U.S. patent number 11,027,115 [Application Number 16/805,017] was granted by the patent office on 2021-06-08 for systems and methods for electroporation.
This patent grant is currently assigned to Mayo Foundation for Medical Education and Research. The grantee listed for this patent is Mayo Foundation for Medical Education and Research. Invention is credited to Samuel J. Asirvatham, Paul A. Friedman.


United States Patent 11,027,115
Asirvatham ,   et al. June 8, 2021

Systems and methods for electroporation

Abstract

This document describes methods and materials for improving
treatment of hypertension. For example, this document describes
methods and devices for electroporation of nerves in the renal area
to treat hypertension.


Inventors: Asirvatham; Samuel J.
(Rochester, MN), Friedman; Paul A. (Rochester, MN)
Applicant:
Name City State Country Type

Mayo Foundation for Medical Education and Research
Rochester MN US
Assignee: Mayo Foundation for Medical
Education and Research
(Rochester, MN)
Family
ID:
1000005601814
Appl.
No.:
16/805,017
Filed: February 28, 2020

Prior Publication Data


Document
Identifier
Publication Date
US 20200197687 A1 Jun 25, 2020

Related U.S. Patent Documents


Application
Number
Filing Date Patent Number Issue Date
PCT/US2018/057076 Oct 23, 2018
62575657 Oct 23, 2017

Current U.S.
Class:
1/1
Current CPC
Class:
A61B
5/053 (20130101); A61N 1/0416 (20130101); A61B
5/024 (20130101)
Current International
Class:
A61N
1/04 (20060101); A61B 5/053 (20210101); A61B
5/024 (20060101)

References Cited
[Referenced By]


U.S. Patent Documents

Foreign Patent Documents

WO 2016/161201 Oct 2016 WO

Other References


International Search Report & Written Opinion in International
Application No. PCT/US2018/057076 dated Jan. 11, 2019, 17 pages.
cited by applicant .
International Preliminary Report on Patentability directed to
related International Patent Application No. PCT/US2018/057076,
dated Apr. 28, 2020; 7 pages. cited by applicant.

Primary Examiner: Dietrich; Joseph M
Attorney, Agent or Firm: Sterne, Kesler, Goldstein & Fox
P.L.L.C.


Parent Case Text


CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation under 35 U.S.C. .sctn. 111(a) of
International Application No. PCT/US2018/057076, filed on Oct. 23,
2018, which claims the benefit of U.S. Provisional Application Ser.
No. 62/575,657, filed on Oct. 23, 2017. The disclosures of the
prior applications are considered part of the disclosure of this
application and are incorporated in their entirety into this
application.


Claims


What is claimed is:

1. A system for providing electroporation, the system comprising: a
first electrode and a second electrode configured to be placed in a
renal area of a patient; a sensor; and a pulse generator coupled to
the first electrode, the second electrode, and the sensor, the
pulse generator comprising: a memory that is capable of storing
computer executable instructions; and a processor that is
configured to facilitate execution of the executable instructions
stored in the memory, wherein the instructions cause the processor
to: generate, via the pulse generator, a stimulation electrical
current to cause stimulation between the first electrode and the
second electrode for the renal area; detect, via the sensor, a
change in blood pressure of the patient resulting from the
stimulation electrical current; and in response to detecting the
change in blood pressure of the patient, generate an
electroporation electrical current to cause reversible or
irreversible electroporation between the first electrode and the
second electrode for the renal area.

2. The system of claim 1, wherein the renal area comprises at least
one of a renal vein, a renal artery, and a renal pelvis.

3. The system of claim 1, wherein the instructions further cause
the processor to change an electrode configuration when no change
in blood pressure of the patient is detected.

4. The system of claim 3, wherein the changing the electrode
configuration comprises at least one of changing a location of the
first electrode or the second electrode, changing a polarity of the
first electrode or the second electrode, and changing a parameter
for the stimulation electrical current.

5. The system of claim 1, wherein the instructions further cause
the processor to: generate, via the pulse generator, a second
stimulation electrical current; and detect, via the sensor, a
physiological response to the second stimulation electrical
current.

6. The system of claim 1, further comprising a third electrode
configured to be located outside of the renal area.

7. The system of claim 6, wherein the instructions further cause
the processor to: change both the first electrode and the second
electrode to an anode or a cathode; change the third electrode to
the other of the anode or the cathode; generate, via the pulse
generator, a second stimulation electrical current; and detect, via
the sensor, a physiological response to the second stimulation
electrical current.

8. The system of claim 7, wherein the instructions further cause
the processor to generate a second electroporation electrical
current in response to detecting the physiological response to the
second stimulation electrical current.

9. The system of claim 1, wherein the first and second electrodes
are configured to be placed near sites of autonomic nervous tissue
in the renal area of the patient.

10. The system of claim 9, wherein the first and second electrodes
are configured to permit electric field distribution over nerves
adjacent the patient's inferior vena cava, descending aorta, or
ureters.

11. The system of claim 1, wherein the electroporation electric
current is configured to be delivered in pulses with a pulse width
in nanoseconds.

12. The system of claim 5, wherein the physiological response is a
change in at least one of heart rate, blood pressure,
transcutaneous impedance, and neural traffic in a peripheral
nerve.

13. A method of providing electroporation, the method comprising:
placing a first electrode and a second electrode in a renal area of
a patient; generating, via a pulse generator, a stimulation
electrical current to cause stimulation between the first electrode
and the second electrode for the renal area; detecting, via a
sensor, a change in blood pressure of the patient resulting from
the stimulation electrical current; and in response to detecting
the change in blood pressure of the patient, generating an
electroporation electrical current to cause reversible or
irreversible electroporation between the first electrode and the
second electrode for the renal area.

14. The method of claim 13, wherein the renal area comprises at
least one of a renal vein, a renal artery, and a renal pelvis.

15. The method of claim 13, further comprising: changing an
electrode configuration when no change in blood pressure of the
patient is detected.

16. The method of claim 15 wherein the changing further comprises
changing at least one of: a location of the first electrode or the
second electrode, a polarity of the first electrode or the second
electrode, and a parameter for the stimulation electrical
current.

17. The method of claim 13, further comprising: generating a second
stimulation electrical current to cause stimulation between the
first electrode and the second electrode; and detecting a
physiological response to the second stimulation electrical
current.

18. The method of claim 13, further comprising placing a third
electrode outside the renal area.

19. The method of claim 18, further comprising: changing both the
first electrode and the second electrode to an anode or a cathode;
changing the third electrode to the other of the anode or the
cathode; generating, via the pulse generator, a second stimulation
electrical current; and detecting a physiological response to the
second stimulation electrical current.

20. The method of claim 19, further comprising generating a second
electroporation electrical current in response to detecting the
physiological response to the second stimulation electrical
current.


Description


BACKGROUND

1. Technical Field

This document relates to methods and materials for improving
treatment of hypertension. For example, this document relates to
methods and devices for electroporation of nerves in the renal area
to treat hypertension.

2. Background Information

Hypertension, commonly known as high blood pressure, is a long-term
condition in which the blood pressure is persistently elevated and
can affect 16-37% of the population globally. Long-term high blood
pressure can be a major risk factor for coronary artery disease,
stroke, heart failure, peripheral vascular disease, vision, and
chronic kidney disease, to name a few. Lifestyle changes and
medications can lower blood pressure and decrease the risk of
health complications. Lifestyle changes can include weight loss,
decreased salt intake, physical exercise, and a healthy diet. If
lifestyle changes are not sufficient, then blood pressure
medications can be used.

Syncope, commonly known as fainting, is a loss of consciousness and
muscle strength characterized by a fast onset, short duration, and
spontaneous recovery and can account for about three percent of
visits to emergency departments, affect about three to six of every
thousand people each year. Fainting can be caused by a decrease in
blood flow to the brain, usually from low blood pressure. Treatment
can include returning blood to the brain by positioning the person
on the ground, with legs slightly elevated or leaning forward and
the head between the knees. For individuals who have problems with
chronic fainting spells, therapy can focus on recognizing the
triggers and learning techniques to keep from fainting. At the
appearance of warning signs, such as lightheadedness, nausea, or
cold and clammy skin, counter-pressure maneuvers that can include
gripping fingers into a fist, tensing the arms, and crossing the
legs or squeezing the thighs together can be used to ward off a
fainting spell.

The autonomic nervous system controls most of the involuntary
reflexive activities of the human body. The system is constantly
working to regulate the glands and many of the muscles of the body
through the release or uptake of the neurotransmitters
acetylcholine and norepinephrine. Autonomic dysregulation involves
malfunctioning of the autonomic nervous system, the portion of the
nervous system that conveys impulses between the blood vessels,
heart, and all the organs in the chest, abdomen, and pelvis and the
brain. Accordingly, autonomic dysregulation can play a major role
in the genesis of hypertension and syncope.

SUMMARY

This document describes methods and materials for improving
treatment of hypertension. For example, this document describes
methods and devices for electroporation of nerves in the renal area
to treat hypertension.

In one aspect, this disclosure is directed to a system for
providing electroporation. The system can include a first electrode
and a second electrode configured to be placed in a renal area of a
patient, a sensor, and a pulse generator coupled to the first
electrode, the second electrode, and the sensor. In some cases, the
pulse generator can include a memory that is capable of storing
computer executable instructions, and a processor that is
configured to facilitate execution of the executable instructions
stored in memory. The instructions can cause the processor to
generate, via the pulse generator, a stimulation electrical current
to cause stimulation between the first electrode and the second
electrode, detect, via the sensor, a physiological response to the
stimulation electrical current, and when the physiological response
is detected, generate an electroporation electrical current to
cause electroporation between the first electrode and the second
electrode. In some cases, the physiological response can be a
change in at least one of heart rate, blood pressure,
transcutaneous impedance, and neural traffic in a peripheral nerve.
In some cases, the renal area can include at least one of a renal
vein, a renal artery, and a renal pelvis. In some cases, the
instructions can further cause the processor to change an electrode
configuration when no physiological response is detected. In some
cases, changing the electrode configuration can include changing at
least one of a location of the first electrode or the second
electrode, changing a polarity of the first electrode or the second
electrode, and changing a parameter for the stimulation electrical
current. In some cases, the instructions can further cause the
processor to generate, via the pulse generator, a second
stimulation electrical current, and detect, via the sensor, a
second physiological response to the second stimulation electrical
current. In some cases, the system can include a third electrode
configured to be located outside of the renal area. In some cases,
the instructions can cause the processor to change both the first
electrode and the second electrode to an anode or a cathode, change
the third electrode to the other of the anode or the cathode,
generate, via the pulse generator, a third stimulation electrical
current, and detect, via the sensor, a third physiological response
to the third stimulation electrical current. In some cases, the
instructions can cause the processor to generate a second
electroporation electrical current when the third physiological
response is detected.

In another aspect, this disclosure is directed to a method of
providing electroporation. The method can include placing a first
electrode and a second electrode in a renal area of a patient, and
generating an electroporation electrical current to cause
electroporation between the first electrode and the second
electrode. In some cases, the renal area can include at least one
of a renal vein, a renal artery, and a renal pelvis. In some cases,
the method can include generating a stimulation electrical current
to cause stimulation between the first electrode and the second
electrode. In some cases, the method can include detecting a
physiological response to the stimulation electrical current. In
some cases, the physiological response can be a change in at least
one of heart rate, blood pressure, transcutaneous impedance, and
neural traffic in a peripheral nerve. In some cases, the
physiologic response can be assessed by an output of a supervised
or unsupervised artificially intelligent network that incorporates
multiple physiologic inputs. In some cases, the artificially
intelligent network can be at least one of a feature extraction
model, a hidden Markov model, a support vector machine, a
convolutional neural network or a recurrent neural network. In some
cases, the method can include changing an electrode configuration
when the physiological response is detected. In some cases,
changing the electrode configuration can include changing at least
one of a location of the first electrode or the second electrode,
changing a polarity of the first electrode of the second electrode,
and changing a parameter for the stimulation. In some cases, the
method can include generating a second stimulation electrical
current to cause stimulation between the first electrode and the
second electrode, and detecting a second physiological response to
the second stimulation electrical current. In some cases, the
method can include placing a third electrode outside the renal
area. In some cases, the method can include changing both the first
electrode and the second electrode to an anode or a cathode,
changing the third electrode to the other of the anode or the
cathode, generating a third stimulation electrical current, and
detecting a third physiological response to the third stimulation
electrical current. In some cases, the method can include
generating a second electroporation electrical current when the
third physiological response is detected.

In another aspect, this disclosure is directed to a system for
providing electroporation. The system can include a memory that is
capable of storing computer executable instructions, and a
processor that is configured to facilitate execution of the
executable instructions stored in memory. The instructions can
cause the processor to generate an electroporation electrical
current to cause electroporation between a first electrode and a
second electrode configured to be located in a renal area of a
patient. In some cases, the renal area can include at least one of
a renal vein, a renal artery, and a renal pelvis. In some cases,
the instructions can cause the processor to generate a stimulation
electrical current to cause stimulation between the first electrode
and the second electrode. In some cases, the instructions can cause
the processor to detect a physiological response to the stimulation
electrical current. In some cases, the physiological response can
be a change in at least one of heart rate, blood pressure,
transcutaneous impedance, and neural traffic in a peripheral nerve.
In some cases, the instructions can cause the processor to change
an electrode configuration when the physiological response is
detected. In some cases, the method can include changing the
electrode configuration comprising changing at least one of a
location of the first electrode or the second electrode, changing a
polarity of the first electrode or the second electrode, and
changing a parameter for the stimulation. In some cases, the
instructions can cause the processor to generate a second
stimulation electrical current to cause stimulation between the
first electrode and the second electrode, and detect a second
physiological response to the second stimulation electrical
current. In some cases, the instructions can cause the processor to
change both the first electrode and the second electrode to an
anode or a cathode, change a third electrode configured to be
located outside the renal area to the other of the anode or the
cathode, generate a third stimulation electrical current, and
detect a third physiological response to the third stimulation
electrical current. In some cases, the instructions can cause the
processor to generate a second electroporation electrical current
when the third physiological response is detected.

Particular embodiments of the subject matter described in this
document can be implemented to realize one or more of the following
advantages. The bipolar electroporation can provide sufficient
energy to be effective without coming into contact with the
structures to be electroporated. The architecture of tissues
surrounding the energy delivery electrodes is not altered,
minimizing complications. Further, the blood vessels are not
burned, which can have detrimental side effects, such as damage to
the vessel and/or coagulum. In addition, small amounts of DC energy
can also minimize the risk of coagulum formation. By minimizing the
risk of coagulum formation, electrodes can be placed in the blood
vessels long term, providing extended electroporation.

Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used to practice the invention, suitable
methods and materials are described herein. All publications,
patent applications, patents, and other references mentioned herein
are incorporated by reference in their entirety. In case of
conflict, the present specification, including definitions, will
control. In addition, the materials, methods and examples are
illustrative only and not intended to be limiting. The details of
one or more embodiments of the invention are set forth in the
accompanying drawings and the description below. Other features,
objects, and advantages of the invention will be apparent from the
description, the drawings, and the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic diagram of a person and a renal area, in
accordance with some embodiments provided herein.

FIG. 2 is a schematic diagram of the renal area of FIG. 1, in
accordance with some embodiments provided herein.

FIG. 3 is a method of electroporation of the renal area of FIG. 1,
in accordance with some embodiments provided herein.

FIG. 4 is a method of targeting specific areas for electroporation
of the renal area of FIG. 1, in accordance with some embodiments
provided herein.

FIG. 5 is a method of confirming electroporation is effective, in
accordance with some embodiments provided herein.

Like reference numbers represent corresponding parts
throughout.

DETAILED DESCRIPTION

This document describes methods and materials for improving
treatment of hypertension. For example, this document describes
methods and devices for electroporation of nerves in the renal area
to treat hypertension.

Autonomic dysregulation involves malfunctioning of the autonomic
nervous system, the portion of the nervous system that conveys
impulses between the blood vessels, heart, and all the organs in
the chest, abdomen, and pelvis and the brain. Accordingly,
autonomic dysregulation can play a major role in the genesis of
hypertension and syncope.

The bipolar electroporation can provide sufficient energy to be
effective without coming into contact with the structures to be
electroporated. Further, the blood vessels are not burned, which
can have detrimental side effects, such as damage to the vessel
and/or coagulum. In addition, small amounts of DC energy can also
minimize the risk of coagulum formation. By minimizing the risk of
coagulum formation, electrodes can be placed in the blood vessels
long term, providing extended electroporation.

Referring to FIGS. 1 and 2, a person 100 has a renal area 102. The
renal area 102 can include a right kidney 104a, and a left kidney
104b. Each kidney 104a and 104b can be attached to a ureter 106a
and 106b, which can lead to a bladder 108.

Kidneys 104a and 104b can filter blood, release and/or retain
water, remove waste, and control concentrations of the blood of
person 100. The substances filtered out can be urine and can travel
through the ureters 106a and 106b to the bladder 108. Ureters 106a
and 106b can each include a renal pelvis (not shown). The renal
pelvis can be a dilated portion of the ureters 106a and 106b that
can attach to the kidneys 104a and 104b to create a basin for
collecting waste and can aid in funneling the waste to the ureters
106a and 106b.

Kidneys 104a and 104b can each include an adrenal gland 110a and
110b, respectively. Adrenal glands 110a and 110b can produce and
secrete hormones. Specifically, the adrenal glands 110a and 110b
can produce aldosterone, which can aid in regulation of mineral
balance and blood volume. Aldosterone can act on the kidneys 104a
and 104b to cause changes in the reabsorption and/or excretion of
sodium, potassium, and hydrogen ions. The amount of sodium present
in the body can affect the extracellular volume, which in turn can
influence blood pressure. Therefore, the effects of aldosterone in
sodium retention can be important for the regulation of blood
pressure. Accordingly, kidneys 104a and 104b can regulate blood
pressure of person 100.

Kidneys 104a and 104b can receive blood from the renal arteries 118
via the descending aorta 114. The kidneys 104a and 104b can filter
the blood received from the renal arteries 118 and can send the
filtered blood to the inferior vena cava 112 via the renal veins
116 for distribution throughout the body, thus aiding in regulation
of blood pressure.

Referring to FIG. 3, a method 300 of electroporation of the renal
area 102 of FIG. 1 can include placing an electrode in the renal
area 102 at 302, and delivering electroporation at 304.

Placing an electrode in the renal area 102 at 302 can include
placing one or more electrodes in the renal area 102. In some
cases, an electrode(s) can be placed in a renal vein 116, a renal
artery 118, a renal pelvis, a perimetric renal space, a parametric
renal space, or a combination thereof. It is understood that in
addition to the renal vein and renal artery, surrounding structures
that may be anatomically situated in a favorable location to permit
electric field distribution over the autonomic nerves of interest
may be utilized, including the inferior vena cava, descending
aorta, as well as the ureters themselves via retrograde or
anterograde cannulation. In some cases, multiple electrodes can be
placed in the renal area 102. In some cases, one or more electrodes
can be on a skin of person 100. In some cases, electrodes can be
placed inside the renal area 102 and on the skin of person 100. In
some cases, retrograde ureterography can be used to place one or
more electrodes. In some cases, laparoscopy can be used to place
one or more electrodes. In some cases, a combination of
implantation techniques can be used. In some cases, an electrode
can be placed via a lead. In some cases, the lead can include
multiple electrodes. In some cases, an electrode can be located on
a balloon placed in the renal area 102. In some cases, a device
with an electrode array can be placed in the renal area 102. In
some cases, linear electrodes can be placed in the renal area 102.
In some cases, an electrode cuff can be placed in the renal area
102. In some cases, the electrode can be an omnipolar (e.g.,
varying monopolar, bipolar, tripolar, etc.) electrode. In some
cases, electrodes can be placed in other vascular structures. In
some cases, electrodes can be placed in other nonvascular
structures. In some cases, electrodes can be placed in a
combination of vascular and nonvascular structures.

Delivering electroporation at 304 can include generating electrical
pulses that can be delivered via the electrodes. In some cases,
electroporation energy can be delivered with a high frequency. In
some cases, electroporation energy can be delivered with a high
voltage (e.g., 10 mV-100 V, or higher). In some cases,
electroporation energy can be delivered as pulses with a pulse
width in the nanoseconds. In some cases, electroporation can be
delivered with a frequency and/or amplitude that causes reversible
electroporation. In some cases, electroporation can be delivered
with a frequency and/or amplitude that causes irreversible
electroporation. In some cases, electroporation can be delivered by
multiple electrodes in the renal area 102. In some cases,
electroporation can be delivered by one or more electrodes in the
renal area 102 and one or more electrodes outside the renal area
102. In some cases, electroporation can be delivered with different
electrode configurations (e.g., varying location of electrodes,
varying number of electrodes, varying polarity of electrodes,
varying intensity of electroporation, etc.). In some cases,
electroporation can be delivered between electrodes on the same
device (e.g., balloon, lead, stent, catheter, etc.). In some cases,
electroporation can be delivered between electrodes on different
devices. In some cases, electroporation can reach a maximum
intensity between electrode poles. In some cases electroporation
energy is modulated so that energy delivery is synchronized to the
QRS complex. This may avoid cardiac arrhythmia, to insure
near-identical fluid volume during energy delivery, and to optimize
similarity of electrode position with each energy pulse. In other
embodiments energy pulsation is independently or additionally
synchronized to respiratory activity.

Referring to FIG. 4, a method 400 of targeting specific areas for
delivering electroporation of the renal area of FIG. 1 can include
placing an electrode in the renal area 102 at 402, providing
stimulation at 404, and monitoring a response at 406.

Placing an electrode in the renal area 102 at 402 can be
substantially similar to placing an electrode at 302 of method
300.

Providing stimulation at 404 can include generating an electrical
pulse between electrodes. In some cases, the electrodes placed in
the renal area 102 can provide stimulation and electroporation. In
some cases, providing stimulation can include providing stimulation
with a plurality of predefined electrode configurations. For
example, providing stimulation can include going through multiple
iterations of electrode configurations in a sequence while
providing stimulation. In some cases, providing stimulation can
include providing high frequency electrical pulses between
electrodes.

Monitoring a response at 406 can include sensing one or more
physiological responses to the stimulation provided at 404. In some
cases, monitoring a response can include sensing one or more
physiological responses to electroporation (e.g., electroporation
at 304, 410, etc.). In some cases, monitoring a response can
include placing sensory probes in or around a vessel (e.g., carotid
vessels, brachial vessels). In some cases, monitoring a response
can include using Doppler. In some cases, monitoring a response can
include monitoring vascular changes. In some cases, monitoring a
response can include monitoring neural effects. In some cases,
monitoring a response can include placing an external sensing
device on patient 100. In some cases, monitoring a response can
include monitoring for a change (e.g., increase, decrease, overall
change, crossing a threshold, amount of change crossing a
threshold, etc.) in a physiological parameter. In some cases, the
physiological parameter can include one or more of heart rate,
blood pressure, transcutaneous impedance, neural traffic in
peripheral nerves, etc. In some cases, monitoring a response can
include monitoring a plurality of responses based on a plurality of
electrode configuration and determining which configuration will
lead to effective treatment upon electroporation based on the
corresponding response. In some cases the response can be the
output of a supervised or unsupervised artificially intelligent
network that incorporates multiple physiologic inputs to determine
response of therapy. Such networks may include hidden Markov
models, support vector machines, or convolutional or recurrent
neural networks.

If no response is detected at 406, method 400 can include changing
an electrode configuration at 408. Changing an electrode
configuration at 408 can include changing an intensity (e.g., pulse
width, frequency, voltage, etc.) of electroporation or stimulation
to be generated. In some cases, changing an electrode configuration
can include moving the device holding the electrode(s) such that a
location of the electrodes is changed. In some cases, changing an
electrode configuration can include changing a polarity of one or
more electrodes. In some cases, changing an electrode configuration
can include changing a combination of electrodes selected to
deliver electroporation and/or stimulation. In some cases,
electrode configurations, intensity, or other stimulation
parameters can be modified and if no response is detected after a
plurality of configurations, the electrodes can be physically moved
to change the location of the electrodes.

If a response is detected at 406, method 400 can include delivering
electroporation at 410, providing stimulation at 412, and
monitoring a response at 414.

Delivering electroporation at 410 can be substantially similar to
delivering electroporation at 304 of method 300.

Providing stimulation at 412 may be substantially similar to
providing stimulation at 404.

Monitoring a response at 414 may be substantially the same as
monitoring a response at 406. If a response is detected at 414,
method 400 can change the electrode configuration at 408. In some
cases, if no response is detected at 414, method 400 can be
considered complete. In some cases, if no response is detected at
414, an electrode configuration can be changed at 408 and method
400 can be repeated until no response is detected at 414 for a
plurality of electrode configurations.

Referring to FIG. 5, a method 500 of confirming electroporation is
effective can include changing all electrodes to either an anode or
a cathode at 502, providing stimulation at 504, and monitoring a
response at 506.

Changing all electrodes to either an anode or a cathode at 502 can
include changing all internal active electrodes to either an anode
or a cathode. In some cases, changing all electrodes to either an
anode or a cathode can include changing a surface electrode to the
other of a cathode or an anode. In some cases, the surface
electrode can be external to the patient, such as on the skin of
the patient. In some cases, the In some cases, changing all
electrodes to either an anode or a cathode can include changing all
of the active electrodes in the renal area to either an anode or a
cathode and changing one or more electrodes outside the renal area
to the other of an anode or a cathode.

Providing stimulation at 504 can be substantially similar providing
stimulation at 404 of method 400.

Monitoring a response at 506 can be substantially similar to
monitoring a response at 406 of method 400.

In some cases, method 500 can include changing an electrode
configuration at 508 can be substantially similar to changing an
electrode configuration at 408 of method 400. In some cases,
changing an electrode configuration can include modifying a
location of the electrodes. In some cases, modifying a location can
include changing selected electrodes. In some cases, modifying a
location can include moving a device on which the electrode is
located.

In some cases, after multiple iterations of modifying the electrode
configuration and still detecting a response when monitoring for a
response, electroporation can be performed with all the internal
electrodes set as either a cathode or an anode and a surface
electrode set as the other of a cathode or an electrode.

In some cases, person 100 can be sedated during parts or all of the
methods described herein. In some cases, the devices implanted for
electroporation can be for single use, such that the devices are
removed upon completion of one or more of methods 300, 400, and/or
500. In some cases, electroporation causes permanent, or
substantially permanent effects.

In some cases, the devices implanted for electroporation can be
implanted for long-term use. In some cases, long-term devices can
manage blood pressure to prevent and/or reduce the effects and/or
occurrences of high blood pressure and/or low blood pressure. In
some cases, the implanted devices can include a subcutaneous
generator. In some cases, the implanted devices can include sensors
for measuring physiological signals (e.g., blood pressure, heart
rate). In some cases, when the physiological signals crosses a
threshold, the implanted devices can provide stimulation at
selected locations. In some cases, devices can be permanently
implanted in only the renal vein.

In some cases, balloon mounted electrodes can be used. In some
cases, the balloon can provide irrigation. In some cases, the
balloon can include embedded elements (e.g., electrodes, and
injection ports). In some cases, the balloon can inject a calcium
solution, autonomic chemical agents, enhancers of field strength,
botulin toxins, saline, or other solutions. In some cases, the
balloon can be shaped like a sea-urchin or porcupine, such that the
balloon includes extension portions. In some cases, the extension
portions can include an electrode and/or an irrigation port, which
can increase the focus of electroporation.

In some cases, electroporation can be reversible. In some cases,
electroporation can be irreversible. In some cases, reversible
electroporation can be delivered to confirm location of stimulation
and, accordingly, nerves, and then irreversible electroporation can
be delivered.

In some cases, the devices and methods described above can be used
near other sites of perivascular and/or autonomic neural tissue.
For example, near the ganglia, such as in the cardiac spaces, the
carotid vessels, the celiac ganglia, hepatic ganglia, and other
sites. In some cases, the devices and methods can be located in the
carotid region, internal and external to the jugular vein, in the
pulmonary artery, in the aorta, in the epicardial space, in the
hepatic vein or artery, in the portal vein, in the superior vena
cava, or other veins and/or arteries. In some cases, modifying the
location of the electrodes, and therefore the location of
electroporation, can provide treatment of different disorders, such
as obesity, diabetes, etc.

While this specification contains many specific implementation
details, these should not be construed as limitations on the scope
of any invention or of what may be claimed, but rather as
descriptions of features that may be specific to particular
embodiments of particular inventions. Certain features that are
described in this specification in the context of separate
embodiments can also be implemented in combination in a single
embodiment. Conversely, various features that are described in the
context of a single embodiment can also be implemented in multiple
embodiments separately or in any suitable subcombination. Moreover,
although features may be described herein as acting in certain
combinations and even initially claimed as such, one or more
features from a claimed combination can in some cases be excised
from the combination, and the claimed combination may be directed
to a subcombination or variation of a subcombination.

Similarly, while operations are depicted in the drawings in a
particular order, this should not be understood as requiring that
such operations be performed in the particular order shown or in
sequential order, or that all illustrated operations be performed,
to achieve desirable results. In certain circumstances,
multitasking and parallel processing may be advantageous. Moreover,
the separation of various system modules and components in the
embodiments described herein should not be understood as requiring
such separation in all embodiments, and it should be understood
that the described program components and systems can generally be
integrated together in a single product or packaged into multiple
products.

Particular embodiments of the subject matter have been described.
Other embodiments are within the scope of the following claims. For
example, the actions recited in the claims can be performed in a
different order and still achieve desirable results. As one
example, the process depicted in the accompanying figures do not
necessarily require the particular order shown, or sequential
order, to achieve desirable results. In certain implementations,
multitasking and parallel processing may be advantageous.

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