Method and apparatus for electrically stimulating cells implanted in the nervous system

• US 20030088274A1
• Filed: 09/30/2002
• Published: 05/08/2003
• Est. Priority Date: 09/28/2001
• Status: Abandoned Application

• Current Assignee: Advanced Neuromodulation Systems Incorporated (Abbott Laboratories)
• Original Assignee: Vertis Neuroscience, Inc. (Northstar Neuroscience, Inc.)
• Inventors: Sheffield, W. Douglas, Blazer, Jeffrey, Firlik, Andrew D., Gliner, Bradford Evan, Levy, Alan J.
• Application Number:
  US10/261,116
• Publication Number:
  US 20030088274A1
• Time in Patent Office: Days
• US Class Current: 607/3
• CPC Class Codes: A61N 1/36017 with leads or electrodes penetrating the skin
• CPC Class Codes: A61N 1/36103 Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke
• CPC Class Codes: A61N 1/3756 Casings with electrodes thereon, e.g. leadless stimulators
• CPC Class Codes: C12N 13/00 Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves

Abstract

The following disclosure describes several methods and apparatus for stimulating cells implanted in the regions of nervous system, such as the brain, spinal cord or peripheral nerves. Accordingly, the functionality of the cells can be improved, for example, by differentiating undifferentiated or partially undifferentiated cells into neurons or other cells having action potentials. The method can also include promoting directional growth and connectivity of fully differentiated neural cells implanted in a patient'"'"'s nervous system through electrical enhancement, for example, electrical stimulation via an anode and cathode. Methods in accordance with the invention can be used to treat brain damage (e.g., stroke, trauma, etc.), brain disease (e.g., Alzheimer'"'"'s, Pick'"'"'s, Parkinson'"'"'s, etc.), and/or brain disorders (e.g., epilepsy, depression, etc.). The methods in accordance with the invention can also be used to enhance neural-function of normal, healthy brains (e.g., learning, memory, etc.), or to control sensory functions (e.g., pain).

Claims

1. A method of cell therapy, comprising:

preparing at least partially undifferentiated cells for implantation;

implanting the at least partially undifferentiated cells at an implantation site of a nervous system of a patient;

positioning at least one electrode in communication with the implantation site of the nervous system of the patient; and

differentiating the at least partially undifferentiated cells into cells with increased neural characteristics when compared to the at least partially undifferentiated cells by applying an electrical potential to the at least one electrode while the electrode is in communication with the implantation site of the nervous system.

2. The method of claim 1 wherein positioning at least one electrode includes positioning at least one electrode at least proximate to the implantation site.

3. The method of claim 1 wherein positioning at least one electrode includes positioning at least one electrode proximate to a native cell and communicating with the at least partially undifferentiated cells via the native cell.

4. The method of claim 1 wherein preparing the at least partially undifferentiated cells includes applying an electrical stimulation to the at least partially undifferentiated cells while the at least partially undifferentiated cells are external to a patient.

5. The method of claim 1 wherein the at least partially undifferentiated cells are selected to include stem cells, precursor cells, and/or progenitor cells.

6. The method of claim 1 wherein implanting the at least partially undifferentiated cells at an implantation site of a nervous system of a patient includes implanting the undifferentiated cells directly into the patient'"'"'s tissue without a substrate and wherein applying an electrical potential includes directing an electrical current from the at least one electrode through the tissue adjacent to the at least partially undifferentiated cells and to the at least partially undifferentiated cells.

7. The method of claim 1 wherein implanting the at least partially undifferentiated cells at an implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells at an implantation site of a spinal cord of a patient.

8. The method of claim 1 wherein implanting the at least partially undifferentiated cells at an implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells at an implantation site of a brain of the patient.

9. The method of claim 1 wherein implanting the at least partially undifferentiated cells at an implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells at an implantation site of a peripheral nerve of the patient.

10. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises positioning a second electrode at least proximate to the implantation site of the nervous system of the patient, and wherein applying an electrical potential includes applying a voltage of from about ±

1 mV to about ±

10 V between the first electrode and the second electrode while the electrodes are at least proximate to the implantation site of the nervous system.

11. The method of claim 1 wherein applying an electrical potential includes generating electrical pulses at a rate of from about 1 to about 1000 Hz.

12. The method of claim 1 wherein differentiating the at least partially undifferentiated cells into cells with increased neural characteristics includes applying an electrical potential to the at least one electrode at a first voltage until the at least partially undifferentiated cells develop action potentials and then applying an electrical potential to the at least one electrode at a second voltage less than the first voltage after the at least partially undifferentiated cells develop action potentials.

13. The method of claim 1 wherein differentiating the at least partially undifferentiated cells into cells with increased neural characteristics includes ceasing to apply an electrical potential to the at least one electrode after the at least partially undifferentiated cells develop increased action potentials.

14. The method of claim 1, further comprising ascertaining a threshold for generating action potentials for the at least partially undifferentiated cells at the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage less than the threshold for generating action potentials.

15. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating action potentials for the at least partially undifferentiated cells at the implantation site of the nervous system; and

positioning a second electrode at least proximate to the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is approximately 10% to approximately 50% less than the threshold for generating an action potential.

16. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating electrophysiologic signals associated with a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is less than the threshold for generating electrophysiologic signals.

17. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating electrophysiologic signals for the at least partially undifferentiated cells at the implantation site of the nervous system; and

positioning a second electrode at least proximate to the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is from about 20% to about 50% less than the threshold for generating electrophysiologic signals.

18. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for eliciting a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is less than the threshold for eliciting the neural function.

19. The method of claim 1 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for eliciting a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is from about 30% to about 60% less than the threshold for eliciting the neural function.

20. A method of cell therapy, comprising:

identifying an implantation site of a nervous system of a patient by generating remotely from a location in the nervous system an intended neural activity and determining the site of the nervous system where the generated neural activity is present;

preparing at least partially undifferentiated cells for implantation;

at the implantation site, implanting the at least partially undifferentiated cells directly into tissue of the patient without an implanted substrate;

positioning a first electrode and a second electrode at least proximate to the implantation site of the nervous system, wherein the first electrode and the second electrode are spaced apart from the at least partially undifferentiated cells; and

differentiating the at least partially undifferentiated cells into cells with increased neural characteristics when compared to the at least partially undifferentiated cells by applying an electrical potential between the first electrode and the second electrode and directing an electrical current through the tissue adjacent to the at least partially undifferentiated cells and to the at least partially undifferentiated cells.

21. The method of claim 20 wherein preparing the at least partially undifferentiated cells includes applying an electrical stimulation to the at least partially undifferentiated cells while the at least partially undifferentiated cells are external to a patient.

22. The method of claim 20 wherein the at least partially undifferentiated cells are selected to include stem cells, precursor cells, and/or progenitor cells.

23. The method of claim 20 wherein implanting the at least partially undifferentiated cells directly into tissue without a substrate includes implanting the at least partially undifferentiated cells at least proximate to a spinal cord of the patient.

24. The method of claim 20 wherein implanting the at least partially undifferentiated cells directly into tissue without a substrate includes implanting the at least partially undifferentiated cells at least proximate to a brain of the patient.

25. The method of claim 20 wherein implanting the at least partially undifferentiated cells directly into tissue without a substrate includes implanting the at least partially undifferentiated cells at least proximate to a peripheral nerve of the patient.

26. The method of claim 20 wherein differentiating the at least partially undifferentiated cells into cells with increased neural characteristics includes directing an electrical current between the first electrode and the second electrode at a first voltage until the at least partially undifferentiated cells develop increased action potentials and then applying an electrical current between the first electrode and the second electrode at a second voltage less than the first voltage after the at least partially undifferentiated cells develop increased action potentials.

27. The method of claim 20 wherein differentiating the at least partially undifferentiated cells into cells with increased neural characteristics includes ceasing to apply an electrical current between the first electrode and the second electrode after the at least partially undifferentiated cells develop increased action potentials.

28. The method of claim 20, further comprising ascertaining a threshold for generating action potentials for the at least partially undifferentiated cells at the implantation site of the nervous system, and wherein applying an electrical potential includes applying a subthreshold voltage less than the threshold for generating action potentials.

29. A method of cell therapy, comprising:

preparing fully differentiated neural cells for implantation;

at an implantation site of a nervous system of a patient, implanting the fully differentiated neural cells directly into tissue without an implanted substrate;

positioning at least one electrode at least proximate to the implantation site of the nervous system of the patient;

applying an electrical potential to the at least one electrode while the electrode is at least proximate to the implantation site of the nervous system; and

enhancing connections between native cells and the fully differentiated neural cells by directing an electrical current from the at least one electrode through the tissue surrounding the fully differentiated neural cells.

30. The method of claim 29 wherein preparing fully differentiated neural cells includes applying an electrical stimulation to the fully differentiated neural cells while the fully differentiated neural cells are external to a patient.

31. The method of claim 29, further comprising directing growth of the fully differentiated neural cells by applying an electrical potential to the at least one electrode while the electrode is at least proximate to the implantation site of the nervous system.

32. The method of claim 29, further comprising generating connectivity of the fully differentiated neural cells by applying an electrical potential to the at least one electrode while the electrode is at least proximate to the implantation site of the nervous system.

33. The method of claim 29 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system of a patient includes implanting the fully differentiated neural cells at an implantation site of a spinal cord of the patient.

34. The method of claim 29 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system of a patient includes implanting the fully differentiated neural cells at an implantation site of a brain of the patient.

35. The method of claim 29 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system includes implanting the fully differentiated neural cells at an implantation site of a peripheral nerve of the patient.

36. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises positioning a second electrode at least proximate to the implantation site of the nervous system of the patient, and wherein applying an electrical potential includes applying a voltage of from about ±

1 mV to about ±

10 V between the first electrode and the second electrode while the electrodes are at least proximate to the implantation site of the nervous system.

37. The method of claim 29 wherein applying an electrical potential includes generating electrical pulses at a rate of from about 1 to about 1000 Hz.

38. The method of claim 29, further comprising ascertaining a threshold for generating action potentials for the fully differentiated neural cells at the implantation site of the nervous system, and wherein applying an electrical potential includes placing a subthreshold voltage less than the threshold for generating action potentials.

39. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating action potentials for the neural cells at the implantation site of the nervous system; and

positioning a second electrode at least proximate to the implantation site of the nervous system and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is approximately 10-50% less than the threshold for generating action potentials.

40. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating electrophysiologic signals associated with a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is less than the threshold for generating electrophysiologic signals.

41. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for generating electrophysiologic signals for the fully differentiated neural cells at the implantation site of the nervous system; and

positioning a second electrode at least proximate to the implantation site of the nervous system and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is 20-50% less than the threshold for generating electrophysiologic signals.

42. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for eliciting a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is less than the threshold for eliciting the neural function.

43. The method of claim 29 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

ascertaining a threshold for eliciting a neural function; and

positioning a second electrode at least proximate to the implantation site of the nervous system and wherein applying an electrical potential includes placing a subthreshold voltage between the first electrode and the second electrode, wherein the subthreshold voltage is 30-60% less than the threshold for eliciting the neural function.

44. A method of cell therapy, comprising:

preparing fully differentiated neural cells for implantation;

at an implantation site of a nervous system of a patient, implanting the fully differentiated neural cells directly into tissue without an implanted substrate;

positioning at least one electrode at least proximate to the implantation site of the nervous system of the patient;

applying an electrical potential to the at least one electrode while the electrode is at least proximate to the implantation site of the nervous system; and

directing growth of the fully differentiated neural cells by directing an electrical current from the at least one electrode through the tissue surrounding the fully differentiated neural cells.

45. The method of claim 44 wherein preparing fully differentiated neural cells includes applying an electrical stimulation to the fully differentiated neural cells while the fully differentiated neural cells are external to the patient.

46. The method of claim 44, further comprising generating connectivity of the fully differentiated neural cells by applying an electrical potential to the at least one electrode while the electrode is at least proximate to the implantation site of the nervous system.

47. The method of claim 44 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system of a patient includes implanting the fully differentiated neural cells at an implantation site of a spinal cord of a patient.

48. The method of claim 44 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system of a patient includes implanting the fully differentiated neural cells at an implantation site of a brain of a patient.

49. The method of claim 44 wherein implanting the fully differentiated neural cells at an implantation site of a nervous system includes implanting the fully differentiated neural cells at an implantation site of a peripheral nerve of a patient.

50. The method of claim 44 wherein the at least one electrode includes a first electrode, and wherein the method further comprises positioning a second electrode at least proximate to the implantation site of the nervous system of the patient, and wherein applying an electrical potential includes applying a voltage of from about ±

1 mV to about ±

10 V between the first electrode and the second electrode while the electrodes are at least proximate to the implantation site of the nervous system.

51. A method of cell therapy, comprising:

preparing at least partially undifferentiated cells for implantation;

applying an electrical stimulation to the at least partially undifferentiated cells while the at least partially undifferentiated cells are external to a patient;

implanting the at least partially undifferentiated cells directly into tissue at an implantation site of a nervous system of the patient after applying the electrical stimulation and without supporting the at least partially undifferentiated implanted cells with a substrate;

positioning a first electrode and a second electrode at least proximate to the implantation site of the nervous system, wherein the first electrode and the second electrode are spaced apart from the at least partially undifferentiated cells; and

differentiating the at least partially undifferentiated cells into cells with increased neural characteristics by directing an electrical current between the first electrode and the second electrodes through the tissue surrounding the at least partially undifferentiated cells and to the at least partially undifferentiated cells.

52. The method of claim 51 wherein the at least partially undifferentiated cells are selected to include stem cells, precursor cells, and/or progenitor cells.

53. The method of claim 51 wherein implanting the at least partially undifferentiated cells directly into tissue at an implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells at least proximate to a spinal cord of a patient.

54. The method of claim 51 wherein implanting the at least partially undifferentiated cells directly into tissue at an implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells at least proximate to a brain of a patient.

55. The method of claim 51 wherein implanting the at least partially undifferentiated cells directly into tissue at an implantation site of a nervous system includes implanting the at least partially undifferentiated cells at least proximate to a peripheral nerve of a patient.

56. The method of claim 51 wherein applying an electrical potential includes applying a voltage of from about ±

1 mV to about ±

10 V between the first electrode and the second electrode while the electrodes are at least proximate to the implantation site of the nervous system.

57. The method of claim 51 wherein applying an electrical potential includes generating electrical pulses at a rate of from about 1 to about 1000 Hz.

58. The method of claim 51 wherein differentiating the at least partially undifferentiated cells into cells with increased neural characteristics includes applying an electrical potential between the first electrode and the second electrode at a first voltage until the at least partially undifferentiated cells develop increased action potentials and then applying an electrical potential between the first electrode and the second electrode at a second voltage less than the first voltage after the at least partially undifferentiated cells develop increased action potentials.

59. A method of cell therapy, comprising:

identifying an implantation site of a nervous system of a patient by generating remotely from a location in the nervous system an intended neural activity and determining the site of the nervous system where the generated neural activity is present;

preparing at least partially undifferentiated cells for implantation;

implanting the at least partially undifferentiated cells directly and without an implanted substrate into tissue at the implantation site of the nervous system of the patient;

positioning a first electrode and a second electrode at least proximate to the implantation site of the nervous system, wherein the first electrode and the second electrode are spaced apart from the at least partially undifferentiated cells;

ascertaining a threshold for generating action potentials for the at least partially undifferentiated cells at the implantation site of the nervous system; and

differentiating the at least partially undifferentiated cells into cells with increased action potentials by applying a subthreshold voltage between the first electrode and the second electrode and directing an electrical current through the tissue surrounding the at least partially undifferentiated cells and to the at least partially undifferentiated cells, wherein the subthreshold voltage is approximately 10%-50% less than the threshold for generating action potentials.

60. The method of claim 59 wherein preparing the at least partially undifferentiated cells includes applying an electrical stimulation to the at least partially undifferentiated cells while the at least partially undifferentiated cells are external to the patient.

61. The method of claim 59 wherein the at least partially undifferentiated cells are selected to include stem cells, precursor cells, and/or progenitor cells.

62. The method of claim 59 wherein implanting the at least partially undifferentiated cells directly and without a substrate into tissue at the implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells directly into tissue without a substrate at an implantation site of a spinal cord of a patient.

63. The method of claim 59 wherein implanting the at least partially undifferentiated cells directly into tissue without a substrate at the implantation site of a nervous system of a patient includes implanting the at least partially undifferentiated cells directly into tissue without a substrate at an implantation site of a brain of a patient.

64. The method of claim 59 wherein implanting the at least partially undifferentiated cells directly into tissue without a substrate at the implantation site of a nervous system includes implanting the at least partially undifferentiated cells directly into tissue without a substrate at an implantation site of a peripheral nerve of a patient.

65. A method of cell therapy for a location of a brain of a patient, comprising:

identifying a stimulation site by generating remotely from the location in the brain an intended neural activity and determining the site of the brain where the generated neural activity is present;

preparing at least partially undifferentiated cells for implantation;

implanting the at least partially undifferentiated cells at the stimulation site;

positioning at least one electrode at least proximate to the at least partially undifferentiated cells; and

differentiating the at least partially undifferentiated cells into cells with increased neural characteristics when compared to the at least partially undifferentiated cells by applying an electrical potential to the at least one electrode while the electrode is at least proximate to the at least partially undifferentiated cells.

66. The method of claim 65 wherein preparing at least partially undifferentiated cells includes applying an electrical stimulation to the at least partially undifferentiated cells while the at least partially undifferentiated cells are external to a patient.

67. The method of claim 65 wherein the at least partially undifferentiated cells are selected to include stem cells, precursor cells, and/or progenitor cells.

68. The method of claim 65 wherein implanting the at least partially undifferentiated cells at the stimulation site includes implanting the undifferentiated cells directly into tissue without a substrate, and wherein applying an electrical potential includes directing an electrical current from the at least one electrode through the tissue surrounding the at least partially undifferentiated cells and to the at least partially undifferentiated cells.

69. The method of claim 65 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

positioning a second electrode at least proximate to the at least partially undifferentiated cells; and

resiliently biasing the first electrode and the second electrode against a surface of the brain.

70. The method of claim 65 wherein the at least one electrode includes a first electrode, and wherein the method further comprises:

positioning a second electrode at least proximate to the at least partially undifferentiated cells; and

resiliently biasing at least one of the first electrode and second electrode against a pia mater of the brain.

71. The method of claim 65, further comprising implanting a stimulation apparatus having an integrated pulse system directly coupled to the at least one electrode so that the stimulation apparatus is adjacent to and/or within the skull of the patient, and wherein positioning at least one electrode includes placing the at least one electrode at least proximate to a pia mater.

72. The method of claim 65, further comprising implanting a stimulation apparatus having an integrated pulse system directly coupled to the first electrode so that the stimulation apparatus is adjacent to and/or within the skull of the patient, and wherein positioning at least one electrode includes inserting the at least one electrode into a cortex of the brain.

73. A method of cell therapy, comprising:

identifying an implantation site in a nervous system of a patient where neural activity has changed in response to a change in neural function;

applying an electrical stimulation to cells capable of differentiating into neurons while the cells capable of differentiating into neurons are external to the patient; and

implanting the cells capable of differentiating into neurons at the implantation site after applying the electrical stimulation.

74. The method of claim 73, further comprising applying an electrical stimulation at least proximate to the implantation site after implanting the cells capable of differentiating into neurons at the implantation site.

75. The method of claim 73 wherein identifying an implantation site in a nervous system of a patient where neural activity has changed in response to a change in neural function includes identifying an implantation site in a spinal cord of a patient where neural activity has changed in response to a change in neural function

76. The method of claim 73 wherein identifying an implantation site in a nervous system of a patient where neural activity has changed in response to a change in neural function includes identifying an implantation site in a brain of a patient where neural activity has changed in response to a change in neural function

77. The method of claim 73 wherein identifying an implantation site in a nervous system of a patient where neural activity has changed in response to a change in neural function includes identifying an implantation site in a peripheral nerve of a patient where neural activity has changed in response to a change in neural function

78. The method of claim 73 wherein cells capable of differentiating into neurons are selected from a group consisting of stem cells, precursor cells, or progenitor cells.

79. The method of claim 73 wherein applying an electrical stimulation comprises placing a voltage of ±

1 mV to ±

10 V across the cells.

80. The method of claim 73 wherein applying an electrical stimulation includes generating electrical pulses at a rate of from about 1 to about 1000 Hz.

81. The method of claim 73, further comprising ascertaining a threshold for generating action potentials for cells capable of differentiating into neurons, and wherein applying an electrical stimulation includes placing a subthreshold voltage across the cells less than the threshold for generating action potentials.

82. The method of claim 73, further comprising ascertaining a threshold for generating action potentials for cells capable of differentiating into neurons, and wherein applying an electrical stimulation includes placing a subthreshold voltage across the cells approximately 10% to approximately 50% less than the threshold for generating action potential.

83. The method of claim 73, further comprising ascertaining a threshold for generating electrophysiologic signals associated with the neural function, and wherein applying an electrical stimulation includes placing a subthreshold voltage across the cells less than the threshold for generating electrophysiologic signals.

84. The method of claim 73, further comprising ascertaining a threshold for generating electrophysiologic signals for cells capable of differentiating into neurons, and wherein applying an electrical stimulation comprises placing a subthreshold voltage across the cells from about 20% to about 50% less than the threshold for generating electrophysiologic signals.

85. The method of claim 73, further comprising ascertaining a threshold for eliciting the neural function, and wherein applying an electrical stimulation includes placing a subthreshold voltage across the cells less than the threshold for eliciting the neural function.

86. The method of claim 73, further comprising ascertaining a threshold for eliciting the neural function, and wherein applying an electrical stimulation includes placing a subthreshold voltage across the, cells from about 30% to about 60% less than the threshold for eliciting the neural function.

89. The method of claim 85 wherein implanting the at least partially undifferentiated cells at the stimulation site includes implanting the at least partially undifferentiated cells directly into tissue without a substrate at the stimulation site, and wherein applying an electrical potential includes directing an electrical current from the electrode assembly through the tissue surrounding the at least partially undifferentiated cells.

87. A method of cell replacement therapy using an apparatus having a support member, a pulse system carried by the support member, and an electrode assembly including first and second electrodes at an interior surface of the support member, comprising:

implanting the support member proximate into a skull of a patient to position the pulse system proximate to the skull and to position the first and second electrodes proximate to a stimulation site on and/or in a brain of the patient;

implanting at least partially undifferentiated cells at the stimulation site;

, and

differentiating the at least partially undifferentiated cells into cells with increased neural characteristics when compared to the at least partially undifferentiated cells by controlling the pulse system to apply an electrical potential between the first and second electrodes at least proximate to the stimulation site.

88. The method of claim 87 wherein the at least partially undifferentiated cells can include stem cells, precursor cells, and/or progenitor cells.

90. The method of claim 87, wherein implanting the support member proximate to a skull of a patient includes positioning the first and second electrodes at least proximate to the stimulation site and resiliently biasing at least one of the first and second electrodes against a surface of the brain.

91. The method of claim 87 wherein implanting the support member proximate to a skull of a patient includes positioning the first and second electrodes at least proximate to the stimulation site and resiliently biasing at least one of the first and second electrodes against a pia mater of the brain.

92. A system for cell therapy for a region of a brain of a patient, comprising:

at least partially undifferentiated cells capable of differentiating into cells with increased neural characteristics when compared to the at least partially undifferentiated cells, the at least partially undifferentiated cells being in a state suitable for implantation into the region of the brain;

an implantable support member configured to be implanted into the patient at least partially within a skull of the patient;

a pulse system carried by the support member;

a first electrode carried by the support member, the first electrode being coupled to the pulse system; and

a second electrode carried by the support member, the second electrode being spaced apart from the first electrode, and the second electrode being coupled to the pulse system.

93. The system of claim 92 wherein the at least partially undifferentiated cells capable of differentiating into neurons are selected to include stem cells, precursor cells and/or progenitor cells.

94. The system of claim 92 wherein the support member includes an attachment element and a housing carried by the attachment element, the attachment element being attachable to the skull, and the housing carrying the first and second electrodes.