CA2251852A1 - Means and methods for the treatment of neurological disorders - Google Patents
Means and methods for the treatment of neurological disordersInfo
- Publication number
- CA2251852A1 CA2251852A1 CA002251852A CA2251852A CA2251852A1 CA 2251852 A1 CA2251852 A1 CA 2251852A1 CA 002251852 A CA002251852 A CA 002251852A CA 2251852 A CA2251852 A CA 2251852A CA 2251852 A1 CA2251852 A1 CA 2251852A1
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- control module
- patient
- electronic circuitry
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/369—Electroencephalography [EEG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/40—Detecting, measuring or recording for evaluating the nervous system
- A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
- A61B5/4094—Diagnosing or monitoring seizure diseases, e.g. epilepsy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/6813—Specially adapted to be attached to a specific body part
- A61B5/6814—Head
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
- G16H20/40—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36014—External stimulators, e.g. with patch electrodes
- A61N1/36025—External stimulators, e.g. with patch electrodes for treating a mental or cerebral condition
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/37211—Means for communicating with stimulators
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- Neurology (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Surgery (AREA)
- Medical Informatics (AREA)
- Pathology (AREA)
- Neurosurgery (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Physiology (AREA)
- Radiology & Medical Imaging (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Primary Health Care (AREA)
- Electrotherapy Devices (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed is a multiple electrode, closed-loop, responsive system for the treatment of certain neurological diseases such as epilepsy, migraine headaches and Parkinson's disease. Brain electrodes would be placed in close proximity to the brain or deep within brain tissue. When a neurological event such as the onset of an epileptic seizure occurs, EEG signals from the electrodes are processed by signal conditioning means in a control module that can be placed beneath the patient's scalp, within the patient's chest, or situated externally on the patient.
Neurological event detection means in the control module will then cause a response to be generated for stopping the neurological event. The response could be an electrical signal to brain electrodes or to electrodes located remotely in the patient's body. The response could also be the release of medication or the application of a sensory input such as sound, light or mechanical vibration or electrical stimulation of the skin. The response to the neurological event can originate from devices either internal or external to the patient. The system also has the capability for multi-channel recording of EEG related signals that occur both before and after the detection of a neurological event. Programmability of many different operating parameters of the system by means of external equipment provides adaptability for treating patients who manifest different symptoms and who respond differently to the response generated by the system.
Neurological event detection means in the control module will then cause a response to be generated for stopping the neurological event. The response could be an electrical signal to brain electrodes or to electrodes located remotely in the patient's body. The response could also be the release of medication or the application of a sensory input such as sound, light or mechanical vibration or electrical stimulation of the skin. The response to the neurological event can originate from devices either internal or external to the patient. The system also has the capability for multi-channel recording of EEG related signals that occur both before and after the detection of a neurological event. Programmability of many different operating parameters of the system by means of external equipment provides adaptability for treating patients who manifest different symptoms and who respond differently to the response generated by the system.
Claims (228)
1. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted beneath the patient's scalp the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted beneath the scalp.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted beneath the patient's scalp the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted beneath the scalp.
2. The system of claim 1 wherein there are exactly two electrodes.
3. The system of claim 2 wherein the control module has an outer surface and at least part of that outer surface is electrically conducting and is one of the electrodes, and at least one of the other electrodes is an active electrode connected to the control module by the electrical conducting means.
4. The system of claim 1 wherein there are at least three electrodes.
5. The system of claim 4 wherein the control module has an outer surface and at least part of that outer surface is electrically conducting and at least one of the other electrodes is an active electrode connected to the control module by the electrical conducting means.
6. The system of claim 1 wherein there are at least four electrodes.
7. The system of claim 6 wherein the control module has an outer surface and at least part of that outer surface is electrically conducting and is one of the electrodes, and at least one of the other electrodes is an active electrode connected to the control module by the electrical conducting means.
8. The system of claim 1 wherein the electrical conducting means includes at least one insulated conducting wire, the wire having a proximal end and a distal end, the proximal end of each wire being joined to the control module and the distal end of each wire being joined to an electrode, the path of the wire from the control module to the electrode including passage between the patient's scalp and cranium.
9. The system of claim 1 wherein the conducting means is an insulated wire, the path of the wire from the control module to the electrode including passage through a hole in the patient's cranium.
10. The system of claim 1 wherein the electrical conducting means includes at least one insulated conducting wire, the wire having a proximal end and a distal end, the proximal end of each wire being joined to the control module and the distal end of each wire being joined to an electrode, the path of the wire from the control module to the electrode including passage between the dura mater of the patient's brain and the patient's cranium.
11. The system of claim 1 wherein at least one electrode is a deep electrode which is placed within the brain.
12. The system of claim 11 wherein the deep electrode is placed within the hippocampus.
13. The system of claim 11 wherein the deep electrode is placed within the thalamus.
14. The system of claim 1 wherein at least one electrode is a surface electrode, the surface electrode being placed on the dura mater of the patient's brain.
15. The system of claim 1 wherein at least one electrode is a sub-scalp electrode, the sub-scalp electrode being placed between the patient's scalp and cranium.
16. The system of claim 1 wherein at least one electrode is a brain surface electrode, the brain surface electrode being placed between the patient's brain and the arachnoid.
17. The system of claim 1 wherein at least one electrode is an arachnoid electrode, the arachnoid electrode being placed between the patient's arachnoid and dura mater.
18. The system of claim 1 wherein at least one electrode is a scalp electrode, the scalp electrode being placed on the outer surface of the patient's scalp.
19. The system of claim 1 wherein at least one electrode is a dura mater surface electrode and at least one other electrode is a deep brain electrode.
20. The system of claim 8 wherein at least one electrode is placed within the posterior half of the patient's cranium, the at least one electrode being at the distal end of the insulated conducting wire which has a first length placed between the patient's scalp and cranium, and a second length being placed between the underside of the cranium and the dura mater, the first length being longer than the second length.
21. The system of claim 8 wherein at least one electrode is placed within the anterior half of the patient's cranium, the at least one electrode being at the distal end of the insulated conducting wire which has a first length placed between the patient's scalp and cranium, and a second length being placed between the underside of the cranium and the dura mater, the first length being shorter than the second length.
22. The system of claim 1 wherein at least one electrode is placed within 2 centimeters of the center of an epileptic focus of an epileptic patient.
23. The system of claim 1 wherein the control module includes an event detection sub-system that is adapted to identify the occurrence of a neurological event by processing of at least one EEG signal being detected from at least one electrode.
24. The system of claim 23 wherein the event detection sub-system includes a signal conditioning means and an event detection means, the signal conditioning means having an input and an output, the event detection means having an input and an output, the input of the signal conditioning means being at least one EEG signal from at least one electrode, the output of the signal conditioning means being at least one of the inputs of the event detection means.
25. The system of claim 24 wherein the signal conditioning means includes one or more signal conditioning steps.
26. The system of claim 25 wherein at least one of the signal conditioning steps is amplification.
27. The system of claim 25 wherein at least one of the signal conditioning steps is automatic gain control.
28. The system of claim 25 wherein at least one of the signal conditioning steps is signal squaring.
29. The system of claim 25 wherein at least one of the signal conditioning steps is signal rectification.
30. The system of claim 25 wherein at least one of the signal conditioning steps is summing of two or more signals.
31. The system of claim 25 wherein at least one of the signal conditioning steps is subtracting one signal from another.
32. The system of claim 25 wherein at least one of the signal conditioning steps is low pass filtering.
33. The system of claim 25 wherein at least one of the signal conditioning steps is high pass filtering.
34. The system of claim 25 wherein at least one of the signal conditioning steps is band pass filtering.
35. The system of claim 25 wherein at least one of the signal conditioning steps is frequency transformation.
36. The system of claim 25 wherein at least one of the signal conditioning steps is analog-to-digital conversion.
37. The system of claim 25 wherein at least one of the signal conditioning steps is digital-to-analog conversion.
38. The system of claim 24 wherein the signal conditioning means utilizes the information of the different propagation times from the focus of a neurological event to the location of each electrode to improve the probability for reliable detection of a neurological event.
39. The system of claim 24 wherein the signal conditioning means includes digital signal processing.
40. The system of claim 1 wherein two electrodes are placed at two different locations, each of the locations being such that the propagation time of the EEG
signal from the focus of a neurological event to each one of the two electrodes is the same.
signal from the focus of a neurological event to each one of the two electrodes is the same.
41. The system of claim 24 wherein two electrodes are placed at two different locations, each of the locations being such that the propagation time of the EEG
signal from the focus of a neurological event to each of the two electrodes is different, the signal conditioning means being adapted to provide an appropriate time delay for each EEG signal from each electrode in order to produce a set of time synchronized EEG signals.
signal from the focus of a neurological event to each of the two electrodes is different, the signal conditioning means being adapted to provide an appropriate time delay for each EEG signal from each electrode in order to produce a set of time synchronized EEG signals.
42. The system of claim 24 wherein the event detection sub-system is programmable.
43. The system of claim 42 wherein the programmability includes the selection of which one or more of the EEG signals will be processed by the signal conditioning means.
44. The system of claim 42 wherein the signal conditioning means includes one or more signal conditioning steps, the implementation of a particular set of one or more signal conditioning steps being programmable.
45. The system of claim 41 wherein the appropriate time delay for each EEG signal for each of the two electrodes is programmable.
46. The system of claim 45 wherein the programmable time delays are set by a command transmitted from the external equipment to the event detection sub-system of the control module by means of the two-way communication.
47. The system of claim 42 wherein the programmable event detection sub-system includes the capability for self-adaptation.
48. The system of claim 45 wherein the programmable time delays are self-adaptive within the event detection sub-system.
49. The system of claim 24 wherein the event detection means includes one or more event detection steps.
50. The system of claim 49 wherein at least one of the event detection steps is a comparison of the output of the signal conditioning means with an event detection threshold.
51. The system of claim 50 wherein the level of the event detection threshold is programmable.
52. The system of claim 49 wherein at least one of the event detection steps is an event density counter/detector which determines if there is a neurological event by comparing the number of counts in a set period of time with a preset number of counts in that said period of time.
53. The system of claim 52 wherein the set period of time is programmable.
54. The system of claim 52 wherein the preset number is programmable.
55. The system of claim 52 wherein the set period of time is between 0.5 and 100 seconds.
56. The system of claim 24 wherein the operation of the signal conditioning means and the event detection means predispose the event detection sub-system to identify a real event while allowing an increase in the number of false identification of events that are not real events.
57. The system of claim 56 wherein the ratio of the number of false identification of events to number of real events detected lies between 1/2 and 5.
58. The system of claim 1 wherein the system for treatment of neurological disorders includes means for stopping a neurological event.
59. The system of claim 58 wherein the means for stopping a neurological event is the application of at least one electrical signal applied to at least one electrode.
60. The system of claim 59 wherein two or more signals are applied to two or more electrodes.
61. The system of claim 60 wherein the two or more signals applied to the two or more electrodes are identical.
62. The system of claim 60 wherein the two or more signals applied to the two or more electrodes are different.
63. The system of claim 62 wherein the difference between the signals applied includes different values for the parameters of amplitude, frequency, phase or any combination of one, two or three of these parameters.
64. The system of claim 63 wherein the means for stopping a neurological event is adapted to provide all signals being received at a neurological focus with essentially identical phase.
65. The system of claim 58 wherein the means for stopping a neurological event includes the electrical shorting together of at least two of the electrodes.
66. The system of claim 65 wherein at least one of the electrodes is located within 2 centimeters of the center of a focus of a neurological event.
67. The system of claim 66 wherein the control module has an outer surface and at least part of that outer surface is electrically conducting and that part of that outer surface is one of the electrodes that is electrically shorted together with at least one other electrode.
68. The system of claim 58 wherein the initiation of the means for stopping a neurological event originates from the electronic circuitry in the control module thus providing an automatic response to the detection of a neurological event.
69. The system of claim 58 wherein the initiation of the means for stopping a neurological event originates from the external equipment thus providing a manual response to the detection of a neurological event.
70. The system of claim 69 wherein the external equipment used to initiate the means for stopping of a neurological event is a physician's workstation.
71. The system of claim 69 wherein the external equipment used to initiate the means for stopping of a neurological event is a patient's initiating device.
72. The system of claim 59 wherein the electrical signal has a biphasic waveform.
73. The system of claim 59 wherein the electrical signal has an rms voltage between 1 millivolt and 10 volts.
74. The system of claim 59 wherein the electrical signal has a frequency between 0.1 and 1000 Hz.
75. The system of claim 59 wherein the electrical signal is a d-c voltage.
76. The system of claim 59 wherein the time period for applying the electrical signal is between 1 millisecond and 30 minutes.
77. The system of claim 1 wherein the electronic circuitry of the control module includes data recording means.
78. The system of claim 77 wherein the data recording means includes the ability to record one or more EEG signals.
79. The system of claim 77 wherein the data recording means includes the ability to simultaneously record two or more EEG signals.
80. The system of claim 77 wherein the data recording means includes analog-to-digital conversion and a digital memory, the digital memory being capable of storing data received or processed by the electronic circuitry of the control module.
81. The system of claim 80 wherein the digital memory is adapted to record data for a time period before the detection of a neurological event.
82. The system of claim 80 wherein the digital memory is adapted to record data for a time period after the detection of a neurological event.
83. The system of claim 80 wherein the digital memory is adapted to record data for a first time period before the detection of a neurological event and a second time period after the detection of the neurological event.
84. The system of claim 81 wherein the time period is between 0.1 and 30 minutes.
85. The system of claim 82 wherein the time period is between 0.1 and 30 minutes.
86. The system of claim 83 wherein the first time period is between 0.1 and 30 minutes and the second time period is between 0.1 and 30 minutes.
87. The system of claim 80 wherein the data recording means includes the capability of storing in the digital memory data pertaining to the frequency spectrum of at least one EEG signal originating from at least one electrode.
88. The system of claim 80 wherein the data recording means includes the capability of storing within the digital memory data originating from a specific set of electrodes which set of electrodes is less than the total number of electrodes located in close proximity to the brain or within the brain.
89. The system of claim 80 wherein the data recording means includes the capability of storing within the digital memory the number of neurological events detected over a specific time period.
90. The system of claim 80 wherein the data recording means includes the capability of storing within the digital memory a date and time of occurrence for each neurological event detected over a specific time period.
91. The system of claim 80 including means for stopping a neurological event, the data recording means including the capability of storing within the digital memory the number, time and date of each activation of the means for stopping a neurological event occurring over a specific time period.
92. The system of claim 1 wherein the electronic circuitry includes a real time clock.
93. The system of claim 92 wherein the real time clock is settable by a command from the external equipment.
94. The system of claim 1 wherein the two-way communication from the control module to the external equipment is by electromagnetic waves.
95. The system of claim 94 wherein the electromagnetic waves are in the radio frequency range.
96. The system of claim 94 wherein the electromagnetic waves are infra-red radiation.
97. The system of claim 1 wherein the two-way communication from the control module to the external equipment is by ultrasonic signals.
98. The system of claim 1 wherein the two-way communication from the control module to the electronic equipment is via electrical conducting means that passes through the patient's scalp.
99. The system of claim 1 wherein the electronic circuitry contains an alarming means, the alarming means being capable of signaling the patient.
100. The system of claim 99 wherein the alarming means signals the patient by mechanical vibrations.
101. The system of claim 99 wherein the alarming means signals the patient by an electrical tickle.
102. The system of claim 1 wherein the control module includes an electric power source for providing electric power to the electronic circuitry.
103. The system of claim 102 wherein the electric power source is a primary battery.
104. The system of claim 102 wherein the electric power source is a rechargeable battery.
105. The system of claim 104 wherein the rechargeable battery is recharged by means of a flat wire coil which receives energy from the external equipment by means of magnetic induction which imposes an alternating magnetic field on the flat wire coil.
106. The system of claim 1 wherein the electric power to operate the electronic circuitry in the control module is provided by means of a flat wire coil which receives energy from the external equipment by means of magnetic induction which imposes an alternating magnetic field on the flat wire coil.
107. The system of claim 1 wherein the electric power for the electronic circuitry of the control module is provided from the external equipment by an electrical conducting means that passes through the patient's scalp.
108. The system of claim 102 wherein the mechanical design of the control module is adapted to allow replacement of the power source without removing the entire control module from its implantation site beneath the patient's scalp.
109. The system of claim 1 wherein the mechanical design of the control module is adapted to allow replacement of the electronic circuitry without removing the entire control module from its implantation site beneath the patient's scalp.
110. The system of claim 58 further comprising a programmable implantable drug delivery system adapted for stopping a neurological event by the infusion of medication into the patient's body.
111. The system of claim 110 wherein the infusion of medication is directed into the cerebrospinal fluid.
112. The system of claim 110 wherein the infusion of medication is directed into the bloodstream.
113. The system of claim 110 wherein the medication is infused directly into brain tissue.
114. The system of claim 110 wherein the means for stopping a neurological event includes both the infusion of medication into the patient's body and the use of at least one electrical signal applied to at least one electrode.
115. The system of claim 1 wherein the control module is implanted within the cranium at a location where cranium bone has been removed.
116. The system of claim 1 wherein the control module is implanted between the patient's cranium and scalp.
117. The system of claim 1 wherein the external equipment includes an external data interface and a physician's workstation, the external data interface providing the two-way communication with the control module and further providing data communication with the physician's workstation.
118. The system of claim 117 wherein the data communication between the external data interface and the physician's workstation is either by a multiplicity of wires or a pair of modems.
119. The system of claim 117 wherein the external data interface includes a cap to be worn by the patient.
120. The system of claim 119 wherein the cap has an emitting and receiving device that is adapted to provide the two-way communication link between the external equipment and the control module implanted beneath the patient's scalp.
121. The system of claim 119 wherein the cap's emitting and receiving device is adapted to provide electrical power to the control module implanted beneath the patient's scalp.
122. The system of claim 119 wherein the control module includes a rechargeable battery and the cap's emitting and receiving device is adapted to provide electrical power to recharge the rechargeable battery.
123. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least three electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least three electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
124. The system of claim 123 wherein the control module is placed within the patient's chest.
125. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain, at least one electrode being a surface electrode, the surface electrode being placed on the dura mater of the patient's brain, and at least one other electrode being a deep brain electrode, the deep brain electrode being placed within the -patient's brain.
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain, at least one electrode being a surface electrode, the surface electrode being placed on the dura mater of the patient's brain, and at least one other electrode being a deep brain electrode, the deep brain electrode being placed within the -patient's brain.
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
126. The system of claim 125 wherein the control module is placed within the patient's chest.
127. A system for the treatment of an epileptic patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain, at least one electrode being placed within two centimeters of the center of an epileptic focus of the epileptic patient.
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain, at least one electrode being placed within two centimeters of the center of an epileptic focus of the epileptic patient.
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
128. The system of claim 127 wherein the control module is placed within the patient's chest.
129. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the electronic circuitry including an event detection sub-system that is adapted to identify the occurrence of a neurological event by processing of at least one EEG signal being detected from at least one electrode;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the electronic circuitry including an event detection sub-system that is adapted to identify the occurrence of a neurological event by processing of at least one EEG signal being detected from at least one electrode;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
130. The system of claim 129 wherein the event detection sub-system includes a signal conditioning means and an event detection means, the signal conditioning means having an input and an output, the event detection means having an input and an output, the input of the signal conditioning means being at least one EEG signal from at least one electrode, the output of the signal conditioning means being the at least one of the inputs of the event detection means.
131. The system of claim 129 wherein the control module is placed within the patient's chest.
132. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for stopping a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for stopping a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
133. The system of claim 132 wherein the means for stopping a neurological event includes the electrical shorting together of at least two of the electrodes.
134. The system of claim 132 wherein the initiation of the means for stopping a neurological event originates from the electronic circuitry in the control module thus providing an automatic response to the detection of a neurological event.
135. The system of claim 132 wherein the initiation of the means for stopping a neurological event originates from the external equipment thus providing a manual response to the detection of a neurological event.
136. The system of claim 135 wherein the external equipment used to initiate the means for stopping of a neurological event is a patient's initiating device thus providing a manual response to the detection of a neurological event.
137. The system of claim 132 wherein the control module is placed within the patient's chest.
138. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the control module having a structure consisting of three major parts, a first part being a thin-walled, generally cylindrical shell that is closed by a thin-walled structure at its bottom and open at its top, a second part being an electronics module containing the electronic circuitry, and a third part being a battery, electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the control module having a structure consisting of three major parts, a first part being a thin-walled, generally cylindrical shell that is closed by a thin-walled structure at its bottom and open at its top, a second part being an electronics module containing the electronic circuitry, and a third part being a battery, electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
139. The system of claim 138 wherein the control module is placed within the patient's chest.
140. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the electronic circuitry of the control module including a data recording means;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry, the electronic circuitry of the control module including a data recording means;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
141. The system of claim 140 wherein the data recording means includes the ability to record one or more EEG signals.
142. The system of claim 140 wherein the data recording means includes the ability to simultaneously record two or more EEG signals.
143. The system of claim 140 wherein the data recording means includes analog-to-digital conversion and a digital memory, the digital memory being capable of storing data received or processed by the electronic circuitry of the control module.
144. The system of claim 143 wherein the digital memory is adapted to record data for a time period before the detection of a neurological event.
145. The system of claim 143 wherein the digital memory is adapted to record data for a time period after the detection of a neurological event.
146. The system of claim 143 wherein the digital memory is adapted to record data for a first time period before the detection of a neurological event and a second time period after the detection of the neurological event.
147. The system of claim 144 wherein the time period is between 0.1 and 30 minutes.
148. The system of claim 145 wherein the time period is between 0.1 and 30 minutes.
149. The system of claim 146 wherein the first time period is between 0.1 and 30 minutes and the second time period is between 0.1 and 30 minutes.
150. The system of claim 143 wherein the data recording means includes the capability of storing in the digital memory data pertaining to the frequency spectrum of at least one EEG signal originating from at least one electrode.
151. The system of claim 143 wherein the data recording means includes the capability of storing within the digital memory data originating from a specific set of electrodes which set of electrodes is less than the total number of electrodes located in close proximity to the brain or within the brain.
152. The system of claim 143 wherein the data recording means includes the capability of storing within the digital memory the number of neurological events detected over a specific time period.
153. The system of claim 143 wherein the data recording means includes the capability of storing within the digital memory the time of occurrence of each neurological event detected over a specific time period.
154. The system of claim 143 including means for stopping a neurological event, the data recording means including the capability for storing within the digital memory the number, time and date of each activation of the means for stopping a neurological event occurring over a specific time period.
155. The system of claim 140 wherein the electronic circuitry includes a real time clock.
156. The system of claim 155 wherein the real time clock is settable by a command from the external equipment.
157. The system of claim 140 wherein the electronic circuitry of the control module generates electrical signals related to the EEG signals received from each electrode, the data recording means being adapted to record and hold any one or more of the electrical signals related to the EEG signals which are generated within the electronic circuitry of the control module.
158. The system of claim 157 wherein the external equipment is adapted to command the data recording means to record and hold any one or more of the electrical signals related to the EEG signals generated within the electronic circuitry of the control module.
159. The system of claim 158 wherein the external equipment that commands the data recording means to record and hold any one or more of the electrical signals generated within the electronic circuitry of the control module is a patient's initiating device.
160. The system of claim 158 wherein the external equipment that commands the data recording means to record and hold any one or more of the electrical signals generated within the electronic circuitry of the control module is a physician's workstation.
161. The system of claim 140 wherein the control module is placed within the patient's chest.
162. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
a programmable implantable drug delivery system adapted to infuse medication into the patient's body;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means, the at least two electrodes and the programmable implantable drug delivery system cooperating to provide a means for stopping a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
a programmable implantable drug delivery system adapted to infuse medication into the patient's body;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means, the at least two electrodes and the programmable implantable drug delivery system cooperating to provide a means for stopping a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
163. The system of claim 162 wherein the infusion of medication is directed into the cerebrospinal fluid.
164. The system of claim 162 wherein the infusion of medication is directed into the bloodstream.
165. The system of claim 162 wherein the means for stopping a neurological event includes both the infusion of medication into the patient's body and the use of at least one electrical signal applied to at least one electrode.
166. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted under the patient's scalp, the control module including electronic circuitry;
a sensor/actuator device implanted within the patient's body at a location remote from the control module, the sensor/actuator device having electronic circuitry, the electronic circuitry of the sensor/actuator device being adapted to communicate with the electronic circuitry of the control module, by signaling means sent through the patient's body;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted under the patient's scalp, the control module including electronic circuitry;
a sensor/actuator device implanted within the patient's body at a location remote from the control module, the sensor/actuator device having electronic circuitry, the electronic circuitry of the sensor/actuator device being adapted to communicate with the electronic circuitry of the control module, by signaling means sent through the patient's body;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module implanted within the patient's body.
167. The system of claim 166 wherein the signaling means is by electrical conduction of an electrical signal through the patient's body.
168. The system of claim 166 wherein the signaling means is by electromagnetic waves sent through the patient's body.
169. The system of claim 169 wherein the electromagnetic waves are in the radio frequency range.
170. The system of claim 166 wherein the signaling means is by mechanical vibrations sent through the patient's body.
171. The system of claim 166 wherein the remote sensor/actuator device includes medication infusion means.
172. The system of claim 166 wherein the remote sensor/actuator device includes electrical stimulation means, the electrical stimulation means including the following; (1) at least part of the electronic circuitry of the remote sensor/actuator device; (2) two or more electrodes; and (3) conducting means from each electrode to the electronic circuitry of the remote sensor/actuator device.
173. The system of claim 166 wherein the remote sensor/actuator device includes electrical sensing means, the electrical sensing means including the following;
(1) at least part of the electronic circuitry of the remote sensor/actuator device;
(2) two or more electrodes; and (3) conducting means from each electrode to the electronic circuitry of the remote sensor/actuator device.
(1) at least part of the electronic circuitry of the remote sensor/actuator device;
(2) two or more electrodes; and (3) conducting means from each electrode to the electronic circuitry of the remote sensor/actuator device.
174. The system of claim 166 wherein the electronic circuitry of the remote sensor/actuator device includes data recording means, the data recording means being adapted to record electrical signals processed within the electronic circuitry of the remote sensor/actuator device.
175. The system of claim 166 wherein the control module includes electrical stimulation means, the electrical stimulation means including at least part of the electronic circuitry of the control module, and also including two or more electrodes and the conducting means from each electrode to the electronic circuitry of the control module, the electrical stimulation means being adapted to apply an electrical stimulation signal to one or more of the electrodes located in close proximity to the patient's brain or within the brain.
176. The system of claim 166 wherein the control module includes electrical sensing means, the electrical sensing means including at least part of the electronic circuitry of the control module, and also including two or more electrodes and the conducting means from each electrode to the electronic circuitry of the control module.
177. The system of claim 166 wherein the electronic circuitry of the control module includes data recording means, the data recording means being adapted to record electrical signals processed within the electronic circuitry of the control module.
178. The system of claim 171 wherein the control module can initiate a command to the remote sensor/actuator device by the signaling means to cause the remote sensor/actuator device's medication infusion means to release medication into the patient's body.
179. The system of claim 172 wherein the control module can initiate a command to the remote sensor/actuator device by the signaling means to cause the remote sensor/actuator device's electrical stimulation means to apply an electrical stimulation signal to one or more of the electrodes placed within the patient's body.
180. The system of claim 174 wherein the control module can initiate a command to the remote sensor/actuator device by the signaling means to cause the remote sensor/actuator device's recording means to record data processed within the electronic circuitry of the remote sensor/actuator device.
181. The system of claim 177 wherein the remote sensor/actuator device can initiate a command to the control module by the signaling means to cause the control module's recording means to record data processed within the electronic circuitry of the control module.
182. The system of claim 175 wherein the remote sensor/actuator device can initiate a command to the control module by the signaling means to cause the control module's electrical stimulation means to apply an electrical stimulation signal to one or more of the electrodes placed in close proximity to the patient's brain or within the brain.
183. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module located external to the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for detecting a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module located external to the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module located external to the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for detecting a neurological event; and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module located external to the patient's body.
184. The system of claim 183 further comprising means for stopping a neurological event.
185. The system of claim 184 wherein the means for stopping a neurological event uses at least one electrical signal applied to at least one electrode.
186. The system of claim 185 wherein two or more signals are applied to two or more electrodes.
187. The system of claim 186 wherein the signals applied to the two or more electrodes are identical.
188. The system of claim 186 wherein the at least two of the signals applied to the two or more electrodes are different.
189. The system of claim 188 wherein the difference between the signals applied includes different values for the parameters of amplitude, frequency, phase or any combination of one, two or three of these parameters.
190. The system of claim 184 wherein the means for stopping a neurological event includes the electrical shorting together of at least two of the electrodes.
191. The system of claim 185 wherein at least one of the electrodes is located within two centimeters from the center of the focus of the neurological event.
192. The system of claim 184 wherein the initiation of the means for stopping a neurological event originates from the electronic circuitry in the control module.
193. The system of claim 184 wherein the initiation of the means for stopping a neurological event originates from the external equipment.
194. The system of claim 185 wherein the electrical signal has a biphasic waveform.
195. The system of claim 183 wherein at least one electrode is placed under the patient's scalp.
196. The system of claim 183 wherein at least one electrode is placed on the patient's scalp.
197. The system of claim 185 wherein the electrical signal has a frequency between 0.1 and 1000 Hz.
198. The system of claim 185 wherein the time period for applying the electrical signal is between 1 millisecond and 30 minutes.
199. The system of claim 183 wherein the electronic circuitry of the control module includes data recording means, the data recording means being adapted to record electrical signals processed within the electronic circuitry of the control module.
200. The system of claim 199 wherein the data recording means includes the ability to record one or more EEG signals.
201. The system of claim 183 wherein the control module is placed behind the patient's ear.
202. The system of claim 184 wherein the control module is adapted to emit sound, the emitted sound being the means for stopping a neurological event.
203. The system of claim 184 wherein the means for stopping a neurological event is a remote sensor/actuator device implanted within the patient's body, the sensor/actuator device having electronic circuitry, the electronic circuitry of the sensor/actuator device being adapted to communicate with the electronic circuitry of the control module by signaling means sent through the patient's body, the signaling means being adapted to allow the control module to command the remote sensor/actuator device to initiate the means for stopping a neurological event.
204. The system of claim 184 wherein the means for stopping a neurological event is a remote actuator located external to the patient's body at a location remote from the control module.
205. The system of claim 204 wherein the external remote actuator contains electronic circuitry, the electronic circuitry of the external remote actuator being adapted to communicate with the electronic circuitry of the control module by signaling means sent through the patient's body, the signaling means being adapted to allow the control module to command the external remote actuator to initiate the means for stopping a neurological event.
206. The system of claim 204 wherein the external remote actuator is adapted to allow the patient to command the remote actuator to initiate the means for stopping a neurological event.
207. The system of claim 204 wherein the external remote actuator is adapted to emit light.
208. The system of claim 204 wherein the external remote actuator is adapted to produce mechanical vibrations.
209. The system of claim 204 wherein the external remote actuator is adapted to emit sound.
210. The system of claim 204 wherein the remote actuator is adapted to deliver electrical stimulation to the skin of the patient.
211. The system of claim 207 wherein the actuator is adapted to fit onto a pair of eyeglasses.
212. The system of claim 209 wherein the actuator is adapted to fit within the patient's ear.
213. The system of claim 203 wherein the implanted remote sensor/actuator device includes medication infusion means.
214. The system of claim 203 wherein the implanted remote sensor/actuactor device includes electrical stimulation means, the electrical stimulation means including at least part of the electronic circuitry of the remote sensor/actuator device, and also including two or more electrodes and the conducting means from each electrode to the electronic circuitry of the remote sensor/actuator device.
215. A system for the treatment of neurological disorders of a human patient, the system comprising:
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for detecting a neurological event;
a remote actuator located external to the patient's body, the remote actuator being adapted to provide a means for stopping a neurological event, and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module located external to the patient's body.
at least two electrodes located in close proximity to the patient's brain or within the brain;
a control module implanted within the patient's body, the control module including electronic circuitry;
electrical conducting means which provide electrical connections between the electrodes and the electronic circuitry of the control module, the electronic circuitry of the control module, the electrical conducting means and the at least two electrodes cooperating to provide a means for detecting a neurological event;
a remote actuator located external to the patient's body, the remote actuator being adapted to provide a means for stopping a neurological event, and external equipment located external to the patient, the external equipment being adapted to provide two-way communication between the external equipment and the control module located external to the patient's body.
216. The system of claim 215 wherein the electronic circuitry of the control module includes data recording means, the data recording means being adapted to record electrical signals processed within the electronic circuitry of the control module.
217. The system of claim 216 wherein the data recording means includes the ability to record one or more EEG signals.
218. The system of claim 215 wherein the external remote actuator contains electronic circuitry, the electronic circuitry of the external remote actuator being adapted to communicate with the electronic circuitry of the control module by signaling means sent through the patient's body, the signaling means being adapted to allow the control module to command the external remote actuator to initiate the means for stopping a neurological event.
219. The system of claim 215 wherein the external remote actuator is adapted to allow the patient to command the remote actuator to initiate the means for stopping a neurological event.
220. The system of claim 215 wherein the external remote actuator is adapted to emit light.
221. The system of claim 215 wherein the external remote actuator is adapted to produce mechanical vibrations.
222. The system of claim 215 wherein the external remote actuator is adapted to emit sound.
223. The system of claim 215 wherein the remote actuator is adapted to deliver electrical stimulation to the skin of the patient.
224. The system of claim 220 wherein the external remote actuator is adapted to fit onto a pair of eyeglasses.
225. The system of claim 222 wherein at least part of the external remote actuator is adapted to fit within the patient's ear.
226. A method for replacing the battery of a control module that is placed generally beneath the scalp of a human patient, the method comprising the following steps:
(a) shaving the hair on the patient's scalp at the site under which the control module is located;
(b) making an incision through the patient's scalp at the site where the hair was removed;
(c) pulling out through the incision a depleted battery that lies within the control module;
(d) placing a new battery at the general position where the used battery was removed; and (e) closing the incision made in the scalp over the site of the control module.
(a) shaving the hair on the patient's scalp at the site under which the control module is located;
(b) making an incision through the patient's scalp at the site where the hair was removed;
(c) pulling out through the incision a depleted battery that lies within the control module;
(d) placing a new battery at the general position where the used battery was removed; and (e) closing the incision made in the scalp over the site of the control module.
227. The method of claim 226 including the following additional steps:
(a) pulling out through the incision an electronics module that lies within the control module;
(b) placing a new electronics module at the general position where the removed electronics module was located.
(a) pulling out through the incision an electronics module that lies within the control module;
(b) placing a new electronics module at the general position where the removed electronics module was located.
228. A method for replacing an electronics module from within a control module that is placed generally beneath the scalp of a human patient, the method comprising the following steps:
(a) shaving the hair on the patient's scalp at the site under which the control module is located;
(b) making an incision through the patient's scalp at the site where the hair was removed;
(c) pulling out through the incision an electronics module that lies within the control module;
(d) placing a new electronics module at the general position where the removed electronics module was located; and (e) closing the incision made in the scalp over the site of the control module.
(a) shaving the hair on the patient's scalp at the site under which the control module is located;
(b) making an incision through the patient's scalp at the site where the hair was removed;
(c) pulling out through the incision an electronics module that lies within the control module;
(d) placing a new electronics module at the general position where the removed electronics module was located; and (e) closing the incision made in the scalp over the site of the control module.
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US20020002390A1 (en) | 2002-01-03 |
DE69832022D1 (en) | 2005-12-01 |
CA2251852C (en) | 2012-12-18 |
US6134474A (en) | 2000-10-17 |
US6360122B1 (en) | 2002-03-19 |
US6061593A (en) | 2000-05-09 |
DE69832022T2 (en) | 2006-07-13 |
US6128538A (en) | 2000-10-03 |
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ATE307638T1 (en) | 2005-11-15 |
EP0911061A2 (en) | 1999-04-28 |
US6016449A (en) | 2000-01-18 |
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