Penetration of cerebral spinal fluid into the brain parenchyma using temporally patterned neuromodulation

Patent metadata

Field	Value
Publication number	US-12076554-B2
Application number	US-202217854078-A
Country	US
Kind code	B2
Filing date	Jun 30, 2022
Priority date	Aug 7, 2019
Publication date	Sep 3, 2024
Grant date	Sep 3, 2024

Abstract

Electrical stimulation of specific facial and lingual nerves creates a more sustained pulsatility activity compared to stimulation of other cranial nerves. Pulsatility of arteries has intrinsic time constraints related to the time for vasodilation/constriction and time to return to baseline (T BL ) after electrical stimulation which may affect the pulsatility response. Control of temporal patterning and the stimulation waveform maximizes the physiological response to cerebral pulsatility and its resulting effects on cerebral spinal fluid penetration into the brain parenchyma for a multitude of therapeutic uses including clearing misfolded proteins and/or administered pharmacological agents, diluting endogenous neurochemical concentrations within the brain, and reducing non-synaptic coupling.

First claim

We claim:

1. An electrical stimulation device for improving waste
clearance through a perivascular system comprising:
an intraoral device receivable within a human mouth;
at least one electrode supported by the intraoral device configured to stimulate a facial nerve;
an electrical generator generating a carrier wave delivered to the at least one electrode having a carrier frequency, the electrical generator stimulating the perivascular system into increased CSF and ISF flow; and
at least one sensor attached to the intraoral device configured to detect biomarkers within the human mouth indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.

2. The electrical stimulation device of claim 1 wherein the biomarkers are analytes of tissue or saliva.

3. The electrical stimulation device of claim 2 wherein the analytes are at least one of amyloid beta peptide, tau protein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A, huntingtin protein, DNA methylation disruptions, and micro-RNA profiles.

4. The electrical stimulation device of claim 2 wherein the at least one sensor is configured to detect increased levels of neuronal cytokines.

5. The electrical stimulation device of claim 1 wherein the biomarkers are at least one of a brain wave frequency and heart rate further indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.

6. The electrical stimulation device of claim 5 wherein the at least one electrode is configured to detect changes in low brain wave frequency.

7. The electrical stimulation device of claim 1 wherein the at least one electrode is adapted to stimulate at least one of a trigeminal nerve, buccal branch nerve, mental branch nerve and facial branch nerve.

8. The electrical stimulation device of claim 1 wherein the intraoral device is a mouthpiece configured to engage a jaw of a user's mouth.

9. An electrical stimulation device for improving waste clearance through a perivascular system comprising:
an intraoral device receivable within a human mouth;
at least one electrode supported by the intraoral device configured to stimulate a facial nerve;
an electrical generator generating a carrier wave delivered to the at least one electrode having a carrier frequency, the electrical generator stimulating the perivascular system into increased CSF and ISF flow; and
at least one sensor supported by the intraoral device configured to detect biomarkers indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow;
wherein the intraoral device is a dental filling configured to be inserted within a cavity of a tooth.

10. An electrical stimulation device for improving waste clearance through a perivascular system comprising:
an intraoral device receivable within a human mouth;
at least one electrode supported by the intraoral device configured to stimulate a facial nerve;
an electrical generator generating a carrier wave delivered to the at least one electrode having a carrier frequency, the electrical generator stimulating the perivascular system into increased CSF and ISF flow;
at least one sensor supported by the intraoral device configured to detect biomarkers indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow;
an electrical modulation generator configured to generate a modulation wave having a predetermined periodicity providing a first period of stimulation of the perivascular system and a second period of relaxation of the perivascular system, the predetermined periodicity selected to increase pulsatility over continuous stimulation of the perivascular system by the carrier frequency; and
a modulator receiving the carrier wave and the modulation wave and modulating the carrier wave for application to the at least one electrode.

11. A method of improving waste clearance through a perivascular system comprising:
positioning at least one electrode supported by an intraoral device in close proximity to a facial nerve;
generating a carrier wave having a carrier frequency stimulating the perivascular system into increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow;
applying the carrier wave to the at least one electrode; and
detecting biomarkers indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.

12. The method of claim 11 wherein the biomarkers are analytes of tissue or saliva.

13. The method of claim 12 wherein the analytes are at least one of amyloid beta peptide, tau protein, lactoferrin, alpha-synuclein, DJ-1 protein, chromogranin A, huntingtin protein, DNA methylation disruptions, and micro-RNA profiles.

14. The method of claim 12 wherein the at least one sensor is configured to detect increased levels of neuronal cytokines.

15. The method of claim 11 wherein the biomarkers are at least one of a brain wave frequency and heart rate further indicating an increased cerebral spinal fluid (CSF) and interstitial fluid (ISF) flow.

16. The method of claim 15 wherein the at least one electrode is configured to detect changes in low brain wave frequency.

17. The method of claim 11 wherein the facial nerve is at least one of a trigeminal nerve, buccal branch nerve, mental branch nerve and facial branch nerve.

18. The method of claim 11 further comprising
generating a modulation wave having a predetermined periodicity providing a first period of stimulation of the perivascular system and a second period of relaxation of the perivascular system, the predetermined periodicity selected to increase waste clearance over continuous stimulation of the perivascular system by the carrier frequency; and
modulating the carrier wave.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Ludwig Kip
• Williams Justin
• Williams Angela
• Poore Samuel

Classifications

• A61N1/36025

  for treating a mental or cerebral condition · CPC title

• A61N1/0432

  Anode and cathode · CPC title

• A61N1/36034

  specified by the stimulation parameters · CPC title

• A61N1/0456

  Specially adapted for transcutaneous electrical nerve stimulation [TENS] · CPC title

• A61N1/0548 Primary

  Oral electrodes · CPC title