Patent Publication Number: US-2004049121-A1

Title: Positioning system for neurological procedures in the brain

Description:
FIELD OF THE INVENTION  
       [0001] The present invention relates generally to intrabody tracking systems, and specifically to methods and devices for tracking the position and orientation of a medical instrument in the brain.  
       BACKGROUND OF THE INVENTION  
       [0002] Many surgical, diagnostic, therapeutic and prophylactic medical procedures require the precise placement of objects such as sensors, treatment units, tubes, catheters, implants and other devices within the body on a temporary or permanent basis. In particular, advances have been made in the field of neuroscience by development of new techniques, many of which require the use of implantable devices or other invasive procedures for treatment of a variety of abnormal conditions associated with the neurological activities and morphology of the brain. These developments include:  
       [0003] Deep Brain Stimulation (DBS) therapy, which is delivered by an implanted medical device, similar to a cardiac pacemaker, which uses mild electrical stimulation to modify brain signals that cause unwanted effects. Targeted cells are stimulated in the subthalamic nucleus (STN) via electrodes that are surgically implanted in the brain and connected to a neurostimulator implanted elsewhere in the body.  
       [0004] Thalamotomy, in which a lesion is made in the thalamus (an area of the brain that produces tremors). Thalamotomy has been shown to effectively reduce tremors in some patients.  
       [0005] Pallidotomy, which is a surgical operation that destroys the pallidum. The purpose of this procedure is to relieve involuntary movements or muscular rigidity as, for example, in Parkinson&#39;s disease.  
       [0006] Fetal neural implant (or nigral implant), which is an experimental technique that involves transplanting fetal tissue into the brain to replace degenerated nerves.  
       [0007] It has been demonstrated that Deep Brain Stimulation (DBS) at high frequencies (100 Hz or higher) can alleviate, diminish, or completely terminate symptoms of tremor, rigidity, akinesia (loss or impairment of voluntary activity) or hemiballism (violent uncontrollable movements of one side of the body). U.S. Pat. Nos. 5,716,377 and 5,833,709 to Rise et al., which are incorporated herein by reference, describe techniques for stimulating the brain to treat movement disorders that result in abnormal motor behavior. A sensor is used to detect the symptoms resulting from the motion disorder and an algorithm analyzes the output from the sensor in order to regulate the stimulation delivered to the brain.  
       [0008] U.S. Pat. Nos. 5,713,923 and 5,978,702 to Ward et al., which are incorporated herein by reference, describe techniques using drugs and electrical stimulation to treat neurological disorders, including epilepsy, by means of an implantable signal generator and electrode coupled to an implantable pump and catheter. A sensor is used to detect a seizure or symptoms resulting from the onset of a seizure. A microprocessor analyzes the output from the sensor in order to regulate the stimulation and drug dosage delivered to the neural tissue.  
       [0009] U.S. Pat. No. 5,800,474 to Benabid et al., which is incorporated herein by reference, discloses a method for preventing seizures experienced by persons with epilepsy. High frequency electrical stimulation pulses are supplied to the STN via electrodes that are surgically implanted in the brain and connected to a neurostimulator implanted elsewhere in the body.  
       [0010] U.S. Pat. No. 5,975,085 to Rise, which is incorporated herein by reference and referred to herein as the &#39;085 patent, describes techniques for using drugs and/or electrical stimulation for treating schizophrenia by means of an implantable signal generator and electrode and an implantable pump and catheter. The catheter is surgically implanted in the brain to infuse the drugs, and one or more electrodes are surgically implanted in the brain to provide electrical stimulation.  
       [0011] U.S. Pat. No. 6,109,269 to Rise et al., which is incorporated herein by reference, describes techniques using drugs, electrical stimulation or both, in a manner analogous to that of the &#39;085 patent, in order to treat addictions. U.S. Pat. No. 6,128,537 to Rise, which is incorporated herein by reference, describes techniques similar to those of the &#39;085 patent for treating anxiety disorder.  
       [0012] U.S. Pat. Nos. 5,735,814 and 5,814,014 to Elsberry et al., which are incorporated herein by reference, describe techniques for infusing drugs into the brain to treat neurodegenerative disorders using an implantable pump and catheter. The drugs are capable of altering the level of excitation of the neurons in the brain. A sensor is used to detect an attribute of the nervous system which reflects the hyperexcitation of the nerve cell projecting onto the degenerating nerve cells. A microprocessor algorithm analyzes the output from the sensor in order to regulate the amount of drug delivered to the brain.  
       [0013] The use of brain implants and other invasive procedures for diagnostic and therapeutic treatments requires a high level of precision in order to reduce damage to surrounding tissue and deleterious side effects. U.S. Pat. No. 5,843,148 to Gijsbers et al., which is incorporated herein by reference, describes a stimulation lead which includes a high spatial resolution tip carrying a plurality of electrodes that can be used in stimulating small neurological brain targets. U.S. Pat. No. 5,865,843 to Baudino, which is incorporated herein by reference, describes a neurological lead for transmission of therapeutic drugs and/or electrical signals to body organs such as the spinal column or brain. More specifically, this patent describes the mechanisms and methods by which such leads are secured to the human body.  
       [0014] U.S. Pat. No. 6,314,310 to Ben-Haim et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes apparatus for determining the position of a surgical tool during X-ray guided surgery.  
       [0015] U.S. Pat. No. 6,076,008 to Bucholz, which is incorporated herein by reference, describes a system for determining the position of a probe relative to the head of a patient during surgery, and displaying corresponding scan images of the same position in the head.  
       [0016] U.S. Pat. Nos. 6,246,898 and 5,797,849 to Vesely et al., which are incorporated herein by reference, describe a method for carrying out medical procedures, including in the brain, using a 3-D tracking and imaging system.  
       [0017] U.S. Pat. No. 6,298,262 to Franck et al., which is incorporated herein by reference, describes a method for positioning a surgical instrument during stereotactic surgery using a guidance fixture and a remote sensing device such as a camera.  
       [0018] U.S. Pat. No. 5,517,990 to Kalfas et al., which is incorporated herein by reference, describes the use of a stereotaxic wand in conjunction with a guide to designate a location and trajectory at which a surgical tool is applied to a patient. During use of the system, the location and trajectory of the wand are superimposed on a diagnostic image on a monitor.  
       [0019] U.S. Pat. No. 6,226,547 to Lockhart et al., which is incorporated herein by reference, describes a catheter tracking system for locating and tracking a position of a catheter within a body using reference transducers.  
       [0020] The following references, which are incorporated herein by reference, may be useful:  
       [0021] Hutchison W D et al., “Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson&#39;s disease,”  Ann Neurol,  44, 622-628 (1988)  
       [0022] Gross R E et al., “Advances in neurostimulation for movement disorders,”  Neurol Res,  22, 247-258 (2000)  
       [0023] Montgomery E B et al., “Mechanisms of deep brain stimulation and future technical developments,”  Neurol Res,  22, 259-66 (2000)  
       [0024] Benabid A L et al., “Future prospects of brain stimulation,”  Neurol Res,  22, 237-246 (2000)  
       [0025] Kupsch A et al., “Neurological interventions in the treatment of idiopathic Parkinson disease: Neurostimulation and neural implantation,”  J Mol Med,  77, 178-184 (1999)  
       [0026] Alesch F et al., “Stimulation of the ventral intermediate thalamic nucleus in tremor dominated Parkinson&#39;s disease and essential tremor,”  Acta Neurochi  ( wien ), 136, 75-81 (1995)  
       SUMMARY OF THE INVENTION  
       [0027] It is an object of some aspects of the present invention to provide improved apparatus and methods for real-time determination of the location and orientation of a medical instrument within the brain during a medical procedure.  
       [0028] It is a further object of some aspects of the present invention to provide improved apparatus and methods for accurately positioning a medical instrument at a target site within the brain during a medical procedure.  
       [0029] It is yet a further object of some aspects of the present invention to provide apparatus and methods for medical instrument positioning within the brain that can be integrated with existing commercially-available mapping support systems.  
       [0030] It is still a further object of some aspects of the present invention to provide apparatus and methods to enable simultaneous access to electrophysiological and anatomical data of the brain.  
       [0031] It is yet an additional object of some aspects of the present invention to provide apparatus and methods to enable more effective and safe treatment of neurological disorders.  
       [0032] In preferred embodiments of the present invention, apparatus and methods for performing a medical procedure in a patient&#39;s brain comprises a medical instrument, such as a probe, catheter, needle, or pacemaker lead, which comprises a plurality of location sensors and one or more electrodes for sensing electrical activity in the brain. Preferably, the instrument also comprises a therapeutic or diagnostic element affixed thereto. Using images typically acquired prior to the procedure, the instrument is inserted into the brain in the vicinity of tissue of interest. Using a combination of absolute location information, anatomical location information, and electrical activity information, the instrument is guided precisely to the location of the target tissue, and the procedure is performed using the therapeutic or diagnostic element.  
       [0033] Typically, target regions within the brain at which procedures are performed are on the order of a few millimeters in size. A combination of both electrophysiological and anatomical data is preferred in these embodiments to accurately identify a target region and its borders within the brain. Anatomical information alone is generally insufficient, because the borders between different electrophysiological regions are, in many cases, not definable by standard imaging tools such as CT or MRI. The addition of measured electrical activity in the target region enables the accurate identification of the target tissue. It is therefore particularly advantageous that these applications of the present invention are able to provide real-time feedback of the location of the probe and the electrical activity at that location in order to determine the position of the probe with respect to local electrophysiological activity at that position. That is, data obtained using techniques that indicate particular x-y-z probe coordinates, even when overlaid on a CT image, are not necessarily sufficient to indicate that the probe is in contact with desired tissue. Similarly, data obtained using techniques that indicate local electrophysiological activity without x-y-z probe coordinates are not able to provide easy guidance to the target region, especially when the probe is mounted on a flexible catheter. However, the combination of these coordinates with electrophysiological data, as provided by these embodiments of the present invention, provides the physician with a high level of confidence that the probe is moving towards and eventually is in contact with the desired target.  
       [0034] Real-time analysis of the signals received from the location sensors and electrodes on the probe within the brain allows the creation of an electrical map indicating the different physiological regions of the brain. Overlaying this electrical map on a CT-generated anatomical map enables precise location and orientation of the probe and allows the surgeon to guide the element to the desired therapeutic or diagnostic site. This is a significant advantage over prior art techniques which have no means of continually updating both the location of the tip of the probe and electrical activity at the location of the probe with respect to the CT images. It is noted that whereas some preferred embodiments of the present invention are described herein with respect to the use of CT images, the application of the described technologies in combination with other imaging modalities (e.g., MRI) is also considered to be within the scope of the present invention.  
       [0035] Synchronization of instrument location information with images showing the environment surrounding the instrument are preferably performed using methods and apparatus known in the art, such as those described in the above-cited patents to Ben-Haim, Bucholz, and Vesely et al. In a preferred embodiment, a stereotactic frame is fixed to the patient&#39;s head and location measurements are made with respect to this frame prior to and during the procedure. Typically, a set of CT images is acquired prior to surgery in order to determine the location of the target region at which the procedure is to be performed. Preferably, features in the image are registered with coordinates of the location sensing system in order to enable synchronization. Typically, a reference position on the frame, possibly including a transducer, is used as a feature of one or more images in order to aid in performing the registration process.  
       [0036] To determine the absolute location of the instrument and assist in placing it at the desired site, methods and apparatus are preferably but not necessarily utilized which are described in co-pending U.S. patent application Ser. No. 10/029,473, entitled, “Wireless position sensor,” filed Dec. 21, 2001, and/or in co-pending U.S. patent application Ser. No. 10/029,595, entitled, “Implantable and insertable tags,” filed Dec. 21, 2001. These applications are assigned to the assignee of the present patent application and are incorporated herein by reference. Preferably, one or more external electromagnetic or ultrasound transducers are placed at fixed positions with respect to the stereotactic frame. The transducers are driven by a control unit to transmit energy towards, or to receive energy transmitted by, the sensors on the instrument, in order to facilitate calculation of the location and orientation, with respect to the frame, of the instrument and the element attached thereto that performs the diagnostic or therapeutic function. Alternatively or additionally, methods and apparatus known in the art are used to facilitate location sensing.  
       [0037] In some applications of the present invention, the element performing the diagnostic or therapeutic function may be adapted for long term implantation within the brain, while for other applications, the element is removed at the end of the procedure.  
       [0038] There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for use in a brain of a subject, including:  
       [0039] an instrument, adapted to be inserted into the brain;  
       [0040] a set of one or more electrodes, adapted to be coupled to the instrument, and adapted to sense electrical activity of the brain and to transmit an electrical activity signal responsive thereto;  
       [0041] a location sensor, adapted to be coupled to the instrument and to transmit a location signal indicative of a location of the instrument; and  
       [0042] a control unit, adapted to analyze the electrical activity signal and the location signal, and adapted to determine, responsive to the analysis, a position of the instrument with respect to an image of the brain, and electrophysiological information regarding tissue at the position.  
       [0043] Preferably, the instrument is adapted to be guided to a target location in the brain responsive to the electrophysiological information and the determined position of the instrument.  
       [0044] For some applications, the control unit is adapted to create an electrical map indicating at least two physiological regions of the brain, responsive to the electrical activity signal and the location signal.  
       [0045] In a preferred embodiment, the location sensor is adapted to transmit the location signal by wireless communication.  
       [0046] In a preferred embodiment, at least one of the electrodes is adapted to be coupled to a distal tip of the instrument. Alternatively or additionally, the location sensor is adapted to be coupled near a distal tip of the instrument. Alternatively, the location sensor is adapted to be coupled to a proximal end of the instrument.  
       [0047] For some applications, the instrument is adapted to facilitate a fetal neural implant, responsive to the control unit determining the electrophysiological information regarding the tissue at the position.  
       [0048] In a preferred embodiment, the control unit is adapted to determine the position of the instrument with respect to an image of the brain acquired prior to insertion of the instrument into the brain. Alternatively or additionally, the control unit is adapted to determine the position of the instrument with respect to an image of the brain acquired while the instrument is in the brain.  
       [0049] For some applications, the image of the brain includes a CT scan, and the control unit is adapted to determine the position of the instrument with respect to the CT scan. For other applications, the image of the brain includes an MRI image, and the control unit is adapted to determine the position of the instrument with respect to the MRI image.  
       [0050] Preferably, the control unit is adapted to register one or more identifiable anatomical features in the image, and to correlate the position of the instrument with the image responsive to the registration.  
       [0051] In a preferred embodiment, the instrument includes a delivery element, adapted to deliver a pharmaceutical at a target location responsive to the electrical signal and the location signal.  
       [0052] Typically, the location sensor includes an electromagnetic transducer. In this case, the apparatus preferably includes one or more external electromagnetic radiators, adapted to be located at respective positions external to the subject and to transmit energy towards the location sensor. Alternatively, the location sensor includes an ultrasound transducer, and the apparatus includes one or more external ultrasound transducers, adapted to be located at respective positions external to the subject, and to transmit ultrasound energy towards the location sensor.  
       [0053] In a preferred embodiment, the apparatus includes a diagnostic element coupled to the instrument.  
       [0054] For some applications, the instrument includes a catheter. In accordance with a preferred embodiment of the present invention, the catheter includes a vascular catheter, adapted to be guided responsive to the location signal to a target location in the brain, through cerebral vasculature of the subject. For example, the catheter may be adapted to be guided responsive to the location signal to a target location in the brain through a venous circulation of the brain and subsequently through tissue of the brain.  
       [0055] The apparatus typically includes a stereotactic frame which is adapted to be fixed to a head of the subject, and the control unit determines the position of the instrument with respect to the frame.  
       [0056] Preferably, the apparatus includes a current-driving electrode, adapted to be placed by the instrument at a target location of the brain and to apply a therapeutic current to the target location. In a preferred embodiment, the control unit is adapted to drive the current-driving electrode to apply the therapeutic current. In a preferred application, the current-driving electrode is adapted to apply Deep Brain Stimulation therapy to the target location. Alternatively or additionally, the current-driving electrode is adapted to apply current configured for treatment of a motor disorder or a mental disorder. Further alternatively or additionally, the current-driving electrode is adapted to apply current configured for performing ablation at the target location, e.g., so as to facilitate performing thalamotomy or performing pallidotomy.  
       [0057] In some preferred embodiments, the current-driving electrode is adapted for long-term implantation in the brain.  
       [0058] There is further provided, in accordance with a preferred embodiment of the present invention, a method for performing a medical procedure in a brain of a subject, including:  
       [0059] inserting an instrument into the brain;  
       [0060] sensing electrical activity of the brain in a vicinity of an electrical-activity sensing site on the instrument, and transmitting an electrical activity signal responsive thereto;  
       [0061] sensing, at a location-sensing site on the instrument, a location of the instrument, and transmitting a location signal responsive thereto;  
       [0062] determining, responsive to the location signal, a position of the instrument with respect to an image of the brain; and  
       [0063] determining, responsive to the electrical activity signal and the determination of the position, electrophysiological information regarding tissue at the position.  
       [0064] The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawing, in which:  
     
    
    
     BRIEF DESCRIPTION OF THE DRAWING  
     [0065]FIG. 1 is a schematic, pictorial illustration of a system for tracking the electrophysiological position of a medical instrument in the brain, in accordance with a preferred embodiment of the present invention.  
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
     [0066]FIG. 1 is a schematic, pictorial illustration of a system  18  for tracking the position and orientation of an instrument  50 , such as a probe, catheter, needle, pharmaceutical-delivery element or pacemaker lead, in a brain  20  of a subject, in accordance with a preferred embodiment of the present invention. Instrument  50  comprises one or more location sensors  40  preferably located at or near the distal end of instrument  50  for determining position and orientation coordinates of the distal end of instrument  50  and one or more electrodes  28  on instrument  50  for sensing electrical activity of tissue, such as brain tissue, and performing anatomical and/or viability mapping. Preferably, the one or more location sensors include at least one or more electromagnetic inductive coils responsive to electromagnetic fields generated by transducers such as electromagnetic field generators  26  in accordance with description below. For purposes of this disclosure, the term “transducers  26 ” means either electromagnetic field generators and/or electromagnetic field receivers or alternatively, ultrasound transmitters and/or receivers. Preferably, instrument  50  also comprises a therapeutic or diagnostic element  24  affixed thereto for providing therapy and/or a diagnostic procedure on target tissue of interest  30 . Instrument  50  is inserted into brain  20  in the vicinity of target tissue of interest  30 . Using a combination of absolute location information (derived from position and orientation coordinates) generated by use of location sensors  40  and electrical activity information generated by use of electrodes  28 , instrument  50  is guided to the precise position of target tissue  30 , for instance, as determined by electrophysiological data recorded thereat or a desired location coordinate which can be a predetermined position as identified on an image of brain  20  or target tissue  30 . Typically, a therapeutic or diagnostic procedure is performed on the target tissue using element  24 . This procedure may be, for example, a procedure described in any of the references cited in the Background section of the present patent application.  
     [0067] Synchronization of absolute location information of instrument  50  with images showing the environment surrounding instrument  50  is preferably performed using methods and apparatus known in the art, such as those described in the above-cited patents to Ben-Haim, Bucholz, and Vesely et al. In a preferred embodiment, a stereotactic frame  22  is fixed to the patient&#39;s head  32  and location measurements are made with respect to frame  22  prior to and during the procedure. Typically, a set of CT, MRI, SPECT, ultrasound or other imaging modality images are acquired prior to surgery in order to determine the location of the region of target tissue  30  within the brain at which the procedure is to be performed. Preferably, features in the image are registered with position and orientation coordinates of the location sensing system in order to enable synchronization. Typically, a reference position on frame  22 , or a reference position sensor on frame  22 , possibly including a transducer (not shown), is used as a feature of one or more images in order to aid in performing the registration process. For some applications, the reference position sensor comprises an electromagnetic position sensor having one or more inductive coils.  
     [0068] To determine the absolute location of instrument  50  and assist in placing it at the desired site, i.e., target tissue  30 , methods and apparatus are preferably utilized which are described in the above-cited U.S. patent application Ser. No. 10/029,473 and/or  10 / 029 , 595  which are incorporated by reference herein. Preferably, the one or more external electromagnetic field generators  26  (or alternatively, ultrasound transducers when location sensor  40  is one or more ultrasonic transducers) are placed at fixed positions external to the patient&#39;s body with respect to stereotactic frame  22 , and location sensors  40  are preferably located on the distal end of instrument  50 . Transducers  26  are driven by a control unit  90 , preferably at a plurality of frequencies, to transmit energy towards location sensors  40  on instrument  50 , by, in the electromagnetic field embodiment, generating electromagnetic fields, or in the ultrasound embodiment, transmitting ultrasonic waves, or, in other embodiments, generating appropriate energy fields. Alternatively, transducers  26  receive energy transmitted by location sensors  40 . Responsive to the received energy, control unit  90  calculates the location, i.e., position and orientation coordinates, of location sensors  40 , distal end of instrument  50 , and element  24  attached thereto, with respect to frame  22 . Alternatively or additionally, methods and apparatus known in the art are used to facilitate location sensing. According to some of these methods, location sensors  40  are located on the proximal end of instrument  50 . Alternatively or additionally, transducers  26  receive energy transmitted by location sensors  40  on instrument  50 , i.e. transducers  26  serve as electromagnetic receivers for electromagnetic fields generated by location sensors  40 , in the electromagnetic embodiment, and as ultrasound receivers for ultrasonic waves transmitted by location sensors  40 , in the ultrasound embodiment.  
     [0069] Although for some applications instrument  50  is generally rigid, as shown in the figure and as is common in the prior art, for other applications, the instrument is generally flexible, e.g., by being made of a flexible material. In some applications, the instrument comprises a vascular catheter, which is preferably guided to target tissue  30  through the cerebral vasculature using the overlay of location data on the image (for example the CT or MRI image), and instrument  50  is subsequently verified to be at target tissue  30  by the electrophysiological data provided to the control unit  90  by the one or more electrodes  28 . Advantageously, the techniques described herein permit the use of such a flexible instrument  50  without requiring it to be mounted to stereotactic frame  22 , and, therefore, without the need to pass instrument  50  through a substantial amount of intermediate brain tissue of brain  20  while approaching target tissue  30 . For some procedures, instrument  50  is passed through the venous circulation of brain  20  to a site close to target tissue  30 , and then passed out of the venous circulation to target tissue  30 , typically without passing through a significant amount of brain tissue following exit from the venous circulation. If local bleeding is anticipated responsive to this last step, then techniques of bleeding control known in the art are preferably used, e.g., pharmaceutical agents, electrocautery or mechanical elements to temporarily or permanently block the site where the instrument exited the venous circulation.  
     [0070] In some applications of the present invention such as, for example, chronic deep brain stimulation, element  24  comprises a stimulator or another element, which may be adapted for long term implantation in brain  20 , while for other applications such as, for example, biopsy, element  24  is removed from the brain at the end of the procedure.  
     [0071] Typically, target regions  30  within brain  20  at which procedures are performed are on the order of a few millimeters in size. Thus, the position and orientation coordinate signals and information (position and orientation coordinates) generated by the one or more location sensors  40  are extremely useful for this purpose. A combination of both electrophysiological and anatomical data is preferred in these embodiments to accurately identify the target region  30  and its borders within the brain  20 . Anatomical information alone is generally insufficient, because the borders between different electrophysiological regions are, in many cases, not definable by standard imaging tools such as CT or MRI. The addition of measured electrical activity in the target region enables the accurate identification of the target tissue. It is also particularly advantageous that the system  18  used for these applications in accordance with these embodiments of the present invention is able to provide real-time feedback of the location (including position and orientation coordinates) of the instrument or probe  50  and the electrical activity at that location (provided by the one or more electrodes  28 ) in order to determine the position of the probe with respect to local electrophysiological activity at that position. That is, data obtained using techniques that indicate particular x-y-z position coordinates and orientation coordinates, such as pitch, yaw and roll, even when overlaid on a CT or MRI image, for example, may not be necessarily sufficient to indicate that the probe is indeed in contact with desired tissue. Similarly, data obtained using techniques that indicate local electrophysiological activity without x-y-z position and pitch, yaw and/or roll orientation coordinates may not be able to provide easy guidance to target region  30 , especially when instrument  50  is a flexible catheter. However, the combination of these position and orientation coordinates with electrophysiological data (provided by one or more electrodes  28 ), as provided by these embodiments of the present invention, provides the physician with a high level of confidence that instrument  50  is moving towards and eventually is in contact with the desired target  30 .  
     [0072] Real-time analysis of the signals received by control unit  90  from the one or more location sensors  40  and one or more electrodes  28  on instrument  50  within brain  20  allows the creation of an anatomical and/or electrophysiological map, such as an electrical map, indicating the different physiological regions of brain  20 , and including target tissue  30 . Overlaying this electrical map on the image, such as the CT- or MRI-generated image (anatomical image map) enables precise location, i.e., position and orientation of the distal end of instrument  50 , and allows the surgeon to guide element  24  to the desired therapeutic or diagnostic site, i.e., target tissue  30 . This is a significant advantage over prior art techniques which have no means of continually updating both the location of the distal end of an instrument and the electrical activity at the location of the instrument with respect to the tissue and CT images. It is noted that whereas some preferred embodiments of the present invention are described herein with respect to the use of CT images, the application of the described technologies in combination with other imaging modalities (e.g., MRI) is also considered to be within the scope of the present invention.  
     [0073] Synchronization of instrument location information with images showing the environment surrounding instrument  50  are preferably performed using methods and apparatus known in the art, such as those described in the above-cited patents to Ben-Haim, Bucholz, and Vesely et al. In a preferred embodiment, stereotactic frame  22  is fixed to the patient&#39;s head, and location measurements are made with respect to this frame  22  prior to and during the procedure. Typically, a set of images, such as CT images, is acquired prior to surgery in order to determine the location of target region  30  at which the procedure is to be performed. Preferably, features in the image are registered with coordinates of location sensing system  18 , in order to enable synchronization. Typically, a reference position or reference position sensor, such as described above, is provided on the frame  22 , and is used as a feature of one or more images in order to aid in performing the registration process.  
     [0074] To determine the absolute location of instrument  50  and assist in placing it at the desired site or target tissue  30 , methods and apparatus are preferably but not necessarily utilized which are described in co-pending U.S. patent application Ser. No. 10/029,473, entitled, “Wireless position sensor,” filed Dec. 21, 2001, and/or in copending U.S. patent application Ser. No. 10/029,595, entitled, “Implantable and insertable tags,” filed Dec. 21, 2001. These applications are assigned to the assignee of the present patent application and are incorporated herein by reference. Preferably, these include the use of the one or more external electromagnetic field or ultrasound transducers (generators)  26 , placed at fixed positions with respect to stereotactic frame  22 . The transducers  26  are driven by control unit  90 , as described above, to transmit energy towards, or to receive energy transmitted by, the sensors on the instrument, depending on the embodiment, in order to facilitate calculation of the location, i.e., position and orientation coordinates, with respect to the frame, of instrument  50  and element  24  attached thereto that performs the diagnostic or therapeutic function. In some applications of the present invention, element  24  performing the diagnostic or therapeutic function may be adapted for long term implantation within the brain, while for other applications, element  24  is removed at the end of the procedure. In a preferred embodiment, the one or more location sensors  40  are adapted to be both powered and/or able to transmit the location signal to the control unit  90  by wireless communication, so that system  18  serves as a telemetric system.  
     [0075] In some preferred embodiments, at least one of electrodes  28  is adapted to be coupled to the distal tip of instrument  50  through connection techniques such as those known in the art. Alternatively or additionally, location sensor  40  or one or more location sensors  40  is adapted to be coupled or connected at or near the distal tip of the instrument  50 , also through techniques known in the art. Alternatively, the location sensor  40  is connected or adapted to be coupled to a proximal end of instrument  50 .  
     [0076] For some applications, instrument  50  is used to facilitate a fetal neural implant, in conjunction with control unit  90  using both electrophysiological information (from the one or more electrodes  28 ) and location information (position and orientation coordinates) regarding target tissue  30  at or near the site targeted for implantation of the fetal tissue.  
     [0077] Additionally, for some applications, control unit  90  is adapted to register one or more identifiable anatomical features of the tissue, for example the tissue of brain  20 , in the image, and to correlate the location (position and orientation coordinates) of the instrument  50  with the image responsive to and in alignment with the registration.  
     [0078] In a preferred embodiment, instrument  50  uses element  24  as a delivery element, such as an injection needle or infusion port, adapted to deliver a pharmaceutical or therapeutical agent, including a therapeutical peptide, protein, nucleic acid or other biological molecular compound at target site  30  based on and responsive to the electrical signals (provided by the one or more electrodes  28 ) and the location signal (provided by the one or more location sensors  40 ).  
     [0079] Typically, location sensor  40  includes an electromagnetic transducer which uses one or more inductive coils. In this case, the apparatus preferably includes one or more external electromagnetic radiators, adapted to be located at respective positions external to the subject and to transmit energy in the form of a generated different, respective electromagnetic field towards location sensor  40 . Alternatively, location sensor  40  includes an ultrasound transducer, and system  18  includes one or more external ultrasound transducers  26 , adapted to be located at respective positions external to the patient or subject, and to transmit ultrasound energy (in the form of ultrasonic waves) towards the location sensor  40 .  
     [0080] In a preferred embodiment of the present invention, system  18  includes a current-driving electrode (not shown), adapted to be placed by instrument  50  at target location  30  of brain  20  in order to apply a therapeutic current to the target location  30 . In a preferred embodiment, control unit  90  operatively communicates with the current driving electrode, and is adapted to drive the current-driving electrode to apply the therapeutic current. In a preferred application, the current-driving electrode is adapted to apply “deep brain stimulation” therapy to target location  30 . Alternatively or additionally, the current-driving electrode is adapted to apply current configured for treatment of a motor disorder or a mental disorder. Further alternatively or additionally, the current-driving electrode is adapted to apply current configured for performing ablation at the target location, e.g., so as to facilitate performing thalamotomy or performing pallidotomy.  
     [0081] In some preferred embodiments, the current-driving electrode is adapted for long-term implantation in the brain.  
     [0082] It will be understood by one skilled in the art that these embodiments of the present invention can be applied in the treatment of a variety of neurological and other disorders associated with the morphology and activity of the brain, including, but not limited to, those described hereinabove.  
     [0083] It will thus be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.