CA2659022A1 - Lead and methods for brain monitoring and modulation - Google Patents

Abstract

An apparatus, a system and methods for modulating and monitoring tissue have an elongate member with proximal and distal ends and a plurality of annular stimulating electrodes axially arranged along the elongate member. The stimulating electrodes are disposed near the distal end and are adapted to pass current into tissue. At least one of the annular stimulating electrodes has at least three independent stimulation points on the electrode. The apparatus also includes a plurality of recording electrodes that are adapted to measure local tissue potentials and a plurality of conductors are coupled with the recording and stimulating electrodes. An optional multiple contact connecting terminal may be coupled with the conductors and is disposed near the proximal end of the elongate member.

Description

LEAD AND METIIODS FOR

BRAIN MONITORING AND MODULATION
BACKGROUND OF THE INVENTION
100011 1. Field of the Invention. This irvention i-elates generally to medical appai-atus and methods, and moi-e specifically to leads used to electrically and/or chemically modulate and monitoi- tissues of the brain.

100021 Implanting medical devices such as probes oi- leads within the cranium is an increasingly important approach for ti-eatment of diseases such as Parkinson's Disease, essential tremor and dystonia. Implants may be used to treat a wide ari-ay of disorders, such as depression, epilepsy, dystonia, obsessive compulsive disordei-, obesity and chronic pain.
Most of these devices interact with the bi-ain by applying cun-ent through an electi-ode. In addition, infusion of drugs through a chronically implanted lead has been pi-oposed in the medical literature either as a primai-y treatment, or as an adjunctive treatment to electrical stimulation, in patients with Alzheimer's and Pai-kinson's Diseases, ainong others.

100031 Current implantable probes are typically configured as small diametei-cylinders or tubes, with several circumferential metal rings near the distal tip, and an electrically passive central axial lumen. The metal rings are used to provide electrical stimulation, while the central axial lumen can be used to deliver the probe over a guidewire or stylet during the implantation procedure.

100041 In most treatment protocols, a sequence of electrical pulses is applied to one or more conducting rings on the probe. Typically monopolar or bipolar stimulation of the conducting rings is used. In monopolar stimulation, a single circumferential ring is stimulated with a charge balanced biphasic electrical pulse, with a return path for the current at a remote site, such as a battery pack or conti-ol module. In bipolar stimulation, a combination of rings are stimulated with charge balanced biphasic electrical pulses of opposite polarity. Stimulation of conducting rings produce a field of action which is more or less synimetric about the probe, with some asymmetries arising because of anisotropy in the electrical properties of the adjacent neural or brain tissue.

100051 A symmetrical electrical field about the probe axis is not always desirable. For example, when the probe is not implanted at the center of the modulation target or when the I

brain target is asymmctric oi- irregular in shape. Additionally, there are otten neui-onal domains ncai- the targeted zonc. which should not be modulated. Moclulating non-target zones can lead to undesirable side effects, including sornatic sensation.
involuntary movement and impaii-ed vision, among others.

100061 It is desii-able to not only modulate brain activity, but also to monitor it along with physiological and pathophysiological states. Monitoi-ing obtains information on neuronal activity neai- the stimulation sites, including fielcl potentials and extracellularly recol-ded action potentials. Such potentials may be observed on an ongoing basis, in the course of electrical stimulation for treatment, and in the course of special stimulation and response experiments designed to assess an individual's brain and the brain to electi-ode intei-face.
Information obtained from monitoring at intei-vals may be used to conti-ol and adjust treatment on an ongoing. day-to-day basis by a patient, or in follow up visits to a health professional. Information obtained fi-om monitoi-ing may also be used to dynamically adjust the treatment by an automated control system or control algoi-ithm. and by updating the parameters of a controller.

100071 Monitoring at intei-vals can be used to track changes in the brain response to stimulation as a function of stimulus magnitude. Clinical decisions can be based upon estimated parameters, such as the threshold stimulus level which barely generates a response, and the stimulus level which just saturates the observed response. The shape of the stimulus response function, for example whether it is concave up, concave down, or linear, may also inform adjustments to treatment. The dynamic range from threshold to saturation measured near the stimulation site may directly correspond to the dynamic range of clinical effect, or it may be correlated with it. In either case, the locally measured dynamic range gives inforination which can accelerate the initial fitting and guide ongoing adjustments in treatment protocol. Brain plasticity in response to treatment may be tracked by changes in the dynamic range.

100081 Consider the application of monitoring at intervals to the treatment of Parkinson's disease. It is well known that the beneficial effects of electrical stimulation to Parkinson's patients do not appear for several minutes or hours after the stimulation protocol is initiated.
If the protocol is discontinued during sleep and resumed at waking, the beneficial effects of treatment may not appear again for many hours. Monitoring at intervals offers the opportunity to track changes in the response to stimulation, so that stimulation can be applied dLU-ing onc pi-otocol in order to br-ing about the beneficial effects, and under another moi-c conservative protocol in oi-der to just maintain the beneficial effects. Such a strategy would conserve battery power, and could also reduce side effects.

100091 By monitoring fi-om moment to moment, a modulatoi-y treatment can be clynam-ically synchronized with natural brain i-hythms upon an observed pathological or normal physiological state. or conti-olled by an automatic control system or control algorithm.
100101 Most procedures curi-ently performed monitor patient motions, behaviors, or brain activity at a site remote from the site of an electi-ically stimulating pi-obe, and this information is used to adjust brain stimulation parameters. Parameters are adjusted on a short time scale, to generate a desired effect and minimize side effects, and on a longer- time scale, to account for brain plasticity. Brain plasticity is due to an adaptive response by the brain to an intervention and it is well known that ongoing responses by the brain to an intervention such as modulating therapy often differ from the initial response. Useful information may also be obtained by monitoring electrical potentials near the site of electrical stimulation and therefore it would be desirable to monitor brain activity at the locus of electrical stimulation.
Monitoring allows the course of the disease and healing processes to be evaluated along with the prognosis foi- various treatinent options.

100111 For these reasons as well as others, it would be desirable to provide iinproved probes for modulating and monitoring tissues such as the brain. It would be particularly desirable to provide an efficient design for generating a directed electrical field that may be steered towards the intended target, and/or away from other brain areas. It is also desirable to provide a probe with an efficient number and size of electrodes as well as connector leads, that integrates both electrical recording and stimulating or modulating capabilities, where the infonnation from recordings is obtained close to the treatment site and can be used to define the stimulating protocol. The protocol can then be adapted either statically or dynamically and as the disease state changes, the therapy can also be adjusted. Recording and monitoring of brain electrical activity is also used to detennine when the stimulation protocol is applied or whether it should be reserved for times when it is more effective, thereby helping to conserve power.

[00121 2. Description of Background Art. Prior patents and publications describing brain modulating probes and methods include: U.S. Publication Nos.
2006/0047325;

2006/0004422; 2005%0015130: 2004-0039434 and U.S. Patent Nos. 7.051.419;
7,047,052;
7,006,872: 6,094.598; 6.038.480: 6,01 1,996; 5,343,144; and 5,716,377.

BRIEF SUMMARY OF THE INVENTION

100131 The invention generally pi-ovides an implantable probe or lead capable of modulating or stimulating tissue and measuring and i-ecording local tissue r-esponses as a r-esult of the modulation. The teims "modulating" and "stimulating" are used interchangeably in order to refer to providing a stimulus that incites or suppresses activity in the tissue. The terms "probe" and "lead" ai-e also used interchangeably in order to i-efer to any device that inay be used to modulate the tissue and/or measure and recoi-d local tissue responses.
Modulation of the tissue may include electrical and/oi- chemical stimulation of the tissue, as well as suppression of tissue activity. Measuring and recording tissue i-esponses often entails measuring local tissue potentials in response to the stimulation but could also include measuring and recording endogenous tissue potentials as well as chemical activity in the tissue. Often, the probe is used in tissues of the brain, typically being implanted into deep brain structui-es, or into the cerebrum oi- cerebellum.

(0014] The invention also provides methods where thei-apeutic modulation may be directed within tissues such as neural structures with improved effectiveness and minimal undesirable side effects. The present invention also includes methods to electrically and/or chemically monitor tissue activity so that the therapeutic intervention inay be modified to improve its effectiveness, or to conserve limited resources such as reagents or electrical charge.

100151 The probe possesses electrodes for stimulating tissue such as the brain, and/or for recording tissue activity by measuring local tissue potentials. The stimulating electrodes are affanged so that they can be activated individually, or in combination. They may alternatively be activated in simultaneous or sequential coordination in order to shape the volume of stimulated brain tissue and regulate the magnitude and timing of activity in a stimulated brain. The probe often has a plurality annular shaped stimulating electrodes disposed axially along the probe. For the most efficient use of the probe, each annular shaped electi-ode has three independent stimulation sites disposed thereon, although a greater number of stimulation sites per annular region may be employed. By "independent stimulation sites,"
it is meant that the electrode is separable into three isolated regions, typically disposed in 120 ares of the annulai- clectrode, whcre cach region may be independently enei-gizcd from an external or othcr cnergy sourcc.

100161 In a first aspect of the invention, an appai-atus for stimulating and monitoring bi-ain tissue compi-ises an elongate membei- having proxiinal and distal ends, and a plurality of annular stimulating electrodes axially arranged along the elongate inember, disposed near the distal end, but may also be disposeci at othei- axial positions. Portions of the elongate member may be flexible, often neai- the proximal end and portions may also be rigid near the distal end. The annular stimulating electrodes are adapted to pass curi-ent into tissue and at least one of the annular stimulating electi-odes has at least thi-ee independent stimulation regions or points. The apparatus will usually but not necessai-ily further- compi-ise a plurality of measuring or recording electrodes disposed ad,jacent to the stimulating electrodes and some of the recording electrodes inay be arranged betwcen annular stiniulating electi-odes and the --ecording electrodes are adapted to measure local tissue potentials. The recording electrodes may be circumferentially disposed about the elongate membei- and sometimes have a circular shaped surface. There may also be a sui-face foi- recording and/or stimulating at or near the tip of the apparatus. The apparatus will usually include a plurality of conductors which are coupled with at least some of the annular stimulating and annular i-ecording electrodes, and an optional multiple contact connecting terminal inay be disposed near the proximal end of the elongate ineinber and that is coupled with the conductors. The apparatus may have one conductor per stimulating and/or one conductor per recording region. Often the apparatus also has a lumen that is axially disposed between the proximal and distal ends and sometimes the lumen is adapted to receive a guidewire or stylet.

100171 Often the tissue being treated is brain tissue, although other tissues may also be treated by the method and system of the present invention. Additionally, the apparatus often includes a lumen axially disposed along or within the elongate member. In some cases the lumen is adapted to receive a guidewire or stylet, which passes through the lumen from a port near the distal end of the elongate meinber. In other cases, one or more ports in coininunication with the lumen are disposed near the distal end of the elongate member and are adapted to deliver a therapeutic agent or other substance to the tissue and/or to receive a chemical substance from the tissue. In some cases, the ports are disposed between the annular stimulating electrodes and in other cases, at least one of the ports is disposed at the distal end of the elongate member. In some embodiments, the ports may comprise a gating member adapted to permit selective enablement of the ports. The gating member may be a semi-pei-meable membi-ane and may be chcmically controlled such as \N"hen the gating member is a chemically reactive hydrogel.

100181 In some einbodiments, an additional stimulating electi-ocie may be disposeci in the lumen, and often this additional electrode is a wire. Thei-apeutic agents may also be delivered thi-ough the lumen. In other embodiments, an additional stimulating electrode may be placed at the distal end of the clongate member and this electrode is also capable of passing current into the tissue. A therapeutic agent may also be used with this oi- other embodiments desci-ibed herein. Often, the conductors are helically wound along the elongate member. A
fii-st group of conductors may be coupled with the stimulating electrodes, and a second group of conductors may be coupled with the recording electrodes. The first gi-oup of conductors may be wound in a helix having a first pitch, and the second gi-oup of conductors may be wound in a helix having a second pitch. In some cases, the first pitch is different than the second pitch. Conductors ai-e often comprised of stainless steel, MP35N or tungsten because of their biocompatibility and compatibility with MRI imaging systems, although other materials such as platinum-iridium alloy ar-e possible. Typically, the plurality of annular-stimulating electi-odes, as well as the i-ecording electrodes may also be compatible with magnetic resonance imaging (MRI). An object is compatible with MRI if it does not significantly distort image quality, cause tissue damage with heating and does not move in the presence of a magnetic field.

10019] In a second aspect of the present invention, ainethod of treating tissue comprises implanting a probe in the tissue. The probe may be coinpatible with magnetic resonance imaging and usually has a plurality of annular stimulating electrodes as well as a plurality of recording electrodes. At least one of the annular stimulating electrodes has at least three independent stimulation points or regions on it. The tissue can then be stimulated with a therapeutic electrical current from the annular stimulating electrodes, and local tissue potentials inay be measured, typically in response to the stimulation with the recording electrodes. Chemical substances from the tissue may also be collected in order to provide feedback on the effectivenss of the stimulation and this may include controlling a gating meinber so as to selectively open or close one or more ports disposed on the probe. The ports may also be adapted to control delivery of a therapeutic agent to and/or received a chemical substance from the tissue. The measured local tissue potentials may be analyzed to provide feedback on the effectiveness of the stimulation, and then stimulation may be adjusted in response to the feedback. Often the tissue being treated is brain tissue, and the method may furthei- compi-ise stinlulating the tissue with a therapeutic agent. The method may also compi-isc releasably coupling the probe to the tissue with an anchor.

100201 In a thii-d aspect of the present invention, a system for tl-eating tissue comprises a tissue probe compatible with magnetic resonance imaging and usually having a plurality of annular stimulating clecti-odes as well as a plurality of recoi-ding electrodes adapted to mcasure local tissue potentials. At least one of the annular stimulating electi-odes has at least three independent stimulation points oi- i-egions on the electrode, and the i-egions ai-e adapted to pass cun-ent into tissue. The system may also include a multiple contact connector coupled with the i-ecording and stimulating electrodes and an implantable and controllable pulse generator that is adapted to provide an electi-ical stimulus to the tissue probe via the nlultiple contact connector. Typically the tissue being treated is brain tissue, and the system often may coniprise an anchoring device. The anchoi-ing device is adapted to reinovably fix the tissue probe to a patient's head. The system also typically includes a patient pi-ograminer that is adapted to conti-ol the pulse generator.

100211 These and other embodiments are desci-ibed in fiarther detail in the following description related to the appended drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS
100221 Fig. I illustrates one embodiment of a tissue monitoi-ing and modulation lead.
100231 Fig. 2 illustrates another embodilnent of a tissue monitoring and modulating lead.
100241 Fig. 3 illustrates yet another embodiment of a tissue monitoring and modulating lead.

100251 Fig. 4 illustrates still another einbodiment of a tissue monitoring and modulating lead.

100261 Fig. 5 illustrates a cross-section of a tissue monitoring and modulation lead.

[0027] Fig. 6 shows a cross-section of an alternative embodiment of a monitoring and modulation lead.

[0028] Fig. 7 shows a cross-section of yet another embodiment of a monitoring and modulation lead.

100291 Fig. 8 shows a cross-scction of still anothcr embodimcnt of a monitoi-ing and modulation lead.

100301 Figs. 9 shows anothei- cross-section of another embodiment of a monitoi-ing and modulation lead.

100311 Figs. 10 shows yet another cross-section of an embodiment of a monitoring and modulation lead.

100321 Figs. I I shows still anothei- cross-section of anothe-- embodiment of a monitoring and modulation lead.

100331 Figs. 12 shows another cross-section of another embodiment of a monitoring and modulation lead.

10034] Figs. 13A-13C highlight the recording and stimulating regions of an exemplary einbodiment of a monitoring and modulation lead.

100351 Fig. 14 illustrates a model of the magnitude of a dipole generated by foui-stimulation sites separated by 90".

100361 Fig. 15 illustrates a model of the magnitude of a dipole generated by three stimulation sites separated by 120 as compared with the model in Fig. 14.

100371 Fig. 16 shows a perspective view of an embodiment of a brain monitoring and modulation lead.

100381 Fig. 17 shows a brain monitoring and modulation lead implanted into a patient's head.

100391 Figs. 18A-18C show sample recordings of brain electrical potentials from two recording electrodes.

100401 Figs. 19A-19C show additional sample recordings of brain electrical potentials from two recording electrodes.

DETAILED DESCRIPTION OF THE INVENTION
[0041] In the drawings like numerals describe substantially similar components. Probes often have annular electrodes on their distal ends. An electrode divided into two stimulation sites is capable of orienting a dipole along one axis. When the annular electrode is divided into thi-ec stimulation sites, a dipole may be generated along any direction in a plane. Thrcc stimulation sites pei- annulai- elccti-ode is therefore advantageous as being tlie minimum number of stimulation sites per electrode i-equii-ed to ot-ient a dipole along any direction in a plane. Using the minimum number of stimulation sites is also advantageous because it minimizes the numbei- of conductoi-s which must pass through the probe and pennits maximum cui-rent density thi-ough any recording site to niodulate the brain tissue.
100421 When cui-rent density is limited by b--ain tissue tolerance, a broken ring of stimulation sites can deliver a greater stimulus in some directions than others. For example, consider four stimulation sites arranged as a bi-oken t-ing ai-ound a cylindrical pi-obe, with two sites aligned with a transverse axis (X), and the other two sites aligned with an or-thogonal transverse axis (Y). This configuration mav generate an electi-ical dipole of any orientation within the plane of the stimulation sites by linear summation of two dipoles i-esulting from passing electrical cui-i-ent between opposite pairs of stimulating sites. To generate a dipole of magnitude (m) and orientation 0 relative to axis (X), a cui-rent of magnitude (m/d) cos 0 is passed through stimulating sites aligned with (X), and magnitude (m/d) sin 0 is passed thi-ough the stimulating sites aligned with (Y), and where d is the distance fi-om the origin.
As 0 changes, the locus of the dipole magnitude traces a circle. It may be desired to linlit the current density at any single electrode to be less than soine maximum value, so that heat or other undesired side effects of stimulation may be limited. With such a constraint, the maximum dipole that may be generated by a broken ring of four stimulation sites as a function of the angle 0 traces a square 243, as seen in Fig. 14. The largest dipole magnitudes are foi- orientations midway between the axes (X) and (Y), at the corners of the square, because both pairs of stimulation sites carry the inaximum pennitted current.
The smallest dipole magnitudes are for orientations along the axes (X) and (Y), because only one pair of stimulation sites carries nonzero current.

100431 Compare the above scenario to an embodiment with three stimulation sites arranged in a broken ring or annulus about a cylindrical probe. If the axial extent of the electrode ring and maximum current density are the same as in the previous example, the maximum magnitude of the current through any electrode is 1/3 greater. When the maximum current is passed through one electrode, the return current is divided in various proportions between the other two electrodes. The maxiinum dipole that can be generated by a ring of three electrodes as a function of 0 traces a hexagon 246, similar to that illustrated in Fig. 15. For most orientations of the stimulating field, the magnitude of the maximum dipole generated by a broken i-ing of three stimulation sites is gi-eatei- than the dipole genei-ated by a broken ring of four stimulation sites as seen by the square 243) from Fig. 14 superimposed in Fig. 15.
100441 Figs. 14 and 15 illusti-ate a simplifieci model which clai-ilies the advantages of using a prime number- of stimulation sites such as three. Thei-e ai-e three stimulation sites on a broken ring in the pi-eferi-ed embodiment of Fig. 1. Fig. 14 illustrates the case of foui- electr-ic monopoles 234a, 234b, 234c and 234d an-anged at points around a circle 230.
Monopoles 234a and 234c are equally and oppositely charged, and generate a dipole, as do monopoles 234b and 234d. The radial position of points on the square 234 i-epresent the maximum net dipole that can be ci-eated by the sum of the two dipoles 234a, 234c and 234b, 234d, subject to the constraint that the inaximum charge on a monopole is of magnitude one.
The sum of the charge of the four monopoles is zero.

100451 Fig. 15 illustrates the case of three electric monopoles 235a, 235b and 235c arranged at points ar-ound a cii-cle 230. The maximum net dipole square 243 of Fig. 15 is superimposed here for reference. Thi-ee electi-ic monopoles genei-ate an oriented dipole more efficiently, as diagramined by maximum net dipole hexagon. Two dipoles are generated by one monopole of one polarity, and two of the opposite or zei-o chai-ge. The sum of the charge of all three monopoles is zero. The radial position of points on the hexagon 246 represent the maximum net dipole that can be created by the sum of the two dipoles, subject to the constraint that the maximum charge on any monopole cannot exceed the inagnitude 1.2. The larger maximum charge constraint is used here because the surface area of each stimulation site of a fixed axial length is greater if each portion occupies 1/3 of the circumference, than if each portion occupies 1/4 of the circumference. The sides of the hexagon nearest the electrodes 235a, 235b, 235c are generated in the situation where the constraining electrodes has positive polarity, and the sides of the hexagon opposite these are generated in the situation when the constraining electrode has negative polarity. It can be seen that the radial position of the hexagon 246 is farther fi-oin the origin than the square 243 at most directions from the origin. For a fixed axial extent of the broken ring, three stimulation sites can deliver a larger effective stimulus compared to four stimulations sites.
Alternatively, for a fixed effective stimulus, the axial length of a broken ring of 3 stimulation sites can be shorter than for a broken ring of 4 stimulation sites. The prefeiTed embodiment of the invention has the advantage over other probes of supporting better steerability of the electric current for the situation in which the maximum current density is constrained. This description of the invention does not pi-eclude using a stimulation protocol in which stimulation sites on diffei-ent broken rings ai-e stimulated simultancously oi- in coordination.

100461 It will be apparent to those skilled in the art that a stimulating probe with a broken ring of 6 stimulation sites (or any other inultiple of 3) can be used in ainanner so as to obtain the advantages of this invention. This may be accomplished by controlling the ring of six stimulation sites as three stimulation sites, each compi-ised of a paii- of adjacent stimulation sites.

100471 Therefore, at any axial position. the number of stimulation sites is a priine number.
A prime number yields moi-e combinatoi-ial possibilities for simultaneously using all electrode sui-faces to achieve diffei-ent stimulation orientations. Using all electrode surfaces keeps current density as low as possible. In a preferred einbodiment, the nwnber of stimulation sites is 3. In anothei- embodiment, the number of stimulation sites is 5.
Configurations with 2, 5 or 7 stimulation sites could achieve the cui-rent density advantages which this invention seeks to achieve also, although to a lesser degree.

100481 Referring now to Fig. 1, a tissue modulating and monitoring pi-obe is illustrated.
Fig. I shows a preferred embodiment of the probe. It is a cylindrical probe, with a flexible probe body 10 and an optional multiple contact connecting tenninal 20a.
Additional details on multiple contact connecting teiminals ai-e disclosed in U.S. Provisional Application No.
60/820,914 the entire contents of which ai-e incorporated herein by reference.
Other connectors may be used and ai-e well known in the art. At the distal end of the probe 30a there are one or more broken annular rings of stimulating sites. The stimulating sites may be aligned with matching angular position on all rings, or may be offset to different angular positions on different rings. There are also one or more circuinferential electrode bands suitable for recording local field potentials, and a recording electrode at or near the most distal point. In this preferred embodiment, the maximum diameter of the multiple contact terminal 20a is the same as the diameter of the flexible probe body 10.

[00491 In this embodiment, at four axial positions, three stimulation sites 33a, 33b, 33c, 34a, 34b, 34c, 35a, 35b, 35c, 36a, 36b, 36c are arranged as broken rings, for a total of 12 stimulation sites. These are better seen in the cross-sectional views of Figs.

5-12. Also in this embodiment are three recording bands 37, 38, 39 arranged in the gaps between the broken rings. The size of the recording sites is suitable for recording local field potentials, with an exposed area ranging from about 0.0005 inmZ to about 0.5mm2 but the area could be up to about 0.8mm'. Some embodiments havc smaller rccording sitcs that improve extracellularly recordings of action potentials. Such recording sites range in exposed area from about 1 .9 x 10 5 nu1r to about 0.002 min', but they could be as large as about 0. 1 mm' .
The form of the rccording sites could be the bare end of an insulated wire, a thin film, ainetal pad, oi- an insulated region with a poi-tion of the insulation removed to expose an electrical conductor within the wall of the device. Altei-native embodiments may have no i-ecording i-ings, oi- may have more recording rings. Additional recording rings or point electrodes may be located along the pi-obe body 10 oi- at the probe tip 32. The embodiment docs not restrict the aligninent of the recording electrodes (bands and/or points) with respect to the stimulation sites.

100501 There must be a nonconductive gap of at least l 00pm between stimulating and recording surfaces, and between recording surfaces, to reduce shunting and improve the isolation of the recor-ded signals. It is desirable that electr-ical signals traversing through the probe do not interfere with each other. It is especially desirable that the high level electrical stimulation signals not interfere with the low level recording signals.
Therefore, it is preferable that the conductors cai-i-ying recoi-ding signals lay in an inner helix, while conductors cairying stimulation signals lay in an outer helix. The pitch of the two helices may be the same or inay be different, so that no pair of stiniulation and recording conductors traverse adjacent paths for an appreciable distance. This minimizes capacitive coupling between any stimulating conductors and any recording conductors. In other embodiments, a conductive coating inay be applied to the outside of the helix of recording conductors. This can be grounded to deci-ease electromagnetic interference between the two types of conductors. In yet another embodiment, a metal foil, which may be grounded, is wrapped between the inner and outer wire helices.

100511 In other embodiments, the conductors carrying recoi-ded signals lay between conductors carrying electrical stimulation signals. This embodiment has the advantage that the conductors lay in a single lamina and can be more compact and more flexible, although in some instances this embodiment may have the disadvantage that when stimulating current modulates a stimulating conductor, the stimulation signal may couple into adjacent recording conductors. Note that not all of the stimulus conductors are required to carry a current at any instant. In many uses of the probe, some of the recording conductors will therefore be well separated from active stimulating conductors at any instant. In another embodiment, the stimulating wires and recording wires course as adjacent groups of conductors in a helix.

100521 The wires should be mechanically strong and electrically conductive.
Suitable ma-terials include alloy MP35N (cobalt chi-ome alloy), stainless steel, and tungsten or tungsten alloy wire which has been gold plated to facilitate continuity with the stimulation sites and to the extra-cranial connector. It is important that the matei-ial be minimally magnetic to maximize MRi compatibility.

[0053] Stimulation sites are made of a rclatively inei-t material which maximizes safe charge ti-ansfei-, such as platinum, iridium oi- an alloy of platinum and ii-idium. The body of the probe is coated by a biocompatible polymer, such as silicone rubber or pol_vurethane, which supports bending with a short i-adius of curvature wher-e the pr-obe exits the cranium.

100541 Fig. 2 illustrates an altei-native embodiment of the probe 30b. Probe 30b is similar to the probe 30a of Fig. I except that it adds ports 40 which may pennit chemical substances to enter or leave the probe lumen. The ports 40 may be covered by a semi-penneable membrane. Alternatively a chemically controlled gating mechanism, such as a cheinically reactive hydrogel, may be placed near the ports. Such a hydrogel can swell oi-contract depending upon the chemical composition of the adjacent medium. The gating mechanism may operate based on bulk swelling and occlusion of the port, or the hydrogel may be formed with a mechanical accessory structure. An example of such as structui-e includes a bimorph beam as described by R. Bashir, J.Z. Hilt, O. Elibol, A. Gupta, and N. A.
Peppas in "Micromechanical Cantilever as an Ultrasensitve pH Microsensor," published in Applied Physics Letters, 81(16):3091-3093, 2002. Another exainple includes a surface covering fenestrated with microports as disclosed by A. Baldi, M. Lei, Y. Gu, R.A.
Siegel and B. Ziaie in an article entitled "A Microstructured Silicon Membrane with Entrapped Hydrogels for Environmentally Sensitive Fluid Gating," published in Sensor and Actuators B, 1 14(l):9-18, 2006, or another example includes a pad which displaces elements suited to forming an occlusive seal as described by A. Baldi, Y. Gu, P.E. Loftness, R.A. Siegel and B. Ziaie in "A
Hydrogel-Actuated Environmentally Sensitive Microvalve for Active Flow Control,"
published in the Journal of Microelectromechanical Systems, 12(5):613-621, 2003. The entire contents of these references are incorporated herein by reference.
[00551 Since the hydrogels may be formulated such that their volume has different chemical dependencies, different hydrogels inay be associated with ports at different pre-determined positions on the lead, so that drugs may be delivered selectively to pre-determined positions on the probe. Likewise, samples of the extra-cellular space or cerebral spinal fluid (CSF) may be obtained from pre-detennined positions on the probe.
Examples of chemical gating inechanisms that ai-e controlled directly by pH include those described previously in "Mici-omechanical Cantilevei- as an Ultrasensitve pH
Microsensor. Gating mechanisnis controlled by the presence of carbon dioxide via a relationship to pH include those described by R. Stecge, H. Sebastiaan, W. Olthuis. P. Bergveld, A. Berg, and J.

Kolkman in "Assessment of a New Prototype Hydrogel C02 Sensor; Comparison with Air Tonometry," as published in The Journal of Clinical Monitoring and Computing 2](2):83-90, 2007. Other examples of gating mechanisms conti-olled by the presence of glucose are disclosed by Theeuwes et al. in U.S. Patent No. 6,997,922. 1'he entire contents of the above listed references are incorporated herein by reference.

100561 Fig. 3 illustrates an alternative enlbodiment of pt-obe 30c in which the probe tip 32a is electi-ically conductive, sei-ving as an additional stimulation site. This could sei-ve as a conventional stimulation site, supporting inonopolar and bipolar stimulation.
In conjunction with a distal ring of stimulation sites 36a-c it forms a group of stimulation sites centered on the vertices of a tetrahedron, suppor-ting steei-ing of the current near- the tip in three dimensions. The embodiment of Fig. 3 also has an additional recording electrode 42 between stimulating electrodes 36a - 36c and distal stimulating electrode 32a. Also, multiple contact connecting terminal 20c has a plurality of electrical contacts axially spaced along two hemi-cylidrical or D-shaped connectors, as further disclosed in U.S. Provisional Patent Application No. 60/820,914 the entire contents of which ai-e incorporated herein by reference.

[0057] Fig. 4 illustrates an alternative embodiment of the probe, 30d, demonstrating that the multiple contact terminal 20d need not have the same diameter as the probe body 10.
Here, contact terminal 20d is a larger diameter cylindrical shaped plug with receptacles for coupling the probe 30d with the rest of the monitoring and modulation system.
This embodiment illustrates that the surface of recording electrodes need not be circular, but may be configured as recording points 43. Alternative embodiments may include multiple recording sites, some configured as rings, and other configured as points. In other embodiments the recording electrodes may take other shapes, including squares, rectangles or irregular shapes. In yet another alternative embodiment, the multiple contact tenninal may allow for a lumen or conduit for the passage fluid within the probe. Fluid may pass in one or more lumens, and may flow into or out of the brain, or both.

[0058] Fig. 5 illustrates an axial cross-sectional view of a preferred embodiment, at section line 101 in Fig. 1. In the preferred embodiment the central lumen 70 is surrounded by a tube 72 made of a biocompatible polymer, such as polyurethane, silicone rubber or polyamide. In alternative embodiinents the lumen is a polymei- coating, and the insulated recoi-ding conductors 60 may reside in the inner lumen. Recording conductors 60 are wound in a helix fi-om the i-ecording sites to their tei-mination at the contact terminal 20.
Likewise, the stimulating conductors 50 are wound in a helix from the stimulation sites to their termination at the contact tenninal 20. In a preferred embodinlent, the stimulating conductors 50 have larger size than the recoi-ding conductors 60 because resistive losses are a greater concern foi-the stimulating conductors 50, but all conductors may be of the same or similar dimension in alternative embodiments. In a preferred embodiment, the pitches of the recording wire helix and the stimulating wire helix are different, to decrease the average capacitive coupling between the wii-es. In alternative embodiments the helices could have the same pitch. The two helices may have the same or opposite orientation (one clockwise, the other countet-clockwise). Conductoi-s 50, 60 are embedded in a flexible polyiner, and are insulated in the prefen-ed embodiment, but could or could not rely on the sun-ounding polymer for insulation in an alternative embodiment. In the preferred embodiment, a layei-of electrically conductive inaterial 74 is interposed between the recording and stimulating conductors, which may be attached to a low impedance electrical reference. Alternative embodiments may use layer 74 or the central lining of the central lumen 72 as an internal stimulating electrode. Alternative embodiments may omit this layer 74 to simplify manufacturing.
Stimulation sites 33a-c lay on the surface of the probe, with gaps of nonconductive material 41 between them. The stimulation sites 33a-c may be of the form of sections of a tube adhered to the pi-obe, and welded or riveted to the conductors 50, or may be fabricated with thin film technology. Examples of thin film technology that could be used to fabricate the probe ai-e described, for example, in U.S. Patent Nos. 7,051,419 and 7,047,082 the entire contents of which are incorporated herein by reference. The conductors 50, 60 in Fig. 5 are shown as having a circular profile to suggest transversely cut round wires, but alternative fonns could use shaped wires such as those having a square, rectangular or elliptical cross-section, or thin film technologies may be used for the conductors. Fig. 5 shows 12 stimulating conductors 50 and 3 recording conductors 60 corresponding to the preferred embodiment, but alternative embodiments could have more or fewer conductors to support various numbers of electrodes.

100591 Fig. 6 illustrates an alternative embodiment, in which the stimulating conductors 50 are arranged in groups rather than uniformly spaced around the circumference of the probe.

Three groups of four ai-c illustrated, but alternatively the conductoi-s could be arranged in 4 groups of thi-ee. Such embodiments could allow for ports communicating betwcen the central lumen 70 and the outside of the probe, or for improved flexibility of the probe in conjunction with reduced wall thickness bctwcen groups of conductors.

100601 Fig. 7 illustrates an axial cross-sectional view of an alternative embodiment, at section line 101 in Fig. 1. In this embodiment, the stimulating and i-ecording conductors ai-e in the same annular space of the probe, unlike prior embodiments where the conductors are separated. Because this embodiment places both conductoi-s in the same annulai-space, the centi-al lumen 70 inay be larger. In a preferred embodiment the stimulating conductors 50 and recording conductors 60 alternate around the helix, but in alternative embodiments the stimulating conductors and recording conductoi-s could course as separate groups. In alternative embodiments, there inay be additional conductors betwecn the stimulating 50 and recording 60 conductors, which may be connected to the point of electrical neutrality. In alternative embodiments, the tube 72 may be coated with an electrically conductive material, which may be connected to the point of electrical neutrality.

100611 Fig. 8 illustrates an alternative embodiment wherein the recording conductors 60 and stimulating conductors 50 are separated into groups. This embodiment has the advantage of reduced opportunities for undesirable capacitive coupling between stimulating and recording conductors compared to the embodiment illustrated in Fig. 7, but increases the opportunities for undesirable capacitive coupling between separate recording conductors.
[0062] Fig. 9 illustrates an embodiment with dual lumens, central 70 and annular 71, to permit delivery or sampling of a fluid (gas or liquid) substance or drug, or sampling of a liquid or volatile substance. The lumens may communicate with ports, shown as 40 in Figs. 2 and 13A-13C, and such communication may be electrically or chemically gated.
The distal ends of the lumens may be closed, permeable, selectively permeable, or open, to release the lumen contents or some fi-action or portion of the lumen contents. The distal ends of the two lumens may communicate with each other, so that one delivers a liquid containing a drug such a levodopa, or a gaseous medium with bioactive effects such as carbon monoxide or nitrous oxide, and another lumen retrieves the medium, after an opportunity to exchange substance or substances with the medium near ports 40 or other openings in the probe. Other therapeutic agents that may be delivered are well known in the art, such as those disclosed in U.S. Patent Nos. 6,094,598 and 6,227,203 both of which, the entire contents are incorporated hei-ein by i-eference ancl often. exti-acellulai- fluid such as cei-ebral spinal fluid (CSF) is sampled. In this embodimcnt. conductors for electrical stimulating and recordino coui-se togethei- within an additional annulus 79 ci-eated by an additional wall 78 in the probe.

100631 Fig. 10 illustl-ates an ai-i-angement similar to that in Fig. 9, except that the conductors for stimulating and i-ecording coul-se through two separate annular rings 76 and 77, both concentric to the inner two lumens 70 and 71. In other embodimeiits, there may be more than two lumens, and the lumens need not be concentric.

100641 Fig. 1 1 illustrates an arrangement similar to that in Fig. 9, except that thei-e is a single lumen 72. Additionally, conductors 50 and 60 are randomly oriented and therefore may allow the probe to be more easily fabricated as opposed to a probe with conductors in a defined pattern.

100651 Fig. 12 illustrates an ari-angement with no lumen for eithei- a guide wire, oi- foi-supporting mass transfer. The conductors course together through the center of the probe.
100661 Figs. 13A-I3C illustrate an ai-rangement for the stimulating and r-ecording conduc-tors, similai- to the embodiments illustrated in Fig. 2. Fig. 13A shows a probe having foui-regions of stiinulating electrodes 36a-36c, 35a-35c, 34a-34c and 33a-33c, with each region having three independent stimulation sites. Additionally, the probe in Fig.
13A has recording electrodes 37, 38 and 39 as well as ports 40. The probe of Fig. 13A is shown in Figs. 13B-13C with the circuinference of the probe unwi-apped, such that the upper edge and the lower edge of the conductors are actually continuous with each other. In the region of the probe tip, the conductors course in the axial direction, and turn to form helical windings along the probe body. Fig. 13B shows the recording electrode conductors 90a, 90b and 90c coursing in the axial direction near the probe tip and then turning to form helical windings along the probe body. Fig. 13C illustrates a similar pattern for stimulating electrode conductors 92a, 92b, 92c, 94a, 94b, 94c, 96a, 96b, 96c and 98a, 98b, 98c.

100671 Fig. 16 shows a perspective view of a monitoring and modulation lead.
In Fig. 16, four stimulation regions on the lead each contain three independent stimulation electrodes.
All three stimulation electrodes 36a, 36b, 36c are only visible on the distal-most region. Two stimulating electrodes are visible in the other regions of the lead including 35a, 35b, 34a, 34b, 33a, 33b. Additionally, the lead has three recording electrodes 37, 38 and 39 as well as an additional recording electrode 52 near the distal lead tip 32. An inner shaft 53 is contained Nvithin ]cad body 10 and may be adapted to accommodate guidewires, stylets, lumens, etc.
prcviously described herein.

100681 Fig. 17 shows a monitoring and modulating probe oi- lead I 2 secui-ed to the skull of a patient 1 I with a fixture 16 and iinplanted into brain tissue 14. An extension lead 18 couples the probe 12 with a controllable pulse generator 19. The lead often runs under the patient's skin, although it may not and the conti-ollable pulse generator 19 may be implanted or it may i-emain external to the body of the patient 11. Additional details on a fixture for securing the probe to the skull ai-e disclosed in U.S. Provisional Patent Application No.
60/908,367 the entii-e contents of which are incorporated herein by reference.

100691 Table I below summarizes data collected that demonstrate that different functional stimulation effects can be achieved by stimulating different stimulation sites around an annular- ring. A lead similar to that illustt-ated in Fig. 16 was inserted into the basal ganglia of an anesthetized cat. The stimulating sites in the most distal annular ring (36a, 36b and 36c) were energized together and independently to electi-ically stimulate the brain. The ground was placed in the tempora]is muscle. Electrical stimulation of sufficient magnitude evoked a response in either the ipsilateral oi- contralateral or both facial muscles.
Stiinulation rnagnitude was delivered in voltage steps, and the motor response was graded on a rank-ordered scale (NR - No Response; THR, Response Threshold; larger numbers correspond to larger magnitude of supra-threshold responses). When site 36a was stimulated alone, the response threshold for ipsilateral movement was lower than for contralateral movement.
When site 36b was stimulated alone, the r-esponse threshold for ipsilateral and contralateral movement was the same. When site 36c was stimulated alone, the threshold for contralateral movement was lower than for ipsilateral movement. When all three sites were stimulated simultaneously, the threshold for ipsilateral movment was lower than for contralateral movement, but the threshold for both ipsilateral and contralateral movement was lower than with stimulation of any single site. Data froin this testing is suinmarized in Table I below, and this pattern of differential stimulation thresholds dernonstrates that stimulating different sites within an annular ring steers electrical current within the brain.

(00701 Figs. 18A-18C demonstrate that the lead can record field potentials, and that different recording sites record different potentials. The recording was obtained from the same lead illustrated in Fig. 16 as discussed above, and with the same placement. The response was evoked by sensory stimulation of the visual pathways by waving a flashlight befoi-e the eyes. In Figs. 18A. Ti-ace TI was i-ecorcled ti-om i-ecording site 38. and in Fig. 18B
trace T2 was recorded ti-om recoi-ding site 39. Specti-um analysis of these tt-aces revealed oscillations at I80 Hz. and 300 Hz. which are believed to i-esult froin unintended coupling to the power grid. A Christiano-Fitzgerald tiltei- was applied to i-emove signal energy neai- these fi-equencies, and the filtered traces are denoted T I a and T2a as shown in Figs. 18A-18C. The trace 0 in Fig. 18C is the arithmetic difference T 1 a - T2a. The traces look similar, but they ai-e not pi-opor-tional, as they would be if they i-esulted principally fi-om electrical cross-talk.
At position A, Tl/Tla has a more sustained positivity compared to T2/T2a. At position B.
the positivity in traces T I/T 1 a and T2/T2a are nearly identical. The amplitude of the triphasic wave between positions B and C differs considerably in traces T 1/T
I a and T2/T2a.
The amplitude of this recorded potential is somewhat less than the amplitudc of an optimally recorded field potential, reflecting the position of the lead near but not in the optic tT-act.
100711 Figs. 19A-19C demonstrate that the lead can record spontaneous activity field potentials charactei-istic of placement in a gi-ey mattei- nucleus. The recoi-ding was obtained from a location 3mm dorsal to the location from which the recording in Figs.
18A-18C was obtained. Because the amplitude of this recording was much greater than the amplitude of interference from the power grid, Christiano-Fitzgerald filtering was not necessary. Trace T1 in Fig. 19A was recorded from recording site 38, and trace T2 in Fig. 19B was recorded from recording site 39. The trace n~ in Fig. 19C is the arithmetic difference TI -T2. The traces look similar, with a time course and amplitude chai-acteristic of field potential recoT-dings.
The diffei-ence trace, A, has several transient waves with duration from 0.5 to 3.5 msec, and amplitude of a few tens of millivolts, characteristic of action potential wavefonns. Togethei-with the recording shown in Figs. 18A-18C, these data demonstrate that a lead such as that illustrated in Fig. 16 can record field potentials from white matter and grey matter, and with suitable signal processing can also record action potential spikes.

Table I
Activated Stiniulation Ipsilateral Facial Muscle Cont--alateral Facial Muscle Surfaces (V) Response Grade Response Grade 36a. 36b. 36c 1.0 NR NR
2.0 NR NR
2.2 THR NR
2.6 1 NR
2.7 1 THR
36a 1.0 NR NR
2.0 NR NR
3.0 NR NR
3.6 THR NR
4.0 1 NR
4.3 1 N R
4.5 2 THR
36b 1.0 NR NR
2.0 N R N R
2.4 THR THR
4.0 2 2 36c 1.0 NR NR
2.0 NR NR
3.0 NR NR
3.5 NR THR
4.0 THR 1 4.5 1 1 5.0 2 2 [0072] While the exemplary embodiments have been described in some detail for clarity of understanding and by way of example, a variety of additional modifications, adaptations and changes may be clear to those of skill in the art. Hence, the scope of the present invention is limited solely by the appended claims.

Claims (40)

1. An apparatus for stimulating and monitoring tissue, the apparatus comprising:
an elongate member having a proximal end and a distal end;
a plurality of annular stimulating electrodes axially arranged along the elongate member and disposed near the distal end, the annular stimulating electrodes being adapted to pass current into tissue, and wherein at least one annular stimulating electrode has at least three independent stimulation points thereon;
a plurality of recording electrodes disposed adjacent to the stimulating electrodes, the recording electrodes being adapted to measure local tissue potentials; and a plurality of conductors coupled with the annular stimulating electrodes and the recording electrodes.

2. An apparatus as in claim 1, wherein a portion of the elongate member near the proximal end is flexible.

3. An apparatus as in claim 1, wherein a portion of the elongate member near the distal end is rigid.

4. An apparatus as in claim 1, wherein at least some of the plurality of recording electrodes are disposed between annular stimulating electrodes.

5. An apparatus as in claim 1, wherein the tissue is brain tissue.

6. An apparatus as in claim 1, further comprising a lumen axially disposed between the proximal and distal ends of the elongate member.

7. An apparatus as in claim 6, wherein the lumen is adapted to receive a guidewire or stylet.

8. An apparatus as in claim 6, further comprising one or more ports near the distal end of the elongate member, the ports in communication with the lumen and adapted to deliver a therapeutic agent to and/or receive a chemical substance from the tissue.

9. An apparatus as in claim 8, wherein the therapeutic agent comprises levodopa.

10. An apparatus as in claim 8, wherein the ports are disposed between the annular stimulating electrodes.

11. An apparatus as in claim 8. wherein at least one of the ports is disposed at the distal end of the elongate member.

12. An apparatus as in claim 8. wherein the ports comprise a gating member adapted to permit selective enablement of the ports.

13. An apparatus as in claim 12, wherein the gating member is a semi-permeable membrane.

14. An apparatus as in claim 12, wherein the gating member is chemically controlled.

15. An apparatus as in claim 14, wherein the gating mechanism is a chemically reactive hydrogel.

16. An apparatus as in claim 6, further comprising a stimulating electrode disposed in the lumen.

17. An apparatus as in claim 16, wherein the stimulating electrode disposed in the lumen is a wire.

18. An apparatus as in claim 1, further comprising a stimulating electrode at the distal end of the elongate member, the stimulating electrode adapted to pass current into the tissue.

19. An apparatus as in claim 1, wherein the plurality of conductors are helically wound along the elongate member.

20. An apparatus as in claim 1, wherein a first group of the conductors are coupled with stimulating electrodes and a second group of the conductors are coupled with the recording electrodes, and wherein the first group of conductors form a helix having a first pitch wrapped around the second group of conductors which also form a helix having a second pitch.

21. An apparatus as in claim 20, wherein the first pitch is different than the second pitch.

22. An apparatus as in claim 1, wherein the conductors are comprised of a material selected from the group consisting of stainless steel. MP35 and tungsten.

23. An apparatus as in claim 1, wherein the plurality of annular stimulating electrodes are compatible with magnetic resonance imaging.

24. An apparatus as in claim 1, further comprising a multiple contact connecting terminal coupled with at least some of the plurality of conductors and disposed near the proximal end of the elongate member.

25. An apparatus as in claim 1, wherein the recording electrodes are circumferentially disposed about the elongate member.

26. An apparatus as in claim 1, wherein the recording electrodes have a circular shaped surface.

27. A method of treating tissue comprising:
implanting a probe in tissue, the probe having a plurality of recording electrodes and a plurality of annular stimulating electrodes, wherein at least one of the annular stimulating electrodes has at least three independent stimulation points thereon;
stimulating the tissue with a therapeutic electrical current from the annular stimulating electrodes;
measuring local tissue potentials with the recording electrodes in response to the stimulation;
analyzing the measured local tissue potentials to provide feedback on the effectiveness of the stimulation; and adjusting the stimulation in response to the feedback.

28. A method as in claim 27, wherein the tissue is brain tissue.

29. A method as in claim 27, further comprising stimulating the tissue with a therapeutic agent.

30. A method as in claim 27, further comprising releasably coupling the probe to the tissue with an anchor.

31. A method as in claim 27, wherein the probe is compatible with magnetic resonance imaging.

32. A method as in claim 27, further comprising collecting a chemical substance from the tissue to provide feedback on the effectiveness of the stimulation.

33. A method as in claim 27, further comprising controlling a gating member so as to selectively open or close one or more ports disposed on the probe.

34. A method as in claim 27, wherein the ports are adapted to control delivery of a therapeutic agent to and/or receive a chemical substance from the tissue.

35. A system for treating tissue the system comprising:
a stimulating and recording probe having a plurality of recording electrodes adapted to measure local tissue potentials and a plurality of annular stimulating electrodes, wherein at least one of the annular stimulating electrodes has at least three independent stimulation points thereon and the stimulating electrodes are adapted to pass current into tissue; and an implantable and controllable pulse generator, the generator adapted to provide an electrical stimulus to the probe.

36. A system as in claim 35, wherein the tissue treated is brain tissue.

37. A system as in claim 35, further comprising an anchoring device, the anchoring device adapted to removably fix the probe to a patient's head.

38. A system as in claim 35, further comprising patient programmer, the patient programmer being adapted to control the pulse generator.

39. A system as in claim 35, further comprising a multiple contact connector electrically coupled with the recording and stimulating electrodes.

40. A system as in claim 35, wherein the tissue probe is compatible with magnetic resonance imaging.