# US 12,005,251 B2 · Neuromodulation to modulate glymphatic clearance

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- Number: US 12,005,251 B2
- Document ID: US12005251B2
- Status: Granted
- Kind: B2
- Application number: 17/884,784
- Filed: 2022-08-10
- Published: 2022-12-01
- Granted: 2024-06-11
- Earliest claimed: 2016-08-26
- Assignees: Wisconsin Alumni Research Foundation; Mayo Foundation for Medical Education and Research
- Applicants: Wisconsin Alumni Research Foundation; Mayo Foundation for Medical Education and Research
- Inventors: Justin Williams; Kip Ludwig; Erika Ross
- Web page: https://patentgrep.com/patent/US12005251B2

## CPC

- A61N 1/056: {Transvascular endocardial electrode systems}
- A61N 1/0456: {Specially adapted for transcutaneous electrical nerve stimulation [TENS]}
- A61N 1/0476: {Array electrodes (including any electrode arrangement with more than one electrode for at least one of the polarities)}
- A61N 1/0484: {Garment electrodes worn by the patient}
- A61N 1/0492: {Patch electrodes (A61N1/0412, A61N1/0428 take precedence)}
- A61N 1/0536: {Preventing neurodegenerative response or inflammatory reaction}
- A61N 1/0551: {Spinal or peripheral nerve electrodes}
- A61N 1/36025: {for treating a mental or cerebral condition}
- A61N 1/36034: {specified by the stimulation parameters}
- A61N 1/36053: {adapted for vagal stimulation (A61N1/36114 takes precedence)}
- A61N 1/36067: {Movement disorders, e.g. tremor or Parkinson disease (stimulating motor muscle A61N1/36003)}
- A61N 1/36082: {Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease}
- A61N 1/36103: {Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke}
- A61N 1/36132: {using patient feedback}
- A61N 1/36146: {specified by the stimulation parameters}
- A61N 1/36175: {Pulse width or duty cycle}
- A61N 1/37516: {Intravascular implants}
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## Abstract

The present invention provides materials and methods for using electrical stimulation to treat a mammal having a proteinopathy (e.g., neurodegenerative diseases) or at risk of developing a proteinopathy are provided. For example, the present invention provides materials and methods for modulating glymphatic clearance (e.g., enhancing glymphatic clearance) of pathogenic proteins.

## Claims

### Claim 1

A method for treating a human having a proteinopathy by inducing glymphatic clearance, comprising:
implanting at a single location a tubular stent supporting at least one electrode within a blood vessel of the human having the proteinopathy wherein the tubular stent includes a tube of insulation material permitting blood to flow therethrough and surrounded by the at least one electrode positioned on an exterior of the tube; and
administering electrical stimulation comprised of electrical pulses to the at least one electrode of the tubular stent at a predetermined temporal pattern operable to direct current outward toward the inner walls of the blood vessel to attract oppositely charged local proteins to the at least one electrode of the tubular stent and create an osmotic gradient to clear the proteins by para-venous efflux and increase glymphatic clearance characterized by increased cerebrospinal fluid flow from the perivascular space into the parenchyma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises at least one of monophasic pulses, symmetrical biphasic pulses, and asymmetrical biphasic pulses.

### Claim 3 (depends on 2)

The method of claim 2, wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises intermittent biphasic pulses on top of a direct current (DC).

### Claim 4 (depends on 3)

The method of claim 3, wherein the electrical stimulation provides a constant current, is charge balanced, and is cathodic leading.

### Claim 5

A method for treating a human having a proteinopathy by inducing glymphatic clearance, comprising:
implanting a tubular stent supporting at least one electrode within a blood vessel of the human having the proteinopathy wherein the tubular stent includes a tube of insulation material permitting blood to flow therethrough and surrounded by the at least one electrode positioned on an exterior of the tube to direct current outward toward a lumen of the blood vessel; and
administering electrical stimulation comprised of electrical pulses to the at least one electrode at a predetermined temporal pattern operable to direct current outward toward the inner walls of the blood vessel to draw oppositely charged local proteins to the at least one electrode and to increase glymphatic clearance characterized by increased cerebrospinal fluid flow from the perivascular space into the parenchyma;
wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises at least one of monophasic pulses, symmetrical biphasic pulses, and asymmetrical biphasic pulses;
wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises intermittent biphasic pulses on top of a direct current (DC);
wherein the electrical stimulation provides a constant current, is charge balanced, and is cathodic leading;
wherein a charge density of the electrical stimulation is less than or equal to 50 microcoulomb/square centimeter to prevent unwanted electrochemical reactions.

### Claim 6 (depends on 5)

The method of claim 5, wherein a frequency of the electrical stimulation is 100 Hz, a current of the electrical stimulation is 10 mA, and a pulse width of the biphasic pulses is 500 microseconds.

### Claim 7 (depends on 1)

The method of claim 1 wherein the tubular stent is a singular tube implanted within the human.

### Claim 8 (depends on 5)

The method of claim 5, wherein the tubular stent is implanted within a sagittal sinus vein of the human.

### Claim 9 (depends on 1)

The method of claim 1 wherein administering electrical stimulation to the at least one electrode is under conditions where the electrical stimulation is effective to enhance convective clearance of misfolded proteins at a distance from the at least one electrode.

### Claim 10

A method for treating a human having a proteinopathy by inducing glymphatic clearance, comprising:
implanting at a single location a tubular stent supporting at least one electrode within a blood vessel of the human having the proteinopathy wherein the tubular stent includes a tube of insulation material permitting blood to flow therethrough and surrounded by the at least one electrode positioned on an exterior of the; and
administering electrical stimulation comprised of electrical pulses to the at least one electrode of the tubular stent at a predetermined temporal pattern to direct current outward toward the inner walls of the blood vessel to attract oppositely charged local proteins to the at least one electrode of the tubular stent to create an osmotic gradient to clear the proteins by para-venous efflux and enhance convective clearance of misfolded proteins from the perivascular space into the parenchyma.

### Claim 11 (depends on 10)

The method of claim 10, wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises at least one of monophasic pulses, symmetrical biphasic pulses, and asymmetrical biphasic pulses.

### Claim 12 (depends on 11)

The method of claim 11, wherein the electrical stimulation is delivered to the at least one electrode by an electric current generator and the electrical stimulation comprises intermittent biphasic pulses on top of a direct current (DC).

### Claim 13 (depends on 10)

The method of claim 10 wherein the tubular stent is a singular tube implanted within the human.

### Claim 14 (depends on 13)

The method of claim 13, wherein the tubular stent is implanted within a sagittal sinus vein of the human.