Device for interacting with neurological tissue and methods of making and using the same

Information

  • Patent Grant
  • 9549708
  • Patent Number
    9,549,708
  • Date Filed
    Thursday, March 31, 2011
    13 years ago
  • Date Issued
    Tuesday, January 24, 2017
    7 years ago
Abstract
Described herein are microelectrode array devices, and methods of fabrication, assembly and use of the same, to provide highly localized neural recording and/or neural stimulation to a neurological target. The device includes multiple microelectrode elements arranged protruding shafts. The protruding shafts are enclosed within an elongated probe shaft, and can be expanded from their enclosure. The microelectrode elements, and elongated probe shafts, are dimensioned in order to target small volumes of neurons located within the nervous system, such as in the deep brain region. Beneficially, the probe can be used to quickly identify the location of a neurological target, and remain implanted for long-term monitoring and/or stimulation.
Description
FIELD

The present disclosure relates generally to field of interacting with biological tissue using electrical probes, and more particularly to interacting with a neurological target through the use of microelectrode probes.


BACKGROUND

Neural recording and neurostimulation are categories of medical devices that are used to interact electrically with tissue. In the case of neural recording, physiological measurements are performed of neurological tissue that can diagnose, or treat, a patient. In the case of neurostimulation, electric charge is transferred to the tissue in order to create a therapeutic outcome, or to generate a diagnosis. Neural recording and neurostimulation devices are used today in the cochlea, the retina, the peripheral nervous system, the spine, the brain, and other parts of the body.


In a particular application where both neural recording and neurostimulation are utilized, conductive electrodes are placed in contact with deep brain structures in order to treat certain neurological conditions. In the case of stimulating the Pedunculopontine Nucleus, for example, as described in U.S. Pat. No. 6,356,784, the therapy can treat the symptoms of Movement Disorders such as Parkinson's disease. In the case of stimulating Brodmann Area 25, for example, as described in U.S. Pat. No. 7,346,395, the therapy can treat the symptoms of Mood and Anxiety Disorders.


Generally, neural recording is performed in deep brain structures by surgically inserting conductive electrodes and amplifying neurological signals using external electronic equipment. Neurostimulation, is performed by surgically implanting conductive electrodes in the target, and using an implantable pulse generator to apply electrical signals to the conductive electrodes.


In some cases, such as described in U.S. Pat. No. 6,016,449, a system has been developed where both neural recording and neurostimulation functions are available in a single, long term implantable, device.


In most techniques, the electrodes used for neural stimulation that are placed in contact with tissue have been metallic, cylindrical, with very sharp distal ends. In most cases, they only contain one microelectrode, which severely limits the amount of physiological information that can be collected from the patient.


In other techniques, the electrodes used for neurostimulation that are placed in contact with tissue have been metallic, cylindrical, and relatively large in size (e.g., 1.27 mm in diameter and 1.5 mm in length). In most cases, there are four or eight cylindrical electrodes placed on a common axis. The stimulation methods are generally invasive, such as with the electrodes used in Deep Brain Stimulation, and the electrode lead is generally attached implantable pulse generator.


Furthermore, advances in micromachining technology have developed whole new applications for medical devices, and in particular, implantable devices such as for the treatment and diagnosis of neurological disorders.


Advances in the imaging of tissue have elucidated the function and anatomy of brain and nervous tissue, permitting the development of new therapies which include electrical stimulation methods. A number of research groups have reported on different approaches for imaging methods, and the construction of implantable devices to deliver therapies. The imaging methods are generally extra-corporeal, and involve large and/or sophisticated equipment such as Magnetic Resonance Imaging systems.


One of the great challenges for clinicians delivering electrical stimulation therapy is in localizing the correct location for electrode placement, and then confining the stimulation field to the appropriate anatomical target to deliver the therapy, without inducing side effects. Clinicians generally combine pre-operative navigational planning derived from Magnetic Resonance Imaging and/or Computed Tomography scan imaging systems, with intra-operative microelectrode recordings of electrophysiological phenomenon to find and locate the optimal target.


Volumes of anatomical interest are commonly found using microelectrode recording techniques which involve invasively inserting metal tips to find the area of interest by its electrophysiological activity. This may be uncertain, time consuming, and repetitive insertions may be hazardous to patient health.


Unfortunately, there are several limitations to current practice including uncertainty, discomfort for the patient, and a heavy financial burden to deliver the therapy. These factors can render the therapy less attractive to clinicians, patients and payers.


It would be a very useful advancement in the art of neural recording and neurostimulation device technology and in the practice of functional neurostimulation if the same device could image a volume of brain tissue, and stimulate the same volume of tissue with precision and safety.


There are many other medical applications for the present device, such as detecting malignant tissue within healthy tissue.


SUMMARY

The present disclosure provides a design and method which permit the imaging of small volumes of tissue along with the capability of stimulating precise areas within the volume of tissue. The imaging method presents an advancement over conventional methods that have relied on expensive and low resolution systems. The stimulation method presents an advancement over conventional techniques which have not permitted the precise steering of electrical fields into the optimal tissue activation volume required to deliver effective therapy. Combined, the imaging and stimulation method offers, for the first time, precise and high resolution stimulation of tissue in specific areas and volumes.


The disclosed devices and methods have special applications in medical use, particularly in the treatment of neurological disorders. Embodiments provide an unprecedented resolution in the imaging of tissue volumes by detecting local differences in electrical characteristics. In this way, some embodiments provide an imaging device, which while invasive and constrained in use, is able to provide a highly accurate registration of the imaged volume. The image registration permits the identification of anatomical structures, their surfaces and volumes, and their electrical characteristics such as, but not limited to, permittivity and conductivity.


When combined with stimulation methods, the device permits stimulation within specific regions, surfaces, and volumes of the registered image. The presently disclosed devices and methods provide the clinician and/or surgeon a tool by which they can both visualize the tissue of interest, and stimulate specific areas within it. This greatly increases the accuracy and safety of a surgery along with an improvement in the chronic therapeutic effects of stimulation.


The use of localized tomographical imaging to determine implant location and stimulation volume is a unique and important advancement in the field of neurological devices. Following the present disclosure, for the first time, clinicians will be able to substantially decrease the uncertainty in device placement, and increase the specificity of the location of stimulation.


The techniques described herein enjoy a number of advantages over conventional techniques to image tissue. Conventional methods in imaging require expensive equipment installations and resolution is increased by high field strengths in the case of Magnetic Resonance Imaging, or high X-ray dosages in the case of Computed Tomography scans. These high fields are not compatible with implantable devices containing metallic features, and artifacts caused by devices translate to image drift, errors, or decreased resolution in the registered image.


By bringing the imaging device into contact with the volume of interest, and measuring local differences in electrical characteristics of the volume, the some embodiments provide for images of unprecedented resolution and fidelity.


Likewise, the techniques for stimulation described herein enjoy a number of advantages over conventional efforts to stimulate tissue in a highly localized manner Conventional methods rely on implantable devices with electrical leads often composed of cylindrical contacts, or metal tips. Most methods rely on stimulation volumes extending only outwards from the device, as in the case of a cylindrical device.


One possible approach to this issue is the use of smaller electrodes, in order to stimulate with greater precision. However, there are practical limitations in surgery which prevent the clinician from precisely targeting the intended region. The image registration is often performed before the surgery, and subsequently navigational software is used to plan the implant trajectory and location. One approach is to incorporate the MRI into the surgery, and perform intra-operative imaging, however, this is economically unviable in many hospitals, and the low field strengths required to maintain compatibility with the implanted devices limit the resolution which can be achieved. For example, a surgeon would implant a cylindrical electrode lead after finding and confirming the stereotactic co-ordinates of the target site. As a more specific example, a neurosurgeon might implant an electrode lead in the Subthalamic Nucleus (STN) to treat the symptoms of Parkinson's Disease. The surgeon might not be able to easily find the STN, and even more commonly, might not be able to locate the area within the STN that they seek to stimulate using electric current. Furthermore, if the clinician seeks to stimulate only a specific area, surface, volume, or population of neurons or fiber bundles in, around, or near the STN, it would not be possible using today's technology because of the size and geometry of existing electrode leads, which are considerably larger than the aforementioned targets.


The presently disclosed devices and methods greatly improve current practice without fundamentally changing the surgical procedures currently in use. As an example, a neurosurgeon targeting the STN would implant the device using stereotactic co-ordinates very close to the STN. The surgeon would then deploy the several prongs from the device into and around the STN. The imaging method would be performed, which would provide the surgeon with a highly localized and high resolution image of the volume of tissue within the prongs of the device. The image will consist of a 2D or 3D tomography of the volume of tissue. The image is constructed using the differences in electrical characteristics of the volume such as, but not limited to, conductivity, permittivity, conductivity and/or permittivity anisotropy. The image can therefore provide information about, but not limited to, the location and direction of fiber tracts, neural cell density, the interface between grey and white matter. The image is created using electrical impedance tomography techniques which involve a sequence of steps by which current is applied between two electrodes and a potential difference is preferably detected across two different electrodes, or the same electrodes. By repeating this procedure across all the electrodes in the periphery of the imaged volume, an image can be registered with the tomographic data using any one of a number of image reconstruction techniques and algorithms.


Once the image has been registered, and the clinician can visualize what the device's exact location is, electrical stimulation can be applied to specific areas of the volume using the principles of neurostimulation and the superposition of electric fields. The clinician can then steer the stimulation field, and the volume of tissue activation, to particular areas of the volume. For example, the image might display the interface between the surface of the STN and fibers that are projecting from it, or to it. The clinician can then choose to stimulate this surface and the volume of activation is directed there by combining signals from several electrodes on the device prongs.


As a result, a previously inaccessible region can be quickly located, and stimulated, thereby decreasing surgical times and increasing the efficacy of treatment. In contrast, conventional devices were limited by the geometrical arrangement and size of electrodes, and by the lack of simultaneous or in-situ imaging when stimulating.


Another serious limitation to conventional devices is post-implantation movement. A patient that is reacting positively to the stimulation therapy might experience a movement of their electrode after implantation and thus, an immediate decrease or full halt in efficacy and the possible introduction of side effects. With the present device, if a device shift occurs, the volume of interest can be re-imaged, and the stimulation volume can be re-directed to the proper region.


The presently described devices and methods benefit from the ability of modern microfabrication techniques to facilitate the construction of the device. Recent advances in surface micromachining permit various electrode geometries consisting of favorable materials such as Platinum and Platinum-Iridium to be manufactured. The electrode substrates can then be assembled onto cut cylindrical components which consist of the prongs of the device. This assembly is further contained in an implantable catheter from which the prongs would extend during surgery.


In one aspect, an implantable neurological probe is disclosed including: an elongated probe assembly; at least one protruding shafts arranged at the distal end of the elongated probe assembly; a plurality of microelectrode elements arranged on the surface of the protruding shafts; at least one electrical contact arranged proximally along the elongated probe assembly; and at least one electrical conductor in electrical communication between at least one of the microelectrode elements and the at least one electrical contact.


In some embodiments, the protruding shafts can be reversibly retracted within the elongated probe assembly. In some embodiments, the elongated probe shaft is configured for insertion into a human body using an accepted procedure for insertion of deep brain stimulation leads. In some embodiments, the diameter of the elongated probe assembly is between 1 mm and 3 mm.


In some embodiments, at least one of the plurality of microelectrode elements is a stimulating electrode and at least one of the plurality of microelectrode elements is a detecting electrode. In some embodiments, at least one of the plurality of microelectrodes elements is both a stimulating electrode and a detecting electrode.


In some embodiments, each microelectrode element is formed on a conductive film, and where each microelectrode element is embedded within two isolating substrates. In some embodiments, the microelectrode embedded substrate is formable into a cylindrical assembly. In some embodiments, the protruding shafts can be formed to bend radial from the longitudinal axis of the cylindrical assembly. In some embodiments, one of the protruding shafts is longitudinal and centered along the longitudinal axis of the cylindrical assembly. In some embodiments, the protruding shafts are stiffened by a supporting member. In some embodiments, the longitudinal protruding shaft is stiffened by a supporting member.


In another aspect, a method for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including an elongated cylindrical member, a plurality of protruding shafts, a plurality of microelectrode elements on each protruding shaft, at least one electrical contact arranged proximally along the probe shaft, and at least one electrical conductor in electrical communication between at least one of the plurality of the microelectrode elements and the at least one electrical contact; retracting the protruding shafts within the elongated cylindrical member before surgical implantation; expanding the protruding shafts in the vicinity of the neurological target site following implantation; recording electrophysiological signals from the neurological target site using at least one of the microelectrode elements on at least one of the protruding shafts; and stimulating the neurological target using at least one of the microelectrode elements on at least one of the protruding shafts.


In some embodiments, the protruding shafts are retracted within the elongated cylindrical member using a flexible pull wire situated in a lumen of the elongated cylindrical member. In some embodiments, the protruding shafts are expanded from within the elongated cylindrical member using a rigid, or semi-rigid, push rod situated in a lumen of the elongated cylindrical member. In some embodiments, the act of positioning the distal end of the neurological probe includes recording neural activity detected by at least one of the plurality of microelectrode elements and repositioning the distal end of the neurological probe as required, until the recorded activity is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.


In some embodiments, the act of positioning the distal end of the neurological probe includes stimulating neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of protruding shafts, performing a clinical evaluation of the efficacy on the stimulation site in the implanted patient, and repositioning the distal end of the neurological probe as required, until the patient's response is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.


In some embodiments, the act of positioning the distal end of the neurological probe includes inhibiting neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of protruding shafts, performing a clinical evaluation of the efficacy on the inhibition site in the implanted patient, and repositioning the distal end of the neurological probe as required, until the patient's response is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.


In another aspect, a method is disclosed for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including an elongated cylindrical member, a plurality of protruding shafts, a plurality of microelectrode elements on each protruding shaft, at least one electrical contact arranged proximally along the probe shaft, and at least one electrical conductor in electrical communication between at least one of the plurality of the microelectrode elements and the at least one electrical contact; retracting the protruding shafts within the elongated cylindrical member before surgical implantation; expanding the protruding shafts in the vicinity of the neurological target site following implantation; applying an oscillating electric current between at least two of the microelectrode elements on at least one of the protruding shafts; and detecting an electric voltage between at least two of the microelectrode elements on at least one of the protruding shafts.


In some embodiments, the act of applying oscillating currents and detecting electric voltages is performed to image the electrical characteristics of the volume of neurological tissue between the protruding shafts.


In another aspect, an implantable neurological probe is disclosed including: an elongated shaft having a distal end and an internal lumen; a support cylinder slidingly disposed in only a distal portion of the internal lumen; a plurality of shafts coupled to the support cylinder and arranged to be selectively extended from the distal end of the elongated shaft; a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer, a stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation; and a pull wire coupled to the support cylinder to selectively retract the support cylinder and plurality of shafts within the internal lumen.


Some embodiments include a push-pull rod which includes the pull wire and the stylet.


In some embodiments, the elongated shaft is configured for insertion into a human body using an accepted procedure for insertion of deep brain stimulation leads.


In some embodiments, the diameter of the elongated shaft is between 1 mm and 3 mm.


In some embodiments, at least one of the plurality of microelectrode elements is a stimulating electrode and at least one of the plurality of microelectrode elements is a detecting electrode. In some embodiments, at least one of the plurality of microelectrodes elements is both a stimulating electrode and a detecting electrode.


In some embodiments, each microelectrode element is formed on a conductive film, and where each microelectrode element is embedded within two isolating substrates.


In some embodiments, the microelectrode embedded substrate is formable into a cylindrical assembly.


In some embodiments, the protruding shafts can be formed to bend radially from the longitudinal axis of the cylindrical assembly.


In some embodiments, one of the protruding shafts extends and is centered along the longitudinal axis of the cylindrical assembly.


In some embodiments, the protruding shafts are stiffened by a supporting member. In some embodiments, the longitudinal protruding shaft is stiffened by a supporting member.


In another aspect, an implantable neurological probe is disclosed including: an elongated shaft having a distal end and an internal lumen; a plurality of shafts arranged to be selectively extended from the distal end of the elongated shaft; and a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer. In some embodiments, the plurality of shafts define a substantially cylindrical volume when fully extended.


In some embodiments, the elongated shaft is configured for insertion into a human body using an accepted procedure for insertion of deep brain stimulation leads.


In some embodiments, the diameter of the elongated shaft is between 1 mm and 3 mm.


In some embodiments, at least one of the plurality of microelectrode elements is a stimulating electrode and at least one of the plurality of microelectrode elements is a detecting electrode.


In some embodiments, at least one of the plurality of microelectrodes elements is both a stimulating electrode and a detecting electrode. In some embodiments, each microelectrode element is formed on a conductive film, and where each microelectrode element is embedded within two isolating substrates. In some embodiments, the microelectrode embedded substrate is formable into a cylindrical assembly. In some embodiments, the protruding shafts can be formed to bend radially from the longitudinal axis of the cylindrical assembly. In some embodiments, one of the protruding shafts extends and is centered along the longitudinal axis of the cylindrical assembly. In some embodiments, the protruding shafts are stiffened by a supporting member. In some embodiments, the longitudinal protruding shaft is stiffened by a supporting member.


In another aspect, a method is disclosed for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including: an elongated shaft having a distal end and an internal lumen; a support cylinder slidingly disposed in only a distal portion of the internal lumen; a plurality of shafts coupled to the support cylinder and arranged to be selectively extended from the distal end of the elongated shaft; a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer, a stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation; and a pull wire coupled to the support cylinder to selectively retract the support cylinder and plurality of shafts within the internal lumen. In some embodiments, the method further includes: retracting the plurality of shafts within the internal lumen before surgical implantation; extending the plurality of shafts in the vicinity of the neurological target site following implantation; recording electrophysiological signals from the neurological target site using at least one of the microelectrode elements on at least one of the protruding shafts; and stimulating the neurological target using at least one of the microelectrode elements on at least one of the plurality of shafts.


In some embodiments, the method includes: after the acts of recording and stimulating, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.


In some embodiments, the protruding shafts are retracted using the pull wire. In some embodiments, the plurality of shafts are extended using the stylet. In some embodiments, the neurological probe includes a push-pull rod which includes the pull wire and the stylet


In some embodiments, the act of recording neurophysiological signals includes recording neural activity detected by at least one of the plurality of microelectrode elements and repositioning the distal end of the elongated shaft as required, until the recorded activity is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.


Some embodiments include stimulating neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of shafts, performing a clinical evaluation of the efficacy on the stimulation site in the implanted patient, and repositioning the distal end of the elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.


Some embodiments include inhibiting neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of shafts, performing a clinical evaluation of the efficacy on the inhibition site in the implanted patient, and repositioning the distal end of elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.


In another aspect, a method is disclosed for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including: an elongated shaft having a distal end and an internal lumen; a support cylinder slidingly disposed in only a distal portion of the internal lumen; a plurality of shafts coupled to the support cylinder and arranged to be selectively extended from the distal end of the elongated shaft; a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer, a stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation; and a pull wire coupled to the support cylinder to selectively retract the support cylinder and plurality of shafts within the internal lumen. Some embodiments include retracting the plurality of shafts within the internal lumen before surgical implantation; expanding the plurality of shafts in the vicinity of the neurological target site following implantation; applying an oscillating electric current between at least two of the microelectrode elements on at least one of the plurality of shafts; and detecting an electric voltage between at least two of the microelectrode elements on at least one of the plurality of shafts.


Some embodiments include: after the act of detecting, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.


Some embodiments include imaging the electrical characteristics of the volume of neurological tissue between the plurality of shafts based on the applied oscillating electric current and the detected electric voltage.


In some embodiments, the neurological probe includes a push-pull rod which includes the pull wire and the stylet.


In another aspect, a method for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including: an elongated shaft having a distal end and an internal lumen; a plurality of shafts arranged to be selectively extended from the distal end of the elongated shaft; and a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer, where the plurality of shafts define a substantially cylindrical volume when fully extended. In some embodiments, the method includes: retracting the plurality of shafts within the internal lumen before surgical implantation; extending the plurality of shafts in the vicinity of the neurological target site following implantation; recording electrophysiological signals from the neurological target site using at least one of the microelectrode elements on at least one of the protruding shafts; and stimulating the neurological target using at least one of the microelectrode elements on at least one of the plurality of shafts.


In some embodiments, the protruding shafts are retracted using a pull wire. In some embodiments, he plurality of shafts are extended using a stylet. In some embodiments, the neurological probe includes a push-pull rod which includes the pull wire and the stylet.


In some embodiments, the act of recording neurophysiological signals includes recording neural activity detected by at least one of the plurality of microelectrode elements and repositioning the distal end of the elongated shaft as required, until the recorded activity is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.


Some embodiments include: after the acts of recording and stimutating, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject


Some embodiments include stimulating neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of shafts; performing a clinical evaluation of the efficacy on the stimulation site in the implanted patient; and repositioning the distal end of the elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.


Some embodiments include inhibiting neural activity by applying electrical signals to at least one of the plurality of microelectrode elements on at least one of the plurality of shafts, performing a clinical evaluation of the efficacy on the inhibition site in the implanted patient, and repositioning the distal end of elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.


In another aspect, a method for finding a neurological target including: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe including: an elongated shaft having a distal end and an internal lumen; a plurality of shafts arranged to be selectively extended from the distal end of the elongated shaft; and a plurality of microelectrode elements disposed on each of the plurality of shafts, the microelectrode elements including a planar substrate having an insulative layer and a plurality of conductive traces disposed on the insulative layer, where the plurality of shafts define a substantially cylindrical volume when fully extended. Some embodiment include retracting the plurality of shafts within the internal lumen before surgical implantation; expanding the plurality of shafts in the vicinity of the neurological target site following implantation; applying an oscillating electric current between at least two of the microelectrode elements on at least one of the plurality of shafts; and detecting an electric voltage between at least two of the microelectrode elements on at least one of the plurality of shafts.


Some embodiments include imaging the electrical characteristics of the volume of neurological tissue between the plurality of shafts based on the applied oscillating electric current and the detected electric voltage.


Some embodiments include: after the act of detecting, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject


Various embodiments may include any of the above described elements or steps alone, or in any suitable combination.





BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views.



FIG. 1 is a perspective view of one embodiment of an elongated microelectrode assembly.



FIG. 2 is a perspective view of a portion of a human anatomy illustrating an exemplary elongated microelectrode assembly implanted therein.



FIG. 3 is a perspective view of a portion of a human anatomy illustrating an exemplary microelectrode structure positioned at a neurological target.



FIG. 4A is a perspective view of a distal portion of the elongated microelectrode assembly of FIG. 1 in the expanded position.



FIG. 4B is a perspective view of a distal portion of the elongated microelectrode assembly of FIG. 1 in the retracted position.



FIG. 5 is a perspective view of a proximal portion of the elongated microelectrode assembly of FIG. 1.



FIG. 6 is a planar view of an embodiment of a microelectrode array film.



FIG. 7 is a perspective view of the embodiment of a microelectrode array film of FIG. 6 after it has been assembled.



FIG. 8A is a planar top view of the microelectrode array film assembly of FIG. 7.



FIG. 8B is a planar side view of the microelectrode array film assembly of FIG. 7.



FIG. 9 is a planar frontal view of the microelectrode array film assembly of FIG. 7.



FIG. 10 is a perspective view of the microelectrode array film assembly of FIG. 7 in the retracted position.



FIG. 11 is a planer view of the retracted microelectrode array film assembly of FIG. 10.



FIG. 12A is a perspective view of a central pin component.



FIG. 12B is a planar side view of the central pin component of FIG. 12A.



FIG. 13A is a perspective view of the outer legs component shown in the expanded position.



FIG. 13B is a perspective view of the outer legs component shown in the retracted position.



FIG. 14 is a perspective view of the microelectrode array film assembly of FIG. 7 shown assembled to the central pin component of FIG. 12A.



FIG. 15 is a perspective view of the microelectrode assembly of FIG. 14 shown assembled to the flexible pull wire, and a microelectronic component.



FIG. 16 is a perspective view of the microelectrode assembly of FIG. 15 shown assembled to helical lead wires, and the outer legs component of FIG. 13A.



FIG. 17 is a perspective view of the microelectrode assembly of FIG. 16 shown assembled to an outer tubing and a stiff push rod.



FIG. 18 is a close-up perspective view of the microelectrode assembly of FIG. 17 showing the flexible pull wire and the stiff push rod in more detail.



FIG. 19A is a perspective view of the perforated end cap.



FIG. 19B is a planar view of the perforated end cap.



FIG. 20 is a cut-away perspective view of the microelectrode assembly of FIG. 4A with segments of the perforated end cap and outer legs component removed.



FIG. 21 is a cut-away perspective view of the retracted microelectrode assembly of FIG. 4B with segments of the perforated end cap and outer legs component removed.



FIG. 22 is a planar view of the microelectrode assembly demonstrating microelectrode elements on the same plane.



FIG. 23 is a perspective view the assembly and planes of FIG. 22.



FIG. 24 is a perspective view of an alternative embodiment of the elongated microelectrode assembly of FIG. 1.



FIG. 25 is a planar front view of the alternative embodiment of FIG. 24.



FIG. 26 is a planar side view of the alternative embodiment of FIG. 24.



FIG. 27 is a perspective view of an alternative embodiment of the elongated microelectrode assembly of FIG. 1.



FIG. 28 is a planar side view of the alternative embodiment of FIG. 27.



FIG. 29 is a perspective view of an alternative embodiment of FIG. 1 where the microelectrode arrays are placed on the outside of the protruding shafts.



FIG. 30 is a planar back view of the alternative embodiment of FIG. 29.



FIG. 31 is a planar side view of the alternative embodiment of FIG. 29 depicting separate stimulation and recording electrodes.



FIG. 32 is a detail perspective view of the alternative embodiment of FIG. 29.



FIG. 33 is an additional detail perspective view of the alternative embodiment of FIG. 29.



FIG. 34 is a component of the alternative embodiment of FIG. 29.



FIG. 35 is an additional component of the alternative embodiment of FIG. 29.



FIG. 36 is yet an additional component of the alternative embodiment of FIG. 29.



FIG. 37 is a perspective view of an alternative embodiment of FIG. 1 where the protruding shafts have been implemented at two different regions of the longitudinal axis.



FIG. 38A is a planar view of the alternative embodiment of FIG. 37.



FIG. 38B is an additional planar view of the alternative embodiment of FIG. 37.



FIG. 39A is a perspective view of the microelectrode array film required in the assembly of the alternative embodiment of FIG. 37.



FIG. 39B is a perspective view of the protruding shaft support required in the assembly of the alternative embodiment of FIG. 37.



FIG. 40A is a perspective view of an alternative embodiment of FIG. 1 where the microelectronic component is not required.



FIG. 40B is a perspective view of the microelectrode array film required in the assembly of the alternative embodiment of FIG. 40A.



FIG. 40C is a perspective view of an alternative embodiment of FIG. 1 where the protruding shafts are not rigidified by the protruding shaft support.



FIG. 40D is a detail perspective view of the alternative embodiment of FIG. 40C.



FIG. 41 is a schematic of a neural recording microelectronic circuit.



FIG. 42 is a schematic of a neural stimulation microelectronic circuit.



FIG. 43 is a schematic of a combined neural recording and stimulation microelectronic circuit.



FIG. 44 demonstrates the Electrical Impedance Tomography method described herein.





DETAILED DESCRIPTION

Described herein are microelectrode array devices, and methods of fabrication and use of the same, to provide highly localized and efficient electrical stimulation of a neurological target, such as individual neurons, groups of neurons, and neural tissue as may be located in an animal nervous system, such as deep within a human brain. In small, difficult to find brain targets such as the Pedunculopontine Nucleus, or in targets that requires highly localized levels of neural stimulation, such as the Subthalamic Nucleus, many microelectrodes are required in the brain region to find the target using electrophysiological recording. A higher number of microelectrodes will increase the chance of finding the neurons required for therapeutic stimulation. The microelectrode, or group of microelectrodes, that are closest to the target brain region will be used for chronic, therapeutic stimulation or inhibition.


The stimulation can be highly localized, because the microelectrode elements can be as small as only 2 μm or large as 2 mm in either of diameter or width. The relative spacing between such microelectrode elements can also be as small as only 2 μm or as large as 2 mm Generally, microelectrodes of about 150 μm in diameter, with about a 1000 μm spacing are particularly efficient in stimulating neural tissue.


An array of such microelectrode elements may consist of one or more such elements (e.g., sixteen elements), each disposed at a respective position, or site. This is in contrast to currently available stimulation leads, such as the Model 3387 or Model 3389 DBS leads commercially available from Medtronic, Inc. of Minneapolis, Minn. Such commercially available devices include relatively large, cylindrical electrodes measuring about 1.5 mm in height, and having a maximum of only four electrodes in use today for deep brain stimulation.


Smaller microelectrode elements can be used to provide neurological stimulation that is highly localized and efficient because an array of such microelectrodes can also be used to identify the stimulation region of interest. For example, one or more microelectrode elements of such an array of microelectrode elements can be used to record neuronal activity in the vicinity of the detecting/recording microelectrode elements. Such refinement offered by the relatively small size and/or spacing of the microelectrode elements can be used to obtain a highly localized map of neuronal activity in the region surrounding the implant. A suitably dimensioned microelectrode array having multiple microelectrode elements positioned in a general vicinity of a neurological target, can be used to locate a precise neurological target without further repositioning, by identifying those one or more microelectrode elements located in a very specific region of the neurological target. The microelectrode array can be programmed to stimulate in a very specific region, for example, using only a certain number of the microelectrode elements to actively stimulate the surrounding neurons and/or neuronal tissue, while other electrode elements of the array remain inactive.


In the embodiments described, the microelectrode arrays are positioned in three dimensional space. This has been a previous limitation of such microelectrode devices, which were usually implement in linear arrays, or two dimensional arrays on films. In the present embodiment microelectrode arrays are positioned along shafts which radiate from a central lumen, in order to cover as much volume in the target region with microelectrode arrays.


In some embodiments, an elongated device including such microelectrode arrays having elements with relatively small size and/or spacing can be used to obtain a highly localized map of neuronal activity in the region surrounding the implant. For example, such a device configured with a linear array of microelectrodes positioned along a length of a distal end of the device can be placed into a patient's brain. Preferably, the elements of the microelectrode array envelop a region including the neurological target. Neurological activity can then be independently detected by one or more of the microelectrode elements. The detected activity may be captured in a recorder or display device, allowing a clinician to identify which one or more of the microelectrode elements is positioned closest to the intended target. Knowing a respective location of each of the microelectrode elements along the device, and determining the distance to a reference, such as the patient's skull, a precise location of the target can be determined as the distance along a trajectory of the device, measured from the reference to the particular microelectrode element. Beneficially, location of the target can be determined without any repositioning of the elongated device, thereby simplifying the medical procedure and reducing patient risk.


In some embodiments, the device is for acute intra-surgical use, being removed after the target has been located, being replaced with a chronic probe, positioned at the determined target location. Alternatively or in addition, the device itself can be left in place as a chronic device, the same microelectrodes, or different ones, being used to record and/or stimulate the neurological target over an extended period.


One embodiment of a microelectrode device illustrated in FIG. 1 includes an elongated microelectrode lead assembly 100 sometimes referred to as an electrode lead. The microelectrode lead assembly 100 includes an external cylindrical member 102 including a microelectrode array assembly 150 located relative to a distal end and one or more electrical contacts 106 located relative to a proximal end. The exemplary microelectrode lead assembly 100 includes one or more microelectrode array shafts 160 adjacent to its distal tip. The microelectrode array assembly 150 has five protruding shafts 160, with disc microelectrode elements disposed along an interior surface of an extended substrate. In the present embodiment four shafts protrude, to one of the anterior, posterior, lateral, or medial directions. An additional shaft protrudes along the same longitudinal axis of the electrode lead, referred to as the central shaft. The microelectrode lead assembly 100 also includes eight electrically conductive, cylindrical contacts, or contact rings (generally 106) distributed along a longitudinal axis of the proximal end of the assembly 100. In the exemplary embodiment, each of the microelectrode elements is in electrical communication with a proximal contact 106 via an embedded microelectronic element. In use, stimulation signals are directed from an implantable pulse generator, or controller to the microelectrode array. Additionally, in use, recording signals are directed from the microelectrode array to an implanted or external data recorder.


The microelectrode lead assembly 100 is preferably sized and shaped for its intended neurological application. For example, the microelectrode lead assembly 100 may be at least partially placed within the central nervous system. Alternatively or in addition, the microelectrode lead assembly 100 may be at least partially placed within other parts or organs of the body, such as the epidural space of the spine, or other locations within the peripheral nervous system, or within an organ such as the liver or heart. Thus the diameter and length of the microelectrode lead assembly 100 may vary depending on the particular anatomical target. Additionally, the configuration of the microelectrode array shafts 160 is also sized and shaped for an intended neurological target. The number, shape, orientation, size, and spacing of the microelectrode elements of the array can be defined in response to the intended neurological target.


In at least some embodiments one or more of the microelectrode elements are sized and or spaced to record from and/or stimulate neurons. The microelectrode lead assembly 100 can be used to detect and/or record neuronal activity at the neurological target. Neuronal activity naturally occurring within the neurological target gives rise to local electromagnetic fields that can be detected by one or more of the microelectrode elements of the microelectrode array. For example, electric fields produced by neurons will polarize one or more of the microelectrode elements. Such polarization gives rise to an electrical potential with respect to a reference, such as electrical ground, or another one of the microelectrode elements. Such electric activity can be further conducted to one or more of the cylindrical contacts 106 through the internal electrical conductors. One or more of the cylindrical contacts 106, in turn, can be connected to one or more additional medical devices for further processing of the detected electrical activity. For example, the cylindrical contacts 106 can be coupled to a display device or recording device for displaying and/or recording electrical activity from the neurological target.


Alternatively or in addition, one or more of the microelectrode elements can be used to electrically stimulate the neurological target. For example, one or more externally generated electrical signals can be applied to one or more of the cylindrical contacts 106. These electrical signals can be conducted through the internal electrical conductors to one or more of the microelectrode elements of the microelectrode array. Depending on the amplitude and polarity of the electrical signals, an electrical field will be induced by the polarized microelectrode elements. Electrical fields induced by such polarization can interact with one or more neurons at the neurological target.


Alternatively or in addition, one or more of the microelectrode elements can be used to perform Electrical Impedance Tomography of a neurological target or other bodily organ. For example, one or more externally generated electrical signals can be applied as a current to one or more of the microelectrode elements. Depending on the physiological characteristics of the tissue being imaged, and depending on the frequencies of the current signals applied, an electrical field will be induced in the tissue. Electrical fields induced by such polarization can be detected by other microelectrode elements, thereby creating a localized image of conductivity, permittivity, and/or other electrical characteristics.


Mechanical components of the implantable neurological lead assembly 100 include the elongated outer cylindrical member 102, which can be a simple polymeric cylinder, or a rigid metallic or rigid polymeric cylinder. The outer cylindrical member 102 can vary in length and diameter but is generally at least about 28 cm long, (e.g., at least 20 cm long, at least 25 cm long, at least 28 cm long, at least 30 cm long, etc.) and around 1.27 mm in diameter (e.g., in the range of 1.0-2.0 mm in diameter).


The neurological lead 100 can be implanted near a neurological target, such as a target brain structure, using common neurosurgical techniques such as stereotaxy or endoscopy. The microelectrode lead assembly 100 can be inserted in its retracted state without support, or within a supporting cannula having an inner dimension slightly larger than the outer dimension of the device. The cannula, when used, would be removed once the microelectrode lead assembly 100 has been suitably positioned. In some embodiments a lumen along the axis of the outer cylindrical member 102 permits the insertion of a rigid stylet which renders the microelectrode lead assembly 100 rigid during surgical implantation. This is particularly helpful during insertion, positioning and repositioning of flexible embodiments of the microelectrode lead assembly 100. The stylet is removed after implantation leaving the probe in its surgical target. In some embodiments the stylet is also a rigid push rod, which is used to expand the microelectrode array shafts 160 into the tissue. In some embodiments, the microelectrode lead assembly 100 contains a flexible pull wire which is used to pull the microelectrode array shafts 160 back into the retracted position. In yet additional embodiments, the microelectrode lead assembly 100 contains only one rigid push-pull rod which is used to both push and pull the microelectrode array shafts 160 in its expanded and retracted position respectively. In yet additional embodiments, where the microelectrode lead assembly 100 is not intended to remain in the patient's brain after surgery, the rigid push-pull rod may be permanently attached to the microelectrode array shafts 160.


A clinician can connect one or more of the microelectrode elements to a display unit or a recording unit through the cylindrical contacts 106. The recording unit, not shown, allows a clinician to identify certain regions of the brain according to their electrical activity. In some embodiments, such recording information can be processed automatically, through the use of a suitably programmed computer processor. The electrodes used to record from the brain can be the same electrodes as those used to stimulate tissue. The recording electrodes can also be separate from those used to stimulate the brain. This situation might be preferred because electrodes destined for recording may be different in size and design than those for stimulation.


The operator can connect the electrodes to an external stimulation source or an implantable source. In either instance, the source can include a pulse generator for applying signals to the electrode sites. The signals from such a pulse generator can be connected directly to the electrodes, or they can be preprocessed using electronics embedded in the device. The electronics can filter certain parts of the original signal. If there are more electrodes than signals, the electronics can route or otherwise interconnect the stimulation source as necessary.


A perspective view of the portion of a human anatomy is illustrated in FIG. 2, showing implantation of an exemplary elongated microelectrode probe assembly 124 position for interaction with a neurological target located deep within the brain. A distal portion of the microelectrode probe assembly 124 is positioned at the neurological target 130, in this instance located within the human brain 132. Several exemplary microelectrode array shafts 134 protrude from the distal portion of the microelectrode probe assembly 124. In some embodiments the proximal end of the microelectrode probe assembly 124 is connected to a first medical device 128. For example, the first medical device 128 may include an electronic assembly implanted external to the brain 132 to minimize invasion into the body. Alternatively or in addition, a second medical device, which again may include an electronic assembly such as a pulse generator 122 can be implanted at a remote portion of the subject body. As shown, a second electronic assembly 122 is implanted within a chest cavity 120. When one or more medical devices, such as the exemplary pulse generator 122 are located remotely in this manner, a cable 126 may also be implanted within the subject's body to interconnect the pulse generator 122 to the electronic assembly 128, when present or directly to cylindrical contacts located at the proximal end of the microelectrode probe assembly 124.


Referring now to FIG. 3, a cross-sectional view of a portion of an anatomy 148 is shown, illustrating an exemplary microelectrode probe assembly 140 positioned at a neurological target 148 (e.g., subthalmic nucleus, shown). The microelectrode probe assembly 140 includes five microelectrode array shafts, 141A, 141P, 141L, 141M, 141C (generally 141) protruding from a cylindrical containment structure 143. On each microelectrode array shaft 141 are three microelectrode elements 145 distributed linearly along the microelectrode array shaft 141. Preferably, the microelectrode probe assembly 140, and its protruding microelectrode electrode arrays shafts 141 are shaped, spaced, and sized to allow one or more of the microelectrode elements 145 to be positioned at the neurological target 149.


As illustrated, one or more of the microelectrode elements 145 of the microelectrode probe assembly 140 are positioned in intimate contact with the neurological target 149. In more detail, each microelectrode element 145 is a disc electrode along a shaft. It is understood that some microelectrode array shafts 141 can be in contact with the neurological target, while other microelectrode array shafts 141 are not (as shown). Additionally, it is understood that some microelectrode elements 145 can be in contact with the neurological target, while other microelectrode elements 145 are not (as shown). In at least some embodiments, one or more of the microelectrode elements 145 are remotely accessible from a proximal end of the probe assembly 140 via one or more electrically conductive leads (not shown).


In at least some embodiments, selectable microelectrode elements 145 can be activated to record and or stimulate the target 149. For example, recordings of neurological activity from microelectrode elements 145 in contact with the target 149 can be used to identify the location of the target 149 relative to the probe assembly 140 or relative to a standard stereotactic reference coordinate. As determined form the recordings, only those microelectrode elements 145 in contact with the target may be activated to stimulate the target.


Any of the supporting structures described herein, such as the supporting structure 140 illustrated here can be a ridged, or semi rigid structure, such as a polymeric cylinder. Alternatively or in addition, the structure can be a flexible structure, such as one or more flexible substantially non conducting substrate (i.e., a bi-electric ribbon) onto which the microelectrode elements 145 are formed as electrically conductive film layers. The one or more microelectrode elements 145 are in communication with electronic circuitry (not shown) through one or more electrical leads (not shown) that can be routed through an internal lumen of a supporting structure 140 and/or formed using elongated film layers along a flexible, ribbon like supporting structure 140.


In some embodiments, the microelectrode elements 145 can be placed into the brain generally for recording and/or stimulation of the cortex and for deep brain stimulation and/or recording of neurological targets including the subthalamic nucleus and the pedunculopontine nucleus. The microelectrode elements 145 can also be placed in other parts of the body, such as the spine, the peripheral nervous system for neural recording and/or neural stimulation of such portions of an animal anatomy. Although microelectrodes are discussed generally throughout the various embodiments, there is no intention to limit the upper or lower size of the microelectrodes. The devices and methods described herein are generally scalable, with a microelectrode size determined according to the intended application. For at least some of the neurological applications, microelectrodes are dimensioned sub-millimeter. In some embodiments, the microelectrodes are formed as planar structures having a diameter of about 150 μm that are arranged in a linear array with center to center spacing of about 1000 μm. The planar structure of the microelectrodes can have regular shapes, such as circles, ellipses, polygons, irregular shapes, or a combination of such regular and/or irregular shapes.


This probe assembly 140 is implantable near a neurological target, such as a target brain structure, using common neurosurgical techniques such as stereotaxy or endoscopy. The device might be inserted without support or within a cannula which may have an inner dimension slightly larger than the outer dimension of the device. Alternatively, or in addition to, the device may have a rigid stylet running along its central axis with an outer diameter that is smaller than the inner diameter of an axial lumen in the device. When used, such a cannula, or a stylet, is generally retracted once the device is in position.


The operator can connect the probe assembly 140 to a recorder unit configured to identify certain regions of the neurological target (e.g., the brain) according to the electrical activity detected by the probe assembly 140. In some embodiments, the microelectrode elements 145 used to record from the neurological target 149 can be the same microelectrodes as those used to stimulate the target in applications in which both recording and stimulation are accomplished. Alternatively or in addition, the microelectrode elements 145 used to record from the neurological target 149 can be separate microelectrode elements 145 from those used to stimulate the target 149. In some embodiments, microelectrodes destined for recording (e.g., 145) may differ in one or more of size, shape, number, and arrangement from those microelectrodes destined for stimulation, e.g., using different microelectrodes.


The microelectrode elements 145 configured for stimulation can be connected to a stimulation source through one or more interconnecting leads. In some embodiment, at least a portion of the stimulation source can be extracorporeal. Alternatively or in addition, the stimulation source can be in vivo. Any implanted elements of the stimulation source are preferably fabricated and/or contained with a hermetically sealed, bio-compatible envelope. Such bio-compatible packaging of signal sources is well known, for example, in the area of artificial pacemakers. The stimulation source, when provided, may be a controllable signal generator producing a desired signal according to a prescribed input. For example, the signal generator may receive an input indicative of a desired output stimulation signal frequency. Such output stimulation signals can have a variety of wave forms, such as pulses, charged balanced pulses, sinusoidal, square wave, triangle wave, and combinations of such basic wave forms.


In some embodiments, the stimulation source includes a pulse generator for applying signals to the microelectrodes site. The signals from the pulse generator can be connected directly to the microelectrodes, or they can be preprocessed using electronics. In some embodiments, such preprocessing electronics are embedded within the implantable device. The preprocessing electronics can filter certain parts of an original signal, such as a cardiac pacemaker signal, in order to select preferred frequency components of the original signal that are at or near a peak resistance frequency of the microelectrodes. For embodiments in which there are more microelectrodes than signals, electronics can route the stimulation signals to preferred one or more of the microelectrodes.


Referring now to FIG. 4A a more detailed view of a distal end of the microelectrode probe assembly 100 is shown. The microelectrode array assembly 150 includes a perforated end-cap 190 which contains the protruding microelectrode array shafts 160A, 160L, 160P, 160M, and 160C (generally 160). The microelectrode arrays shafts 160 are lettered A, L, P, M, and C in order to coincide with the anatomical convention of Anterior, Lateral, Posterior, Medial, and Central positions respectively. Each microelectrode array shaft 160 contains three microelectrode elements 265 in a linear arrangement. The microelectrode elements 265 on microelectrode array shaft 160M are shown and labeled 265Ma, 265Mb, and 265Mc. Microelectrode element 265Ma is the most distal along microelectrode array shaft 160M, whereas microelectrode element 265Mc is the most proximal. Each microelectrode array shaft 160 contains three microelectrode elements 265 on its interior surface.


Referring now to FIG. 4B a more detailed view of a distal end of the microelectrode probe assembly 100 in the retracted position is shown. In this state, the protruding microelectrode shafts 160 have been retracted into the interior of the perforated end-cap 190 and are completely contained within the microelectrode array assembly 150. Also visible are the perforations 192 on the perforated end-cap 190 which correspond to each microelectrode array shaft 160. The perforations 192 are lettered A, L, P, M, and C in order to coincide with the anatomical convention of Anterior, Lateral, Posterior, Medial, and Central positions respectively. The perforated end-cap 190 is attached to the outer cylindrical member 102.


Referring now to FIG. 5 a more detailed view of the proximal end of the microelectrode probe assembly is shown. The cylindrical contacts 106 are arranged along the longitudinal axis of the outer cylindrical member 102. Each of the eight cylindrical contacts 106, 106a through 106h, is electrically connected to a lead wire (not shown) which is in communication with the distal end of the microelectrode lead assembly 100. In the exemplary embodiment each cylindrical contact measures 1.27 mm in diameter, and 2 mm in length. The cylindrical contacts 106 are spaced from each other by insulating cylindrical contacts 107a through 107h (generally 107). In some embodiments there may only be one cylindrical contact 106, while in other embodiments there may be two or more cylindrical contacts 106. Generally there are between four and eight cylindrical contacts 106.


The microelectrode lead assembly 100 contains one removable rigid push rod 170, and one non-removable flexible pull wire 175. The rigid push rod 170 is used to expand the microelectrode array assembly 150 into its expanded state. The flexible pull wire 175 is used to pull the microelectrode array assembly 150 back into is retracted state. As shown, the rigid push rod 170 is composed of three features. The first feature is a hollow rigid stylet 172 that is also used to straighten the microelectrode lead assembly 100 during implantation. The second feature is a longitudinal slit 173 which permits access to the central lumen of the rigid stylet 172. The third feature is the push handle 174 which permits the operator to apply a pressure and expand the microelectrode array assembly 150 at the distal end. As shown, the flexible pull wire 175 has three features. The first feature is a flexible central wire 176 which is permanently attached to the microelectrode array assembly 150 at the distal end. The second feature is a pull handle 178 which the operator can use to retract the microelectrode array assembly at the distal end by pulling. The third feature is a hole 179 in the pull handle 178 which the operator can use to facilitate the pulling action required of the component. Together, push rod 170 and pull rod 175 are used in order to expand and retract the microelectrode array shafts 160 and the distal end of the microelectrode lead assembly 100.


Referring now to FIG. 6 a more detailed view of the microelectrode array film 200 is shown in its non-assembled state. The microelectrode array film 200 is produced using a sequential production method where several films are deposited one atop the other. The first film is a polymeric, isolating film such as polyimide. The second film is a conductive, preferably noble metallic film such as platinum. The second film is structured in order to create metallic traces and discs. The third film is a polymeric, isolating film, such as polyimide. The third and first films are then structured to provide the outline shown in FIG. 6. Embedded metallic layers are not shown, while metallic discs and electrical contacts are exposed. The microelectrode film shafts 260 correspond each to one of the microelectrode array assembly shafts 160 shown previously. The microelectrode film shafts 260 are numbered corresponding to their appropriate shaft, Anterior, Lateral, Posterior, Medial, and Central as 260A, 260L, 260P, 260M, and 260C. The microelectrode film shafts 260 contain the microelectrode elements 265. The microelectrode elements 265 on microelectrode film shaft 260P are labeled as an example, where 265Pa is the most distal microelectrode element and 265Pc is the most proximal microelectrode element. The length of microelectrode film shaft 260C and the spacing of its microelectrode elements 265 differs slightly from the other geometries because it forms part of the central microelectrode array shaft 160 and will not be at an angle to the longitudinal axis of the microelectrode lead assembly 100.


The next feature on the microelectrode array film 200 is the distal structural cylinder 210 which is shown in its flattened state, but once assembled will be used to stabilize the film in its final assembly. The microelectronic platform 212 is where a subsequent microelectronic component will be attached. The microelectronic component is explained in detail below. It is preferably attached to the microelectrode array film 200 while it is still in its flattened state. On the microelectronic platform 212 are arranged the microelectronic platform bond bands 270 which are used to electrically communicate the microelectrode elements 265 to external equipment through the microelectronic component. They are arranged in a two dimensional array. The central structural cylinder 214 which is shown in its flattened state, but once assembled will be used to stabilize the film in its final assembly. The helical ribbon cable 216 which is shown in its flattened state, but once assembly will be used to permit movement of the microelectrode array assembly 150 within the microelectrode lead assembly 100. The proximal structural cylinder 218 is shown in its flattened state, but will be attached to an internal cylinder within the microelectrode lead assembly 100 and is the only non-moving part of the microelectrode array film 200. On the proximal structural cylinder 218 are the proximal contact pads 208 which are used to communicate the elements of the microelectronic component to lead wires that communicate the distal portion of the microelectronic lead assembly 100 to its proximal portion.



FIG. 7 demonstrates the microelectrode array film 200 in its assembled, and expanded state. The central microelectrode film shaft 260C, and the four microelectrode film shafts 260A, 260L, 260P, 260M are shown, with their respective microelectrode elements 265 on the interior of the assembly. The distal structural cylinder 210 is shown curled into its cylindrical state. The microelectronic platform 212 is shown bent it its horizontal position. The central structural cylinder 214 is shown curled into its cylindrical state. The helical ribbon cable 216 is shown curled and pulled into its assembled state. The proximal structural cylinder 218 is shown curled into its position, with proximal contact pads 208 exposed. The microelectrode array film 200 can be assembled into this configuration in steps, or after assembly with subsequent components.



FIG. 8A is a planar side view of the microelectrode array film 200 in its assembled, and expanded state. The important features to note in this view are the slits 211, 215, 219 in the structural cylinders 210, 214 and 216 respectively which are present because of the curling required to assemble the film into its position.



FIG. 8B is a planar top view of the microelectrode array film 200 in its assembled, and expanded state.



FIG. 9 is a planar front view of the microelectrode array film 200 in its assembled, and expanded state. The position of the four angled microelectrode film shafts 260 are shown, and the interior microelectrode elements 265 are visible.



FIG. 10 demonstrates the microelectrode array film 200 in its assembled, and retracted state. The central microelectrode film shaft 260C, and the four microelectrode film shafts 260A, 260L, 260P, 260M are shown, with their respective microelectrode elements 265 on the interior of the assembly. These microelectrode film shafts 260 have moved from their angle position into a closed position. The structural cylinders 210, 214 and 218 have not change in shape. Structural cylinders 210 and 214 have not moved in position relative to each other. Structural cylinders 210 and 214 have both moved closer to structural cylinder 218. This movement has caused the reversible of the helical ribbon cable 216.



FIG. 11 demonstrates a planar side view of the microelectrode array film 200 in its assembled, and retracted state. The anterior microelectrode film shaft 260A and the posterior microelectrode film shaft 260P are in parallel positions.


Referring now to FIG. 12A, a perspective view of the central pin 185 is shown. This pin will be assembled in a subsequent step to the microelectrode array film 200. The central pin has several features including a protruding axial shaft 186, a cylindrical member 188, and a lengthwise slit 189 on the cylindrical member 188. The protruding axial shaft 186 has a bend 187 which permits it to be positioned along the longitudinal axis of the cylindrical member 188. Generally, the component is formed from a rigid cylindrical material such as medical grade stainless steel which has been cut by a laser into the present shape. FIG. 12B demonstrates a side view of the central pin 185.


Referring now to FIG. 13A, a perspective view of the expandable shaft support 180 is shown. The expandable shaft support 180 is composed of cylindrical member 182, from which protrude four semi-rigid shafts into the Anterior direction 181A, the Lateral direction 181L, the Posterior direction 181P, and the Medial direction 181M. The semi-rigid shafts 181 are expanded radially from the longitudinal axis of the cylindrical member 182. Generally, the component is formed from a rigid cylindrical material such as medical grade stainless steel which has been cut by a laser into the present shape. FIG. 13B demonstrates a perspective view of the expandable shaft support 180 in its retracted position.


Referring now to FIG. 14, the central pin 185 is shown assembled onto the central microelectrode film shaft 260C to form the central microelectrode array shaft 160C.


Referring now to FIG. 15, the microelectronic component 300 has been assembled onto the microelectronic component platform 212. Contact pads on the microelectronic component 300 have been attached to their respective microelectronic contact pads 270 on the microelectrode array film. The proximal structural cylinder 218 has been attached and wrapped around the internal elongated cylindrical member 103 which extends to the proximal portion of the microelectrode lead assembly 100. The distal portion of the central pull wire 175 is visible. It is permanently attached to the interior of the central support cylinder 214 and is used to pull the assembly into its retracted position.


Referring now to FIG. 16, microelectrode array film 200 has been assembled onto the interior circumference of the expandable shaft support 180 forming the microelectrode array shafts 160. In addition, the helical lead wires 290 have been wound around the internal cylindrical member 103 and have been attached to their respective proximal contact pads 208.


Referring now to FIG. 17, the microelectrode array shafts 160 are shown with the stiff push rod 170 in contact. The stiff push rod 170 is used to push the assembly into its expanded position. Additionally, the assembly is shown with outer cylindrical member 102 in its assembled position.



FIG. 18 is a close-up perspective view of the interior assembly to demonstrate the positions of the stiff push rod 175 and the flexible pull wire 170.



FIG. 19A is a perspective view of the perforated end-cap 190 which demonstrates the perforations 192 from which the microelectrode shafts will emerge. FIG. 19B is a planar cutaway view demonstrating the cavity 191 within the perforated end-cap 190 in which the entire microelectrode array shaft assembly 160 is housed.



FIG. 20 is a cut-away perspective view with several elements removed for clarity of the assembly in the expanded position. Part of the perforated end cap 190 and the expandable shaft support 180 have been removed in order to reveal the positions of the microelectrode component 300, and the stiff push rod 170.



FIG. 21 is a cut-away perspective view with several elements removed for clarity of the assembly in the retracted position. Part of the perforated end cap 190 and the expandable shaft support 180 have been removed in order to reveal the positions of the microelectrode component 300, and the stiff push rod 170. Most importantly, the microelectrode array shafts 260 are contained within the interior of the perforated end cap 190, and the helical ribbon cable 216 has been reversible compressed into is retracted position.


When the microelectrodes are in use, they are placed on the same plane, in order to improve the operator's understanding of anatomical placement of the electrophysiological recording, and or stimulation. FIG. 22 is a planar view of the microelectrode assembly demonstrating microelectrode elements on the same plane. FIG. 23 is a perspective view the same assembly and same planes of FIG. 22. In this embodiment, the planes are separated by 1 mm, and are parallel. This arrangement requires that the microelectrode elements 265 on the central protruding shaft 160C have a smaller spacing than the microelectrode elements 265 on the anterior, lateral, posterior, medial protruding shafts 160A, 160L, 160P, 160M. In the present embodiment, it has been chosen that the protruding shafts make a 30° angle with the central shafts once expanded. In the expanded position, the most distal microelectrode elements 265 of the five protruding shafts 160 should all be on the same plane 400a. Additionally, the central microelectrode elements 265 of the five protruding shafts 160 should all be on the same plane 400b. Furthermore, the most proximal microelectrode elements 265 of the five protruding shafts 160 should all be on the same plane 400c.


Additional Embodiments

In some embodiments the protruding shafts may be curved, or bent, into a different angle. This may have the advantage that the tips of the protruding shafts can cover a greater volume. FIG. 24 demonstrates an embodiment of a distal microelectrode assembly 550 where the protruding shafts 560 curl away from the longitudinal axis of the elongated probe. On each of the protruding shafts are four microelectrode elements. In some embodiments the central pin may not be necessary, and the embodiment in FIG. 24 does not contain said central pin. FIG. 25 is a planar view of the same embodiment, and FIG. 26 demonstrates an additional view.


In some embodiments it is advantageous for the protruding shafts to be bent in such a manner that when in the expanded state, they remain parallel to the longitudinal axis of the elongated probe. The alternative embodiment of a distal microelectrode assembly 650 shown in FIG. 27 demonstrates protruding shafts 660 that have been bent in order to remain parallel to the longitudinal axis of the said assembly. This creates a cylindrical volume of influence within the confines of the device. Additionally, the central protruding shaft 660C may consist of a single cylindrical electrode, and not an array of microelectrodes. FIG. 28 demonstrates this alternative embodiment in a planar side view.


In some embodiments it is advantageous for the microelectrode array film to be positioned on the exterior of the protruding shafts. FIG. 29 is a perspective view of an alternative embodiment of a distal microelectrode assembly 750 where the microelectrode elements are placed on the outside of the protruding shafts. FIG. 30 demonstrates a planar back view of the alternative embodiment. FIG. 31 is a planar side view of the alternative embodiment of FIG. 29 depicting separate stimulation and recording electrodes. In some embodiments it is advantageous for recording microelectrode elements 766 to be smaller in diameter than the stimulation microelectrode elements 765. Additionally, stimulation microelectrode elements 765 may function advantageously with larger effective surface areas.



FIG. 32 is a detail perspective view of the alternative embodiment of FIG. 29 with perforated end-cap removed. Due to the friction that repeated retraction and expansion of the protruding shafts may create on the microelectrode array film, a slide guide 781 is introduced in this embodiment. Additionally, as shown in FIG. 33, the central pin 781 is implemented as a sharpened cylinder, on which a large microelectrode element 767 has been wrapped. Additionally, a central pin support 782 is introduced which permits alignment and added robustness of the central protruding shaft 760C.



FIG. 34 demonstrates the required protruding shaft support 780 required to implement the alternative embodiment. FIG. 35 demonstrates the slide guide 781, and FIG. 36 depicts the central pin support 782.


In some embodiments it is advantageous to include protruding shafts and different distal distances along the longitudinal axis of the elongated microelectrode probe. FIG. 37 is a perspective view of an alternative embodiment where eight protruding shafts have been implemented at two different distal regions of the longitudinal axis. The components required to implement this embodiment are similar to the previous embodiments presented. Distal microelectrode assembly 850 is composed of an elongated perforated end cap 890 which contains the microelectrode array film 820 and protruding shaft support structure 880. The protruding shafts (generally 860) have been numbered according to their proximal or distal position, as 860P or 860D in general. The protruding shafts have been additionally numbered according to their anatomical position, anterior, lateral, posterior, and medial. For example, the proximal protruding shafts (generally 860P) have been numbered 860PA, 860PL, 860PP, and 860PM.



FIG. 38A is a planar view of the alternative embodiment of FIG. 37 which demonstrates the microelectrode elements (generally 865) in more detail. The microelectrode elements 865 in this embodiment are confined to two elongated elliptical shapes per protruding shaft 860 and are dedicated to neural stimulation. However, it is understood, as with previous embodiments, that the geometry, size, and quantity of microelectrode elements can vary. Additionally, as with previous embodiments, the intended use of the microelectrodes can vary, such as microelectrode elements 860 that are designed specifically for neural recording. FIG. 38B is an additional planar view of the same embodiment.



FIG. 39A is a perspective view of the microelectrode array film 820 required in the assembly of the alternative embodiment of FIG. 37. In this embodiment an extended portion 828 is used to add additional microelectrode array shafts 861 to the designs of previous embodiments. It is understood to those knowledgeable in the art that the same microfabrication and assembly methods are used to implement this alternative embodiment.



FIG. 39B is a perspective view of the protruding shaft support 880 required in the assembly of the alternative embodiment of FIG. 37. As with previous embodiments, this shaft support 880 can be cut from a hollow cylinder of material using a laser etch process. The microelectrode array film 820 is then assembled onto the surface of protruding shaft support 880.


In some embodiments it is advantageous to not require a microelectronic element 300. This may be the case when using the embodiment in a stimulation mode only, or when using low numbers of stimulation sites. FIG. 40A is a perspective view of an alternative embodiment where five protruding shafts 960 are connected directly to the fifteen electrical lead wires 990. The distal microelectrode assembly 950 is therefore in direct electrical communication with the proximal electrical contacts.



FIG. 40B is a perspective view of the microelectrode array film 920 required in the assembly of the alternative embodiment shown in FIG. 40A. In comparison to previous embodiments, it does not have a microelectronic component platform but instead the microelectrodes are electrically connected directly to the lead wire contact pads 908.


In some embodiments it is advantageous to not require that the protruding shafts be rigid, and therefore they do not need to be supported. This may be the case when using the embodiment in delicate tissues. FIG. 40C is a perspective view of an alternative embodiment where five protruding shafts 1060 are not supported by a rigid member, but only consist of the microelectrode array film.



FIG. 40D is a detail perspective view of the internal assembly 1020 of the alternative embodiment shown in FIG. 40C. In comparison to previous embodiments, it does not require a microelectronic component platform but instead the microelectrodes are electrically connected directly to the lead wire contact pads 1008. Furthermore, in comparison to previous embodiments, it does not require a rigid protruding shaft support, but this has been replaced by a cylindrical support 1080. In the present embodiment ten lead wires connect directly to ten microelectrode elements where each flexible shaft 1061 incorporates two microelectrode elements 1065.


Microelectronic Elements


When the embodiment is in used only for neural recording, the microelectronic element 300 may be configured to only collect electrophysiologically recorded data. FIG. 41 demonstrates a schematic of an electronic circuit that could be implemented within microelectronic element 300. Microelectrode elements 365 are in contact with the neurological tissue. Microelectrode elements 365 are lettered a through n, with dots in between to describe a finite number of possible microelectrode elements 365. Generally there is at least one microelectrode element 365, and in the present embodiment fifteen are required. Electrophysiological signals depolarize microelectrode elements 365 and this signal can be captured by the neural recording microelectronic element 320. The microelectrode element 365 chosen to perform the recording can be selected using switchbox 321. The signal is then routed to switchbox 322, which can chosen to either amplify local field potentials using amplifier 324, or spikes using spike amplifier 325. The signal may then be encoded for transmission to the distal end of the microelectrode lead assembly 100. Connected to the distal end should be a decoder 390, and a display, or data capture device, 391. In some embodiments the circuit can be implemented for each microelectrode element 365. Generally, the frequency bandwidth required for the recording is low enough that all microelectrode elements 365 can time-share the same amplification circuit, whilst display 391 can report the recordings simultaneously.


When the embodiment is in used only for neural stimulation, the microelectronic element 300 may be configured to only generate, or alternatively route, stimulation signals. FIG. 42 demonstrates a schematic of an electronic circuit that could be implemented within microelectronic element 300. Microelectrode elements 365 are in contact with the neurological tissue. Stimulation signals are used to stimulate or inhibit neuronal activity and the microelectronic circuit 330 can perform the generation, or routing, of stimulation signals. The microelectrode element 365 chosen to apply the stimulation signal can selected using switchbox 331. In some embodiments, several switches are chosen in order to apply the same signal to several microelectrode elements 365. In some embodiments, several unique signals are generated, or routed, and applied to at least one microelectrode element 365. If the stimulation signal is generated outside of the microelectronic element 300, the signal can be conditioned, and if necessary amplified, using signal conditioner 335. A dedicated lead wire on microelectrode lead assembly 100 can be reserved for this purpose. Additionally, dedicated lead wires on microelectrode lead assembly 100 can be reserved for supplying power to the microelectronic element 330, clock signals, and ground, and command signals.


In some embodiments the operator wishes to record and stimulate with the same microelectrode elements. To perform this method microelectronic element 300 may be implemented with both recording and stimulation functions. FIG. 43 demonstrates a schematic of an electronic circuit that could be implemented within microelectronic element 300. Microelectrode elements 365 are in contact with the neurological tissue. Electrophysiological signals depolarize microelectrode elements 365 and this signal can be captured by the neural recording and stimulation microelectronic element 350. The microelectrode element 365 chosen to perform the recording can be selected using switchbox 351, and switch box 357 can be selected to the recording state. The signal is then routed to switchbox 358, which can chosen to either amplify local field potentials using amplifier 354, or spikes using spike amplifier 353. The signal may then be encoded for transmission to the distal end of the microelectrode lead assembly 100 using encoder 356.


Stimulation signals are used to stimulate or inhibit neuronal activity and the neuronal recording and stimulation microelectronic circuit 350 can perform the generation, or routing, of stimulation signals. The microelectrode element 365 chosen to apply the stimulation signal can be selected using switchbox 351. In some embodiments, several switches are chosen in order to apply the same signal to several microelectrode elements 365. Additionally, switchbox 357 can be in the stimulation state. In some embodiments, several unique signals are generated, or routed, and applied to at least one microelectrode element 365. If the stimulation signal is generated outside of the microelectronic element 300, the signal can be conditioned, and if necessary amplified, using signal conditioner 355. A dedicated lead wire on microelectrode lead assembly 100 can be reserved for this purpose. Additionally, some embodiments may include high-pass filters 360, of which each filter is dedicated to an individual microelectrode element 365, or shared between several microelectrode elements 365. These high-pass filters 360 may be used in order to tune the stimulation signal to the peak resistance frequency of the microelectrode element 365.


Additionally, dedicated lead wires on microelectrode lead assembly 100 can be reserved for supplying power to the neural recording and stimulation microelectronic element 350, clock signals, and ground, and command signals, recorded signals, and stimulation signals.


Electrical Impedance Tomography



FIG. 44 demonstrate how Electrical Impedance Tomography may be performed using the devices described. First, an oscillating current is passed between two microelectrode elements 865Ac and 865Pa. The current oscillation may be of a frequency of 1 Hz-10 MHz with a preference of 1 kHz-100 KHz. Additionally, the current oscillation may include other oscillation frequencies. Subsequently, an electric potential is detected between two other microelectrode elements 865Lc and 865L. Alternatively, the electrode potential can be detected at the site of the microelectrode elements that generated and collected the current. This potential gives an indication of the electrical properties of the imaged tissue. Source and detection electrode are alternated, both in 2D space, and 3D space to generate a volumetric and/or tomographic image of the volume contained within the prongs. The signals emanating and detected at the electrodes sites can change in amplitude, frequency, and other characteristics in order to image different tissue properties such as conductivity, permittivity, conductivity direction and/or anisotropy. From this electrical data an understanding of the tissue architecture can be obtained such as location, direction and type of neural fibers, delineation of different tissue types such as grey matter, white matter, and aqueducts, are but a few examples. The image is then reported to the clinician, additionally it can be fitted to known anatomical data in order to provide a first approximation to the device location. Electrode geometries on the prongs can vary, including a single linear array of electrodes, or electrodes that are side-by-side (not shown).


CONCLUSION

Various embodiments of micro-fabricated neurostimulation devices have been described herein. These embodiments are giving by way of example and are not intended to limit the scope of the present invention. It should be appreciated, moreover, that the various features of the embodiments that have been described may be combined in various ways to produce numerous additional embodiments. Moreover, while various materials, dimensions, shapes, implantation locations, etc. have been described for use with disclosed embodiments, others besides those disclosed may be utilized without exceeding the scope of the invention.


Although some devices described herein are identified as either acute or chronic, it is understood that the device may be used acutely, or chronically. They may be implanted for such periods, such as during a surgery, and then removed. They may implanted for extended periods, or even indefinitely. Similarly, any devices described herein as being chronic, it is understood that such devices may also be used acutely.


The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.


With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity.


It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”


In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.


As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.


One or more or any part thereof of the techniques described herein can be implemented in computer hardware or software, or a combination of both. The methods can be implemented in computer programs using standard programming techniques following the method and figures described herein. Program code is applied to input data to perform the functions described herein and generate output information. The output information is applied to one or more output devices such as a display monitor. Each program may be implemented in a high level procedural or object oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language can be a compiled or interpreted language. Moreover, the program can run on dedicated integrated circuits preprogrammed for that purpose.


Each such computer program is preferably stored on a storage medium or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The computer program can also reside in cache or main memory during program execution. The analysis, preprocessing, and other methods described herein can also be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein. In some embodiments, the computer readable media is tangible and substantially non-transitory in nature, e.g., such that the recorded information is recorded in a form other than solely as a propagating signal.


In some embodiments, a program product may include a signal bearing medium. The signal bearing medium may include one or more instructions that, when executed by, for example, a processor, may provide the functionality described above. In some implementations, signal bearing medium may encompass a computer-readable medium, such as, but not limited to, a hard disk drive, a Compact Disc (CD), a Digital Video Disk (DVD), a digital tape, memory, etc. In some implementations, the signal bearing medium may encompass a recordable medium, such as, but not limited to, memory, read/write (R/W) CDs, R/W DVDs, etc. In some implementations, signal bearing medium may encompass a communications medium such as, but not limited to, a digital and/or an analog communication medium (e.g., a fiber optic cable, a waveguide, a wired communications link, a wireless communication link, etc.). Thus, for example, the program product may be conveyed by an RF signal bearing medium, where the signal bearing medium is conveyed by a wireless communications medium (e.g., a wireless communications medium conforming with the IEEE 802.11 standard).


It is to be understood that any of the signals and signal processing techniques may be digital or analog in nature, or combinations thereof.


While certain embodiments of this invention have been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims
  • 1. An implantable neurological probe, comprising: an elongated shaft having a distal end and an internal lumen;a support cylinder slidingly disposed in only a distal portion of the internal lumen;a plurality of shafts coupled to the support cylinder and arranged for selective extension from the distal end of the elongated shaft;a microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable that separates the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable couples each of the plurality of microelectrode elements with a respective proximal contact pad;a planar substrate having an insulative layer; anda plurality of conductive traces disposed on the insulative layer; anda stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation.
  • 2. The implantable neurological probe of claim 1, comprising a push-pull rod which comprises a pull wire and the stylet.
  • 3. The implantable neurological probe of claim 1, wherein the elongated shaft is configured for insertion into a human body using an accepted procedure for insertion of deep brain stimulation leads.
  • 4. The implantable neurological probe of claim 1, wherein a diameter of the elongated shaft is between 1 mm and 3 mm.
  • 5. The implantable neurological probe of claim 1, wherein at least one of the plurality of microelectrode elements is a stimulating electrode and at least one of the plurality of microelectrode elements is a detecting electrode.
  • 6. The implantable neurological probe of claim 1, wherein at least one of the plurality of microelectrodes elements is both a stimulating electrode and a detecting electrode.
  • 7. The implantable neurological probe of claim 1, wherein each of the plurality of microelectrode elements is disposed on the insulative layer.
  • 8. The implantable neurological probe of claim 7, wherein the microelectrode array film is formable into a cylindrical assembly.
  • 9. The implantable neurological probe of claim 8, wherein each of the plurality of shafts can be formed to bend radially from a longitudinal axis of the elongated shaft.
  • 10. The implantable neurological probe of claim 8, where one of the plurality of shafts extends and is centered along a longitudinal axis of the elongated shaft.
  • 11. The implantable neurological probe of claim 9, where each of the plurality of microelectrode film shafts are stiffened by one of the plurality of shafts.
  • 12. An implantable neurological probe, comprising: an elongated shaft having a distal end and an internal lumen; a plurality of shafts coupled to a support cylinder, the plurality of shafts arranged for selective extension from the distal end of the elongated shaft; and a microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable separating the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable coupling each of the plurality of microelectrode elements with a respective proximal contact pad; a planar substrate having an insulative layer; and a plurality of conductive traces disposed on the insulative layer, wherein the plurality of shafts define a substantially cylindrical volume when fully extended.
  • 13. The implantable neurological probe of claim 12, wherein the elongated shaft is configured for insertion into a human body using an accepted procedure for insertion of deep brain stimulation leads.
  • 14. The implantable neurological probe of claim 12, wherein a diameter of the elongated shaft is between 1 mm and 3 mm.
  • 15. The implantable neurological probe of claim 12, wherein at least one of the plurality of microelectrode elements is a stimulating electrode and at least one of the plurality of microelectrode elements is a detecting electrode.
  • 16. The implantable neurological probe of claim 12, wherein at least one of the plurality of microelectrodes elements is both a stimulating electrode and a detecting electrode.
  • 17. The implantable neurological probe of claim 12, wherein each of the plurality of microelectrode elements is disposed on the insulative layer.
  • 18. The implantable neurological probe of claim 17, wherein the microelectrode array film is formable into a cylindrical assembly.
  • 19. The implantable neurological probe of claim 18, where at least one of the plurality of shafts can be formed to bend radially from a longitudinal axis of the elongated shaft.
  • 20. The implantable neurological probe of claim 18, where one of the plurality of shafts is centered along a longitudinal axis of the elongated shaft.
  • 21. The implantable neurological probe of claim 18, where each of the plurality of microelectrode shafts are stiffened by one of the plurality of shafts.
  • 22. A method of finding a neurological target, comprising: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe comprising: an elongated shaft having a distal end and an internal lumen;a support cylinder slidingly disposed in only a distal portion of the internal lumen;a plurality of shafts coupled to the support cylinder and arranged for selective extension from the distal end of the elongated shaft;a microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable separating the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable coupling each of the plurality of microelectrode elements with a respective proximal contact pad;a planar substrate having an insulative layer; anda plurality of conductive traces disposed on the insulative layer; anda stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation;retracting the plurality of shafts within the internal lumen before surgical implantation;extending the plurality of shafts in the vicinity of the neurological target site following implantation;recording electrophysiological signals from the neurological target site using at least one of the plurality of microelectrode elements; andstimulating the neurological target using at least one of the plurality of microelectrode elements.
  • 23. The method of claim 22, further comprising: after the acts of recording and stimulating, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.
  • 24. The method of claim 22, wherein the plurality of shafts are retracted using a pull wire.
  • 25. The method of claim 22, wherein the plurality of shafts are extended using the stylet.
  • 26. The method of claim 22, wherein the neurological probe comprises a push-pull rod which comprises a pull wire and the stylet.
  • 27. The method of claim 22, wherein the act of recording neurophysiological signals comprises recording neural activity detected by at least one of the plurality of microelectrode elements and repositioning the distal end of the elongated shaft as required, until the recorded activity is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.
  • 28. The method of claim 22, comprising: stimulating neural activity at a stimulation site by applying electrical signals to at least one of the plurality of microelectrode elements;performing a clinical evaluation of the efficacy on the stimulation site in a patient, andrepositioning the distal end of the elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.
  • 29. The method of claim 22, comprising: inhibiting neural activity by applying electrical signals to at least one of the plurality of microelectrode,performing a clinical evaluation of the efficacy on the inhibition site in a patient, andrepositioning the distal end of elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.
  • 30. A method of finding a neurological target, comprising: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe comprising:an elongated shaft having a distal end and an internal lumen;a support cylinder slidingly disposed in only a distal portion of the internal lumen;a plurality of shafts coupled to the support cylinder and arranged for selective extension from the distal end of the elongated shaft;a microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable separating the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable coupling each of the plurality of microelectrode elements with a respective proximal contact pad;a planar substrate having an insulative layer; anda plurality of conductive traces disposed on the insulative layer; anda stylet removably disposed in the internal lumen and configured to contact the support cylinder to selectively extend the plurality of shafts during implantation;retracting the plurality of shafts within the internal lumen before surgical implantation;expanding the plurality of shafts in the vicinity of the neurological target site following implantation;applying an oscillating electric current between at least two of the plurality of microelectrode elements; anddetecting an electric voltage between at least two of the plurality of microelectrode elements.
  • 31. The method of claim 30, further comprising: after the act of detecting, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.
  • 32. The method of claim 30, comprising imaging the electrical characteristics of the volume of neurological tissue between the plurality of shafts based on the applied oscillating electric current and the detected electric voltage.
  • 33. The method of claim 30, wherein the neurological probe comprises a push-pull rod which comprises a pull wire and the stylet.
  • 34. A method of finding a neurological target, comprising: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe comprising: an elongated shaft having a distal end and an internal lumen; a plurality of shafts coupled to a support cylinder, the plurality of shafts arranged for selective extension from the distal end of the elongated shaft; and a microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable separating the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable coupling each of the plurality of microelectrode elements with a respective proximal contact pad; a planar substrate having an insulative layer; and a plurality of conductive traces disposed on the insulative layer; and wherein the plurality of shafts define a substantially cylindrical volume when fully extended; retracting the plurality of shafts within the internal lumen before surgical implantation; extending the plurality of shafts in the vicinity of the neurological target site following implantation; recording electrophysiological signals from the neurological target site using at least one of the plurality of microelectrode elements; and stimulating the neurological target using at least one of the plurality of microelectrode elements.
  • 35. The method of claim 34, wherein the protruding shafts are retracted using a pull wire.
  • 36. The method of claim 35, wherein the plurality of shafts are extended using a stylet.
  • 37. The method of claim 36, wherein the neurological probe comprises a push-pull rod which comprises the pull wire and the stylet.
  • 38. The method of claim 34, wherein the act of recording neurophysiological signals comprises recording neural activity detected by at least one of the plurality of microelectrode elements and repositioning the distal end of the elongated shaft as required, until the recorded activity is indicative of the distal end of the elongated probe shaft being located sufficiently at the neurological target site.
  • 39. The method of claim 34, further comprising: after the acts of recording and stimulating, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.
  • 40. The method of claim 34, comprising: stimulating neural activity at a stimulation site by applying electrical signals to at least one of the plurality of microelectrode elements;performing a clinical evaluation of the efficacy on the stimulation site in a patient, andrepositioning the distal end of the elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.
  • 41. The method of claim 34, comprising: inhibiting neural activity by applying electrical signals to at least one of the plurality of microelectrode elements;performing a clinical evaluation of the efficacy on the inhibition site in a patient, andrepositioning the distal end of elongated shaft as required, until the patient's response is indicative of the distal end of the elongated shaft being located sufficiently at the neurological target site.
  • 42. A method of finding a neurological target, comprising: implanting a neurological probe within a vicinity of a neurological target site, the neurological probe comprising:an elongated shaft having a distal end and an internal lumen;a plurality of shafts coupled to a support cylinder, the plurality of shafts arranged for selective extension from the distal end of the elongated shaft; anda microelectrode array film comprising a first portion coupled toward the distal end of the elongated shaft and a second portion coupled with the support cylinder, the microelectrode array film comprising a plurality of microelectrode film shafts disposed on each of the plurality of shafts, each of the plurality of microelectrode film shafts comprising a plurality of microelectrode elements, the microelectrode array film further comprising: a helical ribbon cable separating the first portion of the microelectrode array film from the second portion of the microelectrode array film, the helical ribbon cable coupling each of the plurality of microelectrode elements with a respective proximal contact pad;a planar substrate having an insulative layer; anda plurality of conductive traces disposed on the insulative layer,wherein the plurality of shafts define a substantially cylindrical volume when fully extended;retracting the plurality of shafts within the internal lumen before surgical implantation;extending the plurality of shafts in the vicinity of the neurological target site following implantation;applying an oscillating electric current between at least two of the plurality of microelectrode elements on at least one of the plurality of shafts;detecting an electric voltage between at least two of the plurality of microelectrode elements on at least one of the plurality of shafts.
  • 43. The method of claim 42, comprising imaging the electrical characteristics of the volume of neurological tissue between the plurality of shafts based on the applied oscillating electric current and the detected electric voltage.
  • 44. The method of claim 32, further comprising: after the act of detecting, retracting the plurality of shafts within the internal lumen and removing the neurological probe from a subject.
CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Stage of PCT International Application Number PCT/EP2011/055045, filed Mar. 31, 2011, which claims priority to U.S. Provisional Application Ser. No. 61/320,089 filed Apr. 1, 2010, the entire contents of the foregoing applications are incorporated by reference herein.

PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/EP2011/055045 3/31/2011 WO 00 12/14/2012
Publishing Document Publishing Date Country Kind
WO2011/121089 10/6/2011 WO A
US Referenced Citations (656)
Number Name Date Kind
4245645 Arseneault et al. Jan 1981 A
4550733 Liss et al. Nov 1985 A
4837049 Byers et al. Jun 1989 A
4917093 Dufresne et al. Apr 1990 A
4928297 Tsutsui et al. May 1990 A
4969468 Byers et al. Nov 1990 A
4989617 Memberg et al. Feb 1991 A
5215088 Normann et al. Jun 1993 A
5391250 Cheney et al. Feb 1995 A
5400784 Durand et al. Mar 1995 A
5419777 Hofling May 1995 A
5496369 Howard, III Mar 1996 A
5524338 Martyniuk Jun 1996 A
5628317 Starkebaum et al. May 1997 A
5643330 Holsheimer et al. Jul 1997 A
5679355 Alexander et al. Oct 1997 A
5683422 Rise Nov 1997 A
5697651 Fernandes Dec 1997 A
5697975 Howard et al. Dec 1997 A
5702429 King Dec 1997 A
5713922 King Feb 1998 A
5713923 Ward et al. Feb 1998 A
5716377 Rise et al. Feb 1998 A
5727552 Ryan Mar 1998 A
5752979 Benabid May 1998 A
5755759 Cogan May 1998 A
5782798 Rise Jul 1998 A
5792186 Rise Aug 1998 A
5797970 Pouvreau Aug 1998 A
5800474 Benabid et al. Sep 1998 A
5800535 Howard, III Sep 1998 A
5814092 King Sep 1998 A
5824029 Weijand et al. Oct 1998 A
5833709 Rise et al. Nov 1998 A
5833714 Loeb Nov 1998 A
5843148 Gijsbers et al. Dec 1998 A
5893883 Torgerson et al. Apr 1999 A
5913882 King Jun 1999 A
5921924 Avitall Jul 1999 A
5927277 Baudino et al. Jul 1999 A
5941906 Barreras et al. Aug 1999 A
5957958 Schulman et al. Sep 1999 A
5975085 Rise Nov 1999 A
5978702 Ward et al. Nov 1999 A
5991668 Leinders et al. Nov 1999 A
6011996 Gielen et al. Jan 2000 A
6018682 Rise Jan 2000 A
6024095 Stanley, III Feb 2000 A
6033403 Tu et al. Mar 2000 A
6038480 Hrdlicka et al. Mar 2000 A
6050992 Nichols Apr 2000 A
6094598 Elsberry et al. Jul 2000 A
6104960 Duysens et al. Aug 2000 A
6109269 Rise et al. Aug 2000 A
6125300 Weijand et al. Sep 2000 A
6128537 Rise Oct 2000 A
6129685 Howard, III Oct 2000 A
6161047 King et al. Dec 2000 A
6205359 Boveja Mar 2001 B1
6205361 Kuzma et al. Mar 2001 B1
6216043 Swanson et al. Apr 2001 B1
6227203 Rise et al. May 2001 B1
6253109 Gielen Jun 2001 B1
6253110 Brabec et al. Jun 2001 B1
6263237 Rise Jul 2001 B1
6266564 Hill et al. Jul 2001 B1
6295476 Schaenzer Sep 2001 B1
6319241 King et al. Nov 2001 B1
6330466 Hofmann et al. Dec 2001 B1
6337997 Rise Jan 2002 B1
6343226 Sunde et al. Jan 2002 B1
6353762 Baudino et al. Mar 2002 B1
6356784 Lozano et al. Mar 2002 B1
6356786 Rezai et al. Mar 2002 B1
6356787 Rezai et al. Mar 2002 B1
6364875 Stanley, III Apr 2002 B1
6366813 DiLorenzo Apr 2002 B1
6374140 Rise Apr 2002 B1
6375666 Mische Apr 2002 B1
6379353 Nichols Apr 2002 B1
6415187 Kuzma et al. Jul 2002 B1
6434431 Camps et al. Aug 2002 B1
6479999 DeMeester et al. Nov 2002 B1
6484059 Gielen Nov 2002 B2
6493590 Wessman et al. Dec 2002 B1
6529774 Greene Mar 2003 B1
6538443 Morich et al. Mar 2003 B2
6549812 Smits Apr 2003 B1
6556873 Smits Apr 2003 B1
6560472 Hill et al. May 2003 B2
6560486 Osorio et al. May 2003 B1
6587733 Cross et al. Jul 2003 B1
6591128 Wu et al. Jul 2003 B1
6594524 Esteller et al. Jul 2003 B2
6597953 Boling Jul 2003 B2
6643552 Edell et al. Nov 2003 B2
6671544 Baudino Dec 2003 B2
6675046 Holsheimer Jan 2004 B2
6687538 Hrdlicka et al. Feb 2004 B1
6690973 Hill et al. Feb 2004 B2
6708064 Rezai Mar 2004 B2
6718208 Hill et al. Apr 2004 B2
6718211 Smits Apr 2004 B2
6741893 Smits May 2004 B2
6745079 King Jun 2004 B2
6757970 Kuzma et al. Jul 2004 B1
6795737 Gielen et al. Sep 2004 B2
6804552 Thompson et al. Oct 2004 B2
6818396 Bloch et al. Nov 2004 B1
6829498 Kipke et al. Dec 2004 B2
6850802 Holsheimer Feb 2005 B2
6871098 Nuttin et al. Mar 2005 B2
6882881 Lesser et al. Apr 2005 B1
6892097 Holsheimer May 2005 B2
6892438 Hill et al. May 2005 B1
6904306 Wu et al. Jun 2005 B1
6909920 Lokhoff et al. Jun 2005 B2
6920359 Meadows et al. Jul 2005 B2
6928320 King Aug 2005 B2
6950706 Rodriguez et al. Sep 2005 B2
6950709 Baudino Sep 2005 B2
6978171 Goetz et al. Dec 2005 B2
6978178 Sommer et al. Dec 2005 B2
6999819 Swoyer et al. Feb 2006 B2
7006859 Osorio et al. Feb 2006 B1
7010351 Firlik et al. Mar 2006 B2
7010356 Jog et al. Mar 2006 B2
7024246 Acosta et al. Apr 2006 B2
7035690 Goetz Apr 2006 B2
7047082 Schrom et al. May 2006 B1
7047084 Erickson et al. May 2006 B2
7050856 Stypulkowski May 2006 B2
7051419 Schrom et al. May 2006 B2
7061240 Ham et al. Jun 2006 B2
7063767 Tyson et al. Jun 2006 B1
7076292 Forsberg Jul 2006 B2
7077822 Howard, III Jul 2006 B1
7107104 Keravel et al. Sep 2006 B2
7133718 Bakken et al. Nov 2006 B2
7146222 Boling Dec 2006 B2
7151961 Whitehurst et al. Dec 2006 B1
7174219 Wahlstrand et al. Feb 2007 B2
7177701 Pianca Feb 2007 B1
7181288 Rezai et al. Feb 2007 B1
7184829 Hill et al. Feb 2007 B2
7187978 Malek et al. Mar 2007 B2
7191016 Marshall et al. Mar 2007 B2
7191018 Gielen et al. Mar 2007 B2
7200439 Zdeblick et al. Apr 2007 B2
7203548 Whitehurst et al. Apr 2007 B2
7204798 Zdeblick et al. Apr 2007 B2
7204833 Osorio et al. Apr 2007 B1
7209787 Dilorenzo Apr 2007 B2
7212851 Donoghue et al. May 2007 B2
7212867 Van Venrooij et al. May 2007 B2
7214189 Zdeblick May 2007 B2
7216000 Sieracki et al. May 2007 B2
7216001 Hacker et al. May 2007 B2
7231256 Wahlstrand et al. Jun 2007 B2
7236822 Dobak, III Jun 2007 B2
7242984 DiLorenzo Jul 2007 B2
7276061 Schaer et al. Oct 2007 B2
7280867 Frei et al. Oct 2007 B2
7282030 Frei et al. Oct 2007 B2
7282050 Starkebaum et al. Oct 2007 B2
7286878 Stypulkowski Oct 2007 B2
7286882 Cole Oct 2007 B2
7288066 Drew Oct 2007 B2
7289851 Gunderson et al. Oct 2007 B2
7289852 Helfinstine et al. Oct 2007 B2
7295880 Gielen Nov 2007 B2
7298143 Jaermann et al. Nov 2007 B2
7307223 Tyson et al. Dec 2007 B2
7313430 Urquhart et al. Dec 2007 B2
7313440 Miesel Dec 2007 B2
7315759 Markowitz et al. Jan 2008 B2
7317947 Wahlstrand et al. Jan 2008 B2
7317948 King et al. Jan 2008 B1
7319899 Keizer Jan 2008 B2
7319904 Cross et al. Jan 2008 B2
7321798 Muhlenberg et al. Jan 2008 B2
7321837 Osorio et al. Jan 2008 B2
7322832 Kronich et al. Jan 2008 B2
7328057 Freas et al. Feb 2008 B2
7328068 Spinelli et al. Feb 2008 B2
7328069 Gerber Feb 2008 B2
7330760 Heruth et al. Feb 2008 B2
7337010 Howard et al. Feb 2008 B2
7343206 Sage et al. Mar 2008 B2
7346395 Lozano et al. Mar 2008 B2
7356369 Phillips et al. Apr 2008 B2
7359837 Drew Apr 2008 B2
7366572 Heruth et al. Apr 2008 B2
7367956 King May 2008 B2
7369891 Augustijn et al. May 2008 B2
7369893 Gunderson May 2008 B2
7369894 Gerber May 2008 B2
7385443 Denison Jun 2008 B1
7388378 Gray et al. Jun 2008 B2
7389147 Wahlstrand et al. Jun 2008 B2
7390311 Hildebrand et al. Jun 2008 B2
7391257 Denison et al. Jun 2008 B1
7392089 Wahlstrand et al. Jun 2008 B2
7395113 Heruth et al. Jul 2008 B2
7400927 Litvin Jul 2008 B1
7406351 Wesselink Jul 2008 B2
7418292 Shafer Aug 2008 B2
7421297 Giftakis et al. Sep 2008 B2
7427280 Gerber Sep 2008 B2
7429938 Corndorf Sep 2008 B1
7433734 King Oct 2008 B2
7442183 Baudino et al. Oct 2008 B2
7447545 Heruth et al. Nov 2008 B2
7450996 MacDonald et al. Nov 2008 B2
7463917 Martinez Dec 2008 B2
7463928 Lee et al. Dec 2008 B2
7474247 Heinks et al. Jan 2009 B1
7479910 Heinks et al. Jan 2009 B1
7483748 Torgerson et al. Jan 2009 B2
7489966 Leinders et al. Feb 2009 B2
7489970 Lee et al. Feb 2009 B2
7491181 Heruth et al. Feb 2009 B2
7497844 Spear et al. Mar 2009 B2
7497863 Solar et al. Mar 2009 B2
7502217 Zhao et al. Mar 2009 B2
7505815 Lee et al. Mar 2009 B2
7505869 Hartlaub Mar 2009 B2
7515961 Germanson et al. Apr 2009 B2
7519431 Goetz et al. Apr 2009 B2
7519432 Bolea et al. Apr 2009 B2
7520890 Phillips Apr 2009 B2
7526339 Lahti et al. Apr 2009 B2
7526340 Drew Apr 2009 B2
7526341 Goetz et al. Apr 2009 B2
7529582 DiLorenzo May 2009 B1
7529586 Wahlstrand et al. May 2009 B2
7542803 Heruth et al. Jun 2009 B2
7546164 King Jun 2009 B2
7546166 Michels et al. Jun 2009 B2
7548775 Kipke et al. Jun 2009 B2
7548786 Lee et al. Jun 2009 B2
7551951 Osorio et al. Jun 2009 B1
7551960 Forsberg et al. Jun 2009 B2
7555345 Wahlstrand et al. Jun 2009 B2
7561921 Phillips et al. Jul 2009 B2
7563141 Alexander et al. Jul 2009 B2
7563541 Howard et al. Jul 2009 B2
7578819 Bleich et al. Aug 2009 B2
7580756 Schulte et al. Aug 2009 B2
7582387 Howard et al. Sep 2009 B2
7590451 Tronnes et al. Sep 2009 B2
7590453 Heruth et al. Sep 2009 B2
7590455 Heruth et al. Sep 2009 B2
7591970 Olson Sep 2009 B2
7594828 Alexander et al. Sep 2009 B2
7594889 St. Ores et al. Sep 2009 B2
7596399 Singhal et al. Sep 2009 B2
7596408 Singhal et al. Sep 2009 B2
7596415 Brabec et al. Sep 2009 B2
7599730 Hunter et al. Oct 2009 B2
7603161 Wurmfeld et al. Oct 2009 B2
7603177 Sieracki et al. Oct 2009 B2
7604629 Gerber et al. Oct 2009 B2
7604644 Schulte et al. Oct 2009 B2
7608458 Soykan et al. Oct 2009 B2
7610083 Drew et al. Oct 2009 B2
7611483 Gerber et al. Nov 2009 B2
7614743 Geiger Nov 2009 B2
7615015 Coleman Nov 2009 B2
7616998 Nuttin et al. Nov 2009 B2
7617002 Goetz Nov 2009 B2
7620454 Dinsmoor et al. Nov 2009 B2
7622303 Soykan et al. Nov 2009 B2
7622988 Denison et al. Nov 2009 B2
7623053 Terry et al. Nov 2009 B2
7623918 Goetz Nov 2009 B2
7623919 Goetz et al. Nov 2009 B2
7623923 Gerber et al. Nov 2009 B2
7623930 Zeijlemaker et al. Nov 2009 B2
7624293 Osorio et al. Nov 2009 B2
7628780 Bonner et al. Dec 2009 B2
7631415 Phillips et al. Dec 2009 B2
7632225 Stypulkowski Dec 2009 B2
7635541 Scott et al. Dec 2009 B2
7637867 Zdeblick Dec 2009 B2
7640059 Forsberg et al. Dec 2009 B2
7640060 Zdeblick Dec 2009 B2
7641992 Howard et al. Jan 2010 B2
7642013 Howard et al. Jan 2010 B2
7647111 Ries et al. Jan 2010 B2
7647116 Bauhahn Jan 2010 B2
7647117 Bauhahn Jan 2010 B2
7647121 Wahlstrand et al. Jan 2010 B2
7650291 Rosenfeld et al. Jan 2010 B2
7653433 Lozano et al. Jan 2010 B2
7657318 King et al. Feb 2010 B2
7657319 Goetz et al. Feb 2010 B2
7660620 Zeijlemaker et al. Feb 2010 B2
7660630 Dudding et al. Feb 2010 B2
7662140 Heruth et al. Feb 2010 B2
7662509 Howard et al. Feb 2010 B2
7663066 Tyson et al. Feb 2010 B2
7664551 Cigaina Feb 2010 B2
7664552 Wahlstrand et al. Feb 2010 B2
7668601 Hegland et al. Feb 2010 B2
7671594 Gray Mar 2010 B2
7676271 Wahlstrand et al. Mar 2010 B2
7676273 Goetz et al. Mar 2010 B2
7676274 Hung et al. Mar 2010 B2
7680540 Jensen et al. Mar 2010 B2
7682355 Gerber et al. Mar 2010 B2
7682745 Howard et al. Mar 2010 B2
7684860 Wahlstrand et al. Mar 2010 B2
7684873 Gerber Mar 2010 B2
7689289 King Mar 2010 B2
7697972 Verard et al. Apr 2010 B2
7697995 Cross et al. Apr 2010 B2
7706124 Zhao et al. Apr 2010 B2
7706889 Gerber et al. Apr 2010 B2
7711421 Shafer et al. May 2010 B2
7711428 Janzig et al. May 2010 B2
7711436 Stone May 2010 B2
7713194 Zdeblick May 2010 B2
7713195 Zdeblick May 2010 B2
7720548 King May 2010 B2
7729768 White et al. Jun 2010 B2
7729780 Vardiman Jun 2010 B2
7738958 Zdeblick et al. Jun 2010 B2
7742823 King et al. Jun 2010 B2
7756588 Jog et al. Jul 2010 B2
7797029 Gibson et al. Sep 2010 B2
7822483 Stone et al. Oct 2010 B2
7853303 Nikumb et al. Dec 2010 B2
7877149 Zdeblick Jan 2011 B2
7899539 Whitehurst et al. Mar 2011 B2
7925329 Zdeblick et al. Apr 2011 B2
7930035 DiLorenzo Apr 2011 B2
7935056 Zdeblick May 2011 B2
7941202 Hetke et al. May 2011 B2
7945336 Sauter-Starace et al. May 2011 B2
7969161 Behzadi et al. Jun 2011 B2
7974705 Zdeblick et al. Jul 2011 B2
7978064 Zdeblick et al. Jul 2011 B2
7979105 Kipke et al. Jul 2011 B2
7983751 Zdeblick et al. Jul 2011 B2
8000794 Lozano Aug 2011 B2
8000808 Hegland et al. Aug 2011 B2
8032224 Miesel et al. Oct 2011 B2
8036737 Goetz et al. Oct 2011 B2
8036743 Savage et al. Oct 2011 B2
8036748 Zdeblick et al. Oct 2011 B2
8055334 Savage et al. Nov 2011 B2
8055353 Kreidler et al. Nov 2011 B2
8099170 Jensen et al. Jan 2012 B2
8114021 Robertson et al. Feb 2012 B2
8115618 Robertson et al. Feb 2012 B2
8121687 Jensen et al. Feb 2012 B2
8123684 Zdeblick Feb 2012 B2
8172762 Robertson May 2012 B2
8187161 Li et al. May 2012 B2
8195308 Frank et al. Jun 2012 B2
8204586 Zdeblick Jun 2012 B2
8258962 Robertson et al. Sep 2012 B2
8261428 Fang et al. Sep 2012 B2
8280514 Lozano et al. Oct 2012 B2
8332020 Zdeblick Dec 2012 B2
8355768 Masmanidis et al. Jan 2013 B2
8412347 Zdeblick Apr 2013 B2
8473061 Moffitt et al. Jun 2013 B2
8473069 Bi et al. Jun 2013 B2
8489203 Ortmann Jul 2013 B2
8788064 Mercanzini et al. Jul 2014 B2
8874232 Chen Oct 2014 B2
8897891 Romero Nov 2014 B2
8938308 Meadows Jan 2015 B2
20020062143 Baudino et al. May 2002 A1
20030004553 Grill et al. Jan 2003 A1
20030023282 Barrett et al. Jan 2003 A1
20030036780 Barrett et al. Feb 2003 A1
20030060822 Schaer et al. Mar 2003 A1
20030083724 Jog et al. May 2003 A1
20030100823 Kipke et al. May 2003 A1
20030135253 Kokones et al. Jul 2003 A1
20030176892 Shalev Sep 2003 A1
20040002635 Hargrove et al. Jan 2004 A1
20040015205 Whitehurst et al. Jan 2004 A1
20040039434 Schrom et al. Feb 2004 A1
20040102828 Lowry et al. May 2004 A1
20040122335 Sackellares et al. Jun 2004 A1
20040133390 Osorio et al. Jul 2004 A1
20040138517 Osorio et al. Jul 2004 A1
20040138536 Frei et al. Jul 2004 A1
20040138720 Naisberg et al. Jul 2004 A1
20040138722 Carroll et al. Jul 2004 A1
20040152958 Frei et al. Aug 2004 A1
20040172089 Whitehurst et al. Sep 2004 A1
20040193021 Zdeblick et al. Sep 2004 A1
20040215288 Lee et al. Oct 2004 A1
20040220637 Zdeblick et al. Nov 2004 A1
20040225335 Whitehurst et al. Nov 2004 A1
20040243011 Plaza Dec 2004 A1
20040249417 Ransbury et al. Dec 2004 A1
20040254483 Zdeblick et al. Dec 2004 A1
20050004627 Gibson et al. Jan 2005 A1
20050008660 Kipke et al. Jan 2005 A1
20050010261 Luders et al. Jan 2005 A1
20050021103 DiLorenzo Jan 2005 A1
20050027284 Lozano et al. Feb 2005 A1
20050033136 Govari et al. Feb 2005 A1
20050038489 Grill Feb 2005 A1
20050049655 Boveja et al. Mar 2005 A1
20050070971 Fowler et al. Mar 2005 A1
20050075681 Rezai et al. Apr 2005 A1
20050113882 Cameron et al. May 2005 A1
20050137647 Wallace et al. Jun 2005 A1
20050143790 Kipke et al. Jun 2005 A1
20050154425 Boveja et al. Jul 2005 A1
20050171558 Abovitz et al. Aug 2005 A1
20050182455 Thrope et al. Aug 2005 A1
20050209511 Heruth et al. Sep 2005 A1
20050209513 Heruth et al. Sep 2005 A1
20050209643 Heruth et al. Sep 2005 A1
20050222642 Przybyszewski et al. Oct 2005 A1
20050240242 DiLorenzo Oct 2005 A1
20050245988 Miesel Nov 2005 A1
20060004422 De Ridder Jan 2006 A1
20060030897 Gilmer et al. Feb 2006 A1
20060041295 Osypka Feb 2006 A1
20060049957 Surgenor et al. Mar 2006 A1
20060058588 Zdeblick Mar 2006 A1
20060058727 Bernabei Mar 2006 A1
20060058855 Gill Mar 2006 A1
20060095105 Jog et al. May 2006 A1
20060116581 Zdeblick et al. Jun 2006 A1
20060129203 Garabedian et al. Jun 2006 A1
20060135877 Giftakis et al. Jun 2006 A1
20060149336 Meadows Jul 2006 A1
20060149337 John Jul 2006 A1
20060167497 Armstrong et al. Jul 2006 A1
20060173263 He et al. Aug 2006 A1
20060173510 Besio et al. Aug 2006 A1
20060178709 Foster et al. Aug 2006 A1
20060195154 Jaax et al. Aug 2006 A1
20060200206 Firlik et al. Sep 2006 A1
20060212090 Lozano et al. Sep 2006 A1
20060241717 Whitehurst et al. Oct 2006 A1
20060258951 Bleich et al. Nov 2006 A1
20060264777 Drew Nov 2006 A1
20060276866 McCreery Dec 2006 A1
20060282014 Kipke et al. Dec 2006 A1
20060293720 Dilorenzo Dec 2006 A1
20060293721 Tarver et al. Dec 2006 A1
20070027498 Maschino et al. Feb 2007 A1
20070027500 Maschino et al. Feb 2007 A1
20070027514 Gerber Feb 2007 A1
20070043268 Russell Feb 2007 A1
20070060974 Lozano Mar 2007 A1
20070067002 Lozano Mar 2007 A1
20070067003 Sanchez et al. Mar 2007 A1
20070088403 Wyler et al. Apr 2007 A1
20070088404 Wyler et al. Apr 2007 A1
20070093870 Maschino Apr 2007 A1
20070100389 Jaax et al. May 2007 A1
20070100392 Maschino et al. May 2007 A1
20070100393 Whitehurst et al. May 2007 A1
20070100398 Sloan May 2007 A1
20070106143 Flaherty May 2007 A1
20070123765 Hetke et al. May 2007 A1
20070123944 Zdeblick May 2007 A1
20070135721 Zdeblick Jun 2007 A1
20070142872 Mickle et al. Jun 2007 A1
20070150024 Leyde et al. Jun 2007 A1
20070173890 Armstrong Jul 2007 A1
20070173896 Zdeblick Jul 2007 A1
20070173897 Zdeblick Jul 2007 A1
20070173901 Reeve Jul 2007 A1
20070173908 Begnaud Jul 2007 A1
20070179558 Gliner et al. Aug 2007 A1
20070179569 Zdeblick Aug 2007 A1
20070185537 Zdeblick Aug 2007 A1
20070185544 Dawant et al. Aug 2007 A1
20070185548 Zdeblick Aug 2007 A1
20070185549 Zdeblick Aug 2007 A1
20070197892 Shen et al. Aug 2007 A1
20070203537 Goetz et al. Aug 2007 A1
20070203546 Stone et al. Aug 2007 A1
20070208394 King et al. Sep 2007 A1
20070213784 Pless Sep 2007 A1
20070213785 Osorio et al. Sep 2007 A1
20070213786 Sackellares et al. Sep 2007 A1
20070219591 Zdeblick et al. Sep 2007 A1
20070225674 Molnar et al. Sep 2007 A1
20070225773 Shen et al. Sep 2007 A1
20070225774 Eskandar et al. Sep 2007 A1
20070233192 Craig Oct 2007 A1
20070249953 Frei et al. Oct 2007 A1
20070249954 Virag et al. Oct 2007 A1
20070250133 Carlson et al. Oct 2007 A1
20070255323 Werder et al. Nov 2007 A1
20070255338 Wahlstrand Nov 2007 A1
20070255374 Kolafa et al. Nov 2007 A1
20070255531 Drew Nov 2007 A1
20070265683 Ehrlich Nov 2007 A1
20070282389 Moxon et al. Dec 2007 A1
20070293908 Cowan et al. Dec 2007 A1
20080021514 Pless Jan 2008 A1
20080021517 Dietrich Jan 2008 A1
20080027289 Zdeblick Jan 2008 A1
20080027487 Patel et al. Jan 2008 A1
20080027503 Marrosu et al. Jan 2008 A1
20080027504 Bedenbaugh Jan 2008 A1
20080027540 Cumming Jan 2008 A1
20080039895 Fowler et al. Feb 2008 A1
20080046012 Covalin et al. Feb 2008 A1
20080046013 Lozano Feb 2008 A1
20080058630 Robertson Mar 2008 A1
20080077186 Thompson et al. Mar 2008 A1
20080077191 Morrell Mar 2008 A1
20080103547 Okun et al. May 2008 A1
20080103548 Fowler et al. May 2008 A1
20080103578 Gerber May 2008 A1
20080114417 Leyde May 2008 A1
20080119900 DiLorenzo May 2008 A1
20080139870 Gliner et al. Jun 2008 A1
20080140152 Imran et al. Jun 2008 A1
20080154328 Thompson et al. Jun 2008 A1
20080154331 John et al. Jun 2008 A1
20080161881 Firlik et al. Jul 2008 A1
20080161896 Sauter-Starace et al. Jul 2008 A1
20080172103 Kao et al. Jul 2008 A1
20080177196 Burdick et al. Jul 2008 A1
20080188905 Swartz Aug 2008 A1
20080195166 Sun et al. Aug 2008 A1
20080195227 Boling et al. Aug 2008 A1
20080208283 Vetter et al. Aug 2008 A1
20080208287 Palermo et al. Aug 2008 A1
20080215125 Farah et al. Sep 2008 A1
20080221642 Humayun et al. Sep 2008 A1
20080242976 Robertson et al. Oct 2008 A1
20080255439 Tang et al. Oct 2008 A1
20080255629 Jenson et al. Oct 2008 A1
20080255647 Jensen et al. Oct 2008 A1
20080269835 Carlson et al. Oct 2008 A1
20080269842 Giftakis et al. Oct 2008 A1
20080275526 Lozano Nov 2008 A1
20080284599 Zdeblick et al. Nov 2008 A1
20080294218 Savage et al. Nov 2008 A1
20080300652 Lim et al. Dec 2008 A1
20080306394 Zdeblick et al. Dec 2008 A1
20080312726 Frank et al. Dec 2008 A1
20080316020 Robertson et al. Dec 2008 A1
20090027504 Lim et al. Jan 2009 A1
20090062879 Li et al. Mar 2009 A1
20090082645 Hafezi et al. Mar 2009 A1
20090105784 Massoud-Ansari et al. Apr 2009 A1
20090118806 Vetter et al. May 2009 A1
20090132042 Hetke et al. May 2009 A1
20090171416 Firlik et al. Jul 2009 A1
20090177144 Masmanidis et al. Jul 2009 A1
20090187196 Vetter Jul 2009 A1
20090204183 Kreidler et al. Aug 2009 A1
20090240314 Kong et al. Sep 2009 A1
20090253977 Kipke et al. Oct 2009 A1
20090256702 Robertson et al. Oct 2009 A1
20090292325 Cederna et al. Nov 2009 A1
20090299174 Wright et al. Dec 2009 A1
20090306728 Wright et al. Dec 2009 A1
20090306729 Doerr Dec 2009 A1
20090312770 Kozai et al. Dec 2009 A1
20090318824 Nishida et al. Dec 2009 A1
20090325424 Aarts et al. Dec 2009 A1
20100014541 Harriman Jan 2010 A1
20100015274 Fill Jan 2010 A1
20100030298 Martens et al. Feb 2010 A1
20100036468 Decre et al. Feb 2010 A1
20100069717 Hafezi et al. Mar 2010 A1
20100076536 Merz et al. Mar 2010 A1
20100087853 Kipke et al. Apr 2010 A1
20100100152 Martens et al. Apr 2010 A1
20100106178 Obermiller et al. Apr 2010 A1
20100114193 Lozano et al. May 2010 A1
20100114234 Zdeblick May 2010 A1
20100114250 Zdeblick May 2010 A1
20100130844 Williams et al. May 2010 A1
20100145216 He et al. Jun 2010 A1
20100145414 Decre et al. Jun 2010 A1
20100152747 Padiy et al. Jun 2010 A1
20100198315 Martens et al. Aug 2010 A1
20100249883 Zdeblick Sep 2010 A1
20100274305 Gliner et al. Oct 2010 A1
20100292602 Worrell et al. Nov 2010 A1
20100298908 Vardiman Nov 2010 A1
20100298917 Vardiman Nov 2010 A1
20100298918 Vardiman Nov 2010 A1
20100312188 Robertson et al. Dec 2010 A1
20100312228 Zdeblick et al. Dec 2010 A1
20100318163 Zdeblick Dec 2010 A1
20100331807 Whitehurst et al. Dec 2010 A1
20110001488 Behzadi et al. Jan 2011 A1
20110022124 Zdeblick et al. Jan 2011 A1
20110034964 Bi et al. Feb 2011 A1
20110034970 Barker Feb 2011 A1
20110040203 Savage et al. Feb 2011 A1
20110071766 Dolan et al. Mar 2011 A1
20110130809 Zdeblick Jun 2011 A1
20110152988 Whitehurst et al. Jun 2011 A1
20110154655 Hetke et al. Jun 2011 A1
20110184495 Wang et al. Jul 2011 A1
20110190860 Harberts et al. Aug 2011 A1
20110196454 Strand et al. Aug 2011 A1
20110208225 Martens et al. Aug 2011 A1
20110213382 Decre et al. Sep 2011 A1
20110218417 Boogaard et al. Sep 2011 A1
20110224757 Zdeblick et al. Sep 2011 A1
20110224765 Harberts et al. Sep 2011 A1
20110224766 Tol et al. Sep 2011 A1
20110282179 Zdeblick Nov 2011 A1
20120004520 Whitworth et al. Jan 2012 A1
20120004527 Thompson et al. Jan 2012 A1
20120004716 Langhammer et al. Jan 2012 A1
20120007734 Berkman et al. Jan 2012 A1
20120022341 Zdeblick Jan 2012 A1
20120035684 Thompson et al. Feb 2012 A1
20120053344 Lagos Gonzalez Mar 2012 A1
20120059444 Pardoel et al. Mar 2012 A1
20120062379 Hafezi et al. Mar 2012 A1
20120095355 Zdeblick Apr 2012 A1
20120109262 Martens May 2012 A1
20120109599 Martens May 2012 A1
20120116188 Frank et al. May 2012 A1
20120136420 Pardoel et al. May 2012 A1
20120150256 Martens Jun 2012 A1
20120184837 Martens et al. Jul 2012 A1
20120253442 Gliner et al. Oct 2012 A1
20120277821 Martens et al. Nov 2012 A1
20120296444 Greenberg et al. Nov 2012 A1
20120303088 Van Kaam et al. Nov 2012 A1
20120303089 Martens et al. Nov 2012 A1
20120303107 Decre et al. Nov 2012 A1
20120316630 Firlik et al. Dec 2012 A1
20130009691 Blanken et al. Jan 2013 A1
20130030366 Robertson et al. Jan 2013 A1
20130046356 Jensen et al. Feb 2013 A1
20130060102 Zdeblick Mar 2013 A1
20130085361 Mercanzini et al. Apr 2013 A1
20130131754 Sarvazyan May 2013 A1
20130144132 Hafezi et al. Jun 2013 A1
20130172716 Lozano et al. Jul 2013 A1
20130193950 Hafezi et al. Aug 2013 A1
20130204318 Young Aug 2013 A1
20130223028 Arne et al. Aug 2013 A1
20130231188 Berberich et al. Sep 2013 A1
20130282090 Decre et al. Oct 2013 A1
20130345780 Tabada et al. Dec 2013 A1
20130345789 Havel et al. Dec 2013 A1
20140039578 Whitehurst et al. Feb 2014 A1
Foreign Referenced Citations (76)
Number Date Country
0 677 743 Oct 1995 EP
0 743 839 Nov 1996 EP
0 892 654 Jan 1999 EP
0 895 483 Feb 1999 EP
0 959 942 Dec 1999 EP
1 048 319 Nov 2000 EP
1 062 973 Dec 2000 EP
1 102 607 May 2001 EP
1 257 320 Nov 2002 EP
1 446 189 Aug 2004 EP
1 514 576 Mar 2005 EP
1 750 798 Feb 2007 EP
1 890 764 Feb 2008 EP
1 931 419 Jun 2008 EP
1 985 579 Oct 2008 EP
1 993 665 Nov 2008 EP
2 046 441 Apr 2009 EP
2 066 396 Jun 2009 EP
2 069 003 Jun 2009 EP
2 131 916 Dec 2009 EP
2 167 188 Mar 2010 EP
2 320 221 May 2011 EP
2 341 979 Jul 2011 EP
2 456 513 May 2012 EP
2 542 303 Jan 2013 EP
2 559 454 Feb 2013 EP
2 604 313 Jun 2013 EP
2 620 179 Jul 2013 EP
2 623 154 Aug 2013 EP
2 626 108 Aug 2013 EP
2 626 109 Aug 2013 EP
2 626 110 Aug 2013 EP
2 626 111 Aug 2013 EP
2 656 875 Oct 2013 EP
2 656 876 Oct 2013 EP
2 674 193 Dec 2013 EP
WO-9810010 Mar 1998 WO
WO-03022354 Mar 2003 WO
WO-03028521 Apr 2003 WO
WO-03066152 Aug 2003 WO
WO 03066153 Aug 2003 WO
WO-03066157 Aug 2003 WO
WO-2004045707 Jun 2004 WO
WO-2005002467 Jan 2005 WO
WO-2005067792 Jul 2005 WO
WO-2005112216 Nov 2005 WO
WO-2006104432 Oct 2006 WO
WO-2007002144 Jan 2007 WO
WO-2007009070 Jan 2007 WO
WO-2007011611 Jan 2007 WO
WO-2007025356 Mar 2007 WO
WO-2007028003 Mar 2007 WO
WO-2007042999 Apr 2007 WO
WO-2007092330 Aug 2007 WO
WO-2007100428 Sep 2007 WO
WO-2007108718 Sep 2007 WO
WO-2008003318 Jan 2008 WO
WO-2008005478 Jan 2008 WO
WO-2008016881 Feb 2008 WO
WO-2008035285 Mar 2008 WO
WO-2008035344 Mar 2008 WO
WO-2008051463 May 2008 WO
WO-2008064269 May 2008 WO
WO-2008068759 Jun 2008 WO
WO-2008075294 Jun 2008 WO
WO-2008077440 Jul 2008 WO
WO-2008089726 Jul 2008 WO
WO-2008107822 Sep 2008 WO
WO-2008109298 Sep 2008 WO
WO-2008133616 Nov 2008 WO
WO-2008133683 Nov 2008 WO
WO-2008138305 Nov 2008 WO
WO-2010014686 Feb 2010 WO
WO-2010055421 May 2010 WO
WO-2011115999 Sep 2011 WO
WO-2013014206 Jan 2013 WO
Non-Patent Literature Citations (76)
Entry
US 8,388,533, 03/2013, Hafezi et al. (withdrawn)
US 8,469,885, 06/2013, Hafezi et al. (withdrawn)
Rousche, et al., “Flexible polyimide-based intracortical electrode arrays with bioactive capability,” IEEE Transactions on Biomedical Engineering 48(3): 361-371 (Mar. 2001).
Sepulveda et al., “Finite Element Analysis of Current Pathways with Implanted Electrodes”, J. Biomed. Eng. 1983, vol. 5, pp. 41-48.
International Search Report for PCT/EP2011/055045 dated Jul. 18, 2011 (4 pages).
U.S. Appl. No. 07/151,961, filed Feb. 3, 1988, Masahiko Okunuki et al.
Australian Patent Examination Report No. 1 dated Jan. 30, 2014 in corresponding Australian Application No. 2010326613, 2 pages.
Australian Patent Examination Report No. 1 dated Jan. 31, 2014 in corresponding Australian Application No. 2009315316, 3 pages.
Benabid, et al. “Combined (Thalamotomy and Stimulation) Stereotactic Surgery of the VIM Thalamic Nucleus for Bilateral Parkinson Disease”, Proceedings of the Meeting of the American Society for Stereotactic and Functional Neurosurgery, Montreal 1987 Appl. Neurophysiol. 50: 344-346.
Canadian Office Action for Application No. 2,743,575 dated Sep. 25, 2014, 3 pages.
Cogan, Stuart F., et al. “Plasma-enhanced chemical vapor deposited silicon carbide as an implantable dielectric coating.” Journal of Biomedical Materials Research Part A 67.3 (2003): 856-867.
Communication from the European Patent Office in Application No. 09795810.2 dated Sep. 14, 2011.
Decision of Rejection and Decision for Dismissal of Amendment in JP Patent Application No. 2011-543841 dated May 15, 2014.
EIC Biomedical, “Thin-film Encapsulation for Neural Recording and Stimulation Electrodes”, Silicon carbide and oxycarbide, Apr. 2008: pp. 1-2.
English translation of Notice of Reasons for Rejection in JP application No. 2011-543841 dated Oct. 21, 2013.
European Communication and Search Report for Application No. 09795810.2 dated Sep. 25, 2013.
European Communication mailed May 22, 2013 including search report for EP application No. 12198290.4-1652.
European Search Report for Appl. Ser. No. 09803534.8 dated Jul. 21, 2011.
European Search Report for Appl. Ser. No. 13169272.5 dated Aug. 30, 2013.
European Search Report for application No. EP 14172592 dated Aug. 28, 2014, 8 pages.
Examination Report for EP09795810.2 dated Jun. 22, 2012.
Examination Report from European Patent Office in 09 795 810.2 dated May 8, 2014.
Examination Report in AU Patent Application No. 2009276603 dated Mar. 3, 2014.
Fierce Medical Devices, “Medtronic Announces First U.S. Implant of World's Smallest, Minimally Invasive Cardiac Pacemaker”, Feb. 20, 2014, pp. 1-3.
Gibney, “St. Jude places its Nanostim leadless pacemaker in a U.K. patient”, Fierce Medical Devices, Jan. 27, 2014, pp. 1-3.
International Preliminary Report on Patentability for PCT/EP2010/068658 dated Jun. 5, 2012.
International Preliminary Report on Patentability for PCT/IB2009/007715 dated May 17, 2011.
International Preliminary Report on Patentability for PCT/US2009/052077 dated Feb. 1, 2011.
International Search Report and Written Opinion for PCT/EP2010/068658 dated Mar. 21, 2011.
International Search Report and Written Opinion in PCT/US09/52077 dated Sep. 25, 2009.
International Search Report for PCT/IB2009/007715 dated Apr. 22, 2010.
Notice of Allowance for U.S. Appl. No. 14/287,917 dated Apr. 15, 2015.
Notice of Reasons for Rejection for Japanese Patent Application No. 2011-543841 dated May 30, 2013.
Notice of Reasons for Rejection in JP Patent Application No. 2011-521276 dated Mar. 3, 2014.
Notice of Reasons for Rejection in JP Patent Application No. 2011-521276 dated May 30, 2013.
Notice of Reasons for Rejections for Japanese Patent Appl. Ser. No. 2012-541491 dated Aug. 28, 2014, 8 pages.
Office Action for Canadian Appl. Ser. No. 2743575 dated Jan. 21, 2015 (4 pages).
Office Action for EPO Appl. Ser. No. 10787404.2 dated May 6, 2015.
Office Action for European Application No. 10787404.2 dated Mar. 26, 2013.
Office Action for Japanese Appl. Ser. No. 2013-501857 dated Jun. 1, 2015.
Office Action for Japanese Appl. Ser. No. 2013-501857 dated Sep. 17, 2014.
Pollak, et al. “Effets de la Stimulation du Noyau Sous-Thalamique Dans La Maladie De Parkinson”, Rev. Neurol (Paris),149, 3, 175-176. Mason, Paris, 1993.
Second Notice of Reasons for Rejection for Japanese Application No. 2012-541491 mailed Apr. 8, 2015.
US Notice of Allowance for U.S. Appl. No. 14/316,154 dated Apr. 20, 2015.
US Notice of Allowance for U.S. Appl. No. 13/512,936 dated Feb. 20, 2014.
US Notice of Allowance for U.S. Appl. No. 13/512,936 dated Nov. 25, 2013.
US Notice of Allowance for U.S. Appl. No. 13/056,261 dated May 8, 2014.
US Notice of Allowance in U.S. Appl. No. 13/128,821 dated Dec. 24, 2013.
US Notice of Allowance in U.S. Appl. No. 13/128,821 dated Mar. 25, 2014.
US Office Action for U.S. Appl. No. 13/128,821 dated Dec. 14, 2012.
US Office Action for U.S. Appl. No. 13/128,821 dated Apr. 24, 2012.
US Office Action for U.S. Appl. No. 14/316,154 dated Dec. 18, 2014.
US Office Action for U.S. Appl. No. 13/512,936 dated Aug. 14, 2013.
US Office Action for U.S. Appl. No. 13/056261 dated Jan. 9, 2014.
US Office Action in U.S. Appl. No. 13/056,261 dated Aug. 7, 2013.
US Office Action on U.S. Appl. No. 14/287,917 dated Sep. 26, 2014.
Written Opinion for PCT/EP2010/068658 dated Jun. 1, 2012.
Written Opinion for Singapore Application No. 201103393-3 dated May 2, 2012.
Written Opinion of the International Search Authority for PCT/IB2009/07715 dated May 12, 2011.
Office Action for Canadian Appl. Ser. No. 2732309 dated Dec. 7, 2015.
US Notice of Allowance for U.S. Appl. No. 14/470,356 dated Apr. 13, 2016.
US Notice of Allowance for U.S. Appl. No. 14/470,356 dated Mar. 18, 2016.
US Office Action for U.S. Appl. No. 14/309,491 dated Mar. 3, 2016.
US Office Action for U.S. Appl. No. 14/470,423 dated Jan. 21, 2016.
US Office Action for U.S. Appl. No. 13/128,821 dated Nov. 14, 2013.
US Corrected Notice of Allowability for U.S. Appl. No. 14/470,356 dated May 18, 2016.
US Notice of Allowance for U.S. Appl. No. 14/309,491 dated May 11, 2016.
Decision of Rejection for Japanese Appl. Ser. No. 2012-541491 dated Oct. 26, 2015.
International Search Report and Written Opinion for PCT Appl. Ser. No. PCT/IB2015/053610 dated Jul. 20, 2015.
International Search Report and Written Opinion for PCT Appl. Ser. No. PCT/IB2015/056437 dated Nov. 5, 2015.
International Search Report and Written Opinion for PCT Ser. Appl. No. PCT/IB2015/056438 dated Nov. 5, 2015.
Office Action for Canadian Appl. Ser. No. 2743575 dated Jun. 11, 2015.
Office Action for Canadian Appl. Ser. No. 2743575 dated Sep. 14, 2015.
Office Action for EPO Appl. Ser. No. 14172592.9 dated Aug. 20, 2015.
US Notice of Allowance for U.S. Appl. No. 14/287,917 dated Jul. 20, 2015.
US Office Action for U.S. Appl. No. 14/309,491 dated Jul. 28, 2015.
Related Publications (1)
Number Date Country
20130085361 A1 Apr 2013 US
Provisional Applications (1)
Number Date Country
61320089 Apr 2010 US