IP Library › Granted Patent US 12,296,106
Granted Patent B2
US 12,296,106 · App. 16/901,592 · Granted May 13, 2025

Methods and devices for providing a stimulus to a subject to induce gamma oscillations

Inventors: Li-Huei Tsai (Cambridge, MA); Emery Brown (Brookline, MA); Hannah Iaccarino (Somerville, MA); Anthony James Martorell (Cambridge, MA); Chinnakkaruppan Adaikkan (Somerville, MA)
Assignee: Massachusetts Institute of Technology
A61M21/00A61H23/00A61N5/062A61N5/0622A61M2021/0022A61M2021/0027A61M2021/0044A61N5/0618A61N2005/063A61N2005/0651A61N2005/0662
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Quick Facts
Patent No.
US 12,296,106
App. No.
16/901,592
Granted
May 13, 2025
Kind
B2
Abstract

A method includes administering a non-invasive stimulus to a subject having a frequency of about 35 Hz to about 45 Hz to induce synchronized gamma oscillations in at least one brain region of the subject.

Claims (114)

1. A method of inducing a change in microglial cells in at least one brain region of a subject to improve cognitive function or to prevent, reduce, or treat cognitive decline, the method comprising:

(a) administering to the subject a non-invasive stimulus having a frequency of about 35 Hz to about 45 Hz; and

(b) inducing the change in the microglial cells in at least one brain region of the subject in response to (a) to improve the cognitive function or to prevent, reduce, or treat the cognitive decline in the subject.

2. The method of claim 1 , wherein the non-invasive stimulus has a frequency of about 40 Hz.

3. The method of claim 1 , wherein the subject is a human.

4. The method of claim 1 , wherein the stimulus is a light stimulus.

5. The method of claim 1 , wherein the stimulus is a sound stimulus.

6. The method of claim 1 , wherein the stimulus is a haptic stimulus.

7. The method of claim 1 , wherein (b) comprises:

inducing the change in microglial cells in the at least one brain region of the subject to improve recognition in the subject.

8. The method of claim 1 , wherein (b) comprises:

inducing the change in microglial cells in the at least one brain region of the subject to improve discrimination in the subject.

9. The method of claim 1 , wherein (b) comprises:

inducing the change in the microglial cells in the at least one brain region of the subject to improve spatial memory in the subject.

10. The method of claim 1 , wherein (b) comprises:

inducing the change in the microglial cells in the at least one brain region of the subject to improve working memory in the subject.

11. The method of claim 1 , wherein (b) comprises:

inducing the change in the microglial cells in the at least one brain region of the subject to improve attention in the subject.

12. The method of claim 1 , wherein (b) comprises increasing a number of the microglial cells in the at least one brain region.

13. The method of claim 1 , further comprising:

(c) promoting clearance of phosphorylated tau protein from the at least one brain region based at least in part on (a).

14. The method of claim 1 , further comprising:

(c) promoting clearance of amyloid beta peptides from the at least one brain region based at least in part on (a).

15. The method of claim 1 , wherein (b) comprises changing a morphology of the microglial cells toward a phagocytic state in the at least one brain region.

16. The method of claim 1 , further comprising:

(c) upregulating genes associated with microglial activity in the at least one brain region in response to (a).

17. The method of claim 16 , wherein (c) comprises upregulation of at least one of Nr4a1, Arc, Npas4, Cd68, B2m, Bsr2, Icam1, Lyz2, Irf7, Spp1, Csf1r, or Csf2ra genes.

18. The method of claim 1 , further comprising:

upregulating genes associated with astrocyte production in the at least one brain region in response to (a).

19. The method of claim 1 , further comprising:

upregulating genes associated with neuron production in the at least one brain region in response to (a).

20. The method of claim 1 , further comprising:

upregulating genes associated with myelinating oligodendrocytes in response to (a).

21. The method of claim 1 , further comprising:

increasing blood vessel diameter in the at least one brain region of the subject in response to (a).

22. A method of inducing a change in microglial cells in at least one brain region of a subject to improve cognitive function or to prevent, reduce, or treat cognitive decline in the subject, the method comprising:

(a) controlling at least one transducer to generate at least one stimulus, the at least one stimulus having a frequency of about 35 Hz to about 45 Hz and including at least one of a light stimulus, a sound stimulus or a haptic stimulus;

(b) administering the at least one stimulus non-invasively to the subject to induce synchronized gamma oscillations in the at least one brain region of the subject; and

(c) inducing the change in the microglial cells in the at least one brain region in response to (b) to cause an improvement in the cognitive function or prevent, reduce or treat the cognitive decline in the subject.

23. The method of claim 22 , wherein the induced synchronized gamma oscillations have a frequency of about 40 Hz.

24. The method of claim 22 , wherein the improvement in the cognitive function is an improvement in recognition.

25. The method of claim 22 , wherein the improvement in the cognitive function is an improvement in discrimination.

26. The method of claim 22 , wherein the improvement in the cognitive function is an improvement in spatial memory.

27. The method of claim 22 , wherein the improvement in the cognitive function is an improvement in working memory.

28. The method of claim 22 , wherein the improvement in the cognitive function is an improvement in attention.

29. The method of claim 22 , wherein (c) comprises increasing a number of microglial cells in the at least one brain region.

30. The method of claim 22 , further comprising:

(d) promoting clearance of phosphorylated tau protein from the at least one brain region based at least in part on (b).

31. The method of claim 22 , further comprising:

(d) promoting clearance of amyloid beta peptides from the at least one brain region based at least in part on (b).

32. The method of claim 22 , wherein (c) comprises changing a morphology of microglial cells toward a phagocytic state in the at least one brain region.

33. The method of claim 22 , further comprising:

(d) upregulating genes associated with microglial activity in the at least one brain region in response to (b).

34. The method of claim 33 , wherein (d) comprises upregulation of at least one of Nr4a1, Arc, Npas4, Cd68, B2m, Bsr2, Icam1, Lyz2, Irf7, Spp1, Csf1r, or Csf2ra genes.

35. The method of claim 22 , further comprising:

upregulating genes associated with astrocyte production in the at least one brain region in response to (b).

36. The method of claim 22 , further comprising:

upregulating genes associated with neuron production in the at least one brain region in response to (b).

37. The method of claim 22 , further comprising:

upregulating genes associated with myelinating oligodendrocytes in response to (b).

38. A system to emit at least one non-invasive stimulus to a subject, induce synchronized gamma oscillations in at least one brain region of the subject, and improve cognitive function or prevent, reduce or treat cognitive decline in the subject via inducing at least one change in microglial cells in the at least one brain region of the subject, the system comprising:

at least one stimulus-emitting device to emit the at least one non-invasive stimulus to the subject;

at least one processor coupled to the at least one stimulus-emitting device to control the at least one stimulus-emitting device;

memory, coupled to the at least one processor, and storing:

executable instructions for the at least one processor;

stimulus parameters including a repetition frequency in a range from 35 Hz to 45 Hz for the at least one non-invasive stimulus; and

a stimulus-generation policy,

wherein:

the at least one processor is configured, based on the stimulus parameters and the stimulus-generation policy stored in the memory, to:

control the at least one stimulus-emitting device to emit the at least one non-invasive stimulus at the repetition frequency to induce the synchronized gamma oscillations and induce the at least one change in the microglial cells in the at least one brain region of the subject.

39. The system of claim 38 , wherein the synchronized gamma oscillations have a frequency of about 40 Hz.

40. The system of claim 38 , wherein the at least one stimulus-emitting device is a light-emitting device.

41. The system of claim 40 , wherein the light-emitting device is selected from the group consisting of a fiber-optic based emitter and a solid-state emitter.

42. The system of claim 41 , wherein the light-emitting device is a solid-state emitter and includes at least one light emitting diode (LED).

43. The system of claim 38 , wherein the at least one stimulus-emitting device includes a display screen.

44. The system of claim 38 , wherein the at least one stimulus-emitting device is a sound-emitting device.

45. The system of claim 44 , wherein the at least one non-invasive stimulus is an audible click train.

46. The system of claim 45 , wherein the audio click train has an audio frequency in a range from 12 Hz to 28 kHz and a sound pressure in a range from 30 dB to 70 dB.

47. The system of claim 38 , wherein the at least one stimulus-emitting device is a haptic device, and the stimulus is a haptic stimulus.

48. The system of claim 38 , wherein the at least one stimulus-emitting device is a light-emitting device, the system further comprising a light occlusion device to reduce ambient light to at least one eye of the subject.

49. The system of claim 48 , further comprising eyewear, wherein the eyewear includes at least one of:

the light-emitting device; or

the light occlusion device.

50. The system of claim 38 , wherein the at least one stimulus-emitting device is a sound-emitting device, the system further comprising a sound canceling device to reduce ambient sound to at least one ear of the subject.

51. The system of claim 50 , further comprising at least one headphone, wherein the at least one headphone includes at least one of:

the sound-emitting device; or

the sound cancelling device.

52. The system of claim 38 , further comprising a scanner to monitor function in the at least one brain region of the subject.

53. The system of claim 38 , further comprising:

a communication interface, coupled to the at least one processor, to communicate with at least one of the subject, a healthcare provider, a caretaker, or a clinical research investigator.

54. The system of claim 38 , wherein the at least one processor is configured, based on the stimulus parameters and the stimulus-generation policy stored in the memory, to:

control the at least one stimulus-emitting device to emit the at least one non-invasive stimulus at the repetition frequency for a duration of an exposure of the subject of at least one hour per day over a time period for repeating the exposure of at least seven days to induce the synchronized gamma oscillations and induce the at least one change in the microglial cells in the at least one brain region of the subject.

55. A method for improving cognitive function or preventing, reducing, or treating cognitive decline in a subject, the method comprising:

(a) administering to the subject at least a non-invasive visual stimulus having a frequency of about 35 Hz to about 45 Hz for at least one hour;

(b) increasing blood vessel diameter in at least one brain region of the subject in response to (a);

(c) inducing a change in microglial cells in the at least one brain region of the subject in response to (a); and

(d) reducing amyloid beta peptides in the at least one brain region of the subject as a result of at least one of (a), (b) or (c) to improve the cognitive function or prevent, reduce or treat the cognitive decline in the subject.

56. The method of claim 55 , further comprising:

reducing tau phosphorylation in the at least one brain region of the subject as a result of at least one of (a), (b) or (c) to improve the cognitive function or prevent, reduce or treat the cognitive decline in the subject.

57. The method of claim 55 , wherein (c) comprises increasing a number of microglial cells in the at least one brain region.

58. The method of claim 55 , further comprising:

promoting clearance of phosphorylated tau protein from the at least one brain region.

59. The method of claim 55 , further comprising:

promoting clearance of amyloid beta peptides from the at least one brain region.

60. The method of claim 55 , wherein (c) comprises changing a morphology of microglial cells toward a phagocytic state in the at least one brain region.

61. The method of claim 55 , further comprising:

(e) upregulating genes associated with increased microglial activation in the at least one brain region in response to (a).

62. The method of claim 61 , wherein (e) comprises upregulation of at least one of Nr4a1, Arc, Npas4, Cd68, B2m, Bsr2, Icam1, Lyz2, Irf7, Spp1, Csf1r, or Csf2ra genes.

63. The method of claim 55 , further comprising:

upregulating genes associated with astrocyte production in the at least one brain region in response to (a).

64. The method of claim 55 , further comprising:

upregulating genes associated with neuron production in the at least one brain region in response to (a).

65. The method of claim 55 , further comprising:

upregulating genes associated with myelinating oligodendrocytes in response to (a).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2020
From: TSAI, LI-HUEI; BROWN, EMERY; IACCARINO, HANNAH; MARTORELL, ANTHONY JAMES; ADAIKKAN, CHINNAKKARUPPAN
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 053224/0142 →
Continuity (4)
Continuation 16375393 · Apr 4, 2019
Continuation 15360637 · Nov 23, 2016
Provisional Application 62259187 · Nov 24, 2015
Related Publication 20200316334A1 · Oct 8, 2020
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