signal evoked from amperometry or an electric potential signal, evoked from potentiometry Different sensing electrodes may be configured to measure the different electrochemical signals, or the same sensing electrode(s) may be used to measure the signals. In some examples, the second electrochemical signal can be measured in response to an electric potential or current waveform delivered to the brain that causes the chemical analyte to generate the electrochemical signal.

[0126] By measuring an electrochemical signal that does not require initial energy for generating the electrochemical signal, followed by measuring an electrochemical signal generated in response to delivered energy, the amount of unwanted stimulation applied to the patient can be reduced. Further, the amount of power consumed by the neuromodulation system can be reduced, thereby necessitating fewer replacements of the pulse generator and increasing the lifetime of the implanted device.

[0127] At block 740, the method 700 can (optionally) include identifying and / or determining characteristics of the chemical analytes (e.g., concentration of the chemical analytes) that are present in the brain. Block 740 can be executed at a control circuit of the neuromodulation system in a similar manner as described with above with respect to method 600 in FIG. 6, and in particular, block 630 of method 600.

[0128] In some examples, an exemplary neuromodulation system (e.g., system 150) can be configured to dynamically adjust stimulation parameters based on measured electrochemical signals. FIG. 8 illustrates an exemplary method 800 for determining stimulation parameters based on a measured electrochemical signal.

[0129] At block 810, the method 800 can (optionally) include delivering initial energy to the brain at one or more stimulating electrodes of the neuromodulation lead. The electrical stimulation can be a current waveform or an electric potential waveform. Alternatively, asdescribed herein, measuring an electrochemical signal at the following block 820 can occur without delivering any initial energy. In some examples, as described herein the initial energy may additionally or alternatively be delivered to one or more sensing electrodes of the neuromodulation lead that are configured for stimulation.

[0130] At block 820, the method 800 includes measuring an electrochemical signal generated by a chemical analyte in the brain at the one or more sensing electrode(s) of the neuromodulation lead. The electrochemical signal can be an electric potential signal or a current signal for example, based on the measurement modality employed.

[0131] At block 830, the method 800 includes determining one or more stimulation parameters based on the measured electrochemical signal. The stimulation parameters can include stimulation onset, pulse width, frequency, pulse train duration, and amplitude of the electrical stimulation. The measured electrochemical signal can additionally or alternatively be used to inform stimulating electrode usage (i.e., which electrode(s) to use to stimulate the brain). In some examples, determining the one or more stimulation parameters may occur after multiple iterations of block 810 and / or block 820. The measured electrochemical signal(s) may be transmitted from the sensing electrode(s) to the control circuit of the neuromodulation system, which may be configured to determine the stimulation parameters based on the electrochemical signal(s). If initial energy was delivered to the brain, determining the stimulation parameters can include modifying the stimulation parameters of the initial energy to generate updated stimulation parameters for electrical stimulation. The updated stimulation parameters can include an increase or a decrease in at least one of the stimulation onset, pulse width, the frequency, the pulse train duration, and the amplitude of the electrical stimulation. The updated stimulation can include increasing or decreasing the quantity of stimulating electrodes used to stimulate the brain. In some examples, electrochemical signals generated by several different chemical analytes can be detected and used to determine the stimulation parameters.

[0132] In some examples, the one or more stimulation parameters (including electrode usage) may be determined dynamically, e.g., using machine learning or other algorithms that are adaptive and can be tailored to meet the needs of a specific individual. The algorithms (e.g., machine learning algorithms) may utilize relative changes in the measured electrochemical signal (and / or the determined concentration of the chemical analyte that generated the signal) to dynamically adjust and update stimulation parameters. In doing so, any negative side effects, e.g., from delivering off-target stimulation, may be minimized, and therapeutic efficacy may be enhanced.

[0133] At block 840, the method 800 includes delivering electrical stimulation at one or more stimulating electrodes of the neuromodulation lead in accordance with the determined (e.g., updated) stimulation parameters. After determining the stimulation parameters at the control circuit, the control circuit may be configured to generate and transmit electrical stimulation in accordance with the stimulation parameters to stimulating electrode(s) on the neuromodulation lead. The method 800 can be repeated any number of times to continuously adapt and refine the stimulation parameters based on the chemical analytes present in the brain.Neuromodulation Systems

[0134] As noted above, the neuromodulation leads described herein can be a component of a neuromodulation system. The neuromodulation system can include at least one neuromodulation lead that is electrically connected to a pulse generator. FIG. 9 illustrates an exemplary neuromodulation system 950 that can be used for neuromodulation system 150 described above with respect to FIG. 1. The neuromodulation system 950 includes a lead 900 and a pulse generator 902. The pulse generator 902 may otherwise be referred to as an implantable pulse generator (IPG), neurostimulator, or an implantable neurostimulator (INS).

[0135] The pulse generator 902 may be cranially mounted to the skull of a patient. It can have a low profile that minimally protrudes from the skull / scalp of the patient. The pulse generator 902 can include a hermetically sealed housing that encloses a control circuit 904 and an energy storage 906. The housing of the pulse generator 902 can include a conductive material to serve as a counter electrode for stimulation and / or chemical analyte detection, as noted above. The pulse generator 902 can include at least one lead connection port that receives the lead 900 and electrically connects the lead 900 to the control circuit 904. For example, as noted above, a proximal portion of the lead 900 can include one or more electrical contacts, and the lead connection port can include corresponding electrical contact(s) that are coupled to the control circuit 904 and facilitate connection between the lead 900 and the control circuit 904. In this manner, energy (e.g., pulses) generated at the control circuit 904 can be transmitted through the lead 900 and delivered to the electrodes (e.g., sensing and / or stimulating electrodes) disposed on the lead 900.

[0136] Exemplary pulse generators, and in particular, exemplary housings of pulse generators, are described in greater detail in U.S. Provisional Application No. 63 / 588,666, the contents of which are incorporated herein in its entirety.

[0137] The control circuit 904 can include an application-specific integrated circuit (ASIC) and / or a low-power microcontroller configured to control the ASIC and other electronic components of the pulse generator. The energy storage 906 can be electrically coupled to the control circuit 904 and can include a battery, such as a rechargeable battery. In one example, the energy storage 906 includes a 50 mAH lithium-ion rechargeable battery. This type of energy storage 906 may power the pulse generator 902 for at least 3 days with 1 charge of the battery.

[0138] In some examples, the energy storage 906 may be rechargeable by an inductive coil (e.g., radiofrequency (RF) antenna) or an ultrasonic transducer of the neuromodulation system. The inductive coil may be disposed external to the housing of the pulse generator 902 but may be implanted proximate to the housing, for example between the surface of the skull and the scalp of the patient. Aside from power transfer, the inductive coil may facilitate communication between the control circuit 904 and an external device 908. For example, the external device 908 may generate and transmit commands for controlling neuromodulation and / or chemical analyte detection parameters. Stimulation (i.e., energy) parameters can include intensity, pulse width, pulse train duration, etc.

[0139] These commands can be transmitted as RF waves to the control circuit 904 via the inductive coil (or RF antenna). The RF waves can be converted to electrical energy for stimulation (and / or chemical analyte measuring). In some examples, the control circuit 904 and the external device 908 may communicate using radio wave backscatter. In some examples, electrochemical signals and other data detected at the electrodes of the lead 900 may be transmitted to the control circuit 904, and from the control circuit 904 may be converted to RF waves to be transmitted to the external device 908 (e.g., via the inductive coil).

[0140] Alternatively, the control circuit 904 and the external device 908 may communicate via ultrasonic waves. The pulse generator 902 may include one or more ultrasonic transducers coupled to the control circuit 904 that receive ultrasonic waves emitted by the external device 908 and convert the ultrasonic waves into electrical energy. The control circuit 904 and the external device 908 may communicate via ultrasonic backscatter. In some examples, the ultrasonic transducer(s) can include a piezoelectric crystal, such as a bulk piezoelectric transducer, a piezoelectric micro-machined ultrasonic transducer (PMUT), or a capacitive micro -machined ultrasonic transducer (CMUT).

[0141] The external device 908 can include similar components to the pulse generator 902 to enable communication with the control circuit 904 of the pulse generator 902. Forexample, the external device 908 can include a communication circuit, a transmitter, and a power management circuit. The transmitter can include one or more ultrasonic transducers or RF coils configured to wirelessly transmits energy (e.g., in the form of ultrasonic waves or RF waves, respectively) to the pulse generator 902. The transmitter of the external device 908 may transmit commands to the control circuit 904 that include instructions for controlling the pulse generator 902, such as instructions to reset itself, enter a specific mode, set device parameters, and / or begin a transmission sequence.

[0142] As used herein, “external” may refer to any region outside of the pulse generator 902. For example, the external device may be external to the patient, in which the pulse generator 902 (including the lead 900) is implanted. The external device 908 may communicate with and / or provide power to the pulse generator 902 when the external device 908 is appropriately placed over the patient’s scalp proximate to the implanted pulse generator 902. In some examples, the external device 908 may be a wearable device above the scalp of the patient. In some examples, the external device 908 may be implanted to the patient, but may be separate from (i.e., external to) the pulse generator 902.

[0143] The communication between the pulse generator 902 and the external device 908 may be a one-way communication (for example, the external device 908 transmitting information to the pulse generator 902, or the pulse generator 902 transmitting information to the external device 908), or a two-way communication (for example, the external device 908 transmitting information to the pulse generator 902, and the pulse generator 902 transmitting information to the external device 908). As noted above, information transmitted from the pulse generator 902 to the external device 908 may rely on, for example, a backscatter communication protocol. For example, the external device 908 may transmit backscatter (e.g., ultrasonic or RF) waves to the pulse generator 902, and the pulse generator 902 can emit backscatter waves that encode the information. The external device 908 can receive the backscatter waves and decipher the information encoded in the received backscatter waves.

[0144] The neuromodulation system 950 can include additional components that are not illustrated in FIG. 9 for simplicity. For example, the pulse generator 902 can include a power management unit configured to store and distribute energy to components of the pulse generator (understood to encompass the energy storage 906), a modulation circuit configured to encode information in an electric current, a transmitter configured to wirelessly receive, convert, and transfer energy from the external device, and / or a memory configured to store data (e.g., electrochemical signals) received from one or more of the sensing electrodes.

[0145] The neuromodulation system 950 can include additional external devices, such as a patient remote controller (e.g., “controller”) and / or a clinician programmer tablet (e.g., “programmer”).

[0146] The clinician’s programmer may be a mobile device (e.g., a smartphone, tablet, etc.) or other separate computer system. The programmer may be used for initial pulse generator setup, programming therapy parameters, data collection, and / or follow-on patient care. The programmer may be configured to communicate with the pulse generator 902 via the external device 908. The programmer may wirelessly communicate with the external device 908, for example, through a network connection, a radio frequency (RF) connection, Bluetooth connection, etc. The programmer may, for example, turn on or off the external device 908 or analyze information encoded in backscatter waves (e.g., ultrasonic backscatter waves or radio frequency backscatter waves) received by the external device 908.

[0147] The patient remote controller may be a mobile device (e.g., a smartphone, tablet, etc.) or other separate computer system. The controller may allow the patient to control particular stimulation parameters, as advised by the clinician, and enter special modes (e.g., an MRI mode), as necessary. The controller may be configured to run validated application software. The controller may be configured to allow the patient to interact with the pulse generator 902 via the external device 908. The controller may wirelessly communicate with the external device 908, for example, through a network connection, a radio frequency (RF) connection, Bluetooth connection, etc. The controller may, for example, turn on or off the external device 908 or analyze information encoded in backscatter waves (e.g., ultrasonic backscatter waves or radio frequency backscatter waves) received by the external device 908. Once a connection is established, the controller may allow the patient to receive real-time or near real-time information, such as information on battery life of components of the system (e.g., the external device 908, the pulse generator 902, etc.).Methods for Implanting Neuromodulation Leads

[0148] A method for implanting neuromodulation leads (e.g., leads 100, 200, etc.) is described herein. The method can include generating an opening in a surface of the skull of a patient. The opening can be a burr hole sized to receive the lead. Alternatively, the opening may be sized to receive a cranially mountable pulse generator of the neuromodulation system. If the opening is sized to receive a pulse generator, generating the opening in the skull can include using a cutting template tool (the profile of which can correspond to the profile of the pulse generator) to generate the appropriate-sized opening in the skull. Exemplary cuttingtemplate tools are described in greater detail in U.S. Provisional Application No. 63 / 509,231, the contents of which have been incorporated herein its entirety.

[0149] The portion of the neuromodulation lead having the sensing (and stimulating) electrodes can be implanted into the brain, such as the brain tissue and / or the surrounding cerebral spinal fluid (CSF), through the generated opening. For example, as noted above, the sensing electrodes on the lead body can be implanted to the striatum. The stimulating electrode(s) on the lead body can be implanted to the subthalamic nucleus. In some examples, the neuromodulation lead can be implanted into the brain using a stylet and stereotactic frame. For example, the lead body may include a lumen that can receive a stylet body, and the stylet body can be used to insert the neuromodulation to the correct position and depth within the brain tissue. Exemplary stylets for implanting the lead to the brain are described in greater detail in U.S. Provisional Application No. 63 / 509,236, the contents of which have been incorporated herein in its entirety.

[0150] The neuromodulation lead can be electrically connected to the pulse generator of the neuromodulation system. As noted above, the neuromodulation lead can include one or more electrical contacts at the proximal portion of the lead body. This proximal portion of the lead can be inserted to a lead connection port that includes corresponding electrical contacts for coupling the neuromodulation lead with a control circuit within the pulse generator.

[0151] The neuromodulation lead may be mounted to the surface of the skull to minimize shifting of the lead once implanted. For example, a lead fixation apparatus may be used to mount the lead to the surface of the skull. Exemplary lead fixation apparatuses that can be used to mount the lead are described in greater detail in U.S. Provisional Application No. 63 / 509,233, the contents of which have been incorporated herein in its entirety.

[0152] The pulse generator of the neuromodulation system can be cranially mounted to the opening in the skull, and the scalp of the patient can be replaced. The neuromodulation leads and systems described herein are not intended to be limited to cranially mounted pulse generators. For example, the pulse generator can be implanted to the chest. In this example, the method can include preparing the implantation site in the chest and implanting the pulse generator there. The neuromodulation lead can be tunneled underneath the skin of the patient between the implantation site of the lead in the skull and the implantation site of the pulse generator in the chest. Alternatively, extension lead(s) can be connected to the neuromodulation lead that is implanted to the brain, and the extension lead(s) can be tunneled to the pulse generator implanted to the chest.Definitions

[0153] As used herein, the singular forms “a”, “an”, and “the” include the plural reference unless the context clearly dictates otherwise.

[0154] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0155] It is understood that aspects and variations of the invention described herein include “consisting” and / or “consisting essentially of’ aspects and variations.

[0156] When a range of values or values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the scope of the present disclosure. Where the stated range includes upper or lower limits, ranges excluding either of those included limits are also included in the present disclosure.

[0157] The section headings used herein are for organization purposes only and are not to be construed as limiting the subject matter described. The description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the described embodiments will be readily apparent to those persons skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiment shown but is to be accorded the widest scope consistent with the principles and features described herein.

[0158] The figures illustrate processes according to various embodiments. In the exemplary processes, some blocks are, optionally, combined, the order of some blocks is, optionally, changed, and some blocks are, optionally, omitted. In some examples, additional steps may be performed in combination with the exemplary processes. Accordingly, the operations as illustrated (and described in greater detail below) are exemplary by nature and, as such, should not be viewed as limiting.

[0159] Finally, it is to be understood that features and preferences described in relation to “embodiments” are distinct preferences and are not limited only to that particular embodiment; they may be freely combined with features from other embodiments, where technically feasible, and may form preferred combinations of features. The description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. Various modifications to the described embodiments will be readily apparent to those persons skilled in the art and thegeneric principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiment shown but is to be accorded the widest scope consistent with the principles and features described herein. Further, sectional headings are provided for organizational purposes and are not to be considered limiting.

[0160] The entire disclosure of the patents and publications referred in this application are hereby incorporated herein by reference for all purposes. To the extent that any reference incorporated by reference conflicts with the instant disclosure, the instant disclosure shall control.EXEMPLARY EMBODIMENTS

[0161] The following embodiments are exemplary and are not intended to limit the scope of any invention described herein.

[0162] Embodiment 1. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode and at least one counter-reference electrode or (b) at least one working electrode, at least one counter electrode, and at least one reference electrode, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in a brain interacting with at least one of the plurality of sensing electrodes.

[0163] Embodiment 2. The lead of embodiment 1 , comprising one or more of stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0164] Embodiment 3. The lead of embodiment 2, wherein the one or more stimulating electrodes are further configured as a sensing electrode for measuring an electrochemical signal generated by one or more chemical analytes interacting with the one or more stimulating electrodes.

[0165] Embodiment 4. The lead of any one of embodiments 1-3, wherein the plurality of sensing electrodes comprises the at least one working electrode and the at least one counter-reference electrode.

[0166] Embodiment 5. The lead of embodiment 4, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes thatoccurs between the at least one working electrode and the at least one counter-reference electrode to generate the electrochemical signal.

[0167] Embodiment 6. The lead of embodiment 4 or 5, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counter-reference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

[0168] Embodiment 7. The lead of any one of embodiments 4-6, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0169] Embodiment 8. The lead of embodiment 7, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

[0170] Embodiment 9. The lead of any one of embodiments 4-8, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counterreference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0171] Embodiment 10. The lead of embodiment 9, wherein the electric potential waveform comprises at least one of a constant electric potential waveform and a pulsed electric potential waveform.

[0172] Embodiment 11. The lead of any one of embodiments 4-10, wherein the at least one working electrode and the at least one counter-reference electrode are segmented from each other on the lead body by a first insulation gap.

[0173] Embodiment 12. The lead of embodiment 11, wherein a surface area of the at least one counter-reference electrode is greater than a surface area of the at least one working electrode.

[0174] Embodiment 13. The lead of any one of embodiments 4-12, wherein the at least one counter-reference electrode at least partially surrounds the first working electrode.

[0175] Embodiment 14. The lead of any one of embodiments 4-13, wherein a first set of electrodes comprising a first working electrode and a first counter-reference electrode is segmented on the lead body from a second set of electrodes comprising a second working electrode and a second counter-reference electrode by a second insulation gap.

[0176] Embodiment 15. The lead of any one of embodiments 1-3, wherein the plurality of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

[0177] Embodiment 16. The lead of embodiment 15, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter electrode.

[0178] Embodiment 17. The lead of embodiment 15 or 16, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode without applying any current waveform to the at least one working electrode or the at least one counter electrode.

[0179] Embodiment 18. The lead of any one of embodiments 15-17, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

[0180] Embodiment 19. The lead of embodiment 18, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

[0181] Embodiment 20. The lead of any one of embodiments 15-19, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0182] Embodiment 21. The lead of embodiment 20, wherein the electric potential waveform comprises a constant electric potential waveform.

[0183] Embodiment 22. The lead of embodiment 20, wherein the electric potential waveform comprises a pulsed electric potential waveform.

[0184] Embodiment 23. The lead of any one of embodiments 15-22, wherein the at least one working electrode and the at least one reference electrode are separated on the lead body by a first insulation gap, and the at least one reference electrode and the at least one counter electrode are separated on the lead body by a second insulation gap.

[0185] Embodiment 24. The lead of any one of embodiments 15-23, wherein a surface area of the at least one counter electrode is greater than a surface area of each of the at least one working electrode and the at least one reference electrode.

[0186] Embodiment 25. The lead of any one of embodiments 15-24, wherein the at least one counter electrode at least partially surrounds each of the working electrode and the counter electrode.

[0187] Embodiment 26. The lead of embodiment 25, wherein the reference electrode at least partially surrounds the working electrode.

[0188] Embodiment 27. The lead of any one of embodiments 1-26, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, wherein a first set of sensing electrodes comprises the at least one working electrode and the at least one counterreference electrode, and wherein a second set of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

[0189] Embodiment 28. The lead of any one of embodiments 1-27, wherein the plurality of sensing electrodes are configured to measure a plurality of electrochemical signals generated during at least one redox reaction caused by a plurality of chemical analytes simultaneously.

[0190] Embodiment 29. The lead of any one of embodiments 1-28, wherein at least one of the plurality of sensing electrodes is configured to operate as a stimulating electrode.

[0191] Embodiment 30. The lead of any one of embodiments 1-29, wherein the plurality of sensing electrodes comprises a plurality of annular electrodes and / or semi-annular electrodes disposed on the lead body.

[0192] Embodiment 31. The lead of any one of embodiments 1-30, wherein the at least one working electrode is a microelectrode.

[0193] Embodiment 32. The lead of any one of embodiments 1-31, wherein the plurality of sensing electrodes are disposed at a distal portion of the lead body.

[0194] Embodiment 33. The lead of any one of embodiments 1-32, wherein the plurality of sensing electrodes comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon oxide, silicon nitride, and nickel.

[0195] Embodiment 34. The lead of any one of embodiments 1-33, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0196] Embodiment 35. The lead of any one of embodiments 1-34, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0197] Embodiment 36. A method for measuring electrochemical signals in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

[0198] Embodiment 37. The method of embodiment 36, comprising, based on the measured electrochemical signal, delivering, via one or more stimulating electrodes disposed on the lead body and / or one or more of the sensing electrodes, electrical stimulation to the brain.

[0199] Embodiment 38. The method of embodiment 36 or 37, comprising: delivering, via one or more of the sensing electrodes disposed on the lead body, an electric potential waveform or a current waveform to the brain; and measuring the electrochemical signal generated based on a response of the one or more chemical analytes to the electric potential waveform or the current waveform.

[0200] Embodiment 39. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode that is a microelectrode and at least one counter-reference electrode, or (b) at least one working electrode that is a microelectrode, at least one counter electrode, and at least one reference electrode, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

[0201] Embodiment 40. The lead of embodiment 39, comprising one or more stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0202] Embodiment 41. The lead of embodiment 40, wherein the one or more stimulating electrodes are further configured as a sensing electrode for measuring an electrochemical signal generated by one or more chemical analytes interacting with the one or more stimulating electrodes.

[0203] Embodiment 42. The lead of any one of embodiments 39-41, wherein the plurality of sensing electrodes comprises the at least one working electrode and the at least one counter-reference electrode.

[0204] Embodiment 43. The lead of embodiment 42, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter-reference electrode to generate the electrochemical signal.

[0205] Embodiment 44. The lead of embodiment 42 or 43, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counterreference electrode in response to a triangular electric potential waveform applied between the at least one working electrode and the counter-reference electrode.

[0206] Embodiment 45. The lead of any one of embodiments 42-44, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counter-reference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

[0207] Embodiment 46. The lead of any one of embodiments 42-45, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0208] Embodiment 47. The lead of embodiment 46, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

[0209] Embodiment 48. The lead of any one of embodiments 42-47, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counterreference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0210] Embodiment 49. The lead of embodiment 48, wherein the electric potential waveform comprises at least one of a constant electric potential waveform and a pulsed electric potential waveform.

[0211] Embodiment 50. The lead of any one of embodiments 39-41, wherein the plurality of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

[0212] Embodiment 51. The lead of embodiment 50, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter electrode.

[0213] Embodiment 52. The lead of embodiment 50 or 51, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one microelectrode or the at least one counter electrode in response to a triangular electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0214] Embodiment 53. The lead of embodiment 50 or 51, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode without applying any current waveform to the at least one working electrode or the at least one counter electrode.

[0215] Embodiment 54. The lead of any one of embodiments 51-53, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

[0216] Embodiment 55. The lead of embodiment 54, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

[0217] Embodiment 56. The lead of any one of embodiments 51-55, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0218] Embodiment 57. The lead of embodiment 56, wherein the electric potential waveform comprises a constant electric potential waveform.

[0219] Embodiment 58. The lead of embodiment 56, wherein the electric potential waveform comprises a pulsed electric potential waveform.

[0220] Embodiment 59. The lead of any one of embodiments 51-58, wherein a first set of electrodes comprising a first counter electrode and a first reference electrode is segmented on the lead body from a second pair of electrodes comprising a second counter electrode and a second reference electrode by a first insulation gap, a first microelectrode disposed in the first insulation gap.

[0221] Embodiment 60. The lead of any one of embodiments 51-59, wherein a third counter electrode at least partially surrounds a third reference electrode and a second microelectrode, the third reference electrode and the third counter electrode segmented by a second insulation gap, and the third reference electrode and the second microelectrode segmented by a third insulation gap.

[0222] Embodiment 61. The lead of any one of embodiments 39-60, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, wherein a first set of sensing electrodes comprises the at least one working electrode that is a microelectrode and the at least one counter-reference electrode, and wherein a second set of sensing electrodes comprises the at least one working electrode that is a microelectrode, the at least one counter electrode, and the at least one reference electrode.

[0223] Embodiment 62. The lead of any one of embodiments 39-61, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, each set of sensing electrodes comprising a working electrode that is a microelectrode, and wherein each microelectrode is configured to measure an electrochemical signal of a specific chemical analyte.

[0224] Embodiment 63. The lead of any one of embodiments 39-62, wherein at least one of the plurality of sensing electrodes is configured to operate as a stimulating electrode.

[0225] Embodiment 64. The lead of any one of embodiments 39-63, wherein the plurality of sensing electrodes are disposed at a distal portion of the lead body.

[0226] Embodiment 65. The lead of any one of embodiments 39-64, wherein the at least one reference electrode comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon nitride, silicon oxide, and nickel.

[0227] Embodiment 66. The lead of any one of embodiments 39-65, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0228] Embodiment 67. The lead of any one of embodiments 39-66, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0229] Embodiment 68. A method for measuring electrochemical signals in a brain, comprising:measuring, at a plurality of sensing electrodes comprising at least one working electrode that is a microelectrode disposed on a lead body, an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

[0230] Embodiment 69. The method of embodiment 68, comprising, based on the measured electrochemical signal, delivering, via one or more stimulating electrodes disposed on the lead body and / or one or more of the sensing electrodes, electrical stimulation to the brain.

[0231] Embodiment 70. The method of embodiment 68 or 69, comprising: delivering, via one or more of the sensing electrodes disposed on the lead body, a triangular electric potential waveform to the brain; and measuring a current signal generated based on a response of the one or more chemical analytes to the triangular electric potential waveform.

[0232] Embodiment 71. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain, wherein one or more sensing electrodes of the plurality of sensing electrodes comprises a chemical-analyte-selective coating that interacts with at least one specific chemical analyte at the one or more sensing electrodes.

[0233] Embodiment 72. The lead of embodiment 71, comprising one or more stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

[0234] Embodiment 73. The lead of embodiment 72, wherein the one or more stimulating electrodes are further configured as a sensing electrode for measuring an electrochemical signal generated by one or more chemical analytes interacting with the one or more stimulating electrodes.

[0235] Embodiment 74. The lead of any one of embodiments 71-73, wherein the chemical-analyte-selective coating comprises one or more ion-selective coatings and / or size- selective coatings.

[0236] Embodiment 75. The lead of any one of embodiments 71-73, wherein the chemical-analyte-selective coating comprises one or more enzymes and / or aptamers.

[0237] Embodiment 76. The lead of any one of embodiments 71-73, wherein the chemical-analyte-selective coating comprises one or more molecularly imprinted polymers (MIPs).

[0238] Embodiment 77. The lead of any one of embodiments 71-76, wherein the plurality of sensing electrodes comprises a first sensing electrode and a second sensing electrode, the first sensing electrode comprising a first chemical-analyte-selective coating that interacts with a first chemical analyte at the first sensing electrode, and the second sensing electrode comprising a second chemical-analyte-selective coating that interacts with a second chemical analyte at the second sensing electrode, the first chemical analyte different from the second chemical analyte.

[0239] Embodiment 78. The lead of any one of embodiments 71-77, wherein the plurality of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode.

[0240] Embodiment 79. The lead of embodiment 78, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counterreference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

[0241] Embodiment 80. The lead of embodiment 78 or 79, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0242] Embodiment 81. The lead of any one of embodiments 78-80, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counterreference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0243] Embodiment 82. The lead of any one of embodiments 71-77, wherein the plurality of sensing electrodes comprises at least one working electrode, at least one counter electrode, and at least one reference electrode.

[0244] Embodiment 83. The lead of embodiment 82, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one referenceelectrode without applying any current waveform to the at least one working electrode or the at least one counter electrode.

[0245] Embodiment 84. The lead of embodiment 82 or 83, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

[0246] Embodiment 85. The lead of any one of embodiments 82-84, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0247] Embodiment 86. The lead of any one of embodiments 71-85, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, wherein a first set of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode, and wherein a second set of sensing electrodes comprises at least one working electrode, at least one counter electrode, and at least one reference electrode.

[0248] Embodiment 87. The lead of any one of embodiments 78-86, wherein the at least one working electrode comprises the chemical-analyte-selective coating.

[0249] Embodiment 88. The lead of any one of embodiments 71-87, wherein the plurality of sensing electrodes are configured to measure a plurality of electrochemical signals generated by a plurality of chemical analytes simultaneously.

[0250] Embodiment 89. The lead of any one of embodiments 71-88, wherein at least one of the plurality of sensing electrodes is configured to operate as a stimulating electrode.

[0251] Embodiment 90. The lead of any one of embodiments 78-89, wherein the at least one working electrode is a microelectrode.

[0252] Embodiment 91. The lead of any one of embodiments 78-90, wherein the plurality of sensing electrodes are disposed at a distal portion of the lead body.

[0253] Embodiment 92. The lead of any one of embodiments 78-91, wherein the plurality of sensing electrodes comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon oxide, silicon nitride, and nickel.

[0254] Embodiment 93. The lead of any one of embodiments 78-92, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine,norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0255] Embodiment 94. The lead of any one of embodiments 78-93, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0256] Embodiment 95. A method for measuring electrochemical signals in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain, wherein one or more of the sensing electrodes of the plurality of sensing electrodes comprises a chemical-analyte-selective coating that interacts with at least one specific chemical analyte at the one or more sensing electrodes.

[0257] Embodiment 96. The method of embodiment 95, comprising, based on the measured electrochemical signal, delivering, via one or more stimulating electrodes disposed on the lead body and / or one or more of the sensing electrodes, electrical stimulation to the brain.

[0258] Embodiment 97. The method of embodiment 95 or 96, comprising: delivering, via one or more of the sensing electrodes disposed on the lead body, an electric potential waveform or a current waveform to the brain; and measuring the electrochemical signal generated based on a response of the one or more chemical analytes to the electric potential waveform or the current waveform.

[0259] Embodiment 98. An implantable neuromodulation system, comprising: the lead of any one of embodiments 2-35, 39-67, and 71-94; and a pulse generator configured to receive a portion of the lead to electrically couple the lead to a control circuit of the pulse generator, wherein the control circuit is configured to receive the measured electrochemical signal from the plurality of sensing electrodes and determine the one or more chemical analytes present in the brain based on the measured electrochemical signal.

[0260] Embodiment 99. The implantable neuromodulation system of embodiment 98, wherein the control circuit is configured to generate and transmit electrical energy to the one or more stimulating electrodes and one or more of the plurality of sensing electrodes.

[0261] Embodiment 100. The implantable neuromodulation system of embodiment 99, wherein the control circuit is configured to receive a command from an external device, thecommand configured to cause the control circuit to deliver the electrical energy to the brain via the one or more stimulating electrodes and / or the one or more sensing electrodes.

[0262] Embodiment 101. The implantable neuromodulation system of embodiment 100, comprising a radio frequency (RF) antenna coupled to the control circuit such that the control circuit receives the command from RF waves emitted by the external device.

[0263] Embodiment 102. The implantable neuromodulation system of embodiment 101, wherein the control circuit is configured to communicate with the external device using radio wave backscatter.

[0264] Embodiment 103. The implantable neuromodulation system of embodiment 101 or 102, wherein the control circuit receives energy from the RF waves emitted by the external device.

[0265] Embodiment 104. The implantable neuromodulation system of any one of embodiments 101-103, wherein the RF antenna is configured to be implanted beneath a scalp external to a housing of the pulse generator.

[0266] Embodiment 105. The implantable neuromodulation system of embodiment 100, comprising one or more ultrasonic transducers coupled to the control circuit such that the control circuit receives the command from ultrasonic waves emitted by the external device.

[0267] Embodiment 106. The implantable neuromodulation system of embodiment 105, wherein the control circuit is configured to communicate with the external device using ultrasonic backscatter.

[0268] Embodiment 107. The implantable neuromodulation system of embodiment 105 or 106, wherein the control circuit receives energy from the ultrasonic waves emitted by the external device.

[0269] Embodiment 108. The implantable neuromodulation system of any one of embodiments 105-107, wherein the one or more ultrasonic transducers are configured to be disposed within a housing of the pulse generator.

[0270] Embodiment 109. The implantable neuromodulation system of any one of embodiments 98-108, comprising an energy storage electrically coupled to the control circuit and configured to be disposed within the housing of the pulse generator.

[0271] Embodiment 110. The implantable neuromodulation system of embodiment 109, wherein the energy storage is a rechargeable battery.

[0272] Embodiment 111. The implantable neuromodulation system of any one of embodiments 100-110, comprising the external device configured to communicate with the control circuit of the pulse generator.

[0273] Embodiment 112. A method of implanting the lead of any one of embodiments 1- 35, 39-67, and 71-94, comprising: generating an opening in a surface of a human skull; and implanting a portion of the lead comprising the plurality of sensing electrodes in the brain through the opening.

[0274] Embodiment 113. The method of embodiment 112, wherein implanting the portion of the lead comprises implanting the plurality of sensing electrodes disposed on the lead body in a basal ganglia or a cortex of the brain.

[0275] Embodiment 114. The method of embodiment 112 or 113, wherein the lead comprises one or more stimulating electrodes are disposed on the lead body, and the method comprises implanting a portion of the lead comprising the one or more stimulating electrodes in the basal ganglia or the cortex of the brain.

[0276] Embodiment 115. The method of any one of embodiments 112-114, comprising electrically connecting the lead to a pulse generator configured to be implanted in the human skull.

[0277] Embodiment 116. The method of embodiment 115, wherein the lead comprises one or more electrical contacts disposed on a proximal portion of the lead body and configured to electrically connect to a lead connection port of the pulse generator.

[0278] Embodiment 117. The method of any one of embodiments 112-116, wherein the opening is a burr hole sized to receive the lead.

[0279] Embodiment 118. The method of any one of embodiments 112-116, wherein the opening is sized to receive the pulse generator.

[0280] Embodiment 119. The method of any one of embodiments 112-118, comprising mounting a proximal portion of the lead to the surface of the skull using a lead fixation apparatus configured to receive a portion of the lead body.

[0281] Embodiment 120. The method of any one of embodiments 112-119, wherein the lead body comprises a lumen configured to receive a stylet body for implanting the lead to the brain.

[0282] Embodiment 121. A neuromodulation system, comprising: a neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain; anda control circuit electrically coupled to the plurality of sensing electrodes and configured to determine a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

[0283] Embodiment 122. The system of embodiment 121, wherein the control circuit is configured to determine the concentration of the one or more chemical analytes in the brain based on calibration curve data corresponding to each of the one or more chemical analytes, the calibration curve data describing a relationship between current, concentration, and electric potential for each of the one or more chemical analytes.

[0284] Embodiment 123. The system of embodiment 121 or 122, wherein the plurality of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode.

[0285] Embodiment 124. The system of embodiment 123, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counterreference electrode to generate the electrochemical signal.

[0286] Embodiment 125. The system of embodiment 123 or 124, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counter-reference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

[0287] Embodiment 126. The system of embodiment 125, wherein, without applying any current waveform at the at least one working electrode or the at least one counter-reference electrode, the control circuit is configured to determine the concentration of at least one chemical analyte present in the brain.

[0288] Embodiment 127. The system of any one of embodiments 123-126, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a predetermined current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0289] Embodiment 128. The system of embodiment 127, wherein, based on the electric potential measured in response to the applied predetermined current waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined current waveform.

[0290] Embodiment 129. The system of any one of embodiments 123-128, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter-reference electrode in response to a predetermined electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0291] Embodiment 130. The system of embodiment 129, wherein, based on the current signal measured in response to the applied predetermined electric potential waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined electric potential waveform.

[0292] Embodiment 131. The system of any one of embodiments 123-130, wherein the at least one working electrode is a microelectrode.

[0293] Embodiment 132. The system of embodiment 131, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one microelectrode or the at least one counterreference electrode in response to a predetermined triangular electric potential waveform applied between the at least one working electrode and the counter-reference electrode.

[0294] Embodiment 133. The system of embodiment 132, wherein, based on the current signal measured in response to the applied predetermined triangular potential waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined triangular electric potential waveform.

[0295] Embodiment 134. The system of embodiment 121 or 122, wherein the plurality of sensing electrodes comprises at least one working electrode, at least one counter electrode, and at least one reference electrode.

[0296] Embodiment 135. The system of embodiment 134, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter electrode.

[0297] Embodiment 136. The system of embodiment 134 or 135, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode without applying any current waveform to the at least one working electrode or the at least one counter electrode.

[0298] Embodiment 137. The system of embodiment 136, wherein, without applying any current waveform at the at least one working electrode, the at least one counter electrode, or the at least one counter-reference electrode, the control circuit is configured to determine the concentration of at least one chemical analyte present in the brain.

[0299] Embodiment 138. The system of any one of embodiments 134-137, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a predetermined current waveform applied at the at least one working electrode or the at least one counter electrode.

[0300] Embodiment 139. The system of embodiment 138, wherein, based on the electric potential measured in response to the applied predetermined current waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined current waveform.

[0301] Embodiment 140. The system of any one of embodiments 134-139, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to a predetermined electric potential waveform to between the at least one working electrode relative to the at least one reference electrode.

[0302] Embodiment 141. The system of embodiment 140, wherein, based on the current signal measured in response to the applied predetermined electric potential waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined electric potential waveform.

[0303] Embodiment 142. The system of any one of embodiments 134-141, wherein the at least one working electrode is a microelectrode.

[0304] Embodiment 143. The system of embodiment 142, wherein the at least one working or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to a predetermined triangular electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0305] Embodiment 144. The system of embodiment 143, wherein, based on the current signal measured in response to the applied predetermined triangular potential waveform, the control circuit is configured to determine the concentration of a chemical analyte corresponding to the predetermined triangular electric potential waveform.

[0306] Embodiment 145. The system of any one of embodiments 121-144, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, wherein a first set of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode, and wherein a second set of sensing electrodes comprises at least one working electrode, at least one counter electrode, and at least one reference electrode.

[0307] Embodiment 146. The system of any one of embodiments 121-145, wherein the plurality of sensing electrodes are configured to measure a plurality of electrochemical signals generated by a plurality of chemical analytes simultaneously.

[0308] Embodiment 147. The system of embodiment 146, wherein the control circuit is configured to determine the concentration of each chemical analyte of the plurality of chemical analytes simultaneously.

[0309] Embodiment 148. The system of any one of embodiments 121-147, wherein the plurality of sensing electrodes comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon oxide, silicon nitride, and nickel.

[0310] Embodiment 149. The system of any one of embodiments 121-148, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0311] Embodiment 150. The system of any one of embodiments 121-149, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0312] Embodiment 151. An implantable neuromodulation system, comprising the system of any one of embodiments 121-150, wherein the control circuit is of a pulse generator that receives a portion of the lead to electrically couple the lead to the control circuit.

[0313] Embodiment 152. The implantable neuromodulation system of embodiment 151, wherein the lead comprises one or more stimulating electrodes disposed on the lead body and configured to deliver electrical energy to the brain, the control circuit electrically coupled to the one or more stimulating electrodes and one or more of the plurality of sensing electrodes to generate and transmit the electrical energy to the one or more stimulating electrodes and the one or more sensing electrodes.

[0314] Embodiment 153. The implantable neuromodulation system of embodiment 152, wherein the control circuit is configured to receive a command from an external device, thecommand configured to cause the control circuit to deliver the electrical energy to the brain via the one or more stimulating electrodes and / or the one or more sensing electrodes.

[0315] Embodiment 154. The implantable neuromodulation system of embodiment 153, comprising a radio frequency (RF) antenna coupled to the control circuit such that the control circuit receives the command from RF waves emitted by the external device.

[0316] Embodiment 155. The implantable neuromodulation system of embodiment 154, wherein the control circuit is configured to communicate with the external device using radio wave backscatter.

[0317] Embodiment 156. The implantable neuromodulation system of embodiment 154 or 155, wherein the control circuit receives energy from RF waves emitted by the external device.

[0318] Embodiment 157. The implantable neuromodulation system of any one of embodiments 154-156, wherein the RF antenna is configured to be implanted beneath a scalp external to a housing of the pulse generator.

[0319] Embodiment 158. The implantable neuromodulation system of embodiment 153, comprising one or more ultrasonic transducers coupled to the control circuit such that the control circuit receives the command from ultrasonic waves emitted by the external device.

[0320] Embodiment 159. The implantable neuromodulation system of embodiment 158, wherein the control circuit is configured to communicate with the external device using ultrasonic backscatter.

[0321] Embodiment 160. The implantable neuromodulation system of any one of embodiments 158 or 159, wherein the control circuit receives energy from ultrasonic waves emitted by the external device.

[0322] Embodiment 161. The implantable neuromodulation system of any one of embodiments 158-160, wherein the one or more ultrasonic transducers are configured to be disposed within a housing of the pulse generator.

[0323] Embodiment 162. The implantable neuromodulation system of any one of embodiments 151-161, comprising an energy storage electrically coupled to the control circuit and configured to be disposed within the housing of the pulse generator.

[0324] Embodiment 163. The implantable neuromodulation system of embodiment 162, wherein the energy storage is a rechargeable battery.

[0325] Embodiment 164. The implantable neuromodulation system of any one of embodiments 153-163, comprising the external device configured to communicate with the control circuit of the pulse generator.

[0326] Embodiment 165. A method for determining concentration of a chemical analyte in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; and determining, at a control circuit electrically coupled to the plurality of sensing electrodes, a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

[0327] Embodiment 166. The method of embodiment 165, comprising, based on the determined concentration of the one or more chemical analytes, delivering, via one or more stimulating electrodes disposed on the lead body and / or one or more of the sensing electrodes, electrical stimulation to the brain.

[0328] Embodiment 167. The method of embodiment 165 or 166, comprising: delivering, via one or more of the sensing electrodes, a predetermined current waveform or predetermined potential waveform to the brain; measuring the electrochemical signal generated based on a response of the one or more chemical analytes to the predetermined current waveform or the predetermined potential waveform; and determining the concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

[0329] Embodiment 168. A method of controlling electrochemical signal detection, comprising: measuring, at one or more sensing electrodes of a plurality of sensing electrodes of a neuromodulation lead, a first electrochemical signal generated by one or more chemical analytes present in a brain; and based on a determination that the first electrochemical signal reaches a threshold, measuring, at the one or more sensing electrodes of the neuromodulation lead, a second electrochemical signal generated by the one or more chemical analytes present in the brain, the second electrochemical signal different from the first electrochemical signal.

[0330] Embodiment 169. The method of embodiment 168, comprising determining, based on the second electrochemical signal measured at the one or more sensing electrodes, the one or more chemical analytes present in the brain.

[0331] Embodiment 170. The method of embodiment 168 or 169, comprising delivering, via one or more of the sensing electrodes, an electric potential waveform or a currentwaveform to the brain to cause the one or more chemical analytes in the brain to generate the second electrochemical signal.

[0332] Embodiment 171. The method of any one of embodiments 168-170, wherein the first electrochemical signal comprises one or more electric potential signals and the second electrochemical signal comprises one or more current signals.

[0333] Embodiment 172. The method of any one of embodiments 168-171, wherein the threshold is a predetermined threshold based on an increase or a decrease in the first electrochemical signal measured at the one or more sensing electrodes.

[0334] Embodiment 173. The method of any one of embodiments 168-172, wherein the plurality of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode.

[0335] Embodiment 174. The method of embodiment 173, wherein measuring the first electrochemical signal at the one or more sensing electrodes comprises measuring, at the at least one working electrode and the at least one counter-reference electrode, an electric potential signal between the at least one working electrode and the at least one counterreference electrode without applying a current waveform at the at least one working electrode or the at least one counter-reference electrode.

[0336] Embodiment 175. The method of embodiment 173, wherein measuring the first electrochemical signal comprises measuring, at the at least one working electrode and the at least one counter-reference electrode, an electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0337] Embodiment 176. The method of any one of embodiments 173-175, wherein measuring the second electrochemical signal comprises measuring, at the at least one working electrode or the at least one counter-reference electrode, a current signal at the at least one working electrode or the at least one counter-reference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0338] Embodiment 177. The method of any one of embodiments 173-175, wherein the at least one working electrode is a microelectrode, and measuring the second electrochemical signal comprises measuring, at the at least one working electrode or the at least one counterreference electrode, a current signal passing through the at least one working electrode or the at least one counter-reference electrode in response to a triangular electric potential waveformapplied between the at least one working electrode and the at least one counter-reference electrode.

[0339] Embodiment 178. The method of any one of embodiments 168-172, wherein the plurality of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

[0340] Embodiment 179. The method of embodiment 178, wherein measuring first electrochemical signal at the one or more sensing electrodes comprises measuring, at the at least one working electrode and the at least one reference electrode, an electric potential signal between the at least one working electrode and the at least one reference electrode without applying a current waveform at the at least one working electrode or the at least one counter electrode.

[0341] Embodiment 180. The method of embodiment 178, wherein measuring the first electrochemical signal comprises measuring, at the at least one working electrode and the at least one reference electrode, an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

[0342] Embodiment 181. The method of any one of embodiments 178-180, wherein measuring the second electrochemical signal comprises measuring, at the least one working electrode or the at least one counter electrode, a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0343] Embodiment 182. The method of any one of embodiments 178-180, wherein the at least one working electrode is a microelectrode, and measuring the second electrochemical signal comprises measuring, at the at least one working electrode or the at least one counter electrode, a current signal passing through the at least one working electrode or the at least one counter electrode in response to a triangular electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0344] Embodiment 183. The method of any one of embodiments 168-182, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0345] Embodiment 184. The method of any one of embodiments 168-183, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0346] Embodiment 185. A neuromodulation system, comprising: a neuromodulation lead, comprising: a lead body; one or more stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to a brain; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in the brain; and a control circuit electrically coupled to the one or more stimulating electrodes and the plurality of sensing electrodes, the control circuit configured to: receive the electrochemical signal measured by the plurality of sensing electrodes; based on the measured electrochemical signal, determine one or more stimulation parameters for the electrical stimulation; and generate and transmit the electrical stimulation in accordance with the one or more stimulation parameters to the one or more stimulating electrodes.

[0347] Embodiment 186. The system of embodiment 185, wherein the one or more stimulating parameters comprises at least one of a pulse width, a frequency, a pulse train duration, and an amplitude of the electrical stimulation.

[0348] Embodiment 187. The system of embodiment 185 or 186, wherein, based on the measured electrochemical signal, the control circuit is configured to determine at least one stimulating electrode of the one or more stimulating electrodes to transmit the electrical stimulation to.

[0349] Embodiment 188. The system of any one of embodiments 185-187, wherein the control circuit is configured to generate and transmit an initial energy to the one or more stimulating electrodes, thereby causing the one or more stimulating electrodes and / or the at least one sensing electrode to deliver the initial energy to the brain, and wherein the plurality of sensing electrodes are configured to measure the electrochemical signal generated by the one or more chemical analytes in response to the initial energy.

[0350] Embodiment 189. The system of embodiment 188, wherein determining the one or more stimulation parameters for the electrical stimulation comprises modifying the one or more stimulation parameters from the initial energy based on the measured electrochemical signal to generate one or more updated stimulation parameters for the electrical stimulation.

[0351] Embodiment 190. The system of embodiment 189, wherein the one or more updated stimulation parameters for the electrical stimulation comprises an increase or a decrease in at least one of a pulse width, a frequency, a pulse train duration, and an amplitude of the electrical stimulation.

[0352] Embodiment 191. The system of any one of embodiments 188-190, wherein the system is configured to transmit the electrical stimulation to one or more stimulating electrodes different from the one or more stimulating electrodes that delivered the initial electrical stimulation.

[0353] Embodiment 192. The system of any one of embodiments 185-191, wherein the one or more stimulating electrodes are further configured as a sensing electrode for measuring an electrochemical signal generated by one or more chemical analytes present in the brain.

[0354] Embodiment 193. The system of any one of embodiments 185-192, wherein at least one of the plurality of sensing electrodes is configured to operate as a stimulating electrode.

[0355] Embodiment 194. The system of any one of embodiments 185-193, wherein the plurality of sensing electrodes comprises at least one working electrode and at least one counter-reference electrode.

[0356] Embodiment 195. The system of embodiment 194, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counter-reference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

[0357] Embodiment 196. The system of embodiment 194 or 195, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal between the at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

[0358] Embodiment 197. The system of embodiment 196, wherein the control circuit is configured to transmit the current waveform to the at least one working electrode or the at least one counter-reference electrode.

[0359] Embodiment 198. The system of any one of embodiments 194-197, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter-reference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

[0360] Embodiment 199. The system of embodiment 198, wherein the control circuit is configured to transmit the electric potential waveform to between the at least one working electrode and the at least one counter-reference electrode.

[0361] Embodiment 200. The system of any one of embodiments 194-199, wherein the at least one working electrode is a microelectrode.

[0362] Embodiment 201. The system of embodiment 200, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counterreference electrode in response to a triangular electric potential waveform applied between the at least one working electrode and the counter-reference electrode.

[0363] Embodiment 202. The system of embodiment 200 or 201, wherein the control circuit is configured to transmit the triangular electric potential waveform to between the at least one working electrode and the at least one counter-reference electrode.

[0364] Embodiment 203. The system of any one of embodiments 185-193, wherein the plurality of sensing electrodes comprises at least one working electrode, at least one counter electrode, and at least one reference electrode.

[0365] Embodiment 204. The system of embodiment 203, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode without applying a current waveform at the at least one working electrode or the at least one counter electrode.

[0366] Embodiment 205. The system of embodiment 203 or 204, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

[0367] Embodiment 206. The system of embodiment 205, wherein the control circuit is configured to transmit the current waveform to the at least one working electrode or the at least one counter electrode.

[0368] Embodiment 207. The system of any one of embodiments 203-206, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0369] Embodiment 208. The system of embodiment 207, wherein the control circuit is configured to transmit the electric potential waveform to the at least one working electrode relative to the at least one reference electrode.

[0370] Embodiment 209. The system of any one of embodiments 203-208, wherein the at least one working electrode is a microelectrode.

[0371] Embodiment 210. The system of embodiment 209, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to a triangular electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

[0372] Embodiment 211. The system of embodiment 210, wherein the control circuit is configured to transmit the triangular electric potential waveform to the at least one working electrode relative to the at least one reference electrode.

[0373] Embodiment 212. The system of any one of embodiments 185-211, wherein the plurality of sensing electrodes are configured to measure a plurality of electrochemical signals generated by a plurality of chemical analytes simultaneously.

[0374] Embodiment 213. The system of any one of embodiments 185-212, wherein the plurality of sensing electrodes comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon oxide, silicon nitride, and nickel.

[0375] Embodiment 214. The system of any one of embodiments 185-213, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

[0376] Embodiment 215. The system of any one of embodiments 185-214, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

[0377] Embodiment 216. An implantable neuromodulation system, comprising the system of any one of embodiments 185-215, wherein the control circuit is of a pulse generator that receives a portion of the lead to electrically couple the lead to the control circuit.

[0378] Embodiment 217. The implantable neuromodulation system of embodiment 216, wherein the control circuit is configured to receive a command from an external device, the command configured to cause the control circuit to deliver the electrical stimulation to the brain via the one or more stimulating electrodes and / or the one or more sensing electrodes.

[0379] Embodiment 218. The implantable neuromodulation system of embodiment 217, comprising a radio frequency (RF) antenna coupled to the control circuit such that the control circuit receives the command from RF waves emitted by the external device.

[0380] Embodiment 219. The implantable neuromodulation system of embodiment 218, wherein the control circuit is configured to communicate with the external device using radio wave backscatter.

[0381] Embodiment 220. The implantable neuromodulation system of embodiment 218 or 219, wherein the control circuit receives energy from RF waves emitted by the external device.

[0382] Embodiment 221. The implantable neuromodulation system of any one of embodiments 218-220, wherein the RF antenna is configured to be implanted beneath a scalp external to a housing of the pulse generator.

[0383] Embodiment 222. The implantable neuromodulation system of embodiment 217, comprising one or more ultrasonic transducers coupled to the control circuit such that the control circuit receives the command from ultrasonic waves emitted by the external device.

[0384] Embodiment 223. The implantable neuromodulation system of embodiment 217, wherein the control circuit is configured to communicate with the external device using ultrasonic backscatter.

[0385] Embodiment 224. The implantable neuromodulation system of embodiment 222 or 223, wherein the control circuit receives energy from ultrasonic waves emitted by the external device.

[0386] Embodiment 225. The implantable neuromodulation system of any one of embodiments 222-224, wherein the one or more ultrasonic transducers are configured to be disposed within a housing of the pulse generator.

[0387] Embodiment 226. The implantable neuromodulation system of any one of embodiments 216-225, comprising an energy storage electrically coupled to the control circuit and configured to be disposed within the housing of the pulse generator.

[0388] Embodiment 227. The implantable neuromodulation system of embodiment 226, wherein the energy storage is a rechargeable battery.

[0389] Embodiment 228. The implantable neuromodulation system of any one of embodiments 217-227, comprising the external device configured to communicate with the control circuit of the pulse generator.

[0390] Embodiment 229. A method for stimulating a brain based on electrochemical signals, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; determining, at a control circuit electrically coupled to the plurality of sensing electrodes, one or more stimulation parameters for electrical stimulation of the brain based on the measured electrochemical signal; and delivering, at one or more stimulating electrodes disposed on the lead body and electrically coupled to the control circuit, the electrical stimulation in accordance with the one or more stimulation parameters to the brain.

[0391] Embodiment 230. The method of embodiment 229, comprising determining at least one stimulating electrode of the one or more stimulating electrodes to use for delivering the electrical stimulation.

[0392] Embodiment 231. The method of embodiment 229 or 230, comprising: delivering, at the one or more stimulating electrodes, an initial electrical stimulation to the brain; measuring, at the one or more sensing electrodes, the electrochemical signal generated by the one or more chemical analytes present in the brain; and modifying the one or more stimulation parameters from the initial electrical stimulation based on the measured electrochemical signal to generate one or more updated stimulation parameters for the electrical stimulation.

[0393] Embodiment 232. The method of embodiment 231, comprising changing at least one stimulating electrode of the one or more stimulating electrodes used to deliver the electrical stimulation.

[0394] Embodiment 233. The method of embodiment 231 or 232, comprising delivering, at the one or more stimulating electrodes, the electrical stimulation to the brain in accordance with the one or more updated stimulation parameters.EXAMPLES

[0395] The following examples are exemplary and are not intended to limit the scope of any invention or inventions described herein.

[0396] Several studies, including in vitro (Examples 1-4 and 5A-5E) and in vivo (Examples 6A-6C) lab studies were performed to assess the chemical analyte sensing modalities described herein. The results of the studies are described below with reference to FIGS. 10A-10B, 11, 12, 13A-13B, 14A-14E, and 15A-15D.Example 1: Passive Potentiometry - No Current Applied

[0397] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a Platinum- Iridium (Pt-Ir) working electrode disposed on a neuromodulation lead, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag-AgCl) reference electrode. The chemical analyte dopamine was introduced to the electrochemical cell incrementally over a time span of 600 s until a concentration of 1 pM was reached. No current was applied between the sensing electrodes (e.g., the working and counter electrode). The electric potential between the sensing electrodes was measured as a function of time and as a function of concentration of the chemical analyte in the PBS.

[0398] Results: FIG. 10A depicts the measured electric potential signal as the chemical analyte dopamine was introduced to the beaker, without applying any energy between the sensing electrodes. FIG. 10B depicts the relationship between measured potential and dopamine concentration. As shown, without any energy applied at the sensing electrodes, the measured electric potential signal decreased with increasing concentration of the chemical analyte.Example 2: Active Potentiometry - Constant Current Waveform

[0399] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a Platinum- Iridium (Pt-Ir) working electrode disposed on a neuromodulation lead, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag-AgCl) reference electrode. The chemical analytes dopamine, serotonin, and norepinephrine were introduced to the electrochemical cell incrementally until a concentration of 5 pM (of each of the chemical analytes) was reached. A constant current of 300 nA was applied at the counter electrode. Electric potential was measured as a function of concentration for each of the chemical analytes.

[0400] Results: FIG. 11 depicts measured potential signals for each of the three chemical analytes - dopamine, serotonin, and norepinephrine - in response to the constant current applied at the counter electrode. As shown in FIG. 11, for each of the three chemical analytes, the electric potential signal of the working electrode measured relative to the electric potential of the reference electrode decreased non-linearly with increasing analyte concentration.Example 3: Active Potentiometry — Pulsed Current Waveform

[0401] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a Platinum- Iridium (Pt-Ir) working electrode disposed on a neuromodulation lead, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag-AgCl) reference electrode. The chemical analytes dopamine, serotonin, and norepinephrine were introduced to the electrochemical cell incrementally until a concentration of 5 pM (of each of the chemical analytes) was reached. A biphasic current pulse of 400 nA with a 0.5 s pulse train duration was applied at the counter electrode. Electric potential was measured as a function of concentration for each of the chemical analytes.

[0402] Results: FIG. 12 depicts measured potential signals for each the three chemical analytes - dopamine, serotonin, and norepinephrine - in response to the pulsed current waveform applied at the counter electrode. As shown in FIG. 12, for each of the three chemical analytes, the electric potential signal of the working electrode measured relative to the electric potential of the reference electrode decreased non-linearly with increasing analyte concentration.Example 4: Amperometry - Constant Electric Potential

[0403] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a Platinum- Iridium (Pt-Ir) working electrode disposed on a neuromodulation lead, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag-AgCl) reference electrode. The chemical analytes dopamine, serotonin, and norepinephrine were introduced to the electrochemical cell incrementally over a time span of 250 s until a concentration of 5 pM (of each of the chemical analytes) was reached. An electric potential waveform having a magnitude of 0.7 V was applied to the working electrode relative to the reference electrode. Current was measured as a function of time and as a function of concentration of the analytes in PBS.

[0404] Results: FIG. 13 A depicts a measured current signal for the chemical analyte dopamine, generated in response to the constant electric potential waveform applied to the working electrode (relative to the reference electrode). As shown in FIG. 13 A, the measured current signal increased with increasing concentration of the target analytes when the constant electric potential waveform was applied to the working electrode relative to the potential of the reference electrode. FIG. 13B depicts measured current signals for each the three chemical analytes - dopamine, serotonin, and norepinephrine - in response in response to the constant electric potential applied to the working electrode. As shown in FIG. 13B, for each of the three chemical analytes, the working electrode measured a current signal that increased almost linearly with analyte concentration.Example 5 A: Fast-Scan Cyclic Voltammetry (In Vitro)

[0405] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a working electrode that is a carbon fiber, glass-insulated microelectrode, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag- AgCl) reference electrode. The chemical analyte dopamine was introduced to the electrochemical cell until a concentration of 100 nM of dopamine in PBS was reached. A triangular electric potential waveform was applied at the working electrode. The triangular electric potential waveform was swept between -0.4 V (the holding potential) and 1.3 V (the switching potential). The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. Current was measured as a function of applied electric potential.

[0406] Results: FIG. 14A depicts the current signal measured in response to the triangular electric potential waveform applied at the microelectrode. As shown in FIG. 14A, the measured current signal included contributions from a reduction reaction (Ired) and an oxidation reaction (Lx), each of which were measured in response to the first electric potential peak of the triangular electric potential waveform. The right-most current signal (lox) was measured from the oxidation of dopamine into dopamine-o-quinone based on the applied potential scanned from -0.4 V to 1.3 V. The left- most current signal was measured from the subsequent reduction of the dopamine-o-quinone when the applied potential was scanned from 1.3 V to -0.4 V. FIG. 14A demonstrates the ability of voltammetry for detecting the chemical analyte dopamine.Example 5B: FSCV at Various Concentrations of Chemical Analyte

[0407] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a working electrode that is a carbon fiber, glass-insulated microelectrode, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag- AgCl) reference electrode. The chemical analyte dopamine (DA) was introduced incrementally to the electrochemical cell until the each of the following concentrations of dopamine in the PBS were reached: 25 nM, 100 nM, 400 nM, and 1600 nM. A triangular electric potential waveform was applied at the working electrode. The triangular electric potential waveform was swept between -0.4 V (the holding potential) and 1.3 V (the switching potential). The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. Current was measured as a function of applied electric potential for each of the four concentrations of chemical analyte.

[0408] Results: FIG. 14B depicts current signals measured in response to the applied triangular electric potential waveform for the various concentrations of dopamine (DA) ranging from 25 nM to 1600 nM. FIG. 14B demonstrates that the ability of voltammetry for detecting a wide range of physiologically relevant dopamine levels.Example 5C: Repeatability of FSCV

[0409] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a working electrode that is a pyrolytic carbonmicroelectrode, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag- AgCl) reference electrode. The chemical analyte dopamine was introduced to the electrochemical cell at a concentration of 5 pM in the PBS. Ascorbic acid, a known chemical for producing chemical fouling of electrodes, was introduced to the solution in the beaker at a concentration of 200 pM to promote chemical fouling of the electrochemical cell. A triangular electric potential waveform was applied at the working electrode. The triangular electric potential waveform was swept between -0.4 V (the holding potential) and 1.0 V (the switching potential). The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. The electrochemical cell was subjected to a total of 35 FSCV sensing events in the fouling solution, where each sensing event consisted of 300 cycles of the triangular electric potential waveform. The fouling resistance of the pyrolytic carbon microelectrode was assessed periodically (once every 5 sensing events, i.e., every 1500 cycles) by measuring the oxidation and reduction currents in a separate test solution comprising 50nM dopamine in PBS. These oxidation and reduction currents were plotted as a function of the total number of sensing events in the fouling solution.

[0410] Results: FIG. 14C depicts the oxidation and reduction current signals measured in response to intermittent exposure to 50 nM dopamine solution in PBS across several (35) sensing events. As shown in FIG. 14C, for both the oxidation and reduction reaction, the measured current signal remained fairly consistent over the 35 sensing events, demonstrating the repeatability and fouling resistance of voltammetric sensing (FSCV) using carbon-based microelectrodes.. This repeatability can indicate use of the measurement modality in a neuromodulation lead because the lead could necessitate fewer replacements over time.Example 5D: Bilinearity of FSCV

[0411] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a working electrode that is a pyrolytic carbon microelectrode, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag- AgCl) reference electrode. Several different physiologically relevant concentrations of the chemical analyte dopamine (DA) ranging from 10-1600 nM were incrementally introduced to the electrochemical cell until the desired concentration of dopamine in PBS was reached. The dopamine concentrations included 10 nM, 25 nM, 50 nM, 100 nM, 200 nM, 400 nM, 800 nM, and 1600 nM. A triangular electric potential waveform was applied at the workingelectrode. The triangular electric potential waveform was swept between -0.4 V (the holding potential) and 1.0 V (the switching potential). The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. Current signals generated by the dopamine in the electrochemical cell were measured for each of the different concentrations of dopamine. The peak current signals (oxidation and reduction currents) were plotted as a function of concentration of dopamine in PBS.

[0412] Results: FIG. 14D depicts the peak oxidation and reduction current signals as a function of concentration of the chemical analyte dopamine. As shown in FIG. 14D, the current signals obtained from voltammetric measurement of dopamine were bilinear across the range of physiologically relevant dopamine concentrations. The nearly constant slopes of the oxidation current signal (or peak) and the reduction current signal (or peak) can aid calibration of the neuromodulation lead by facilitating a more accurate translation of arbitrary values of current signals obtained from in vivo voltammetry into dopamine concentration values.Example 5E: Low Hysteresis ofFSCV

[0413] Methods: An electrochemical cell was prepared in vitro in a beaker containing a solution of phosphate buffer saline (PBS). The electrochemical cell consisted of a three- electrode sensing electrode setup - a working electrode that is a pyrolytic carbon microelectrode, a counter electrode that is a platinum (Pt) coil, and silver-silver chloride (Ag- AgCl) reference electrode. Several different physiologically relevant concentrations of the chemical analyte dopamine (DA) ranging from 10-1600 nM were introduced to the electrochemical cell. Specifically, in one trial, the dopamine concentration in the electrochemical cell was increased incrementally from 10 nM, 25 nM, 50 nM, 200 nM, 400 nM, 800 nM, to 1600 nM in PBS. In another trial, the dopamine concentration in the electrochemical cell was decreased incrementally from 1600 nM to 10 nM (i.e., 1600 nM, 800 nM, 400 nM, 200 nM, 100 nM, 50 nM, 25 nM, to 10 nM). Between each incremental change in the latter trial, the PBS solution containing dopamine was discarded and replaced with a blank PBS solution. For example, beginning with a blank PBS solution, dopamine was added until a concentration of 1600nM of dopamine in PBS was reached. After performing FSCV and recording the oxidation and reduction currents, this PBS solution containing 1600nM dopamine was discarded and replaced with a fresh PBS solution containing OnM dopamine. Dopamine was added to this fresh PBS solution until a concentration of 800nM of dopamine in PBS was reached, and the process continued until lOnM of dopamine in PBSwas reached. A triangular electric potential waveform was applied at the working electrode. The triangular electric potential waveform was swept between -0.4 V (the holding potential) and 1.0 V (the switching potential). The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. Current signals generated by the dopamine in the electrochemical cell were measured at each of the different concentrations of dopamine in the increasing (i.e., forward) and decreasing (i.e., reverse) trials.

[0414] Results: FIG. 14E depicts the measured current signal at various concentrations of dopamine between 10-1600 nM in the two above-described trials. As shown in FIG. 14E, the current signals at different dopamine concentrations were nearly identical in the forward (10 nM to 1600 nM) and reverse (1600 nM to 10 nM) trials, highlighting the low hysteresis of voltammetry on carbon microelectrodes. Low hysteresis can enable accuracy of sensing dopamine regardless of the direction in which the concentration of dopamine varies (e.g., increasing or decreasing) before and / or during measurements. More generally, the low hysteresis of voltammetry shown in this Example can indicate the potential influence of historic dopamine exposures on the dopamine sensitivity of carbon-based microelectrodes.Example 6A: In vivo FSCV Measurements

[0415] Methods: Two separate microscale leads containing stimulating and sensing electrodes (respectively) were implanted to the brain of an anesthetized rat. The stimulating electrode was a Pt-Ir microelectrode implanted to the median forebrain bundle (MFB) of the rat’s brain. The sensing electrode was a carbon fiber microelectrode implanted to the striatum of the rat’s brain. A triangular electric potential waveform was applied at the stimulating electrode. The triangular electric potential waveform was swept between -0.4 V and 1.3 V. The scan rate of the triangular electric potential waveform was 400 V / s. The frequency of the triangular electric potential waveform was 10 Hz. The current signals were measured by the sensing electrode for 20 seconds in response to the applied triangular electric potential waveform.

[0416] Results: FIG. 15A depicts the current signals generated by the chemical analyte dopamine in response to the applied triangular FSCV waveform over time. As shown in FIG. 15A, stimulating the MFB (depicted by the slant lines) produced the expected transients in striatal dopamine concentration, which was recorded by the concomitant increase and subsequent decrease in dopamine oxidation (dark shading focused around the potential of about 1 V) and reduction (light shading focused around the potential of about -0.4 V)currents. FIG. 15B is a different representation of the same data illustrated in FIG. 15A, highlighting the measured current at 3 different times - 9, 10, and 15 seconds after stimulation. FIGS. 15A-15B demonstrate the efficacy of voltametric sensing in vivo. More generally, the relationship between applied potential and measured current depicted in FIGS. 15A-15B is similar to that which is depicted in FIGS. 14A-14B, demonstrating agreement between in vitro and in vivo voltammetry.Example 6B: Voltammetry with Varying Stimulation Pulse Width

[0417] Methods: Two separate microscale leads containing stimulating and sensing electrodes (respectively) were implanted to the brain of an anesthetized rat. The stimulating electrode was a Pt-Ir electrode implanted to the median forebrain bundle (MFB) of the rat’s brain. The sensing electrode was a carbon fiber microelectrode implanted to the striatum of the rat’s brain. A bi-phasic electric potential stimulation pulse was applied at the stimulating electrode. The pulse width of the stimulation was varied between 0.5-2 ms (0.5, 1, and 2 ms). The amplitude of the stimulation was 300 pA. The pulse train duration was 5 s. Current signals were measured in response to the stimulation for each of the different pulse widths. The peak current signals were plotted against stimulation pulse width.

[0418] Results: FIG. 15C depicts the peak current signals measured at the different stimulation pulse widths 0.5, 1, and 2 ms. As shown in FIG. 15C, the measured current signal from voltammetry increased when the duration of the bi-phasic electric potential stimulation pulse (at the MFB) was increased. It is hypothesized that an increase in pulse width of the applied MFB stimulation can cause greater activation of the dopaminergic fibers that extend from the MFB to the striatum, thereby increasing the extracellular concentration of striatal dopamine.Example 6C: Voltammetry with Varying Stimulation Amplitude

[0419] Methods: Two separate microscale leads containing stimulating and sensing electrodes (respectively) were implanted to the brain of an anesthetized rat. The stimulating electrode was a Pt-Ir electrode implanted to the median forebrain bundle (MFB) of the rat’s brain. The sensing electrode was a carbon fiber microelectrode implanted to the striatum of the rat’s brain. A bi-phasic electric potential stimulation pulse was applied at the stimulating electrode. The amplitude of the stimulation was varied between 100-300 pA (100, 200, and 300 pA). The pulse width of the stimulation was 2 ms. The frequency of the stimulation was 60 Hz. The pulse train duration of the stimulation was 5 s. Current signals were measured inresponse to the stimulation for each of the different amplitudes. The peak current signals were plotted against stimulation amplitude.

[0420] Results: FIG. 15D depicts the peak current signals measured at the different stimulation amplitudes 100, 200, and 300 pA. As shown in FIG. 15D, the measured current signal from voltammetry increased when the strength of the bi-phasic electric potential stimulation pulse (at the MFB) was increased. It is hypothesized that an increase in amplitude of the applied MFB stimulation can cause greater activation of the dopaminergic fibers that extend from the MFB to the striatum, thereby increasing the extracellular concentration of striatal dopamine.Conclusion

[0421] The foregoing description, for the purpose of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the techniques and their practical applications. Others skilled in the art are thereby enabled to best utilize the techniques and various embodiments with various modifications as are suited to the particular use contemplated.

[0422] Although the disclosure and examples have been fully described with reference to the accompanying figures, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of the disclosure and examples as defined by the claims.

Claims

CLAIMSWhat is claimed is:

1. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode and at least one counter-reference electrode or (b) at least one working electrode, at least one counter electrode, and at least one reference electrode, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in a brain interacting with at least one of the plurality of sensing electrodes.

2. The lead of claim 1, comprising one or more of stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to the brain.

3. The lead of claim 2, wherein the one or more stimulating electrodes are further configured as a sensing electrode for measuring an electrochemical signal generated by one or more chemical analytes interacting with the one or more stimulating electrodes.

4. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes comprises the at least one working electrode and the at least one counter-reference electrode.

5. The lead of claim 4, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter-reference electrode to generate the electrochemical signal.

6. The lead of claim 4, wherein the at least one working electrode and the least one counter-reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one counter-reference electrode without applying any current at the at least one working electrode or the at least one counter-reference electrode.

7. The lead of claim 4, wherein the at least one working electrode and the at least one counter-reference electrode are configured to measure the electric potential signal betweenthe at least one working electrode and the at least one counter-reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter-reference electrode.

8. The lead of claim 7, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

9. The lead of claim 4, wherein the at least one working electrode or the at least one counter-reference electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter-reference electrode in response to an electric potential waveform applied between the at least one working electrode and the at least one counter-reference electrode.

10. The lead of claim 9, wherein the electric potential waveform comprises at least one of a constant electric potential waveform and a pulsed electric potential waveform.

11. The lead of claim 4, wherein the at least one working electrode and the at least one counter-reference electrode are segmented from each other on the lead body by a first insulation gap.

12. The lead of claim 11, wherein a surface area of the at least one counter-reference electrode is greater than a surface area of the at least one working electrode.

13. The lead of claim 4, wherein the at least one counter-reference electrode at least partially surrounds the first working electrode.

14. The lead of claim 4, wherein a first set of electrodes comprising a first working electrode and a first counter-reference electrode is segmented on the lead body from a second set of electrodes comprising a second working electrode and a second counter-reference electrode by a second insulation gap.

15. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

16. The lead of claim 15, wherein the plurality of sensing electrodes are configured to enable redox cycling by the one or more chemical analytes that occurs between the at least one working electrode and the at least one counter electrode.

17. The lead of claim 15, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode without applying any current waveform to the at least one working electrode or the at least one counter electrode.

18. The lead of claim 15, wherein the at least one working electrode and the at least one reference electrode are configured to measure an electric potential signal between the at least one working electrode and the at least one reference electrode in response to a current waveform applied at the at least one working electrode or the at least one counter electrode.

19. The lead of claim 18, wherein the current waveform comprises at least one of a pulsed current waveform and a constant current waveform.

20. The lead of claim 15, wherein the at least one working electrode or the at least one counter electrode is configured to measure a current signal passing through the at least one working electrode or the at least one counter electrode in response to an electric potential waveform applied to the at least one working electrode relative to the at least one reference electrode.

21. The lead of claim 20, wherein the electric potential waveform comprises a constant electric potential waveform.

22. The lead of claim 20, wherein the electric potential waveform comprises a pulsed electric potential waveform.

23. The lead of claim 15, wherein the at least one working electrode and the at least one reference electrode are separated on the lead body by a first insulation gap, and the at least one reference electrode and the at least one counter electrode are separated on the lead body by a second insulation gap.

24. The lead of claim 15, wherein a surface area of the at least one counter electrode is greater than a surface area of each of the at least one working electrode and the at least one reference electrode.

25. The lead of claim 15, wherein the at least one counter electrode at least partially surrounds each of the working electrode and the counter electrode.

26. The lead of claim 25, wherein the reference electrode at least partially surrounds the working electrode.

27. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes comprises at least two sets of sensing electrodes, wherein a first set of sensing electrodes comprises the at least one working electrode and the at least one counter-reference electrode, and wherein a second set of sensing electrodes comprises the at least one working electrode, the at least one counter electrode, and the at least one reference electrode.

28. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes are configured to measure a plurality of electrochemical signals generated during at least one redox reaction caused by a plurality of chemical analytes simultaneously.

29. The lead of any one of claims 1-3, wherein at least one of the plurality of sensing electrodes is configured to operate as a stimulating electrode.

30. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes comprises a plurality of annular electrodes and / or semi-annular electrodes disposed on the lead body.

31. The lead of any one of claims 1-3, wherein the at least one working electrode is a microelectrode.

32. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes are disposed at a distal portion of the lead body.

33. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes comprises at least one of platinum, iridium, gold, titanium, carbon, silicon, silicon oxide, silicon nitride, and nickel.

34. The lead of any one of claims 1-3, wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated by one or more chemical analytes including: dopamine, serotonin, acetylcholine, norepinephrine, histamine, choline, N-acetyl aspartate, epinephrine, ascorbic acid, lactate, and pyruvate.

35. The lead of any one of claims 1-3, wherein the chemical analytes are present in an intercranial space of the brain comprising brain tissue and / or cerebral spinal fluid (CSF).

36. A method for measuring electrochemical signals in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

37. The method of claim 36, comprising, based on the measured electrochemical signal, delivering, via one or more stimulating electrodes disposed on the lead body and / or one or more of the sensing electrodes, electrical stimulation to the brain.

38. The method of claim 36 or 37, comprising: delivering, via one or more of the sensing electrodes disposed on the lead body, an electric potential waveform or a current waveform to the brain; and measuring the electrochemical signal generated based on a response of the one or more chemical analytes to the electric potential waveform or the current waveform.

39. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and comprising (a) at least one working electrode that is a microelectrode and at least one counter-reference electrode, or (b) at least one working electrode that is a microelectrode, at least one counter electrode, and at least one reference electrode,wherein the plurality of sensing electrodes are configured to measure an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

40. A method for measuring electrochemical signals in a brain, comprising: measuring, at a plurality of sensing electrodes comprising at least one working electrode that is a microelectrode disposed on a lead body, an electrochemical signal generated during a redox reaction caused by one or more chemical analytes present in the brain interacting with at least one of the plurality of sensing electrodes.

41. A neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain, wherein one or more sensing electrodes of the plurality of sensing electrodes comprises a chemical-analyte-selective coating that interacts with at least one specific chemical analyte at the one or more sensing electrodes.

42. A method for measuring electrochemical signals in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain, wherein one or more of the sensing electrodes of the plurality of sensing electrodes comprises a chemical-analyte-selective coating that interacts with at least one specific chemical analyte at the one or more sensing electrodes.

43. An implantable neuromodulation system, comprising: the lead of any one of claims 2, 3, 39, and 41; and a pulse generator configured to receive a portion of the lead to electrically couple the lead to a control circuit of the pulse generator, wherein the control circuit is configured to receive the measured electrochemical signal from the plurality of sensing electrodes and determine the one or more chemical analytes present in the brain based on the measured electrochemical signal.

44. The implantable neuromodulation system of claim 43, wherein the control circuit is configured to generate and transmit electrical energy to the one or more stimulating electrodes and one or more of the plurality of sensing electrodes.

45. The implantable neuromodulation system of claim 44, wherein the control circuit is configured to receive a command from an external device, the command configured to cause the control circuit to deliver the electrical energy to the brain via the one or more stimulating electrodes and / or the one or more sensing electrodes.

46. The implantable neuromodulation system of claim 45, comprising a radio frequency (RF) antenna coupled to the control circuit such that the control circuit receives the command from RF waves emitted by the external device.

47. The implantable neuromodulation system of claim 46, wherein the control circuit is configured to communicate with the external device using radio wave backscatter.

48. The implantable neuromodulation system of claim 46, wherein the control circuit receives energy from the RF waves emitted by the external device.

49. The implantable neuromodulation system of claim 46, wherein the RF antenna is configured to be implanted beneath a scalp external to a housing of the pulse generator.

50. The implantable neuromodulation system of claim 49, comprising one or more ultrasonic transducers coupled to the control circuit such that the control circuit receives the command from ultrasonic waves emitted by the external device.

51. The implantable neuromodulation system of claim 50, wherein the control circuit is configured to communicate with the external device using ultrasonic backscatter.

52. The implantable neuromodulation system of claim 50, wherein the control circuit receives energy from the ultrasonic waves emitted by the external device.

53. The implantable neuromodulation system of claim 50, wherein the one or more ultrasonic transducers are configured to be disposed within a housing of the pulse generator.

54. The implantable neuromodulation system of claim 43, comprising an energy storage electrically coupled to the control circuit and configured to be disposed within the housing of the pulse generator.

55. The implantable neuromodulation system of claim 54, wherein the energy storage is a rechargeable battery.

56. The implantable neuromodulation system of claim 45, comprising the external device configured to communicate with the control circuit of the pulse generator.

57. A method of implanting the lead of any one of claims 1-3, 39, and 41, comprising: generating an opening in a surface of a human skull; and implanting a portion of the lead comprising the plurality of sensing electrodes in the brain through the opening.

58. A neuromodulation system, comprising: a neuromodulation lead, comprising: a lead body; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in a brain; and a control circuit electrically coupled to the plurality of sensing electrodes and configured to determine a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

59. An implantable neuromodulation system, comprising the system of claim 58, wherein the control circuit is of a pulse generator that receives a portion of the lead to electrically couple the lead to the control circuit.

60. A method for determining concentration of a chemical analyte in a brain, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; anddetermining, at a control circuit electrically coupled to the plurality of sensing electrodes, a concentration of the one or more chemical analytes in the brain based on the measured electrochemical signal.

61. A method of controlling electrochemical signal detection, comprising: measuring, at one or more sensing electrodes of a plurality of sensing electrodes of a neuromodulation lead, a first electrochemical signal generated by one or more chemical analytes present in a brain; and based on a determination that the first electrochemical signal reaches a threshold, measuring, at the one or more sensing electrodes of the neuromodulation lead, a second electrochemical signal generated by the one or more chemical analytes present in the brain, the second electrochemical signal different from the first electrochemical signal.

62. A neuromodulation system, comprising: a neuromodulation lead, comprising: a lead body; one or more stimulating electrodes disposed on the lead body and configured to deliver electrical stimulation to a brain; and a plurality of sensing electrodes disposed on the lead body and configured to measure an electrochemical signal generated by one or more chemical analytes present in the brain; and a control circuit electrically coupled to the one or more stimulating electrodes and the plurality of sensing electrodes, the control circuit configured to: receive the electrochemical signal measured by the plurality of sensing electrodes; based on the measured electrochemical signal, determine one or more stimulation parameters for the electrical stimulation; and generate and transmit the electrical stimulation in accordance with the one or more stimulation parameters to the one or more stimulating electrodes.

63. An implantable neuromodulation system, comprising the system of claim 62, wherein the control circuit is of a pulse generator that receives a portion of the lead to electrically couple the lead to the control circuit.

64. A method for stimulating a brain based on electrochemical signals, comprising: measuring, at a plurality of sensing electrodes disposed on a lead body implanted to the brain, an electrochemical signal generated by one or more chemical analytes present in the brain; determining, at a control circuit electrically coupled to the plurality of sensing electrodes, one or more stimulation parameters for electrical stimulation of the brain based on the measured electrochemical signal; and delivering, at one or more stimulating electrodes disposed on the lead body and electrically coupled to the control circuit, the electrical stimulation in accordance with the one or more stimulation parameters to the brain.

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