WO2013165697A1

WO2013165697A1 - Indirect and non-invasive trigeminal neuromodulation for the treatment of disease

Info

Publication number: WO2013165697A1
Application number: PCT/US2013/037147
Authority: WO
Inventors: Denise Barbut; Allan Rozenberg; Axel Heinemann
Original assignee: Vigilant Medical Solutions, Inc.
Priority date: 2012-04-30
Filing date: 2013-04-18
Publication date: 2013-11-07

Abstract

An apparatus and method for neuromodulating a trigeminal nerve to treat a variety of medical conditions is provided. The apparatus comprises a plurality of stimulating electrodes configured to contact a portion of a skin of a patient over any of three divisions of a trigeminal nerve wherein the electrode contact is enhanced by means of a conductive gel. The method includes neuromodulating a trigeminal nerve including non-invasively stimulating a trigeminal nerve of a patient; and increasing cerebral blood flow.

Description

INDIRECT AND NON-INVASIVE TRIGEMINAL NEUROMODULATION FOR THE TREATMENT OF DISEASE

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0001] The present invention relates to a system and method for non-invasive trigeminal neuro-modulation. In particular, the invention involves non-invasively stimulating the trigeminal nerve and the accompanying autonomic fibers within the nasal or oral cavity.

2. Background of the Related Art

[0002] Neurostimulation is used to treat a variety of ailments. Deep brain stimulation (DBS) for the treatment of Parkinson's, for example, requires placement of the stimulating electrodes deep within brain tissue, an invasive neurosurgical procedure. Vagal nerve stimulation (VNS) for the treatment of epilepsy also requires a surgical procedure to position the stimulating wire around the vagus nerve in the neck. Similarly, stimulating sympathetic and parasympathetic ganglia requires invasive procedures for access. For example, stimulating the cervical chain requires a cut down in the neck and stimulating the sphenopalatine ganglion requires needle insertion through the mucosa of the palate.

[0003] At the very least, methods described to date require direct contact with the ganglion itself or the post-ganglionic nerve fibers. As an example, stimulating the post-ganglionic parasympathetic fibers at the ethmoid foramen requires direct contact with the nerve endings [0004] In the case of the trigeminal nerve, the trigeminal branches to be accessed for neuromodulation can involve the surface branches of any of the 3 divisions of the trigeminal nerve, ophthalmic, maxillary and mandibular nerves. Further, the trigeminal and autonomic ganglia cannot be accessed non-invasively but the postganglionic fibers can be stimulated non-invasively by direct contact at the nerve endings.

[0005] Based on these shortcomings, a method of trigeminal neuromodulation which is non-implantable, non-invasive, does not involve breach of the skin or mucous membrane, and does not require direct contact with the target nerve endings is needed.

[0006] Further, what is needed is modulation that can be achieved at a significant distance from the target nerve.

[0007] More specifically, what is needed is non-invasive method for treating diseases, for example to increase cerebral blood flow in patients with cerebral ischemia.

BRIEF SUMMARY OF THE INVENTION

[0008] The shortcomings of conventional therapies described herein are overcome by the apparatus and method for stimulating the trigeminal nerve and the accompanying autonomic fibers in a patient in accordance with the invention.

[0009] The method in accordance with the invention stimulates the trigeminal nerve and the accompanying autonomic fibers within the nasal or oral cavity, without having precise knowledge of the position of the catheter. [0010] In another aspect of the invention, a method of neuromodulation of postganglionic nerve fibers that does not require direct contact with the nerve or the ganglion is provided.

[0011] In another aspect of the invention, a method of non-invasive stimulation of the trigeminal nerve for the purpose of increasing cerebral blood flow in cerebral ischemia is provided.

[0012] In another aspect of the invention, the modulation may be performed non- invasively without requiring implantation or a surgical procedure.

[0013] In another aspect of the invention, a method of non-invasively stimulating the trigeminal nerve for the purpose of increasing cerebral blood flow in Alzheimer's disease is provided.

[0014] In another aspect of the invention, a method of non-invasively stimulating the trigeminal nerve for the purpose of decreasing neurogenic inflammation is provided.

[0015] In another aspect of the invention, the trigeminal nerve and the accompanying autonomic fibers within the nasal or oral cavity are modulated using ultrasound, cryotherapy, radiofrequency, heat therapy, electrically, electromagnetic wave mediated treatment and combinations of the foregoing.

[0016] In another aspect of the invention, the stimulation may be done in the nose, the mouth, any of the cutaneous or mucosal divisions of the three branches of the trigeminal nerve, and combinations of the foregoing. [0017] In another aspect of the invention, the non-invasive stimulation of the trigeminal nerve may be done for the purpose of decreasing neurogenic inflammation in the lung, such as acute respiratory distress syndrome and for increasing or decreasing blood pressure.

[0018] In another aspect of the invention, an apparatus and method for non- invasively stimulating the trigeminal nerve to treat migraine or other forms of headache is provided.

[0019] In further aspects, the invention may be set forth in any of the following clauses:

1. A method of neuromodulating post-ganglionic nerve fibers in a patient comprising: non-directly contacting of the nerve or the ganglion.

2. The method of clause 1 wherein the nerve comprises the trigeminal nerve and the associated autonomic fibers alongside said trigeminal nerve.

3. The method of clause 1 wherein the relevant nerve comprises any of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

4. The method of clause 1 wherein the nerve comprises any of the cutaneous branches of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

5. The method of clause 1 wherein the nerve comprises any of the mucosal branches of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

6. The method of clause 1 wherein the nerve and associated autonomic fibers alongside the trigeminal nerve terminate within the nasal cavity.

7. The method of clause 1 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

8. The method of clause 1 wherein neuromodulating the nerve does not require a surgical procedure.

9. The method of clause 1 wherein neuromodulating is does not require implanting a modulating electrode.

10. The method of clause 1 further comprising providing an electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

1 1. The method of clause 10 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

12. The method of clause 1 wherein the neuromodulating is done electrically.

13. The method of clause 1 wherein the neuromodulating is done using radiofrequency energy.

14. The method of clause 1 wherein the neuromodulating is done using ultrasound.

15. The method of clause 1 wherein the neuromodulating is done using cryotherapy.

16. The method of clause 1 wherein the neuromodulating is done using heat therapy.

17. The method of clause 1 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

18. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and increasing cerebral blood flow. 19. The method of clause 18 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

20. The method of clause 18 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

21. The method of clause 18 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

22. The method of clause 18 wherein the stimulating is done in the nose.

23. The method of clause 18 wherein the stimulating is done in the mouth.

24. The method of clause 18 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

25. The method of clause 18 wherein said neuromodulating does not require a surgical procedure.

26. The method of clause 18 wherein said neuromodulating does not require implantation of a modulating electrode.

27. The method of clause 18 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

28. The method of clause 27 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane

29. The method of clause 18 wherein said neuromodulating is done electrically

30. The method of clause 18 wherein the neuromodulating is done using radiofrequency energy.

31. The method of clause 18 wherein the neuromodulating is done using ultrasound. 32. The method of clause 18 wherein the neuromodulating is done using cryotherapy.

33. The method of clause 18 wherein the neuromodulating is done using heat therapy.

34. The method of clause 18 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

35. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve in a patient; and increasing cerebral blood flow in cerebral ischemia.

36. The method of clause 35 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

37. The method of clause 35 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

38. The method of clause 35 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

39. The method of clause 35 wherein the stimulating is done in the nose.

40. The method of clause 35 wherein the stimulating is done in the mouth.

41. The method of clause 35 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

42. The method of clause 35 wherein said neuromodulating does not require a surgical procedure.

43. The method of clause 35 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

44. The method of clause 35 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

45. The method of clause 35 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane

46. The method of clause 35 wherein the neuromodulating is done electrically.

47. The method of clause 35 wherein the neuromodulating is done using radiofrequency energy.

48. The method of clause 35 wherein the neuromodulating is done using ultrasound.

49. The method of clause 35 wherein the neuromodulating is done using cryotherapy.

50. The method of clause 35 wherein the neuromodulating is done using heat therapy.

51. The method of clause 35 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

52. A method of neuromodulating a nerve comprising: non-invasively stimulating the trigeminal nerve; and increasing cerebral blood flow in patients having Alzheimer's disease.

53. The method of clause 52 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

54. The method of clause 52 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

55. The method of clause 52 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

56. The method of clause 52 wherein the stimulating is done in the nose.

57. The method of clause 52 wherein the stimulating is done in the mouth. 58. The method of clause 52 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

59. The method of clause 52 wherein neuromodulating does not require a surgical procedure.

60. The method of clause 52 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

61. The method of clause 52 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

62. The method of clause 61 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

63. The method of clause 52 wherein the neuromodulating is done electrically.

64. The method of clause 52 wherein the neuromodulating is done using radiofrequency energy.

65. The method of clause 52 wherein the neuromodulating is done using ultrasound.

66. The method of clause 52 wherein the neuromodulating is done using cryotherapy.

67. The method of clause 52 wherein the neuromodulating is done using heat therapy.

68. The method of clause 52 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

69. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and decreasing neurogenic inflammation.

70. The method of clause 69 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

71. The method of clause 69 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

72. The method of clause 69 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

73. The method of clause 69 wherein the stimulating is done in the nose.

74. The method of clause 69 wherein the stimulating is done in the mouth.

75. The method of clause 69 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

76. The method of clause 69 wherein the neuromodulating does not require a surgical procedure.

77. The method of clause 69 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

78. The method of clause 69 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

79. The method of clause 69 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

80. The method of clause 69 wherein the neuromodulating is done electrically.

81. The method of clause 69 wherein the neuromodulating is done using radiofrequency energy. 82. The method of clause 69 wherein the neuromodulating is done using ultrasound.

83. The method of clause 69 wherein the neuromodulating is done using cryotherapy.

84. The method of clause 69 wherein the neuromodulating is done using heat therapy.

85. The method of clause 69 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

86. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and decreasing neurogenic inflammation in a brain of the patient suffering from stroke, head injury or cardiac arrest.

87. The method of clause 86 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

88. The method of clause 86 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

89. The method of clause 86 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

90. The method of clause 86 wherein the stimulating is done in the nose.

91. The method of clause 86 wherein the stimulating is done in the mouth.

92. The method of clause 86 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

93. The method of clause 86 wherein the neuromodulating does not require a surgical procedure.

The method of clause 86 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

95. The method of clause 86 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

96. The method of clause 86 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

97. The method of clause 86 wherein the neuromodulating is done electrically.

98. The method of clause 86 wherein the neuromodulating is done using radiofrequency energy.

99. The method of clause 86 wherein the neuromodulating is done using ultrasound.

100. The method of clause 86 wherein the neuromodulating is done using cryotherapy.

101. The method of clause 86 wherein the neuromodulating is done using heat therapy.

102. The method of clause 86 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

103. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and decreasing neurogenic inflammation in the lung wherein said neurogenic inflammation is caused by acute respiratory stress syndrome.

104. The method of clause 103 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

105. The method of clause 103 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

106. The method of clause 103 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

107. The method of clause 103 wherein the stimulating is done in the nose.

108. The method of clause 103 wherein the stimulating is done in the mouth.

109. The method of clause 103 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

1 10. The method of clause 103 wherein said neuromodulating does not require a surgical procedure.

1 11. The method of clause 103 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

112. The method of clause 103 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

1 13. The method of clause 112 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

114. The method of clause 103 wherein the neuromodulating is done electrically.

115. The method of clause 103 wherein the neuromodulating is done using radiofrequency energy.

116. The method of clause 103 wherein the neuromodulating is done using ultrasound.

117. The method of clause 103 wherein the neuromodulating is done using cryotherapy.

118. The method of clause 103 wherein the neuromodulating is done using heat therapy. 1 19. The method of clause 103 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

120. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve; and decreasing inflammation in a medical condition of a patient.

121. The method of clause 120 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

122. The method of clause 120 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

123. The method of clause 120 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

124. The method of clause 120 wherein the stimulating is done in the nose.

125. The method of clause 120 wherein the stimulating is done in the mouth.

126. The method of clause 120 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

127. The method of clause 120 wherein neuromodulating does not require a surgical procedure.

128. The method of clause 120 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

129. The method of clause 120 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

130. The method of clause 129 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane. 131. The method of clause 120 wherein the neuromodulating is done electrically

132. The method of clause 120 wherein the neuromodulating is done using radiofrequency energy.

133. The method of clause 120 wherein the neuromodulating is done using ultrasound.

134. The method of clause 120 wherein the neuromodulating is done using cryotherapy.

135. The method of clause 120 wherein the neuromodulating is done using heat therapy.

136. The method of clause 120 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

137. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and increasing or decreasing blood pressure of the patient.

138. The method of clause 137 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

139. The method of clause 137 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

140. The method of clause 137 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

141. The method of clause 137 wherein the stimulating is done in the nose.

142. The method of clause 137 wherein the stimulating is done in the mouth.

143. The method of clause 137 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing. 144. The method of clause 137 wherein the neuromodulating does not require a surgical procedure.

145. The method of clause 137 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

146. The method of clause 137 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

147. The method of clause 146 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

148. The method of clause 137 wherein the neuromodulating is done electrically.

149. The method of clause 137 wherein the neuromodulating is done using radiofrequency energy.

150. The method of clause 137 wherein the neuromodulating is done using ultrasound.

151. The method of clause 137 wherein the neuromodulating is done using cryotherapy.

152. The method of clause 137 wherein the neuromodulating is done using heat therapy.

153. The method of clause 137 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

154. A method of modulating a trigeminal nerve of a patient comprising: non- invasively stimulating the trigeminal nerve; and increasing cerebral blood flow wherein the absorption of medication following oro-nasal or facial delivery is enhanced.

The method in clause 154 wherein the medication acts on the central nervous system.

156. The method in clause 154 wherein the medication acts in the systemic circulation.

157. The method in clause 154 wherein the medication acts topically.

158. The method of clause 154 wherein an effect of the stimulating is increased by simultaneous placement of drugs in a gel in a nasal cavity or mouth of the patient.

159. The method of clause 154 wherein the neuromodulating does not require a surgical procedure.

160. The method of clause 154 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

161. The method of clause 154 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

162. The method of clause 161 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

163. The method of clause 154 wherein the neuromodulating is done electrically.

164. The method of clause 154 wherein the neuromodulating is done using radiofrequency energy.

165. The method of clause 154 wherein the neuromodulating is done using ultrasound.

166. The method of clause 154 wherein the neuromodulating is done using cryotherapy.

167. The method of clause 154 wherein the neuromodulating is done using heat therapy. 168. The method of clause 154 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

169. A device comprising a stimulating electrode configured to contact the mucous membranes of the nose or mouth to neuromodulate the trigeminal nerve; and a conductive gel in contact with the electrode for enhancing electrical contact of said electrode.

170. The device of clause 169 wherein the conductive gel is low impedance.

171. The device of clause 169 wherein conductive gel is a hydrogel which is formed around the electrode wire.

172. The device of clause 169 wherein the conductive gel contains a medication

173. The device of clause 169 wherein conductive gel emanates from a lumen attached to the modulating wire

174. The device of clause 169 wherein the conductive gel is placed separately to wire

175. The device of clause 169 wherein the electrode is positioned alongside a nasal prong for delivering gases or mists

176. The device of clause 169 wherein the electrode is attached to nasal prongs for delivering gases or mists.

177. The device of clause 169 wherein a camera is attached to the electrode to assist with placement.

178. A device comprising: a plurality of stimulating electrodes configured to contact a portion of a skin of a patient over any of three divisions of a trigeminal nerve wherein the electrode contact is enhanced by means of a conductive gel.

179. The device of clause 178 wherein the conductive gel is low impedance.

180. The device of clause 178 wherein conductive gel is a hydrogel which is formed around the electrode wire. 181. The device of clause 178 wherein the conductive gel contains a medication.

182. The device of clause 178 wherein conductive gel emanates from a lumen attached to the modulating wire.

183. A method of neuromodulating a nerve comprising non-invasively stimulating a trigeminal nerve; and dissipating the effects of a migraine headache.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] For a better understanding of the invention, and to show how the same may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, in which:

[0021] FIG. 1 is a graph illustrating the effect of non-specific intranasal electrical stimulation on cerebral blood flow.

[0022] FIG. 2 is a perspective view of an intranasal delivery catheter for noninvasive neuromodulation of the trigeminal nerve and associated autonomic fibers in accordance with the invention.

[0023] FIG. 3 is a perspective view of another aspect of an intranasal device for non-invasive neuromodulation of the trigeminal nerve and associated autonomic fibers in accordance with the invention.

[0024] FIG. 4 is an illustration of the device of FIG. 4 inserted in intranasal cavity including a stimulator with electrodes in accordance with the invention. DETAILED DESCRIPTION OF THE INVENTION

[0025] We have discovered a new method of neuromodulation that does not direct contact with nerve endings, and in which stimulation is performed at some distance from the nerve endings. We have further discovered that the stimulation can be performed without specific knowledge of the exact position of the stimulating catheter.

[0026] The method in accordance with the invention does not involve an invasive procedure or surgical procedure. There is no breach of the skin or of the mucous membrane, no direct contact with a ganglion or a post-ganglionic nerve and no requirement for implantation of the stimulating electrode.

[0027] A stimulation wire is positioned within the nasal cavity, preferably several centimeters beyond the entrance to the nares and stimulation performed. The wires can be held in place by a variety of devices for the duration of the stimulation and then removed. The method has several advantages. Firstly, it would allow access to anatomically difficult locations and enable the procedure to be performed even by those not entirely familiar with the anatomy; secondly it would constitute a totally non-invasive method of neuromodulation, without any breach of skin or mucous membrane. Thirdly, it would enable treatment of a variety of conditions outside of catheterization laboratories and in places such as emergency rooms or ambulances. The inventors of the present invention have tested this method of neuromodulation intranasally and determined that stimulation "at a distance," as hereinafter disclosed, increases cerebral blood flow. Stimulating catheters were placed about 1cm into the nares in the rat and stimulation performed at varying stimulation parameters. Cerebral blood flow was measured in the brain using cortical Laser Doppler technique.

[0028] As can be seen in FIG. 1 stimulation at a distance from any of the known trigeminal branches increases cerebral blood flow in a dose-dependent fashion. The increase was observed at 5-7V, increased at 10V and increased further at 20V. Response occurred within seconds of initiating the stimulation and returned to baseline values immediately after discontinuing the stimulation.

[0029] While we have shown that non-invasive trigeminal stimulation at a distance from the post-ganglionic nerve fibers increases cerebral blood flow in the rat, the method in accordance with the invention may also be used to treat other conditions non-invasively. Such conditions may include hypertension, neurovascular conditions such as migraine or neurogenic inflammation as might occur after head injury, cardiac arrest or stroke, or even seizure disorders.

[0030] Furthermore, while the method in accordance with the invention is disclosed herein as being performed intranasally, it may also be performed intra- orally or over the anterior cranium and face or in any of the cutaneous dermatomes of the trigeminal nerve including the back of the pinna, the forehead or temple, the gums or palate and the skin over the face.

[0031] Referring now to FIG. 2, during intranasal stimulation, the stimulating electrode may also be positioned in proximity of the target neural structure by being fastened alongside nasal prongs for gas delivery. Patients requiring oxygen or other gases, such as volatile anesthetic agents, may simultaneously be positioned for neuromodulation if the need arises. Similarly, the electrode may be attached to a securing device such as a spring loaded nasal septal clip as best seen in FIGS. 3 and 4 to keep the electrode in position during the modulation.

[0032] Stimulating branches of cranial nerves containing autonomic nerve fibers can generate a neurovascular response such as subcutaneous vascular dilatation. This may potentially, increase the absorption of drugs transcutaneously or transmucosally. Where required, a conductive (and/or medicated) gel may be placed in the location being stimulated separately from the stimulating wire or may be delivered through a second lumen on the catheter containing the stimulating wire. As an example, the branches of the trigeminal nerve may be accessed in this manner and stimulated without penetration through the nasal or oral mucosa or facial skin and without directly contacting the target nerve. The stimulator electrode would be positioned in close proximity of the nerve branch in the nose or mouth or on the surface of the skin following placement of a conductive gel containing medication. Following the discontinuation of the stimulation, the stimulator electrode would be easily removed since it was never in direct contact with the tissue in question.

[0033] The pulse duration may be between 0.1-20 millisecond, preferably 0.2-2 millisecond, and more preferably 0.5 millisecond. The duration of the stimulation may be 3 seconds to 24 hours. The degree of stimulation may be coupled to feedback from cerebral or systemic physiologic parameters. For example, when stimulating the forehead or the retro-auricular space, feedback from cerebral oximetry or EEG may be used to modify the stimulation parameters. Furthermore, the stimulating wire may be physically coupled to the EEG or oximetry patch. [0034] Those of skill in the art will appreciate that the neuromodulation technique in accordance with the invention is limited to electrical stimulation but may also include ultrasound, radiofrequency, cryotherapy, heat treatment, infrared, ultraviolet or other electromagnetic spectrum frequencies as well as other methods of activating nerves.

[0035] Those of skill in the art will also appreciate that while the condition of prime interest is cerebral ischemia, increases in cerebral blood flow using the inventive method of stimulation may also be of value in chronic conditions involving diminished blood flow, such as Alzheimer's or other dementias or in neurogenic inflammation, such as brain swelling, acute respiratory stress syndrome or systemic inflammatory conditions.

[0036] Various modifications and additions may be made to the exemplary embodiments disclosed herein without departing from the scope of the invention. For example, while the embodiments disclosed herein refer to particular features, the scope of this invention also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present invention is intended to embrace all such alternative, modifications and variations as fall within the scope of the claims and equivalents thereof.

Claims

What is claimed is:

1. A method of neuromodulatmg post-ganglionic nerve fibers in a patient comprising: non-directly contacting of the nerve or the ganglion.

2. The method of claim 1 wherein the nerve comprises the trigeminal nerve and the associated autonomic fibers alongside said trigeminal nerve.

3. The method of claim 1 wherein the relevant nerve comprises any of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

4. The method of claim 1 wherein the nerve comprises any of the cutaneous branches of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

5. The method of claim 1 wherein the nerve comprises any of the mucosal branches of the three divisions of the trigeminal nerve and the associated autonomic fibers alongside the trigeminal nerve.

6. The method of claim 1 wherein the nerve and associated autonomic fibers alongside the trigeminal nerve terminate within the nasal cavity.

7. The method of claim 1 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

8. The method of claim 1 wherein neuromodulating the nerve does not require a surgical procedure.

9. The method of claim 1 wherein neuromodulating is does not require implanting a modulating electrode.

10. The method of claim 1 further comprising providing an electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

11. The method of claim 10 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

12. The method of claim 1 wherein the neuromodulating is done electrically.

13. The method of claim 1 wherein the neuromodulating is done using radiofrequency energy.

14. The method of claim 1 wherein the neuromodulating is done using ultrasound.

15. The method of claim 1 wherein the neuromodulating is done using cryotherapy.

16. The method of claim 1 wherein the neuromodulating is done using heat therapy.

17. The method of claim 1 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

18. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and increasing cerebral blood flow.

19. The method of claim 18 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

20. The method of claim 18 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

21. The method of claim 18 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

22. The method of claim 18 wherein the stimulating is done in the nose.

23. The method of claim 18 wherein the stimulating is done in the mouth.

24. The method of claim 18 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

25. The method of claim 18 wherein said neuromodulating does not require a surgical procedure.

26. The method of claim 18 wherein said neuromodulating does not require implantation of a modulating electrode.

27. The method of claim 18 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

28. The method of claim 27 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane

29. The method of claim 18 wherein said neuromodulating is done electrically

30. The method of claim 18 wherein the neuromodulating is done using radiofrequency energy.

31. The method of claim 18 wherein the neuromodulating is done using ultrasound.

32. The method of claim 18 wherein the neuromodulating is done using cryotherapy.

33. The method of claim 18 wherein the neuromodulating is done using heat therapy.

34. The method of claim 18 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

36. The method of claim 35 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

37. The method of claim 35 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

38. The method of claim 35 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

39. The method of claim 35 wherein the stimulating is done in the nose.

40. The method of claim 35 wherein the stimulating is done in the mouth.

41. The method of claim 35 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

42. The method of claim 35 wherein said neuromodulating does not require a surgical procedure.

43. The method of claim 35 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

44. The method of claim 35 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

45. The method of claim 35 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane

46. The method of claim 35 wherein the neuromodulating is done electrically.

47. The method of claim 35 wherein the neuromodulating is done using radiofrequency energy.

48. The method of claim 35 wherein the neuromodulating is done using ultrasound.

49. The method of claim 35 wherein the neuromodulating is done using cryotherapy.

50. The method of claim 35 wherein the neuromodulating is done using heat therapy.

51. The method of claim 35 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

53. The method of claim 52 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

54. The method of claim 52 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

55. The method of claim 52 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

56. The method of claim 52 wherein the stimulating is done in the nose.

57. The method of claim 52 wherein the stimulating is done in the mouth.

58. The method of claim 52 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

59. The method of claim 52 wherein neuromodulating does not require a surgical procedure.

60. The method of claim 52 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

61. The method of claim 52 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

62. The method of claim 61 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

63. The method of claim 52 wherein the neuromodulating is done electrically.

64. The method of claim 52 wherein the neuromodulating is done using radiofrequency energy.

65. The method of claim 52 wherein the neuromodulating is done using ultrasound.

66. The method of claim 52 wherein the neuromodulating is done using cryotherapy.

67. The method of claim 52 wherein the neuromodulating is done using heat therapy.

68. The method of claim 52 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

70. The method of claim 69 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

71. The method of claim 69 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

72. The method of claim 69 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

73. The method of claim 69 wherein the stimulating is done in the nose.

74. The method of claim 69 wherein the stimulating is done in the mouth.

75. The method of claim 69 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

76. The method of claim 69 wherein the neuromodulating does not require a surgical procedure.

77. The method of claim 69 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

78. The method of claim 69 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

79. The method of claim 69 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

80. The method of claim 69 wherein the neuromodulating is done electrically.

81. The method of claim 69 wherein the neuromodulating is done using radiofrequency energy.

82. The method of claim 69 wherein the neuromodulating is done using ultrasound.

83. The method of claim 69 wherein the neuromodulating is done using cryotherapy.

84. The method of claim 69 wherein the neuromodulating is done using heat therapy.

85. The method of claim 69 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

86. A method of neuromodulating a nerve comprising: non-invasively stimulating a trigeminal nerve of a patient; and decreasing neurogenic inflammation in a brain of the patientsuffering from stroke, head injury or cardiac arrest.

87. The method of claim 86 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

88. The method of claim 86 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

89. The method of claim 86 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

90. The method of claim 86 wherein the stimulating is done in the nose.

91. The method of claim 86 wherein the stimulating is done in the mouth.

92. The method of claim 86 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

93. The method of claim 86 wherein the neuromodulating does not require a surgical procedure.

94. The method of claim 86 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

95. The method of claim 86 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

96. The method of claim 86 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

97. The method of claim 86 wherein the neuromodulating is done electrically.

98. The method of claim 86 wherein the neuromodulating is done using radiofrequency energy.

99. The method of claim 86 wherein the neuromodulating is done using ultrasound.

100. The method of claim 86 wherein the neuromodulating is done using cryotherapy.

101. The method of claim 86 wherein the neuromodulating is done using heat therapy.

102. The method of claim 86 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

104. The method of claim 103 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

105. The method of claim 103 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

106. The method of claim 103 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

107. The method of claim 103 wherein the stimulating is done in the nose.

108. The method of claim 103 wherein the stimulating is done in the mouth.

109. The method of claim 103 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

1 10. The method of claim 103 wherein said neuromodulating does not require a surgical procedure.

111. The method of claim 103 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

112. The method of claim 103 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

113. The method of claim 112 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

114. The method of claim 103 wherein the neuromodulating is done electrically.

115. The method of claim 103 wherein the neuromodulating is done using radiofrequency energy.

1 16. The method of claim 103 wherein the neuromodulating is done using ultrasound.

117. The method of claim 103 wherein the neuromodulating is done using cryotherapy.

118. The method of claim 103 wherein the neuromodulating is done using heat therapy.

119. The method of claim 103 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

121. The method of claim 120 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

122. The method of claim 120 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

123. The method' of claim 120 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

124. The method of claim 120 wherein the stimulating is done in the nose.

125. The method of claim 120 wherein the stimulating is done in the mouth.

126. The method of claim 120 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

127. The method of claim 120 wherein neuromodulating does not require a surgical procedure.

128. The method of claim 120 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

129. The method of claim 120 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

130. The method of claim 129 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

131. The method of claim 120 wherein the neuromodulating is done electrically

132. The method of claim 120 wherein the neuromodulating is done using radiofrequency energy.

133. The method of claim 120 wherein the neuromodulating is done using ultrasound.

134. The method of claim 120 wherein the neuromodulating is done using cryotherapy.

135. The method of claim 120 wherein the neuromodulating is done using heat therapy.

136. The method of claim 120 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

138. The method of claim 137 wherein the stimulating is done in any of the three divisions of the trigeminal nerve.

139. The method of claim 137 wherein the stimulating is done in any of the cutaneous divisions of the three branches of the trigeminal nerve.

140. The method of claim 137 wherein the stimulating is done in any of the mucosal divisions of the three branches of the trigeminal nerve.

141. The method of claim 137 wherein the stimulating is done in the nose.

142. The method of claim 137 wherein the stimulating is done in the mouth.

143. The method of claim 137 further comprising providing stimulating parameters wherein the stimulating parameters are adjusted based on measured physiologic parameters such as cerebral oximetry, EEG recordings and combinations of the foregoing.

144. The method of claim 137 wherein the neuromodulating does not require a surgical procedure.

145. The method of claim 137 wherein the neuromodulating is performed without requiring implantation of a modulating electrode.

146. The method of claim 137 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

147. The method of claim 146 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

148. The method of claim 137 wherein the neuromodulating is done electrically.

149. The method of claim 137 wherein the neuromodulating is done using radiofrequency energy.

150. The method of claim 137 wherein the neuromodulating is done using ultrasound.

151. The method of claim 137 wherein the neuromodulating is done using cryotherapy.

152. The method of claim 137 wherein the neuromodulating is done using heat therapy.

153. The method of claim 137 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

155. The method in claim 154 wherein the medication acts on the central nervous system.

156. The method in claim 154 wherein the medication acts in the systemic circulation.

157. The method in claim 154 wherein the medication acts topically.

158. The method of claim 154 wherein an effect of the stimulating is increased by simultaneous placement of drugs in a gel in a nasal cavity or mouth of the patient.

159. The method of claim 154 wherein the neuromodulating does not require a surgical procedure.

160. The method of claim 154 wherein said neuromodulating is performed without requiring implantation of a modulating electrode.

161. The method of claim 154 further comprising providing a neuromodulation electrode for neuromodulating said nerve; discontinuing said neuromodulating; and removing said electrode from the patient.

162. The method of claim 161 further comprising securing said neuromodulation electrode by means of a removable securing device which does not breach the skin or the mucous membrane.

163. The method of claim 154 wherein the neuromodulating is done electrically.

164. The method of claim 154 wherein the neuromodulating is done using radiofrequency energy.

165. The method of claim 154 wherein the neuromodulating is done using ultrasound.

166. The method of claim 154 wherein the neuromodulating is done using cryotherapy.

167. The method of claim 154 wherein the neuromodulating is done using heat therapy.

168. The method of claim 154 wherein the neuromodulating is done using electromagnetic wave mediated treatment.

170. The device of claim 169 wherein the conductive gel is low impedance.

171. The device of claim 169 wherein conductive gel is a hydrogel which is formed around the electrode wire.

172. The device of claim 169 wherein the conductive gel contains a medication

173. The device of claim 169 wherein conductive gel emanates from a lumen attached to the modulating wire

174. The device of claim 169 wherein the conductive gel is placed separately to wire

175. The device of claim 169 wherein the electrode is positioned alongside a nasal prong for delivering gases or mists

176. The device of claim 169 wherein the electrode is attached to nasal prongs for delivering gases or mists.

177. The device of claim 169 wherein a camera is attached to the electrode to assist with placement.

179. The device of claim 178 wherein the conductive gel is low impedance.

180. The device of claim 178 wherein conductive gel is a hydrogel which is formed around the electrode wire.

181. The device of claim 178 wherein the conductive gel contains a medication.

182. The device of claim 178 wherein conductive gel emanates from a lumen attached to the modulating wire.

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