Systems and methods of neuromodulation of lumbar sympathetic chain

Abstract

Neuromodulation of the lumbar sympathetic chain can cause vasodilation in at least one of a subject's legs. At least two electrode contacts can be interfaced with the lumbar sympathetic chain of a subject; and an electrical signal can be delivered to the lumbar sympathetic chain via the at least two electrode contacts to cause the vasodilation.

Description

SYSTEMS AND METHODS OF NEUROMODULATION OF LUMBAR SYMPATHETIC CHAINREFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 676,039 filed July 26, 2024, and U.S. Provisional Application No. 63 / 563,098 filed March 8, 2024, the entire disclosure of each is hereby incorporated by reference herein in its entirety.FIELD

[0002] The present disclosure relates generally to systems and methods for facilitating modulation (c.g., electrical ncuromodulation), and more particularly in some embodiments to systems and methods for facilitating therapeutic modulation of a subject’s lumbar sympathetic chain (LSC) to cause vasodilation, for example in an arm, leg, or abdomen of a subject.BACKGROUND

[0003] The lumbar sympathetic chains are a pair of longitudinal ganglionic cords on both sides of the lumbar vertebral column, which carry pre- and post-ganglionic sympathetic fibers to the legs via the hypogastric complex. This pathway is mediated by immediate and sustained release of vasodilator S-nitrosothiols. For many years, vasoconstriction has been known to be an effect of LSC stimulation (e.g., for pain relief). Vasoconstriction is known to lead to decreased blood flow and increased blood pressure.SUMMARY

[0004] Under certain stimulation conditions, stimulation or activation of the lumbar sympathetic chain (LSC) can lead to vasodilation (and a corresponding decrease in blood pressure and increase in blood flow) in, for example, the abdomen, the subject’s ipsilateral leg or arm (same side of the subject as the stimulation), vasodilation (and a corresponding decrease in blood pressure and increase in blood flow) in the subject’s contralateral leg or arm (opposite side of the subject as the stimulation), and / or vasodilation in both the subject’s ipsilateral and contralateral leg or arm. Such neuromodulation of the subject’s LSC to modulate vasoactive properties or cause vasodilation (e.g., when a physiological parameter of the subject that meets or exceeds a threshold value for the physiological parameter) can be used to treat conditionsincluding, but not limited to, neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, diabetic vascular disease like diabetic peripheral microvascular disease, heart failure (e.g., heart failure with preserved ejection fraction (HFpEF)), endometriosis, microvascular diseases, vasodilatory issues like Raynaud’s phenomenon (e.g., vasospasm), and hypertension.

[0005] The systems and devices described herein can be minimally invasive (e.g., not requiring open surgery but can be delivered percutaneously, laparoscopically, or endoscopically through a small incision in the skin). The systems and devices do not need to stimulate the patient all the time and rely on a relatively low frequency, so the implantable devices may be sufficiently small to be delivered through a needle. For example, the implantable device does not necessarily require an implantable stimulator or power source. The implantable device may include one or more electrode contacts and a stimulator. The system may be fully implantable, but in other configurations, the stimulator may be external, or a combination between an internal component and an external component. In the case of multiple electrode contacts, the electrode contacts may be on a single implantable structure or separately implanted. Each of the one or more electrode contacts may be delivered in a region between the muscle and the spinal column. Depending on the indication, the stimulation may be unilateral or bilateral.

[0006] The one or more electrode contacts may be delivered in electrical communication with the lumbar sympathetic chain to stimulate ganglion on a left and / or right side of the lumbar region of the spinal column, for example at any one or more levels from LI to SI, e.g., LI, L2, L3, L4, L5, SI. Other levels in the sacrum region may also be stimulated. The one or more electrodes may apply direct electrical stimulation to the cell bodies in the ganglion on one or both sides of the spinal column in the lumbar region, which may include, for example, a lumbosacral region. Additionally or alternatively, one or more electrode contacts may be delivered to apply direct electrical stimulation to the interganglionic segments or interconnecting fibers between the left and right ganglia. The device may be able to independently stimulate left or right ganglion and / or the interganglionic segments. Additionally or alternatively, one or more electrode contacts may be delivered to apply direct electrical stimulation to the dorsal or ventral rami connecting the sympathetic ganglion to the spinal column in the lumbar region. In some embodiments, the system may deliver electricalstimulation only to ganglion in the lumbar sympathetic chain but does not directly stimulate efferent or afferent nerves extending from the lumbar sympathetic chain. In various embodiments, the delivered electrical stimulation does not stimulate muscle (e.g., multifidus muscle) but only stimulates nerves.

[0007] Depending on the indication, the systems described herein may be open or closed loop. In an open loop system, the implantable device may be patient-activated, for example through attaching or activating a wearable component (e.g., on a patch, armband, belt, shoulder strap, etc.) or an application on a smartphone or tablet. As a default, the implantable device may be turned off and only turned on upon patient-activation. In a closed-loop system, the system may include one or more sensors for detecting a physiological parameter, patient activity, or an environmental parameter, and stimulation may be turned on and off based on the data detected by the one or more sensors. In some implementations, the system may be activated according to programmed timing parameters (e.g., turned on and off according to predetermined time schedules).

[0008] Certain aspects of the disclosure relate to a system having a pulse generator configured to generate an electrical signal designed to stimulate a lumbar sympathetic chain of a subject and methods of using the system. The pulse generator may be implantable or external or split between internal and external components, portions or devices (e.g., an internal pulse generator can be externally powered by an external device or component via inductive coupling, which may allow for reduced size of the internal component(s)). The system may have one or more electrode contacts, for example at least two electrode contacts, configured to interface with the lumbar sympathetic chain to deliver the electrical signal from the pulse generator. Each of the electrode contacts may directly apply electrical stimulation to the ganglia or rami in the lumbar sympathetic chain. Stimulation of the lumbar sympathetic chain with the electrical signal causes vasodilation, for example in at least one of a subject’s abdomen, legs, or arms. A more detailed disclosure of the system is described below.

[0009] Certain aspects of the disclosure relate to a method including interfacing one or more electrode contacts, for example at least two electrode contacts, with a lumbar sympathetic chain of a subject such as at the ganglion or rami. Each of the electrode contacts may directly apply electrical stimulation to the ganglia or rami in the lumbar sympathetic chain. The method may include delivering an electrical signal to the lumbar sympathetic chain viathe one or more electrode contacts to cause vasodilation, for example in at least one of the subject’s legs, arms, or abdomen. The vasodilation may occur ipsilateral or contralateral to the one or more electrode contacts. Electrical stimulation may be continuous for vasodilation in one or both legs or arms, or the electrical stimulation may be intermittent to toggle vasodilation in each leg or arm. In some embodiments, stimulation parameters and / or locations may be adjusted to cause a response in afferent nerves, efferent nerves, or toggle between afferent and efferent nerves.

[0010] In several embodiments, the systems described herein have one or more of the following advantages:• improve peripheral circulation;• decrease blood pressure;• decrease vascular resistance;• alleviate pain symptoms;• enable adjustment of therapy in response to a condition of the patient or side effects;• be minimally invasive;• have a minimal effect on cardiac load; and / or• reduce the need for pharmacological or other therapies.

[0011] Certain aspects of this disclosure relate to a method of treating a condition in a subject, comprising electrically stimulating the LSC at a lateral side of a vertebral column via a first and second electrode contact, and causing vasodilation in a limb (e.g., arm or leg) on the first lateral side and / or in a limb on a second lateral side opposite the first lateral side. The method may further include electrically stimulating the lumbar sympathetic chain on a second lateral side of the vertebral column opposite the first lateral side via a third electrode contacts and a fourth electrode contact on the second lateral side, and causing vasodilation in a limb on the second lateral side and / or causing vasodilation in a limb on the first lateral side. The first electrical contact and the second electrical contact may be on a first implantable electrode, and the third electrical contact and the fourth electrical contact may be on a second implantable electrode. The first and second implantable electrodes may be inserted within the subject percutaneously. The condition may be neuropathy, pain, exercise tolerance, heart failure, hypertension, or endometriosis.

[0012] The method may further include detecting, by one or more sensors, a physiological parameter or condition of the subject, and varying one or more of, for example, an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition. The physiological parameter or condition may comprise, for example, blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity. The one or more sensors may be configured to detect muscle stimulation or vibration.

[0013] The electrical stimulation may be carried out at a fixed frequency, for example, between 0.1 Hz and 20 Hz (between 0.1 Hz to 6 Hz, between 1 Hz and 5 Hz, between 4 Hz and 10 Hz, between 2 Hz and 8 Hz, between 5 Hz and 15 Hz, between 8 Hz and 20 Hz, between 10 Hz and 20 Hz, overlapping ranges thereof, or any value within the recited ranges). The method may further include increasing a voltage until vasodilation on a contralateral side is caused. The method may further include toggling electrical stimulation between different currents and / or voltages.

[0014] In some implementations, electrically stimulating the LSC may further cause vasodilation in the subject’s abdomen.

[0015] The method may further include inserting and positioning the first electrode contact and the second electrode contact within the subject at a position adjacent one or more of an LI lumbar vertebral body, L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body. Electrically stimulating the LSC on the first lateral side of the vertebral column via the first electrode contact on the first lateral side and the second electrode contact on the first lateral side may include simultaneously electrically stimulating lumbar sympathetic ganglia adjacent multiple vertebral bodies of a lumbar region. The method may additionally include positioning the first electrode contact and / or the second electrode contact on the first lateral side of the vertebral column adjacent an anterior one-third portion of one or more of a LI vertebral body, L2 vertebral body, L3 vertebral body, L4 vertebral body, or L5 vertebral body and anteromedial muscular' fascia. Electrically stimulating the LSC may accelerate wound healing.

[0016] Some aspects of the present disclosure relate to a method of treating a condition in a subject, comprising positioning a first electrode contact and a second electrode contact on a first lateral side of a vertebral column of the subject, and electrically stimulatingthe LSC on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact. Electrically stimulating may include increasing voltage until causing vasodilation in a limb on a first lateral side of the subject corresponding to the first lateral side of the vertebral column, and increasing voltage until causing vasodilation in a limb on a second lateral side of the subject opposite the first lateral side of the subject. The method may additionally include positioning a third electrode contact and a fourth electrode contact on a second lateral side of a vertebral column of the subject opposite the first lateral side of the vertebral column, and electrically stimulating the LSC on the second lateral side of the vertebral column of the subject via the third electrode contact and the fourth electrode contact, and increasing voltage until causing vasodilation in a limb on the first and second lateral side of the subject, and toggling between electrically stimulating the LSC on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column of the subject via the third electrode contact and the fourth electrode contact. Stimulation may be performed at a frequency of no more than 20 Hz. The method may further include detecting, by one or more sensors, a physiological parameter or condition of the subject, varying one or more of an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition.

[0017] The method may further include receiving, by a controller from an external device, an instruction to electrically stimulate the lumbar sympathetic chain via one the first electrode contact and the second electrode contact, third electrode contact or fourth electrode contact. After electrically stimulating the LSC, an electrical shock (e.g., defibrillation) may be delivered to the patient’s heart. The method may be used for treating a condition such as neuropathy, pain, exercise tolerance, heart failure, or hypertension.

[0018] Other aspects of the disclosure relate to a method of treating a condition in a subject comprising positioning a first implantable electrode on a first lateral side of a vertebral column of the subject at a position between an LI lumbar vertebral body and an SI sacral vertebral body, and electrically stimulating one or more lumbar sympathetic ganglia adjacent one or more vertebrae between the LI lumbar vertebral body and the SI sacral vertebral body using the first implantable electrode sufficient to cause vasodilation in a limb or abdomen of the subject. The first implantable electrode may include at least two spaced-apart electrode contacts. Positioning the first implantable electrode on the first lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the S 1 sacral vertebral body may comprise percutaneously inserting the first implantable electrode within the subject, positioning the first implantable electrode at aposition adjacent one or more of an L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body, positioning at least one electrode contact of the first implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebral body and the SI sacral vertebra, and / or positioning the first implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebral body and the S 1 sacral vertebral body. The first implantable electrode may be an octrode including eight electrical contacts. Other numbers of electrical contacts may also be used. Electrically stimulating using the first electrode may be sufficient to cause vasodilation in an ipsilateral arm or leg corresponding to the first lateral side of the vertebral column, and / or a contralateral arm or leg corresponding to an opposite lateral side of the vertebral column.

[0019] The method may further include positioning a second implantable electrode on a second lateral side of the vertebral column of the subject opposite the first lateral side at a position between the LI lumbar vertebral body and the SI sacral vertebral body, and electrically stimulating one or more lumbar sympathetic ganglia on the second lateral side adjacent one or more vertebrae between the LI lumbar vertebral body and the SI sacral vertebral body using the second implantable electrode sufficient to cause vasodilation in a limb or abdomen of the subject. The second implantable electrode may have at least two spacedapart electrode contacts. The second implantable electrode may be an octrode including eight electrical contacts. Other numbers of electrical contacts may also be used.

[0020] Positioning the second implantable electrode on the second lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the SI sacral vertebral body may include percutaneously inserting the second implantable electrode within the subject, and / or positioning the second electrode at a position adjacent one or more of an L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body. The method may further include positioning at least one electrode contact of the second implantable electrode at a position adjacent an anterior one-third portion of one of the L2 lumbar vertebral body, the L3 vertebral body and the L4 lumbar vertebral body, and / orpositioning the second implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebral body and the SI sacral vertebral body. Electrically stimulating using the second electrode may be sufficient to cause vasodilation in an ipsilateral arm or leg corresponding to the second lateral side of the vertebral column. Electrically stimulating using the first electrode and / or the second electrode may be sufficient to also cause vasodilation in the abdomen of the subject.

[0021] Some aspects of the present disclosure relate to a system for treating a condition in a subject, including a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject, a second electrode contact configured to be positioned on the first lateral side of the subject of the vertebral column of the subject, a third electrode contact configured to be positioned on a second lateral side (opposite of the first lateral side) of the vertebral column of the subject, a fourth electrode contact configured to be positioned on the second lateral side of the vertebral column of the subject, and a stimulator configured to electrically stimulate the LSC on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate a lumbar sympathetic chain on the second lateral side of the vertebral column. The stimulator is configured to send signals to the first electrode contact and the second electrode contact to cause vasodilation in at least one of a limb on the first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side of the subject, and / or send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in at least one of the limb on the second lateral side of the subject or the limb on the first lateral side of the subject.

[0022] Some aspects of the present disclosure relate to a system for treating a condition in a subject including a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject, a second electrode contact configured to be positioned on the first lateral side of the subject of the vertebral column of the subject, a third electrode contact configured to be positioned on a second lateral side (opposite of the first lateral side) of the vertebral column of the subject, a fourth electrode contact configured to be positioned on the second lateral side of the vertebral column of the subject, and a stimulator configured to electrically stimulate the LSC on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate alumbar sympathetic chain on the second lateral side of the vertebral column. The stimulator is configured to send signals to the first electrode contact and the second electrode contact to cause vasodilation in at least one of a limb on a first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side, send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in at least one of the limb on the second lateral side of the subject or the limb on the first lateral side of the subject, and / or toggle between sending the signals to the first electrode contact and the second electrode contact and sending the signals to the third electrode contact and the fourth electrode contact.

[0023] Some aspects of the present disclosure relate to a system for treating a condition in a subject including a first implantable electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject at a position between an LI lumbar vertebral body and an SI sacral vertebral body, and a stimulator configured to electrically stimulate the LSC on the first lateral side of the vertebral column at a position between an LI lumbar vertebral body and an SI sacral vertebral body via the first electrode contact. The stimulator is configured to send signals to the first electrode contact to cause vasodilation in at least one of a limb on the first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side of the subject. The first implantable electrode may include at least two spaced-apart electrode contacts (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 electrode contacts) and / or an octrode including eight electrical contacts. The system may further include a second implantable electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject opposite the first lateral side at a position between an LI lumbar vertebral body and an SI sacral vertebral body, and the stimulator may further be configured to send signals to the second electrode contact to cause vasodilation in one of a limb or abdomen of the subject. The second implantable electrode may include at least two spaced-apart electrode contacts (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 electrode contacts) and / or an octrode including eight electrical contacts.

[0024] Other aspects of the present disclosure relate to a method of treating a condition in a subject, the including electrically stimulating the LSC on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a second electrodecontact on the first lateral side to cause vasodilation in a leg on the first lateral side or a leg on a second lateral side. The method may include positioning the first electrode contact and / or the second electrode contact on the first lateral side of the vertebral column corresponding to an anterior one-third portion of one or more of an LI vertebral body, L2 vertebral body, L3 vertebral body, L4 vertebral body, or L5 vertebral body. The first electrode contact and / or the second electrode contact may be disposed on an electrode lead configured to transition between a straightened (e.g., rigid) configuration and an implantation (e.g., flexible and / or non-straight) configuration, and positioning the first electrode contact and or the second electrode contact may include percutaneously introducing the electrode lead in the straightened configuration into the subject via an introducer, navigating the electrode lead in the straightened configuration to the first lateral side of the vertebral column via the introducer, and decoupling the electrode lead from the introducer, causing the electrode lead to transition from the straightened configuration to the implantation configuration.

[0025] Certain aspects of the disclosure relate to a system having one or more implantable electrode contacts and methods of using the system. For example, the system may include a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject, and optionally, a second electrode contact configured to be positioned on the first lateral side of the subject of vertebral column of the subject. Optionally, the system may include a third electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side, and / or a fourth electrode contact configured to be positioned on the second lateral side of a vertebral column of the subject. One or more of the electrode contacts may be on the same implantable structure or separately deliverable. The system may be used to treat the following: neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), endometriosis, exercise intolerance, heart failure (e.g. HFpEF), hypertension, diabetic vascular disease, microvascular diseases, or other vasodilatory issues.

[0026] The system may include a stimulator (also referred to herein as a pulse generator) configured to electrically stimulate a lumbar sympathetic chain on the first and / or second lateral side of the vertebral column via any of the electrode contacts. The stimulator may be implantable or external or split between internal components, portions or devices (e.g., an internal pulse generator can be externally powered by an external device or component viainductive coupling, which may allow for reduced size of the internal component(s)). The stimulator may be configured to send signals to any one of the electrode contacts, for example to cause vasodilation in the abdomen or a contralateral and / or ipsilateral leg or arm. The electrode contacts may be stimulated at the same time and / or independently from each other. For example, the stimulator can toggle between sending the signals to the first electrode contact and the second electrode contact and sending the second signals to the third electrode contact and the fourth electrode contact. The stimulator may be configured to send signals to the first electrode contact and the second electrode contact to: increase current or voltage until causing vasodilation in an ipsilateral leg or arm (e.g., until vasodilation results or occurs); and increase voltage for longer than ipsilateral leg until causing vasodilation in a contralateral leg or arm (e.g., until vasodilation results or occurs). For example, increasing the voltage may include increasing the voltage from a first voltage of less than or equal 1 V to a second voltage less than or equal to 12 V, for example from a first voltage of at least 1 V to a second voltage less than or equal to 6 V, for example from about 1.5 V to about 4 V, from about 4 V to about 6 V, from about 6 V to about 10 V, from 10 V to about 12 V, or overlapping ranges thereof. The first and second voltages may be dependent on the non-therapeutic diagnosis of voltage thresholds described further below.

[0027] The signal may have a fixed pulse width and / or a fixed frequency. The fixed pulse width may be at least about 0.1 ms and / or less than or equal to about 2000 ms, for example at least about 50 microseconds and / or less than or equal to about 1000 ms, such as between 250 microseconds and 500 microseconds, between 50 microseconds and 250 microseconds, between 500 microseconds and 1 ms, between 1 ms and 100 ms, between 100 ms and 500 ms, overlapping ranges thereof, or any value within the recited ranges. The frequency may be at least about 0.1 Hz and / or less than or equal to 5000 Hz, for example less than or equal to 100 Hz or less than or equal to 20 Hz (e.g., approximately 0.1 Hz, approximately 2 Hz, approximately 3 Hz, approximately 4 Hz, approximately 5 Hz, approximately 6 Hz, approximately 10 Hz, approximately 15 Hz, approximately 16 Hz, approximately 18 Hz, approximately 20 Hz, approximately 50 Hz, approximately 100 Hz, approximately 500 Hz, approximately 1000 Hz, approximately 2000 Hz, approximately 3000 Hz, approximately 4000 Hz, approximately 500 Hz, ranges between such values, or any valuewithin the recited ranges). In some implementations, the pulse width and / or frequency may be varied.

[0028] In some implementations, the method may include electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and / or the second electrode contact until reaching steady state. After reaching the steady state, the method may include electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact for a first duration. After the first duration, the method may include stopping electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact. After stopping electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, the method may include electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column of the subject via the third electrode contact and the fourth electrode contact until reaching steady state. After reaching the steady state, the method may include electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column via the third electrode contact and the fourth electrode contact for a second duration. After the second duration, the method may include stopping electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column via the third electrode contact and the fourth electrode contact. Further steps may include, after stopping electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column via the third electrode contact and the fourth electrode contact, electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column of the subject via the first electrode contact and the second electrode contact until reaching steady state. Where applicable, the first duration and the second duration may be a same duration. The first duration can be between at least about 30 seconds and / or less than or equal to 5 minutes, for example between one minute and four minutes. In other embodiments, the first duration may be different (e.g., longer or shorter) than the second duration.

[0029] Where the first lateral side is a left side, the method may be used to treat pain in a left leg of the subject. Where the first lateral side is a right side, the method may beused to treat pain in a right leg of the subject. The method may include instructing initiation of exercise after causing vasodilation in the contralateral leg.

[0030] Certain methods herein include stimulating lumbar sympathetic nerve activity, for example electric stimulating. Stimulating lumbar sympathetic nerve activity may cause vasodilation in hindlimb beds or renal beds. Stimulating may include unilaterally or bilaterally stimulating a lumbar sympathetic chain.

[0031] Certain methods herein include electrically stimulating a lumbar sympathetic chain on one or both lateral sides of the vertebral column via one or more implantable electrode contacts. Electrically stimulating may include applying electrical signals to the electrode contact(s) to cause vasodilation in a contralateral leg or an ipsilateral leg. The method may be used to treat neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, heart failure (e.g., HFpEF), hypertension, diabetic vascular disease, endometriosis, vasospasm, microvascular diseases, or other vasodilatory issues.

[0032] Certain methods herein may include positioning one or more electrode contacts on first and second lateral sides of the vertebral column. The method may include electrically stimulating a lumbar sympathetic chain on the first lateral side via one or more electrode contacts. Electrically stimulating on the first lateral side may include causing vasodilation in a leg or arm on the first lateral (ipsilateral) side and / or causing vasodilation in a leg or arm on the second lateral (contralateral) side. Electrically stimulating on the first lateral side may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in a leg on the ipsilateral lateral side and / or increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in a leg on the contralateral lateral side. The method may include electrically stimulating a lumbar sympathetic chain on the second lateral side of the vertebral column of the subject via one or more electrode contacts. Electrically stimulating on the second lateral side may include causing vasodilation in a leg on the second lateral (ipsilateral) side and / or causing vasodilation in a leg on the first lateral (contralateral) side. Electrically stimulating on the second lateral side may include increasing voltage until vasodilation in a leg on the ipsilateral side is caused and / or increasing voltage until vasodilation in a leg on the contralateral side is caused. Electrically stimulating can include increasing voltage to cause vasoconstriction in one or both legs or arms. The methodmay include toggling between electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column and electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column or toggling between any of the above- mentioned stimulation parameters to achieve the desired effect.

[0033] Certain methods herein are directed toward treating pain in a subject. The method may include electrically stimulating a lumbar sympathetic chain on one lateral side of a vertebral column via a first electrode contact on the one lateral side and a second electrode contact on the one lateral side. Electrically stimulating may include causing vasodilation in a contralateral arm or leg, for example by increasing current or voltage.

[0034] Certain methods herein are related to a non-therapeutic diagnostic method of diagnosing vasodilation thresholds in a subject, the method may include positioning a first electrode contact on a first lateral side of a vertebral column of the subject. The method may further include positioning a second electrode contact on the first lateral side of the subject of vertebral column of the subject. The method may include electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and / or the second electrode contact. Electrically stimulating the lumbar sympathetic chain on the first lateral side may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in a leg or arm on the first lateral (ipsilateral) side and having little or no effect on a leg or arm on the second lateral (contralateral) side. The method may include recording as VI -1 the voltage that causes vasodilation in the leg or arm on the ipsilateral side and has little or no effect on the arm or leg on the contralateral side. The method may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in the arm or leg on the ipsilateral side and causing vasodilation (e.g., until vasodilation results or occurs) in the leg on the contralateral side and recording as Vl-2 the voltage that causes vasodilation in the leg on the ipsilateral side and vasodilation in the leg on the contralateral side. The method may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in the arm or leg on the contralateral side and causing vasoconstriction or having no effect in the leg on the ipsilateral side and recording as VI -3 the voltage that causes vasodilation in the arm or leg on the contralateral side and causes vasoconstriction or has no effect in the leg on the ipsilateral side. The method may include further increasing voltage until causing vasoconstriction (e.g., until vasoconstriction results oroccurs) or having no effect in the leg on the ipsilateral side and causing vasoconstriction or having no effect in the leg on the contralateral side and recording as VI -4 the voltage that causes vasoconstriction or has no effect in the leg on the ipsilateral side and causes vasoconstriction or has no effect in the leg on the contralateral side. These methods may be used to determine appropriate voltages or stimulation parameters for inducing vasodilation or vasoconstriction in each arm or leg. The electrical stimulation may be continuously applied at one of the above-determined voltages to achieve the desired effect or toggled between any of the above-mentioned voltages. In some embodiments, both vasoconstriction and vasodilation are achieved in the same vessel at different time points. In some embodiments, vasoconstriction and vasodilation are achieved in different vessels and may overlap at a point in time.

[0035] The non-therapeutic diagnostic method may include positioning a third electrode contact on a second lateral side, opposite the first lateral side, of a vertebral column of the subject. The method may further include positioning a fourth electrode contact on the second lateral side of vertebral column of the subject. The method may include electrically stimulating a lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact. Electronically stimulating the lumbar sympathetic chain on the second lateral side may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in a leg or arm on the second lateral (ipsilateral) side and having no effect on a leg or arm on the first lateral (contralateral) side. The method may include recording as V2-1 the voltage that causes vasodilation in the leg or arm on the ipsilateral side and has no effect on the leg or arm on the contralateral side. The method may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in the leg or arm on the ipsilateral side and causing vasodilation in the leg or arm on the contralateral side and recording as V2-2 the voltage that causes vasodilation in the leg or arm on the ipsilateral side and vasodilation in the leg or arm on the contralateral side. The method may include increasing voltage until causing vasodilation (e.g., until vasodilation results or occurs) in the leg or arm on the contralateral side and causing vasoconstriction (e.g., until vasoconstriction results or occurs) or having no effect in the leg or arm on the ipsilateral side and recording as V2-3 the voltage that causes vasodilation in the leg or arm on the contralateral side and causes vasoconstriction or has no effect in the leg or armon the ipsilateral side. The method may include increasing voltage until causing vasoconstriction or having no effect in the leg or arm on the ipsilateral side and causing vasoconstriction or having no effect in the leg or arm on the contralateral side and recording as V2-4 the voltage that causes vasoconstriction or has no effect in the leg or arm on the ipsilateral side and causes vasoconstriction or has no effect in the leg or arm on the contralateral side.

[0036] Certain methods herein relate to a method of inducing bilateral vasodilation from neurostimulation on one lateral side of a lumbar sympathetic chain. The method may include positioning one or more electrode contacts with the lumbar sympathetic chain on the one lateral side of a vertebral column of the subject. The method may include electrically stimulating the lumbar sympathetic chain on the one lateral side of vertebral column via the one or more electrode contacts and causing vasodilation of both arms and / or legs of the subject without increasing mean arterial pressure or heart rate. The vasodilation may treat neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, heart failure (e.g., HFpEF), hypertension, endometriosis, vasospasm, diabetic vascular disease, or other vasodilatory issues.

[0037] Certain methods herein relate to a method of treating hypertension. The method can include delivering an electrical signal to stimulate a lumbar sympathetic chain via one or more electrode contacts on a first lateral side of a vertebral column of a subject, for example a first electrode contact and a second electrode contact. The electrical signal can include a constant frequency, for example 20 Hz or no more than 20 Hz. The electrical signal can include a voltage of at least about 1.5 V and / or less than or equal to about 3.5 V. After delivering the electrical signal, the blood flow increases, and vascular resistance decreases in both legs of the subject.

[0038] In some embodiments, a diagnostic method of finding vasodilation thresholds comprises positioning a first electrode contact on a first lateral side of a vertebral column of the subject, positioning a second electrode contact on the first lateral side of the subject of vertebral column of the subject, and electrically stimulating a lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact. Various access techniques can be used to position the electrical contacts including, for example, utilizing vascular access, utilizing open surgical techniques, and / orminimally invasive techniques that utilize catheters and / or needles. Electrically stimulating can comprise increasing voltage and / or current until causing vasodilation in an ipsilateral leg or arm and increasing voltage until causing vasodilation in a contralateral leg or arm.

[0039] In an aspect, the present disclosure can include a method for causing vasodilation in a subject’ s leg or arm by neuromodulation of the LSC. The method can include interfacing at least two electrode contacts with a LSC of a subject; and delivering an electrical signal to the LSC via the at least two electrode contacts to cause vasodilation in at least one of the subject’s legs or arm.

[0040] In some embodiments, a method comprises interfacing at least two electrode contacts with a lumbar sympathetic chain of a subject; and delivering an electrical signal to the lumbar sympathetic chain via the at least two electrode contacts to cause vasodilation in at least one of the subject’s legs or arms. In some embodiments, the electrical signal may be delivered to the electrode contacts via an implantable pulse generator (“IPG”).

[0041] The at least one or two electrodes may interface with the lumbar sympathetic chain at any level from LI through SI (LI, L2, L3, L4, L5, SI), for example Ll- L4, L5-S1, or L3-L5 level of the subject. The vasodilation may occur in the at least one of the subject’s legs or arms, ipsilateral or contralateral to the at least two electrode contacts. The delivering may further comprise delivering the electrical signal to the lumbar sympathetic chain when a physiological parameter of the subject meets or exceeds a threshold value for the physiological parameter. The physiological parameter may comprise a systolic pressure, a diastolic pressure, a pulse pressure, a mean arterial pressure, a perfusion value, a neural conduction value, a pain indicator, a heart rate, a circulation value, a skin temperature, a change in skin color, a quantification of skin microvasculature and / or arterial / arteriolar blood flow using ultrasound probes or Galvanic skin conductance probes, skin temperature (assessed by infra-red imaging or temperature probe) dyspnea upon exercise, and / or increase in six-minute walk test distance. The electrical signal may comprise a repeating sequence of pulses for a first time followed by a delay for a second time. The second time may be longer than the first time. Each of the pulses may deliver an intensity based on a stimulation intensity required to cause the vasodilation in at least one of the subject’s legs at a constant low frequency and varying current or voltage. The intensity may be a multiple of the stimulation intensity required to cause the vasodilation in at least one of the subject’s legs or arms. The multiple may be from0.1 to 15. The method may further comprise treating at least one of neuropathy, pain in various regions (c.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, diabetic vascular disease like diabetic peripheral microvascular disease, heart failure (e.g., HFpEF), vasodilatory issues like Raynaud’s phenomenon or vasospasm, or hypertension. The at least two electrode contacts may be connected to an external pulse generator or an implantable pulse generator that generates the electrical signal. In certain embodiments, the implantable pulse generator can be provided with or without a battery and / or the external pulse generator can be provided with or without the battery.

[0042] In an aspect, the present disclosure can include a system that can be used to cause vasodilation in a subject’s leg by neuromodulation of the LSC. The system can include a pulse generator that can be configured to generate an electrical signal designed to stimulate the LSC of the subject. The system can also include at least two electrode contacts coupled to the pulse generator. The at least two electrode contacts can be configured to interface with the LSC to deliver the electrical signal. Stimulation of the LSC with the electrical signal can cause vasodilation in at least one of the subject’s arms or legs.

[0043] In some embodiments, a system comprises a pulse generator configured to generate an electrical signal designed to stimulate a lumbar sympathetic chain of a subject; and at least two electrode contacts coupled to the pulse generator and configured to interface with the lumbar sympathetic chain to deliver the electrical signal. Stimulation of the lumbar sympathetic chain with the electrical signal causes vasodilation in at least one of a subject’s arms or legs.

[0044] The pulse generator may be an external pulse generator. The pulse generator may be an implantable pulse generator. The pulse generator may be configured to generate the electrical signal when a physiological parameter of the subject exceeds a threshold value for the physiological parameter. The threshold value may be stored in a memory that is accessible by a component associated with the pulse generator. The physiological parameter may comprise a systolic pressure, a diastolic pressure, a pulse pressure, a mean arterial pressure, a perfusion value, a neural conduction value, a pain indicator, a heart rate, a circulation value, a skin temperature, a change in skin color, a quantification of skin microvasculature and / or arterial / arteriolar blood flow using Doppler flow probes or skin conductance probes, dyspnea upon exercise, and / or increase in six-minute walk test distance. Each of the pulses may deliveran intensity based on a stimulation intensity required to cause the vasodilation in at least one of the subject’s legs or arms at a constant low frequency and varying current or voltage. The intensity may be a multiple of the stimulation intensity required to cause the vasodilation in at least one of the subject’s legs. The multiple may be from 0.1 to 15. The stimulation intensity required to cause the vasodilation in at least one of the subject’s legs or arms at a constant low frequency and varying current or voltage value may be stored in a memory that is accessible by a component associated with the pulse generator.

[0045] Certain aspects are directed toward a method of electrically stimulating a lumbar sympathetic chain via an implantable electrode contact. Electrically stimulating can include causing vasodilation in the musculoskeletal system of hands, legs, and abdomen and / or producing change in a biomarker that offload the patient’s heart and cardiopulmonary congestion. The electrical stimulation may improve ventilation or peripheral congestion. In some embodiments, electrical stimulation may cause vasodilation in an arm or a leg. The electrical stimulation can be at pre-programmed intervals and / or pre-programmed periods of time, such as at least one minute and / or no more than two hours. The stimulation may be at a fixed frequency.

[0046] Systems for electrically stimulating the lumbar sympathetic chain may include an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain. The system may include a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may include a processor configured to receive a preprogrammed instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may be implantable or wearable. The pre-programmed instruction may include instructions to send the signal at pre-determined intervals during a day, pre-determined periods of time, and / or pre-programmed stimulation parameters.

[0047] Certain aspects of the disclosure relate to a method of modulating a vasoactive property in a patient. The method may include receiving an instruction to electrically stimulate a lumbar sympathetic chain via an implantable electrode contact. The instruction may be received by a controller, for example pre-programmed, automated, or from an external device. The method may include activating a stimulator to send a signal to theimplantable electrode contact and electrically stimulating the lumbar sympathetic chain vi the implantable electrode contact.

[0048] Electrically stimulating a first side of the lumbar sympathetic chain at a first current or first voltage can cause vasodilation in an ipsilateral arm or leg and / or the entire abdomen. Electrically stimulating the first side of the lumbar sympathetic chain at a second current or second voltage can cause vasodilation in a contralateral arm and / or leg. Electrically stimulating the first side of the lumbar sympathetic chain at a third current or third voltage can cause vasoconstriction in the ipsilateral arm and / or leg. The method may include toggling electrical stimulation between different currents and / or voltages to achieve different vasoactive properties or effects at different locations. The electrical stimulation can reduce pulmonary capillary wedge pressure.

[0049] Some methods may include detecting physical exertion using one or more sensors. The electrical stimulation may occur after detecting physical exertion of the patient. The method may include suspending or reducing electrical stimulation after detecting physical exertion of the patient above a threshold. The method may include automatically electrically stimulating in response to detecting the physical exertion or prompting the patient to activate the stimulator in response to detecting the physical exertion. The one or more sensors may include at least one of an electrical sensor, an accelerometer, or a gyrometer (gyroscope).

[0050] The method may include detecting the physical exertion by measuring a physiological parameter using the one or more sensors. The physiological parameter may be blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity. The method may include deactivating the stimulator when physical exertion above a certain threshold is no longer detected. The electrical stimulation may be at a frequency of no more than 20 Hz and / or at a fixed frequency.

[0051] The method may include electrically stimulating after detecting a cold temperature. For example, the method may include automatically electrically stimulating in response to detecting the cold temperature or prompting the patient to activate the stimulator in response to detecting the cold temperature. The method may include detecting the cold temperature using one or more sensors. The method may include electrically stimulating so long as the cold temperature is detected.

[0052] Certain aspects of the disclosure relate to a method of modulating a vasoactive property in a patient. The method may include detecting, by one or more sensors, a physiological parameter or condition of the patient; activating a stimulator to send a signal to the implantable electrode contact; and electrically stimulating the lumbar sympathetic chain via the implantable electrode contact based on the detected physiological parameter or condition. The method may include varying one or more of an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition.

[0053] The method may include varying electrical stimulation between wake and sleep. For example, the method may include suspending or reducing electrical stimulation during sleep. The method may include increasing electrical stimulation during sleep if no side effects are detected.

[0054] The method may include varying electrical stimulation based on a side effect of the electrical stimulation detected by the one or more sensors. The method may include detecting, by the one or more sensors, muscle stimulation or vibration or measures of autonomic tone indicative of sympathetic activation. The physiological parameter may include blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity.

[0055] The method may include varying electrical stimulation based on a posture of the patient. The method may include varying electrical stimulation based on a time of day.

[0056] Certain aspects of the disclosure relate to a method of modulating a vasoactive property in a patient. The method may include alternating electrically stimulation of a lumbar sympathetic chain via a first implantable electrode contact and electrical stimulation for a different therapy. For example, the method may include electrically stimulating baroreceptors via a second implantable electrode contact, defibrillating the patient’s heart, or delivering stimulation to the patient's heart (e.g., anti-tachycardia pacing). The method may include preventing simultaneous stimulation between the electrical stimulation of the lumbar sympathetic chain and the baroreceptors. In some aspects, the techniques described herein relate to a method, wherein electrical stimulation can cause an improvement in performance of the second therapy, for example a reduction in a defibrillation threshold or an increase in anti-tachycardia pacing success.

[0057] Certain aspects of the disclosure relate to a system for electrically stimulating a lumbar sympathetic chain of a patient. The system can include an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator can include a communication module configured to communicate with an external device. The stimulator can include a processor operably connected to the communication module. The processor can be configured to receive an instruction from the external device to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may be implantable. The one or more sensors may be configured to detect physical activity of the patient. The one or more sensors may be configured to measure a physiological parameter of the patient.

[0058] Certain aspects of the disclosure relate to a system for electrically stimulating a lumbar sympathetic chain of a patient. The system may include an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain. The system may include one or more sensors configured to detect a physiological parameter or a condition of the patient. The system may include a processor configured to receive data from the one or more sensors. The system may include a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may be configured to receive an instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain based on the data received from the one or more sensors. The stimulator may be implantable or wearable.

[0059] The one or more sensors may be configured to detect the physiological parameter. The one or more sensors may include an optical sensor or a ventilation sensor. The physiological parameter may include blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity. The one or more sensors may include an electrical sensor, a gyrometer, or an accelerometer.

[0060] The one or more sensors may be configured to detect the condition of the patient. The condition of the patient may be physical activity, an uncomfortable sensation orpain, or an efficacy of the electrical stimulation. The processor may be configured to automatically receive the instruction in response to the one or more sensors detecting the physiological parameter of the condition of the patient. An external device may be configured to receive instructions from the patient to send the instruction to the processor. The processor may be configured to receive the data from the one or more sensors when the electrical stimulation is active and inactive; compare the data from when the electrical stimulation is active and the data from when the electrical stimulation is inactive; and adjust a stimulation parameter of the electrical stimulation based on the comparison between the data. The processor may be on-board the stimulator or remote from the stimulator.

[0061] The processor may be configured to adjust a stimulation parameter of the instruction based on the data received from the one or more sensors. The stimulation parameter may include an amplitude, frequency, pulse width, duty cycle, and / or stimulation vector. The processor may be configured to adjust the stimulation parameter without adjusting the implantable electrode contact.

[0062] The processor may be configured to continuously receive data from the one or more sensors, for example at pre-determined intervals or on demand. The one or more sensors may be implantable or contained in an external monitoring device configured to wirelessly communicate with the stimulator.

[0063] Certain aspects of the disclosure relate to a system for electrically stimulating a lumbar sympathetic chain of a patient. The system can include an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator can include a processor configured to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain when activated by the patient. The stimulator may be configured to be activated by a wearable component or other external device. The stimulator may be configured to be activated when placed into electrical communication with the implantable electrode contact.

[0064] Certain aspects of the disclosure relate to a method of treating conditions such as diabetic vascular disease and neuropathy in a patient. The method may include receiving an instruction to electrically stimulate a lumbar sympathetic chain via an implantableelectrode contact; activating a stimulator to send a signal to the implantable electrode contact; and electrically stimulating the lumbar sympathetic chain via the implantable electrode contact, wherein electrically stimulating includes causing vasodilation in a leg, arm, or abdomen. The instruction may be received by a controller, either pre-programmed, automated, or from an external device. The electrical stimulation may cause accelerated wound healing. The external device is a wearable device. The electrical stimulation may include stimulating at a fixed frequency.

[0065] Certain aspects of the disclosure relate to a system for electrically stimulating a lumbar sympathetic chain of a patient. The system may include an implantable electrode contact configured to be delivered into contact with the lumbar sympathetic chain; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may include a processor configured to receive an instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The system may include an external device configured to send the instruction to the processor. In other embodiments, the instruction may be preprogrammed or automated based on a condition or parameter detected by one or more sensors. The implantable electrode contact may be an acute or sub-acute device. The external device may be a wearable device. The stimulator may be implantable.BRIEF DESCRIPTION OF THE DRAWINGS

[0066] The foregoing and other features of the present disclosure will become apparent upon reading this specification with reference to the accompanying drawings, in which:

[0067] FIG. 1 is a schematic diagram showing an example of a system that can use neuromodulation of a subject’s lumbar sympathetic chain (LSC) under certain therapeutic conditions to cause vasodilation in at least one of the subject’s legs.

[0068] FIG. 1A is a schematic diagram of the LSC and ganglia.

[0069] FIG. 2 shows an example of actions taken to determine whether and when to deliver an electrical signal to the LSC.

[0070] FIGS. 3 and 4 are process flow diagrams illustrating example methods for neuromodulating a subject’s LSC under certain therapeutic conditions to cause vasodilation in at least one of the subject’s legs.

[0071] FIG. 5 is a diagrammatic representation of the lumbar sympathetic chains and the level of L4-L5.

[0072] FIG. 6 is a graphical representation of vasodilation thresholds.DETAILED DESCRIPTION

[0073] The sympathetic nervous system is part of the autonomic nervous system generally associated with the “Fight or Flight” response. Generally, the “Fight or Flight” response is an innate principal survival mechanism by which the body prepares itself for intense physical activity (e.g., in the presence of danger) by accelerating heart rate, dilating pupils, dilating bronchioles, inhibiting digestion, increasing cardiac output, raising blood pressure, constricting blood vessels, and the like. This vasoconstriction occurring in the “Fight or Flight” response generally occurs in core organs, like the intestines and liver. The essential hemodynamic adjustments including increased cardiac output, reduced blood flow (vasoconstriction) in non-essential (at that moment) vascular beds such as intestinal and hepatic beds result in a large increase in blood-flow to the skeletal musculature of the leg, which is accommodated by a simultaneous neurogenic (post-ganglionic lumbar sympathetic)- mediated vasodilation of the microvasculature in the leg. The vasculature in the muscle beds of the legs, for example, undergoes vasodilation during the “Fight or Flight” response.

[0074] The present disclosure generally relates to neuromodulation of a subject’s lumbar sympathetic nerve activity to cause vasodilation in one or both of a subject’s legs. Neuromodulation of a subject’s sympathetic nerve activity may additionally cause vasodilation in one or both of a subject’s arms and / or abdomen. Vasodilation refers to the widening of blood vessels, increasing blood flow, which can be used to treat conditions as varied as neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, diabetic peripheral microvascular disease, heart failure (e.g., HFpEF), hypertension, peripheral artery disease, diabetic neuropathic vasculopathy, diabetic peripheral vascular disease, endometriosis, microvascular diseases, erectile disfunction, etc. The neuromodulation under certain stimulation conditions (e.g. conditions that provide a stimulation intensity required to cause the vasodilation in at least one of the subject’s legs or arms (e.g., at a constant low frequency and varying current or voltage)) can occur when a physiological parameter of the subject that meets or exceeds a threshold value that is set for the physiological parameter. The change in the physiological parameter may be produced bythe electrical stimulation. The change in the physiological parameter may be a change in one or more biomarkers, for example biomarkers that offload the heart and cardiopulmonary congestion. Examples of the physiological parameter can include (or can be indicative of) a systolic pressure, a diastolic pressure, a pulse pressure, a mean arterial pressure, a perfusion value, a neural conduction value, a pain indicator, a heart rate, a circulation value, a skin temperature (e.g. sensational warmth), a change in skin color, a quantification of skin microvasculature and / or arterial / arteriolar blood flow using Doppler flow probes or skin conductance probes, dyspnea upon exercise, an increase in six-minute walk test distance, a paresthesia, and / or the like.

[0075] Pharmacological Modulation of the sympathetic system using adrenergic agonists is thought to produce vasoconstriction. However, this concept is restricted to pharmacomodulation of vascular tone. Neurogenic vasodilation is independent of pharmacological agents and is an innate part of the body’s physiological control (fight or flight response). Here, stimulating the peripheral source of this sympathetic tone to the peripheral vessels that innervate the extremities results in vasodilation or vasodilatory effects seen in the fight or flight reflex, without the associated cardi-accelerator effects seen in the fight or flight reflex. The cardio-accelerator effects are due to activation of baroreceptors to sustain situations of high cardiac output. In accordance with several embodiments, our proposed ability to modulate the peripheral vascular tone by modulating nerve signals in the lumbar sympathetic chain will result in therapeutic benefits across a range of disease conditions. Without being limited or held to any particular theory, the modulation can stimulate the lumbar sympathetic chain to cause vasodilation of the leg or arm on the same side as the modulation (i.e., ipsilateral side) and / or the leg or arm on the opposite side of the modulation (i.e., contralateral side). Between 0 Volts and a first voltage Vi that varies but can be systematically identified, modulation causes a small vasodilation of the leg on the same side as the modulation and may not affect the leg on the opposite side. Between Vi and a second voltage V2 that varies but can be systematically identified, modulation causes vasodilation of the leg on the same side as the modulation and a small vasodilation is seen on the contralateral or opposite side. Between V and a third voltage V3 that varies but can be systematically identified, modulation causes vasodilation of the leg on the same side as the modulation and causes vasodilation of the leg on the opposite side. Between V3 and a fourth voltage V4 that varies but can be systematicallyidentified, modulation causes vasodilation of the leg on the opposite side as the modulation while producing vasoconstriction on the same side. The side of the modulation can be selected based on the intended effect. The side of modulation can toggle between sides of the vertebral column to produce the intended vasodilatory effect in both legs. In some embodiments, both vasoconstriction and vasodilation are achieved in the same vessel at different time points. In some embodiments, vasoconstriction and vasodilation are achieved in different vessels and may overlap at a point in time.Stimulation of Lumbar Sympathetic Chain

[0076] FIG. 1 is a schematic diagram showing an example of a system 10 that can use neuromodulation of a subject’s lumbar sympathetic chain (LSC) (e.g., the right LSC 12a and / or the left LSC 12b) under certain therapeutic conditions to cause vasodilation in at least one of the subject’s arms or legs. The system 10, in one embodiment, can take advantage of the discovery that, although the “Fight or Flight” response that is mediated by the sympathetic nervous system tends to constrict blood vessels related to core organs (e.g., intestines, liver, etc.), vessels far from the core (e.g., in the leg musculature) may have the ability to vasodilate either physiologically or due to direct neural stimulation of the LSC. The system 10 can exploit this property by neuromodulating the LSC under certain stimulation conditions to cause this vasodilation within at least one of the arms or legs. In some embodiments, a vasodilation response, without vasoconstriction is achieved. In some embodiments, decreased congestion is achieved in a limb or other body part, thereby reducing pressure on the heart. This, in some embodiments, may be achieved by avoiding or reducing vasoconstriction and / or enhancing vasodilation. In some embodiments, post stimulation, vasodilation in a limb or other part is increased by at least 10%, at least 25%, or more. In some embodiments, post stimulation vasodilation is increased at a level sufficient to improve ventilation and / or improve peripheral congestion. In some embodiments, the stimulation can cause an increase in blood flow and / or a corresponding decrease in blood pressure without causing a significant increase in heart rate or cardiac load.

[0077] Generally, the sympathetic chains refer to a pair of ganglionated longitudinal cords of the sympathetic nervous system situated on each side of the spinal column, extending from the base of the skull to the coccyx. The LSC 12a, 12b sits between the anterior one-third portion of the LI, L2, L3, L4, and L5 vertebral bodies and the anteromedialmuscular fascia. FTG. 1 schematically illustrates the lumhar region of the spinal column (SPINE) from the LI - L5 regions (defined by the five lumbar vertebrae, which arc not explicitly individually illustrated). The LSC 12a, 12b defines a portion of the sympathetic chains running in the LI - L5 regions of the spine and anterolateral to bodies of the five lumbar vertebrae (e.g., the anterior one-third portion of the lumbar vertebral bodies). The LSC 12a, 12b is located at approximately the anterior one-third portion of the LI, L2, L3, L4, and L5 vertebral bodies. The LSC 12a, 12b sits outside of the spinal column (e.g., outside of epidural column) making it attractive for neuromodulation because the location of the LSC is surgically accessible via image guidance and minimally invasive techniques. Placing one or more electrodes (E) 14a and / or 14b in communication with the LSC 12a and / or 12b (at the L2, L3, L4, and / or L5 level such as the anterior one-third of the vertebral bodies of the lumbar region) can enable manipulation of downstream branches that regulate vasomotor functions. As such, by delivering a specially configured stimulation to the LSC 12a and / or 12b by a contact or contacts of the electrodes 14a and / or 14b, vasodilation within the legs and / or arms and / or abdomen can be induced. The ability to produce vasodilation can enable modulation of critical physiology for diseases and conditions, like neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, diabetic vascular disease like diabetic peripheral microvascular disease, heart failure (e.g., HFpEF), endometriosis, microvascular diseases, vasodilatory issues like Raynaud’s phenomenon or vasospasm, hypertension, and / or the like.

[0078] FIG. 1A is a schematic diagram of the LSC 12a, 12b and ganglia, more specifically lumbar ganglia 100. FIG. 1A extends from the L2 vertebra 102 to the L5 vertebra 105. FIG. 1A shows the left crus 108, the medial arcuate ligament 110, the psoas major 112, and the hypogastric plexus 114. The LSC s 12a, 12b are a pair of longitudinal ganglionic cords on both sides of the vertebral column, which carry pre- and post-ganglionic sympathetic fibers to the legs via the hypogastric plexus 114. Surgical access to the LSC 12a, 12b in humans is relatively uninhibited. The LSC 12a, 12b controls the microcirculation in the legs and feet. The LSC 12a, 12b are located lateral and anterior to each lumbar vertebral body (e.g., each of the LI, L2, L3, L4, L5 vertebral bodies). The LSC 12a, 12b contain a therapeutic target for neuromodulation (“stimulation location”) located approximately at the anterior one-third of the LI, L2, L3, L4, and L5 vertebral bodies.

[0079] FIG. 5 also illustrates the anatomical location of the LSC 12a, 12b relative to the vena cava 116, the aorta 118, the iliolumbar artery 120 and vein 121 (the artery 120 extending from the aorta 118 and the vein 121 extending from the vena cava 116), the psoas major 112 (also shown in FIG. 1A), and the lumbar artery and vein 122, 123 (the artery 122 extending from the aorta 118 and the vein 123 extending from the vena cava 116).

[0080] Sympathetic innervation of the microvasculature can elicit changes in arterial blood flow that serve the physiological (e.g., metabolic) needs of target organs. Activation of sympathetic nerves can elicit vasoconstriction (diminished blood flow) in organs such as intestines and liver. Depending on the stimulation parameters and / or stimulation location, for example, the physiological or direct electrical stimulation of the LSC 12a, 12b can elicit a pronounced vasoconstriction and / or vasodilation (increase in blood flow) in muscle beds of the legs or arms or renal beds. The stimulation location can include, for example, interganglionic segments between each lumbar sympathetic ganglia, direct modulation of sympathetic ganglia alone, direct modulation of ganglia with electrodes overlapping an interganglionic segment between Ll-Sl, for example, between L1-L4, between L2-L3, or between L3-L5. The anterior one-third of the LI, L2, L3, L4, and L5 vertebral bodies may be an ideal location for electrode placement and for targeting the stimulation location. For example, in some embodiments, the electrode may be implanted at a location between the anterior one-third of the L3 vertebral body and the anteromedial muscular fascia in order to stimulate the LSC. Stimulating at a posterior portion (e.g., the posterior two-thirds) of the LI, L2, L3, L4, or L5 vertebral bodies may miss targeting a desired or therapeutically efficacious stimulation location. In accordance with several embodiments, this novel approach may fill an urgent unmet need to treat high blood pressure (e.g., hypertension) or other conditions described herein without drug therapy.Example Systems for Lumbar Sympathetic Chain Neuromodulation

[0081] Referring again to FIG. 1, the system 10 can include one or more electrodes 14a and / or 14b coupled to a pulse generator 16 (also referred to herein as a stimulator or a stimulation device). The electrodes 14a and / or 14b can be used to deliver the stimulation to the LSC 12a and / or 12b. The electrodes 14a and / or 14b can be internal or implantable electrodes (e.g., paddle electrodes, cuff electrodes, percutaneous electrodes, etc.) placed by image guidance and / or other minimally invasive techniques, or external electrodes (e.g., skin surfaceelectrodes) placed according to landmarks that can be felt externally. Each of the electrodes 14a and / or 14b can include two or more electrode contacts, which arc configured or adapted to interface with the LSC 12a and / or 12b to deliver the electrical stimulus to the LSC 12a and / or 12b. For example, each of the electrodes 14a and / or 14b can include two electrode contacts, four electrode contacts, six electrode contacts, eight electrode contacts, ten electrode contacts, twelve electrode contacts, fourteen electrode contacts, sixteen electrode contacts, eighteen electrode contacts, or more. An electrode contact can be considered to be adapted for such placement based on, for example, its size, material, anchorability, etc. One or more electrode contacts may be positioned on a first lateral (e.g., anterolateral) side of a vertebral column of a patient. Depending on the procedure, one or more additional electrode contacts may be positioned on a second lateral (e.g., anterolateral) side of the vertebral column (e.g. opposite the first anterolateral side).

[0082] In some embodiments, the electrodes 14a and 14b may be on an electrode lead, and may be delivered (e.g., percutaneously, laparoscopically or endoscopically) to the LSC. The spacing between the one or more electrode contacts of the electrodes 14a and 14b may be wide enough to allow the electrodes 14a and 14b to span more than one of the LI, L2, L3, L4, L5, vertebral bodies. For example, in some embodiments, the one or more electrode contacts may be spaced more than approximately 4 mm apart from each other. The electrodes 14a and 14b may be delivered to the LSC by either a rostral approach (e.g., superior-to-inferior) or a caudal approach (e.g., inferior-to- superior). When delivery is made via a rostral approach, the electrode lead may be laterally introduced into the patient (e.g, via an incision) at approximately the T 12, LI level and navigated down the spinal column until the electrodes 14a and 14b are positioned at the stimulation location (e.g., the anterior one-third portion of the L2 and L3 vertebral bodies). Alternatively, the electrode lead may be laterally introduced from a more superior location (e.g., higher than the T12, LI level) before being navigated down the spinal column until the electrodes 14a and 14b are positioned at the stimulation location. When delivery is made via a caudal approach, the electrode lead may be laterally introduced into the patient (e.g, via an incision) approximately at or just above the level of iliac crest, just lateral to the iliolumbar ligament or at approximately the L5 level, and navigated up the spinal column until the electrodes 14a and 14b reach the stimulation location (e.g., the anterior one- third of the L2 and L3 vertebral bodies). In some embodiments, the electrode lead may beintroduced into the patient by an introducer needle (e.g. a 14-gauge introducer needle or a 7 French introducer) with a curved tip to angle the electrode lead towards the stimulation location.

[0083] Both approaches may require the electrode lead to be anchored after implantation in order to prevent lead migration and maintain the electrodes 14a and 14b at the stimulation site. This anchoring may be achieved by one or more bi-directional tines located along the length of the electrode lead. For example, the electrode lead may have one or more tines located proximally of the electrodes 14a and 14b, and / or one or more tines located distally of the electrodes 14a and 14b. In some instances, there may be one or more tines located between the electrodes 14a, 14b. The locations of the one or more tines may be concentric in cross-section. Additionally, or alternatively, the electrode lead may be anchored in position by way of a lead anchor that is sutured to the muscle fascia.

[0084] Lead migration may additionally or alternatively be prevented by way of a soft or flexible electrode lead design. In some embodiments, the electrode lead may transition between a straightened configuration (e.g., a rigid straightened configuration) suited for delivery and navigation towards the LSC, and an implantation configuration that is flexible and / or non- straightened. For example, the electrode lead may be in the straightened configuration when coupled to an introducer as it is being navigated towards the LSC, and transition to the implantation configuration where the electrode lead assumes a soft, flexible shape when the electrode lead is decoupled from the introducer. In some embodiments, the electrode lead may have or assume a flexible pre-formed non-straight shape in the implantation configuration. The flexible pre-formed shape may be designed to mold or contour or conform to the anatomy at the stimulation location (e.g., the anterior one-third of the LI, L2, L3, L4, and L5 vertebral bodies). For example, the electrode lead may be maintained in a straightened configuration during delivery to the LSC by way of a stylet, and once the electrode contacts are positioned at the stimulation location, the stylet is removed, allowing the electrode lead to revert back to its flexible shape in the implantation configuration In another example, the soft or flexible electrode lead may be sheathed or surrounded by a catheter that maintains the electrode lead in a straightened configuration as the electrode lead is navigated towards the LSC, and once the electrode contacts are positioned at the stimulation location, the catheter or sheath is removed, allowing the electrode lead to revert back to its flexible shape in theimplantation configuration. Additionally or alternatively, the electrode lead may be made from a shape memory material that causes the electrode lead to assume a pre-formed shape designed to contour or conform to the anatomy at the stimulation site when the electrode lead is exposed to the subject’s internal temperature.

[0085] Depending on the indication, the systems described herein may be open loop, closed loop or semi-closed loop. For example, the systems and devices described herein can be actuated manually, semi-automatically, and / or fully automatically.

[0086] In an open-loop system, the system may be programmed stimulate for a predetermined amount of time upon activation, for example at least about one minute and / or less than or equal to two hours, such as less than or equal to 1 hour, less than or equal to 30 minutes, less than or equal to 20 minutes, less than or equal to 15 minutes, less than or equal to 10 minutes, or less than or equal to 5 minutes, ranges between such values, or any value within the recited ranges. The stimulator may include a processor configured to be programmed with instructions for electrical stimulation. The instructions may include one or more parameters, including but not limited to, the number of times per day, the time intervals throughout the day, the duration, the frequency, current, amplitude, or pulse width. Ranges for any of these parameters are set forth throughout this disclosure.

[0087] In a closed-loop system, stimulation may be activated based on a reading from one or more sensors. The stimulator may include a processor configured to receive an instruction to send a signal for electrical stimulation in response to the one or more sensors measuring a physiological parameter or detecting a condition of the patient. The instruction may be automatic based on the reading from the one or more sensors. In other systems, the system may prompt the user to send the instruction in response to the one or more sensors measuring a physiological parameter or detecting a condition of the patient.

[0088] The one or more sensors may be implanted or wearable. If implanted, the one or more sensors may be implanted near the one or more electrodes 14a, 14b or at a remote location within the body. The one or more sensor readings may trigger electrical stimulation based on a comparison between the detected measurement and a threshold value. The threshold value may be pre-programmed or calibrated based on the patient. The sensor(s) may include a gyrometer, accelerometer, pho toplethy smogram (PPG), blood pressure sensor, flow sensor, temperature sensor, and / or other physiological sensors. The one or more sensors may be usedin a reactive or preventative manner. For example, the one or more sensors may detect a concern from a physiological parameter that may warrant treatment. In other examples, the one or more sensors are used to detect certain activity, lack of activity, or sympathetic neurological tone, which puts the patient at a higher risk for an event that may warrant preventative treatment.

[0089] In a semi-closed loop system, stimulation may be activated based on a combination of pre-programmed instructions and readings from one or more sensors. In yet other systems, the electrical stimulation may be on-demand. The processor may be configured to receive an instruction to provide electrical stimulation in response to activation by the patient or responder. For example, the system may include an actuator external to the patient that may be triggered by the patient or a responder. The stimulation may be activated by an application on an external device such as a smartphone or tablet. As another example, the stimulation may be activated by a user actuator on a dedicated external device for the system. The dedicated external device may be a wearable component, for example a patch or wearable on a strap, wristband, or otherwise.

[0090] As discussed above, each electrode 14a, 14b can include multiple electrode contacts. For example, the LSC 12a on the right side of the spine can be stimulated using two electrode contacts of the electrode 14a. For another example, the LSC 12b on the left side of the spine can be stimulated using two electrode contacts of the electrode 14b. For another example, the LSC 12a and / or the LSC 12b can be stimulated using one electrode contact of the electrode 14a and one electrode contact of the electrode 14b. Stimulation can be bipolar between the electrode contacts. In some embodiments, stimulation can be monopolar, using one electrode contact on one side of the spine, and a return electrode pad (e.g., on a thigh) or an implantable pulse generator (“IPG”) may be used as a return electrode. In certain embodiments, a stimulation device can be provided that includes at least one electrode contact and a sink that can be used as a ground, reference or return electrode. In some implementations, the device could include multiple electrodes with at least one cathode and one anode. In some implementations, the electrode contacts can be from an implanted spinal cord stimulator. The electrode contacts can be directional, focused, etc. to target specific anatomy (e.g., aiming signals at one side of the spine). The electrodes 14a, 14b may be positioned proximate to, and not encircle, for example, target nerves. The electrodes 14a, 14b may be positioned on theanterior one-third portion of one or more of the LI , L2, L3, L4, and L5 vertebral bodies (e.g., the anterior one-third portion of the L2 vertebral body, the anterior third of the L3 vertebral body, etc.).

[0091] Stimulation of the LSC 12a and / or 12b with a specifically configured electrical signal can cause vasodilation in at least one leg (e.g., contralateral and / or ipsilateral to the stimulation). The resulting vasodilation can be measured, for example, by one or more of visual observation (e.g., increase in skin pallor of the lower extremity), vascular Doppler, or other methods of detecting vascular reactivity. In some implementations, the device used to power the implant could include methods to measure skin blood flow (e.g., using infrared light). In some embodiments, the LSC or other nerves described herein are a species of tissue that can be modulated with the electrodes 14a and / or 14b.

[0092] The pulse generator 16 can be an external pulse generator, an internal pulse generator (IPG), or a pulse generator with components split between both internal and external (e.g., the pulse generator 16 can be externally powered via inductive coupling). The pulse generator 16 can comprise wired or wireless communication (e.g., configured to communicate with the electrodes 14a, 14b, a hospital system, a computer, a handheld device such as a phone or tablet, etc.). The pulse generator 16 can generate an electrical signal designed to stimulate the LSC 12a and / or 12b to provide vasodilation in one or more of the legs. The stimulation frequency can be at least about 2 Hz and less than or equal to 5000 Hz, for example less than or equal to 1000 Hz, less than or equal to 500 Hz, less than or equal to 100 Hz, less than or equal to 20 Hz, less than or equal to 15 Hz, less than or equal to 10 Hz, less than or equal to 5 Hz, ranges between such values, or any value within the listed ranges. The stimulation can have a low frequency (e.g., approximately 20 hertz (Hz) or less), a low amplitude (e.g., approximately 12 volts (V) or less (e.g., approximately 10 V or less, approximately 8 V or less, approximately 6V or less, etc.)), and / or a small pulse width (e.g., less than 1 millisecond (ms)) and / or a low current (e.g., between 1-10 milliamps (mA)). For example, the current can be at least about 1 milliamp and / or less than or equal to 10 milliamps, for example less than or equal to 9 milliamps, less than or equal to 8 milliamps, less than or equal to 7 milliamps, less than or equal to 6 milliamps, or less than or equal to 5 milliamps. The pulse width can be less than or equal to 2 milliseconds, for example less than or equal to 1 millisecond, less than or equal to0.5 millisecond or less than or equal to 0.3 millisecond. For example, the pulse width may be between 250 microseconds and 500 microseconds.Example Methods for Lumbar Sympathetic Chain Neuromodulation

[0093] In some implementations, the therapy can be intermittent or continuous. For example, intermittent therapy could comprise applying the electrical signal one or more times per day for a period of time (e.g., at least 1 minute and / or less than or equal to two hours, for example between 30 seconds and five minutes per application, between 10 and 20 minutes per application, between 15 and 25 minutes per application, etc.). The electrical signal may be activated at least two times a day and / or less than or equal to 10 times a day, for example less than or equal to eight times a day, less than or equal to 5 times a day, less than or equal to 4 times a day, less than or equal to 3 times a day, etc. The electrical signal may be automatically activated at specific times of day, upon user activation, based on a sensor reading, programmed instructions on the stimulator 16, or otherwise. Depending on the indication, the electrical stimulation may be limited to a particular time of day. For example, for treating pain symptoms, electrical stimulation may only be applied during daytime hours (e.g., hours where the patient is generally awake) or before physical activity. The electrical stimulation may be activated in response to instructions from an algorithm. The algorithm may be predictive and / or responsive. For example, for treating heart failure, a predictive algorithm may provide electrical stimulation at times corresponding to a pre-defined threshold R-R interval value. In another example, for treating heart failure, a responsive algorithm may provide electrical stimulation in response to registering (e.g., based on measurements from one or more sensors) that a heartbeat hasn’t occurred.

[0094] In the case of bilateral electrode placement, stimulation can be alternated from side to side (e.g., stimulation can be alternated between the right LSC 12a and the left LSC 12b) or in some implementations one side can be treated first or both sides could be treated at the same time. Multiple pulse shapes can be used such as, for example, biphasic pulses with the ability to provide multiple phases for charge balancing (e.g., recharge phases that can be 1 to 4 times as long (with amplitude scaled to match the charge injection in phase)). In some implementations, the signal can comprise a constant current with a variable voltage. The electrical signal can include a repeating sequence of pulses for a first time period and a delay for a second time period. In some instances, the second time period can be longer than the firsttime period. In other instances, the first time period can have the same duration as the second time period). Each of the pulses can deliver an intensity that can include at least a portion of the stimulation intensity required to cause the vasodilation in at least one of the subject’s legs, for example at a constant low frequency and varying current or voltage. The intensity can be a multiple of the stimulation intensity required to cause the neuromodulation (e.g., between a multiple of 0.1 and a multiple of 15).

[0095] FIG. 2 shows an example of actions taken to determine whether and when to deliver an electrical signal to the LSC. The pulse generator 16, or a component in communication with the pulse generator 16, can include a non-transitory memory (e.g., any memory that is not a transitory signal) storing instructions and a processor (e.g., a hardware processor) that accesses the non-transitory memory and executes the instructions. At least a portion of the operations shown in FIG. 2 can be based on the instructions that are stored in the non-transitory memory and executed by the processor. The pulse generator could also include one or more wireless communication chips (e.g., Bluetooth low energy), applicationspecific integrated circuit (ASIC) capable of converting voltage from a battery or a wireless link to generate stimulation current, various sensors, and / or a processor processing for physiological signals and / or algorithms for close loop control.

[0096] A physiological parameter or physiological value 22 can be received by the pulse generator 16. The physiological value 22 can be recorded, for example, by a sensor and / or input by a user. The physiological value 22 can be, for example, a systolic pressure, a diastolic pressure, a pulse pressure, a mean arterial pressure, a perfusion value, a neural conduction value, a pain indicator, a heart rate, a circulation value, a skin temperature, a change in skin color, a quantification of skin microvasculature and / or arterial / arteriolar blood flow using Doppler flow probes or skin conductance probes, dyspnea upon exercise, increase in six- minute walk test distance, paresthesia and / or the like. A stored threshold value 24 can be retrieved (e.g., from the non-transitory memory, from a remote source, and / or the like). The stored threshold value 24 can be specific to the physiological value 22. For example, the stored threshold value 24 can be determined for the subject based on previous data from the subject and / or previous data from a similar subject population (e.g., suffering from the same disease and / or healthy, but exhibiting one or more of the same physical qualities).

[0097] The physiological value 22 can be compared to the stored threshold value 24, for example by a processor or comparator of the pulse generator 16 or in communication with the pulse generator 16. When the physiological value 22 is found to exceed the stored threshold value, as indicated by the box 26, an electrical signal can be delivered to the subject’s LSC, as indicated by the box 28. If the physiological value 22 does not exceed the stored threshold value 24, no stimulation can be generated, as indicated by the box 29. In some instances, the question of whether the physiological value 22 exceeds the stored threshold value 24 can include determining whether the stimulation is necessary. For example, if the physiological value 22 only exceeds the stored threshold value 24 by a small amount (e.g., the stored threshold value 24 for systolic pressure is 150 mmHg, and the physiological value 22 for systolic pressure is 152 mmHg), the stimulation may not be truly necessary. As another example, when the stored threshold value 24 for systolic pressure is 150 mmHg and the physiological value 22 for systolic pressure is 175 mmHg, the stimulation may be entirely necessary. Accordingly, a second threshold value may be stored or set to determine whether a stimulation will be sent at box 28 or not sent at box 29. For example, in addition to querying whether the physiological value 22 exceeds the stored threshold value 24 at box 26, a further query can determine if the amount by which the physiological value 22 exceeds the stored threshold value 24 satisfies the second threshold. In the examples above, both situations satisfy the first query (152 mmHg exceeds 150 mmHg, and 175 mmHg exceeds 150 mmHg), but if the second threshold is 5 mmHg, the case where the systolic blood pressure is 152 mmHg would not require stimulation (the difference of 2 mmHg being less than 5 mmHg), resulting in box 29, but the case where the systolic blood pressure is 175 mmHg (the difference of 25 mmHg being greater than 5 mmHg) would require stimulation, resulting in box 28.

[0098] FIGS. 3 and 4 are process flow diagrams illustrating example methods for neuromodulating a subject’s LSC under certain therapeutic conditions to cause vasodilation in at least one of the subject’s legs. FIG. 3 shows a method 30 for neuromodulating a subject’s LSC under certain therapeutic conditions to cause vasodilation in the subject’s leg. FIG. 4 shows an example implementation of a method 34, which can be performed as part of the method 30. The methods 30, 34 can be executed using the system 10 shown in FIG. 1 and / or using actions described with respect to FIG. 2. One or more aspects of the method 30 and / orthe method 34 can be stored in a non-transitory memory (e.g., any computer memory that is not a transitory signal) and executed by a processor (c.g., any hardware processor).

[0099] For purposes of simplicity, the methods 30 and 34 are shown and described as being executed serially; however, it is to be understood and appreciated that the present disclosure is not limited by the illustrated order, as some steps or boxes could occur in different orders and / or concurrently with other steps or boxes shown and described herein. Moreover, not all illustrated aspects may be required to implement the methods 30, 34, nor are the methods 30, 34 necessarily limited to the illustrated aspects.

[0100] Referring now to FIG. 3, illustrated is a method 30 for neuromodulating a subject’s LSC under certain therapeutic conditions to cause vasodilation in the subject’s leg. The vasodilation provided by the method 30 can be used to treat a variety of medical conditions, including but not limited to neuropathy, pain in various regions (e.g., pelvic pain, back pain, lower limb pain, knee pain etc.), exercise intolerance, diabetic vascular disease like diabetic peripheral microvascular disease, heart failure (e.g., HFpEF), endometriosis, microvascular diseases, vasodilatory issues like Raynaud’s, hypertension, and / or the like.

[0101] In box 32, at least two electrode contacts (e.g., two or more contacts of one or both of the electrodes 14a and / or 14b) can be interfaced with the subject’s LSC (e.g., LSC 12a and / or LSC 12b). For example, the interfacing can happen between the LI and L5 level of the spine (e.g., LI, L2, L3, L4, and / or L5). In some implementations, the interfacing can happen on the anterior third of one or more of the LI, L2, L3, L4, and / or L5 vertebral bodies. The at least two electrode contacts can be contacts of an implantable electrode (e.g., paddle electrodes, cuff electrodes, percutaneous electrodes, helical lead etc.) or an external electrode (e.g., a surface electrode).

[0102] In box 34, an electrical signal (e.g., configured and generated by pulse generator, which may be an external pulse generator, an implantable pulse generator, a pulse generator with a combination of external and implantable parts, etc.) can be delivered to the LSC via the at least two electrode contacts to cause vasodilation in at least one of the subject’s legs. The vasodilation can occur ipsilateral to the stimulation and / or contralateral to the stimulation. As an example, the electrical signal can include a repeating sequence of pulses for a first time period and a delay for a second time period (in some instances, the second time period can be longer than the first time period). Each of the pulses can deliver an intensity thatcan include at least a portion of the stimulation intensity required to cause the vasodilation in at least one of the subject’s legs at a constant low frequency and varying current or voltage. The intensity can be a multiple of the stimulation intensity required to cause the vasodilation (e.g., between a multiple of 0.1 times and a multiple of 15).

[0103] FIG. 4 illustrates an example implementation of box 34 from FIG. 3. In box 42, a physiological parameter can be received (e.g., by the pulse generator or a component associated with the pulse generator). Additionally, or alternatively, the physiological parameter can be experienced by the patient. The physiological parameter can be, for example, a systolic pressure, a diastolic pressure, a pulse pressure, a mean arterial pressure, a perfusion value, a neural conduction value, a pain indicator, a heart rate, a circulation value, a skin temperature, a change in skin color, a quantification of skin microvasculature and / or arterial / arteriolar blood flow using Doppler flow probes or skin conductance probes, dyspnea upon exercise, increase in six-minute walk test distance, paresthesia, and / or the like. In box 44, the physiological parameter can be compared to a threshold value (e.g., stored in memory, retrieved from a remote source, and / or the like). The comparison may be performed, for example, by the pulse generator, a component associated with the pulse generator, a component in communication with the pulse generator, etc. The threshold value can be specific to the physiological parameter and can be determined for the subject based on previous data from the subject, previous data from a similar subject population (e.g., suffering from the same disease and / or healthy, but exhibiting one or more of the same physical qualities). If the physiological parameter exceeds the threshold value, an electrical signal can be delivered to the subject’s LSC (in box 46). If the physiological parameter does not exceed the threshold value, no stimulation can be generated (do nothing in box 48).

[0104] In some implementations, the stimulus may be open loop. The stimulation may be activated by the user and / or activated at preset times as set by the clinician or the programmer. For example, the stimulation may be activated at least two times per day and / or less than eight times per day, for example two times, three times, four times, five times, six times, seven times, or eight times a day. The activation may be programmed at specific times of day. Each time the stimulation is activated, the stimulation may remain activated for a preset duration, for example at least about one minute and / or less than or equal to two hours, for example less than or equal to one hour, less than or equal to thirty minutes, less than or equalto twenty minutes, less than or equal to fifteen minutes, less than or equal to ten minutes, or less than or equal to five minutes. The stimulation may have a low frequency of less than or equal to about 20 Hz, for example less than or equal to about 15 Hz, less than or equal to about 10 Hz, less than or equal to about 5 Hz, ranges between such values, or any value within the recited ranges. The stimulation may have a current of no more than 5 mA, for example no more than 4 mA, no more than 3 mA, no more than 2 mA, or no more than 1 mA. A pulse width may be less than or equal to 1 millisecond, or less than or equal to 500 microseconds, or less than or equal to 300 microseconds.

[0105] The systems and methods described herein may also be used with certain vasodilation conditions triggered by exercise or cold, thus limiting quality of life. For example, patients having heart failure with preserved ejection fraction (HFpEF) or other vasodilatory issues like Raynaud’s may experience these issues. In this situation, it may be desirable for the system to be closed-loop or semi-closed-loop and triggered when one or more sensors detect a particular event and / or physiological parameter. For example, the one or more sensors may include a gyrometer / accelerometer, pressure sensor, optical sensor for PPG, or otherwise. The one or more sensors may be external to the patient and / or implantable.

[0106] The system may automatically trigger stimulation in response to the detected event and / or parameter or alert the patient to activate stimulation. In the latter scenario, the patient may have a dedicated remote control or may be able to activate the stimulation using an application on a smartphone or tablet. In the case of the dedicated remote control, the remote control may be wearable (e.g., on a belt, shoulder strap, arm band, etc.).

[0107] For vasodilatory issues that may be triggered by physical exertion, the system may activate stimulation upon detecting a change in movement that might be indicative of exercise. These closed or semi-closed systems will ensure stimulation is turned on during disease exertion, serving to reduce pulmonary capillary wedge pressure increases during exercise. Additionally or alternatively, the system may allow the user to self-administer stimulation before doing any exercise.

[0108] For vasodilatory issues triggered by environmental conditions (e.g., environmental temperature), the stimulation may be activated upon detecting a change in environmental temperature or body temperature. In the case of Raynaud’s, symptoms may arise in response to cold temperature (e.g., less than or equal to 50 degrees F, less than or equalto 40 degrees F, or less than or equal to 35 degrees F, etc.). Closed or semi-closed systems will ensure stimulation is turned on when a change in temperature is detected, for example the patient steps into cold weather or opens the refrigerator. Though it is possible the system may allow the user to self-administer stimulation going into cold temperature. Once activated, the stimulation may remain activated until the patient is no longer in the cold temperature. The stimulation may be automatically deactivated in response to one or more sensor readings or deactivated by the patient. This can improve micro-circulation, which leads to reduced claudication-like symptoms.

[0109] For hypertension, electrical stimulation may be delivered to the LSC. The electrical signal can include a constant frequency, for example 20 Hz or no more than 20 Hz. The electrical signal can include a voltage of at least about 1.5 V and / or less than or equal to about 3.5 V. After delivering the electrical signal, the blood flow increases, and vascular resistance decreases in both legs of the subject.

[0110] Electrical stimulation of the lumbar sympathetic chain in a chronic setting will be a potent vasodilator in several embodiments. Lumbar sympathetic nerve stimulation increases extracellular superoxide dismutase expression in arterioles independently of a- and P-adrenoceptor activation.

[0111] Direct electrical stimulation of the LSC may be an effective novel strategy for improving impaired blood flow in the legs of type 1 diabetic subjects. Direct electrical stimulation of the LSC may be an effective strategy to improve impaired blood flow in the legs and / or feet of type 1 or type 2 diabetic humans. Electrical stimulation of the LSC on one side of the spine might elicit profound increases in hindlimb blood flow in the ipsilateral and / or contralateral side of diabetic subjects, side of.

[0112] FIG. 6 is a graphical representation of vasodilation thresholds. Non- therapeutic diagnostic methods may be performed to diagnose vasodilation thresholds in a subject. As an example, stimulation electrode contacts are placed proximate to the LSC on one side of the spine and electrical stimulation is applied at a constant parameters such as frequency (e.g., , about 0.1 Hz, about 1 Hz, about 5 Hz, about 10 Hz, about 15 Hz, about 20 Hz, and ranges therebetween including but not limited to between about 0.1 Hz and about 20 Hz and between about 15 Hz and about 20 Hz) and pulse width (e.g., about 0.1 ms, about 0.5 ms, about 1 ms, about 2 ms, about 3 ms, about 4 ms, about 5 ms, and about 6 ms, about 7 ms, about 10ms, and ranges therebetween including but not limited to between about 0.1 ms and about 10 ms and between about 4 ms and about 6 ms). Voltage of the electrical stimulation is varied. Although FIG. 6 stalls at 0 V, the initial voltage could be any suitable voltage. Between 0 V and Vi in the area 1502, the electrical stimulation has no effect or causes vasoconstriction in the ipsilateral leg (on the same side of the spine as the stimulation) and has no effect on a contralateral leg (on the opposite side of the spine as the stimulation). At a first threshold Vi, and between Vi and V2 in the area 1504, the stimulation causes vasodilation in the ipsilateral leg but still has no effect on the contralateral leg. At a second threshold V2, and between V2 and V3 in the area 1506, the stimulation causes vasodilation in the ipsilateral leg and causes vasodilation in the contralateral leg. At a third threshold V3, and between V3 and V4 in the area 1508, the stimulation causes vasodilation in the contralateral leg but has no effect or causes vasoconstriction in the ipsilateral leg. At a fourth threshold V4, stimulation at V4 or higher in the area 1510 may have no effect in the contralateral leg. At the fourth threshold V4, stimulation at V4 or higher in the area 1510 may cause the subject to experience pain due to the stimulation. The thresholds Vi, V2, V3, and V4 can vary from subject to subject, and even in the same subject based, for example, on electrode contact placement, LSC nerve density, sympathetic tone, room temperature, room pressure, illness, use of a heating pad, etc. In general, Vi is expected to be between about 1.5 V and about 4 V, V2 is expected to be between about 4 V and about 6 V, V3 is expected to be between about 6 V and about 10 V, and V4 is expected to be between about 10 V and about 12 V. Prior to the discovery of the thresholds Vi, V2, V3, and V4 by the applicant, stimulation of the LSC was typically thought to only cause vasoconstriction in the ipsilateral leg, because testing was most likely in area 1502 and / or 1510. References showing testing of only ipsilateral effects, for example, cannot be predictive of contralateral effects in the absence of teaching of a contralateral threshold.

[0113] If a subject is experiencing right knee pain, for example, electrode contacts can be placed proximate to the LSC on the right side (or the left side or both sides) of the spine and voltage can be tested until in between Vi and V2 to cause vasodilation in the right leg. As described herein, the vasodilation can reduce the pain in the right leg. The stimulation is preferably set not right at Vi or V2 because in that case a small change in the threshold Vi or V2 may then cause unintended effects by shifting into area 1502 or 1506. The set voltage maybe about halfway between Vi and V2. The set voltage may be about a quarter way between Vi and V2 (e.g., closer to V2). Other set voltages between Vi and V2 arc also possible.

[0114] Electrode contacts can also or alternatively be placed proximate to the LSC on the left side of the spine. The electrode contacts can be placed only on the left side, for example, if the subject has a problem with the right side. The electrode contacts can be placed on the left side and the right side, each for unilateral stimulation, for example, to alternate between sides as described herein. The electrode contacts can be placed on the left side and the right side, each for unilateral stimulation, for example, to avoid vasoconstriction in the right leg (e.g., because voltages less than Vj and greater than V4 do not cause contralateral vasoconstriction). Voltage can be tested until in between V2 and V4 to cause vasodilation in the right leg. Even if the subject does not have left knee pain, a set voltage between V3 and V4 can cause vasodilation in the right leg and the left leg. The set voltage can be between V 3 and V4 to avoid causing vasodilation in the left leg. The voltage is preferably not set right at V2, V3, or V4. The set voltage may be about half-way between V2 and V4 (e.g., if agnostic to affecting the left leg), halfway between V2 and V3 (e.g., if avoiding affect the left leg), half way between V3 and V4 (e.g., if intending to affect left leg). The set voltage may be about a quarter way between V2 and V4 (e.g., closer to V3). The set voltage may be about a quarter way between V2 and V3 (e.g., closer to V3). The set voltage may be about a quarter way between V3 and V4 (e.g., closer to V3). Other set voltages between V2 and V4, V2 and V3, and V3 and V4 are also possible.

[0115] If electrode contacts are placed on both sides of the spine, unilateral stimulation can be switched or alternated or toggled between the right electrode contacts and the left electrode contacts. Switching stimulation can reduce overall pain. Switching stimulation can be on a duty cycle basis. For example, stimulation can be ramped up until reaching steady state using the right set of electrode contacts and then operated for a first duration. After the first duration, the right set of electrodes can be ramped down or shut off. Then the stimulation can be ramped up until reaching steady state using the left set of electrode contacts and then operated for a second duration. After the second duration, the left set of electrodes can be ramped down or shut off. Then the stimulation can be ramped up until reaching steady state using the right set of electrode contacts and then operated for a third duration, which may be the same or different than the first duration, and so on.

[0116] Several embodiments disclosed herein can be particularly advantageous because they include one, several, or all of the following benefits: (i) the ability to selectively effect vasodilation in only an ipsilateral hindlimb, only a contralateral hindlimb, or both an ipsilateral hindlimb and a contralateral hindlimb from unilateral stimulation; (ii) the ability to toggle stimulation from different sides of the vertebral column; and / or (iii) the ability to cause hindlimb vasodilation without the use of medicaments. In some embodiments, the devices and methods described herein can be used to treat a subject (e.g. for pain symptoms). In some embodiments, the devices and methods described herein can be used to diagnose a subject (e.g., determining vasodilation thresholds can itself be useful). For example, lack of thresholds may indicate an issue with lumbar sympathetic nerve activity.

[0117] If electrode contacts are placed on both sides of the spine, simultaneous unilateral stimulation can be applied.

[0118] Although voltage is illustrated in and described with respect to FIG. 6, other stimulation parameters can be modified while voltage is held constant. For example, frequency may be increased and / or decreased to find thresholds (pi, q>2, q>3, and 4 (corresponding to thresholds Vj, V2, V3, and V4, respectively).

[0119] Although primarily described herein with respect to electrical stimulation, other types of stimulation and / or neuromodulation are also contemplated. For example, the system may comprise one or more of the following means for modulation: a pressure element, a radiofrequency electrode, high power short duration RF (HPSD RF), an ultrasound element, a laser element, steam, thermal element, alcohol, a microwave element, an acoustic element, a vibratory element, a cryogenic element, a thermal delivery device, a chemical delivery device, and / or the like. But in some embodiments, the only neuromodulation applied by the system may be electrical stimulation to the exclusion of the other modulation methods described here.

[0120] The system may include one or more sensors for side effect detection. In some implementations, this may include the same sensors used for activation and / or deactivation of the electrical stimulation. There may be sensors to detect any of the below- mentioned side effects.

[0121] For example, the system may include one or more sensors to detect muscle stimulation or vibration. The one or more sensors can include an accelerometer, gyrometer, electrical sensor, or otherwise. Collateral muscle stimulation is associated with uncomfortablesensation and pain. For example, the muscle stimulation or vibration may be detected during the onset of LSC stimulation. The system may be able to compare sensor signals during “stimulation off’ to signals during “stimulation on.” The system may adjust a stimulation parameter based on detected muscle stimulation or vibration and / or the comparison between “stimulation off’ and “stimulation on.”

[0122] The system may include one or more sensors to measure autonomic tone. Stimulation that results in uncomfortable sensation or pain also triggers a sympathetic surge, which can be detected in measures of autonomic tone. The one or more sensors can detect cardiac measures such as an increase in heart rate (HR) or a decrease in heart rate variability (HRV). Other measures include skin sympathetic nerve activity (SKNA), heart rate recovery (HRR), heart rate turbulence (HRT), and baroreflex sensitivity (BRS). As with detection of muscle stimulation, the system is able to compare measures during “stimulation off’ to measures during “stimulation on.” The system may adjust a stimulation parameter based on detected cardiac measure and / or the comparison between “stimulation off” and “stimulation on.”

[0123] Additionally or alternatively to the sensor-based systems described above, the system may collect feedback from the patient, for example from a dedicated device or a general-purpose external device like an application on a smartphone or tablet. The patient can indicate when they are experiencing an uncomfortable side effect. The patient could be given a dedicated device that they could place over the pulse generator. The dedicated device could be a handheld magnet. When placed over the pulse generator, the dedicated device could trigger a reed switch to indicate the presence of a side effect. Alternatively, the patient could have a handheld device that is wirelessly connected to the pulse generator and allows the patient to indicate the presence, type, and / or severity of side effect on a digital interface. In some embodiments, side effects detected by a sensor could prompt the user for feedback.

[0124] The pulse generator could be configured to respond to the presence of the side effect by automatically adjusting stimulation parameters (amplitude, frequency, pulse width, duty cycle, and / or stimulation vector) according to a specified algorithm. Upon adjustment, the system would repeat detection of the side effect and make further adjustments if the side effect condition remains.

[0125] For the systems described herein, stimulation parameters may be selected and adjusted. The stimulation parameters may be selected and adjusted without physically repositioning the stimulation lead. For example, the stimulation parameters may include amplitude, frequency, pulse width, duty cycle, polarity, mono-phasic, bi-phasic (symmetric or asymmetric), and / or stimulation vector. The stimulation parameter could be adjusted during the implant visit, or during subsequent outpatient clinic visits. Alternatively, the adjustment could occur outside of the clinic, on a regular schedule or in response to a physician trigger.

[0126] The system may include one or more sensors to allow for stimulation adjustment in response to physiological parameters that would allow stimulation therapy to be optimized. For example, adjustment could be based on physiological measurements that are indicative of therapy efficacy, including autonomic measures (e.g., heart rate, heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, etc.) or measures of peripheral blood flow. The one or more sensors could be the same as or different from any of the sensors described above for activation or side effect detection. The one or more sensors could be implantable and / or be contained in one or more separate, external monitoring devices that communicate wirelessly with the pulse generator. If external, the one or more sensors could communicate with the PG via wireless (e.g., secure Bluetooth) or intrabody means. The sensors could be integrated into a charging strap that is worn periodically by the patient at home. These sensors may be ECG, blood flow, or side effect sensors.

[0127] Because LSC stimulation modulates the autonomic nervous system, the therapeutic effect may be different based on the patient’s autonomic state. For example, autonomic tone may be different during exercise I activity or during sleep. As a result, it may be advantageous to provide different levels of LSC stimulation during these different states, both to enhance the efficacy of the therapy (avoid understimulation) and to improve the safety of the therapy (avoid overstimulation).

[0128] For example, in some embodiments, there may be a suspension or reduction of LSC stimulation during exercise or activity. The system may provide variable LSC stimulation delivery during wake and sleep. There may be a suspension or reduction of stimulation during sleep to reduce stimulation related sensation and side effects. If sensation or side effects are not an issue, there may be an increase in stimulation during sleep to enhancetherapeutic benefit. Any stimulation property may be increased or decreased, including but not limited to, any of amplitude, frequency, pulse width, and / or duty cycle.

[0129] Detection of activity may be done with one or more sensors. The sensors may be the same or different from those used for activation or detection of side effects. For example, the system may include an accelerometer to detect activity or posture. The accelerometer could detect whether the patient is upright or prone. This may be indicative of whether the patient is asleep. The one or more sensors may include a ventilation sensor for detection of respiratory rate via minute ventilation sensor. Stimulation may be activated by the time of day. This may be programmed by default.Heart Failure

[0130] Heart failure (HF) is a debilitating chronic condition that affects over 6 million adults in the United States, resulting in 1.3 million hospitalizations and 85,000 deaths annually. Approximately 50% of HF patients have preserved ejection fraction (HFpEF, LVEF>50%) or mildly reduced ejection fraction (HFmrEF, 49%>LVEF>40%). HFpEF has a 5-year mortality rate of over 75%, which is greater than most cancers. However, despite the significant morbidity and mortality, there are currently limited treatment options for HFpEF. According to the most recent AHA / ACC / HFSA heart failure management guidelines, there are currently no treatments to address the underlying disease. Instead, recommended treatment is limited to the use of diuretics for congestion reduction and symptom relief, as well as the management of comorbidities such as hypertension, coronary artery disease, and atrial fibrillation.

[0131] The pathophysiology of HFpEF is driven by arterial stiffening and endothelial dysfunction. In these patients, "increased systemic vascular resistance (afterload) increases ventricular wall stress, causes myocardial injury, reduces LV pump performance, and increases the likelihood of severe cardiac events.” HFpEF patients have increase systemic vascular resistance (SVR) due to endothelial dysfunction, arterial stiffness, inflammation, fibrosis, and impaired nitric oxide bioavailability, leading to elevated blood pressure, increased left ventricular end-diastolic pressure (“LVEDP”), and prolonged left ventricular (“LV”) pressure decay. Increased SVR greatly increases the risk of cardiovascular events, with patients with elevated SVR at an 8.14-fold increased risk of HF rehospitalization.

[0132] The systems and methods described herein may be used in patients with heart failure, particularly HFpEF. For example, the patients may have reduced effort tolerance and significant dyspnea (NYHA Class III / IV). While examples below are described with respect to heart failure, the systems and methods may be used to modulate vasoactive properties in a patient, for example in patients with vasodilatory issues like Raynaud’s.

[0133] For example, the systems herein may include an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain. The implantable electrode contact may be implanted at a location between the muscle and the spinal column to deliver electrical stimulation to the lumbar sympathetic chain. This may be in contrast to any nerves extending from the lumbar sympathetic chain.

[0134] The system may include a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain. The stimulator may be implanted or external to the patient such as on a wearable component. The stimulator may include a processor configured to receive a pre-programmed instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain.

[0135] In some implementations, the stimulator may be pre-programmed to send the signal at pre-determined intervals or periods of time. For example, electrically stimulating the lumbar sympathetic chain multiple times a day can lead to improvement in ventilation and improved peripheral congestion (akin to venodilators used in heart failure treatment - e.g nitroglycerin to decongest the heart). For example, the electrical stimulation can occur at least two times a day and / or less than eight times a day or any number of times there between.

[0136] The electrical stimulation can be pre-programmed by the clinician. The electrical stimulation can be titrated to be turned on for at least 1 minute and / or less than or equal to 2 hours, for example less than or equal to 1 hour, less than or equal to 30 minutes, less than or equal to 10 minutes, or less than or equal to five minutes.

[0137] In other implementations, the system may be patient activated or automatically activated upon detection of an event or physiological parameter. The stimulator may remain in a low-power or off state until activated to send the signal to the implantable electrode contact. The stimulator may be activated by a user input on an external device such as a wearable component (e.g., patch or on a wearable strap) or a mobile device (e.g., smartphone or tablet). The stimulator may be activated by attachment of the wearable component in connection with or close proximity to the electrodes.

[0138] The system may include a communication module configured to communicate with an external device and a processor configured to receive an instruction from the external device. The communication module and the processor may be integrated into the stimulator or separately attached to the stimulator. The stimulator, including the communication module and processor, may be implantable. In other scenarios, the stimulator may be implantable, but the communication module and / or processor may be external to the patient.

[0139] The stimulator may send the signal to the implantable electrode contact upon detection of an event or physiological parameter. For example, the system may include one or more sensors to detect the event or measure a physiological parameter. The event or physiological parameter may be indicative of physical activity by the patient or an environmental condition like cold temperature. It may be desirable to activate the device if, and only if, the patient is active (e.g., exercise). This may serve to reduce pulmonary capillary wedge pressure increase during exercise. The one or more sensors may include a gyrometer or accelerometer to detect physical exertion of the patient. The one or more sensors may include an optical sensor, for example to obtain a photoplethysmogram. The one or more sensors may detect a physiological parameter such as blood pressure, blood flow, temperature, or any other physiological parameter. The stimulator may be automatically activated upon detection of the event or physiological parameter and / or remain active so long as the event or physiological parameter is detected.

[0140] The stimulation parameters can have any of the profiles described above. For example, the electrical stimulation can have a current amplitude of less than or equal to 20 mA, for example less than or equal to 10 mA or less than or equal to 5 mA. The pulse width can be at least about 50 microseconds and / or less than or equal to 2000 microseconds, such as between 250 microseconds and 500 microseconds, or less than or equal to 500 microseconds or less than or equal to 300 microseconds. The frequency can be at least about 2 Hz and / or less than or equal to about 5000 Hz, for example less than or equal to 1000 Hz, less than or equal to 500 Hz, less than or equal to 100 Hz, or less than or equal to 20 Hz.

[0141] Patients with HFpEF who receive LSC stimulation therapy may have other cardiac comorbiditics and receive other device therapies. In this situation, it may be advantageous to either coordinate therapy delivery or to integrate the therapies into a single implantable system. In several embodiments, neuromodulation therapies described herein may be used in combination with other implantable systems, including but not limited to, implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRT) devices, and baroreflex activation therapy (BAT). When used in combination, the LSC stimulation may improve the efficacy of these other therapies, reduce side effects, or reduce the amount of these other therapies. Communication and synchronization between the devices may occur with wireless (e.g., secure Bluetooth) or intrabody means. Alternatively, communication may occur through a central external unit, for example a bedside RF telemetry unit.

[0142] As one example, therapy synchronization may include alternating LSC stimulation and BAT stimulation. Because both therapies modulate the autonomic nervous system, preventing simultaneous stimulation would avoid interaction between the two therapies. As another example, there may be LSC stimulation prior to defibrillation to reduce defibrillation threshold and reduce defibrillation-related pain. There may be LSC stimulation to improve anti-tachycardia pacing (ATP) efficacy. Similarly, autonomic modulation of cardiac depolarization and repolarization may improve ATP efficacy when stimulation is synchronized with ATP. Diabetic Vascular Disease

[0143] The systems and methods described herein may be used in patients with diabetic vascular disease or at risk for diabetic vascular disease. For example, the systems and methods described herein may be used with patients having fulminant diabetes and / or possibly have reduced peripheral circulation due to diabetic complications (vasculopathy and neuropathy) leading to reduced vascular reactivity.

[0144] Electrical stimulation of the lumbar' sympathetic vasodilator system is a therapeutic strategy to restore functional levels of blood flow in the legs and feet including subjects with diabetes. For example, impaired baroafferent control of sympathetic nerve activity can be modulated in diabetic subjects. Type 1 diabetes presents a series of neural and hemodynamic problems for the subject, many of which have no beneficial therapies. Ahallmark of diabetes is inadequate perfusion of skeletomusculature of the legs and feet. These changes in flow arc due to reduced splanchnic sympathetic vasoconstrictor drive to the mesentery and greatly reduced lumbar sympathetic vasodilator drive to the hindlimbs. Another hallmark of diabetes is impaired sensory processing by the brain, and especially cardiovascular circuitry within the brainstem.

[0145] For diabetic patients with vascular disease or at risk of vascular disease such as diabetic peripheral neuropathy, the systems described herein can be in the form of an acute or sub-acute implant for use in the hospital or extended home care. Vascular complications in diabetic patients can cause ulcers and impair wound healing. The systems and methods described herein may be used with diabetic patients being treated for wounds. For example, the systems and methods may enable accelerated wound healing to prevent amputation or reduce the region for amputation (e.g., digit / toe amputation). Since these patients may have impaired wound healing capabilities, the system may include an acute or sub-acute implant coupled with a wearable component (e.g., belt, shoulder strap, arm strap, patch, or otherwise) to activate the implant. This minimizes the size of the implant and the size of any possible incision. For example, the one or more electrodes and / or stimulator may be implantable. Any electronics including but not limited to the stimulator, processor(s), battery, antenna, transmitter(s), sensor(s), or the like may be incorporated into the wearable.Chronic Knee Pain

[0146] The systems and methods of performing neuromodulation to the lumbar sympathetic ganglia described herein may be used to treat patients experiencing chronic knee pain. For example, a lumbar sympathetic blockade may be used to alleviate or eliminate knee pain in a patient. Additionally or alternatively, knee pain can be treated by chemical (e.g., phenol or alcohol) ablation or thermal radio-frequency ablation. Embolization of the genicular nerves innervating the knee may also be an effective treatment for alleviating knee pain in a patient.

[0147] The systems described herein can be in the form of an acute or sub-acute implant for use in the hospital or extended home care. The system may include an acute or subacute implant coupled with a wearable component (e.g., belt, shoulder strap, arm strap, patch, or otherwise) to activate the implant. This minimizes the size of the implant and the size of any possible incision. For example, the one or more electrodes and / or stimulator may beimplantable. Any electronics including but not limited to the stimulator, processor(s), battery, antenna, transmittcr(s), scnsor(s), or the like may be incorporated into the wearable.

[0148] Applying neurostimulation at different levels of frequency may help alleviate knee pain through different physiological processes. For example, a higher frequency of stimulation (e.g., at frequencies greater than 40Hz, or at frequencies greater than 1000Hz, or at frequencies greater than 5000Hz) may be advantageous by providing a stronger blocking effect on the LSC, which, in turn may decrease blood flow in a patient’s lower limbs. In another example, applying stimulation at lower frequencies (e.g., at frequencies less than 2 Hz or at frequencies less than 5 Hz) may be advantageous by allowing for augmenting or increasing blood flow to the knee, which may also ameliorate knee pain.Pelvic Pain

[0149] The systems and methods described herein may additionally be used to treat patients with pelvic pain. Endometriosis is a form of chronic pelvic pain, which affects more than 8.6 million Americans. This is approximately 10% of the US population of women aged 15 to 55 years. Laparoscopic surgeries can help by removing uterine fibroids, but the procedure has a low success rate. Accordingly, an alternative method for treating pelvic pain, such as that caused by endometriosis, is desirable.

[0150] When surgery and medical therapy fail, sympathetic sacral neuromodulation (i.e., at the S3 root) may help alleviate pelvic pain symptoms. A sympathetic blockade of the LSC may additionally offer some relief. However, the benefits of the injections wear off in 3 to 6 months, leaving the patient with few options beyond repeated injections, ad nauseam.

[0151] The systems described herein can be in the form of an acute or sub-acute implant for use in the hospital or extended home care. The system may include an acute or subacute implant coupled with a wearable component (e.g., belt, shoulder strap, arm strap, patch, or otherwise) to activate the implant. This minimizes the size of the implant and the size of any possible incision. For example, the one or more electrodes and / or stimulator may be implantable. Any electronics including but not limited to the stimulator, processor(s), battery, antenna, transmitter(s), sensor(s), or the like may be incorporated into the wearable.

[0152] Applying neurostimulation at different levels of frequency may help alleviate pelvic pain through different physiological processes. For example, a higherfrequency of stimulation (e.g., at frequencies greater than 40Hz, or at frequencies greater than 1000Hz, or at frequencies greater than 5000Hz) may be advantageous by providing a stronger blocking effect on the LSC, which, in turn, may decrease blood flow to the pelvis. In another example, applying stimulation at lower frequencies (e.g., at frequencies less than 2 Hz, or at frequencies less than 5 Hz) may be advantageous by allowing for augmenting or increasing the blood flow to the pelvis, which may also ameliorate pelvic pain.Pharmacological Therapies

[0153] In several embodiments, the neuromodulation therapies described herein can be used to replace pharmacological (drug) therapies. In other embodiments, however, drug therapies may be used in combination with the neuromodulation therapies described herein, but with reduced frequency or dose, thus reducing undesired side effects. For example, a certain drug (or drug combination) may be administered for a shorter overall duration, fewer times per day / week / month, and / or at a lower dose when combined with the neuromodulation described herein. In addition to reducing undesired pharmacological side effects, this may also reduce addiction or dependence. The neuromodulation described herein may also be used to taper or otherwise wean subjects off of pain and other medications.

[0154] Certain experiments are described with respect to application of medicaments, for example to induce certain physiological conditions before, during, and / or after stimulation. The devices and methods described herein can be used without medicaments (e.g., without medicaments inducing certain physiological conditions). Anesthetics and other medicaments that enable electrode contact placement, for example, may be used.

[0155] The foregoing description and examples arc set forth merely to illustrate the inventive concepts and are not intended as being limiting. Each of the disclosed aspects and examples of the present disclosure may be considered individually or in combination with other aspects, examples, and variations of the disclosure. In addition, unless otherwise specified, none of the steps of the methods of the present disclosure are confined to any particular order of performance. Modifications of the disclosed examples incorporating the spirit and substance of the disclosure may occur to persons skilled in the art and such modifications are within the scope of the present disclosure. Furthermore, all references cited herein are incorporated by reference in their entirety. Headings used herein are for organizational purposes only and should not be used to unduly limit claim scope or embodiments.

[0156] Certain experiments are described with respect to application of medicaments, for example to induce certain physiological conditions before, during, and / or after stimulation. The devices and methods described herein can be used without medicaments (e.g., without medicaments inducing certain physiological conditions). Anesthetics and other medicaments that enable electrode contact placement, for example, may be used.

[0157] While the methods and devices described herein may be susceptible to various modifications and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular devices or methods disclosed, but, to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the various examples described and the appended claims. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with an example can be used in all other examples set forth herein. Any methods disclosed herein need not be performed in the order recited. Depending on the example, one or more acts, events, or functions of any of the algorithms, methods, or processes described herein can be performed in a different sequence, can be added, merged, or left out altogether (e.g., not all described acts or events are necessary for the practice of the algorithm). Algorithms, modules, blocks, steps, boxes, elements, features, etc. may be stored in machine-readable memory. In some examples, acts or events can be performed concurrently, e.g., through multi-threaded processing, interrupt processing, or multiple processors or processor cores or on other parallel architectures, rather than sequentially. Further, no element, feature, block, box, or step, or group of elements, features, blocks, boxes, or steps, are necessary or indispensable to each example. Additionally, all possible combinations, subcombinations, and rearrangements of systems, methods, features, elements, modules, blocks, boxes, and so forth are within the scope of this disclosure. The use of sequential, or time-ordered language, such as “then,” “next,” “after,” “subsequently,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to facilitate the flow of the text and is not intended to limit the sequence of operations performed. Thus, some examples may be performed using the sequence of operations described herein, while other examples may be performed following a different sequence of operations.

[0158] The various illustrative logical blocks, boxes, modules, processes, methods, and algorithms described in connection with the examples disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, operations, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.

[0159] The various illustrative logical blocks and modules described in connection with the examples disclosed herein can be implemented or performed by a machine, such as a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0160] The blocks, operations, or steps of a method, process, or algorithm described in connection with the examples disclosed herein can be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, an optical disc (e.g., CD- ROM or DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. A storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. The processor and the storagemedium can reside in an ASTC. The ASIC can reside in a user terminal. In the alternative, the processor and the storage medium can reside as discrete components in a user terminal.

[0161] Conditional language used herein, such as, among others, “can,” “might,” “may,” “e.g.,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that some examples include, while other examples do not include, certain features, elements, and / or states. Thus, such conditional language is not generally intended to imply that features, elements, blocks, and / or states are in any way required for one or more examples or that one or more examples necessarily include logic for deciding, with or without author input or prompting, whether these features, elements and / or states are included or are to be performed in any particular example.

[0162] The methods disclosed herein may include certain actions taken by a practitioner; however, the methods can also include any third-party instruction of those actions, either expressly or by implication. For example, actions such as “positioning an electrode contact” include “instructing positioning of an electrode contact.”

[0163] The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” include the recited numbers and should be interpreted based on the circumstances (e.g., as accurate as reasonably possible under the circumstances, for example ±5%, ±10%, ±15%, etc.). For example, “about 4 V” includes “4 V.” Phrases preceded by a term such as “substantially” include the recited phrase and should be interpreted based on the circumstances (e.g., as much as reasonably possible under the circumstances). For example, “substantially parallel” includes “parallel.” Unless stated otherwise, all measurements are at standard conditions including temperature and pressure. The phrase “at least one of’ is intended to require at least one item from the subsequent listing, not one type of each item in the subsequent listing. For example, “at least one of A, B, and C” can include A, B, C, A and B, A and C, B and C, or A, B, and C.

[0164] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains. As used herein, the singular forms “a,” “an,” and “the” can also include the plural forms, unless the context clearly indicates otherwise. As used herein, the terms“comprises” and / or “comprising,” can specify the presence of stated features, steps, operations, elements, components, and / or groups, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups. As used herein, the term “and / or” can include any and all combinations of one or more of the associated listed items. As used herein, the terms “first,” “second,” etc. should not limit the elements being described by these terms. These terms are only used to distinguish one element from another. Thus, a “first” element discussed below could also be termed a “second” element without departing from the teachings of the present disclosure. The sequence of operations (or acts / steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise. As used herein, the term “neuromodulation” can refer to an electrical signal delivered as a therapy to neural tissue. In some instances, the neural tissue can include at least a portion of the sympathetic chain. For example, the sympathetic chain can refer to the lumbar sympathetic chain. As used herein, the term “sympathetic chain” can refer to either of a pair of ganglionated longitudinal cords of the sympathetic nervous system of which one is situated on each side of the spinal column, extending from the base of the skull to the coccyx. As used herein, the term “lumbar sympathetic chain” or “LSC” can refer to a portion of the sympathetic chain that lies anterolateral to bodies of the five lumbar vertebrae (L1-L5). Notably, the LSC has a consistent location that is surgically accessible via image guidance and minimally invasive techniques. The LSC has downstream branches that regulate vasomotor, somatosensory, and pelvic floor functions. As used herein, the term “sympathetic nervous system” can refer to a portion of the autonomic nervous system that activates the “Fight or Flight” response (generally accelerating heart rate, dilating pupils, dilating bronchioles, inhibiting digestion, constricting blood vessels, increasing cardiac output, and raising blood pressure, etc.), which prepares the body for intense physical activity. As used herein, the term “electrical signal” can refer to a time-varying voltage or current. As an example, the electrical signal can be represented by a waveform (a graphical representation of changes in current or voltage over time). As used herein, the term “electrode contact” can refer to a material acting as a conductor through which electricity enters or leaves. At least a portion of the material can be a biocompatible material. As used herein, the term “vasodilation” can refer to the dilation of blood vessels, which decreases blood pressure. As used herein, the terms “subject” and “patient” can be used interchangeably and refer to any warm-blooded organism including, butnot limited to, a human being, a pig, a rat, a mouse, a dog, a cat, a goat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc.

Claims

WHAT TS CLAIMED TS:

1. A method of treating a condition in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a second electrode contact on the first lateral side, wherein electrically stimulating comprises at least one of: causing vasodilation in a limb on the first lateral side; or causing vasodilation in a limb on a second lateral side opposite the first lateral side; and electrically stimulating a lumbar sympathetic chain on a second lateral side of the vertebral column opposite the first lateral side via a third electrode contact on the second lateral side and a fourth electrode contact on the second lateral side, wherein electrically stimulating comprises at least one of: causing vasodilation in a limb on the second lateral side; or causing vasodilation in a limb on the first lateral side.

2. The method of claim 1, wherein the first electrical contact and the second electrical contact are on a first implantable electrode, wherein the third electrical contact and the fourth electrical contact are on a second implantable electrode, and wherein the first and second implantable electrodes are inserted within the subject percutaneously.

3. The method of claim 1, further comprising: detecting, by one or more sensors, a physiological parameter or condition of the subject; and varying one or more of an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition.

4. The method of claim 3, wherein the physiological parameter or condition comprises blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity.

5. The method of claim 3, wherein the one or more sensors are configured to detect muscle stimulation or vibration.

6. The method of claim 1, wherein the limb is a leg.

7. The method of claim 1, wherein the limb is an arm.

8. The method of any one of claims 1 to 7, wherein the electrically stimulating comprises stimulating at a fixed frequency.

9. The method of claim 8, wherein the fixed frequency is between 0.1 Hz and 20 Hz.

10. The method of any one of claims 1 to 7, wherein the electrically stimulating comprises increasing a voltage until vasodilation on a contralateral side is caused.

11. The method of any one of claims 1 to 7, further comprising toggling electrical stimulation between different currents and / or voltages.

12. The method of any one of claims 1 to 7, wherein the electrically stimulating the lumbar sympathetic chain further causes vasodilation in an abdomen.

13. The method of any one of claims 1 to 7, wherein electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact on the first lateral side and the second electrode contact on the first lateral side comprises inserting and positioning the first electrode contact and the second electrode contact within the subject at a position adjacent one or more of an LI lumbar vertebral body, L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body.

14. The method of any one of claims 1 to 7, wherein electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact on the first lateral side and the second electrode contact on the first lateral side comprises simultaneously electrically stimulating lumbar sympathetic ganglia adjacent multiple vertebral bodies of a lumbar region.

15. The method of any one of claims 1 to 7, further comprising positioning the first electrode contact and / or the second electrode contact on the first lateral side of the vertebral column adjacent an anterior one-third portion of one or more of a LI vertebral body, L2 vertebral body, L3 vertebral body, L4 vertebral body, or L5 vertebral body and anteromedial muscular fascia.

16. The method of any one of claims 1 to 7, wherein the electrically stimulating the lumbar sympathetic chain further comprises accelerating wound healing.

17. The method of any one of claims 1 to 7, wherein the condition is neuropathy, pain, exercise tolerance, heart failure, or hypertension.

18. The method of any one of claims 1 to 7, wherein the condition is endometriosis.

19. A method of treating a condition in a subject, the method comprising: positioning a first electrode contact on a first lateral side of a vertebral column of the subject; positioning a second electrode contact on the first lateral side of the vertebral column of the subject; electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein electrically stimulating comprises: increasing voltage until causing vasodilation in a limb on a first lateral side of the subject corresponding to the first lateral side of the vertebral column; and increasing voltage until causing vasodilation in a limb on a second lateral side of the subject opposite the first lateral side of the subject; positioning a third electrode contact on a second lateral side of a vertebral column of the subject opposite the first lateral side of the vertebral column; positioning a fourth electrode contact on the second lateral side of the vertebral column of the subject; electrically stimulating a lumbar sympathetic chain on the second lateral side of the vertebral column of the subject via the third electrode contact and the fourth electrode contact, wherein electronically stimulating comprises: increasing voltage until causing vasodilation in a limb on the second lateral side of the subject; and increasing voltage until causing vasodilation in a limb on the first lateral side of the subject; and toggling between electrically stimulating the lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and electrically stimulating the lumbar sympathetic chain on the second lateral side of the vertebral column of the subject via the third electrode contact and the fourth electrode contact.

20. The method of claim 19, wherein electrically stimulating comprises stimulating at a frequency of no more than 20 Hz.21 . The method of claim 19, further comprising detecting, by one or more sensors, a physiological parameter or condition of the subject; and varying one or more of an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition.

22. The method of claim 19, further comprising receiving, by a controller from an external device, an instruction to electrically stimulate the lumbar sympathetic chain via one the first electrode contact and the second electrode contact, third electrode contact or fourth electrode contact.

23. The method of any one of claims 19 to 22, further comprising after electrically stimulating the lumbar sympathetic chain, delivering an electrical shock to the patient’s heart.

24. The method of any of claims 19 to 22, wherein the condition is neuropathy, pain, exercise tolerance, heart failure, or hypertension.

25. A method of treating a condition in a subject, the method comprising: positioning a first implantable electrode on a first lateral side of a vertebral column of the subject at a position between an LI lumbar vertebral body and an SI sacral vertebral body; and electrically stimulating one or more lumbar sympathetic ganglia adjacent one or more vertebrae between the LI lumbar vertebral body and the SI sacral vertebral body using the first implantable electrode sufficient to cause vasodilation in a limb or abdomen of the subject.

26. The method of claim 25, wherein the first implantable electrode comprises at least two spaced- apart electrode contacts.

27. The method of claim 25, wherein positioning the first implantable electrode on the first lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the SI sacral vertebral body comprises percutaneously inserting the first implantable electrode within the subject.

28. The method of claim 25, wherein positioning the first implantable electrode on the first lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the SI sacral vertebra comprises positioning the first implantable electrode at a position adjacent one or more of an L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body.

29. The method of claim 28, further comprising positioning at least one electrode contact of the first implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebra and the SI sacral vertebra.

30. The method of claim 27, further comprising positioning the first implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebral body and the SI sacral vertebral body.

31. The method of claim 25, wherein the first implantable electrode comprises an octrode including eight electrical contacts.

32. The method of claim 25, wherein the electrically stimulating using the first electrode is sufficient to cause vasodilation in an ipsilateral arm or leg corresponding to the first lateral side of the vertebral column.

33. The method of claim 25, wherein the electrically stimulating using the first electrode is sufficient to cause vasodilation in a contralateral arm or leg corresponding to an opposite lateral side of the vertebral column.

34. The method of claim 25, further comprising positioning a second implantable electrode on a second lateral side of the vertebral column of the subject opposite the first lateral side at a position between the LI lumbar vertebral body and the SI sacral vertebral body; and electrically stimulating one or more lumbar sympathetic ganglia on the second lateral side adjacent one or more vertebrae between the LI lumbar vertebral body and the SI sacral vertebral body using the second implantable electrode sufficient to cause vasodilation in a limb or abdomen of the subject.

35. The method of claim 34, wherein the second implantable electrode comprises at least two spaced-apart electrode contacts.

36. The method of claim 34, wherein positioning the second implantable electrode on the second lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the SI sacral vertebral body comprises percutaneously inserting the second implantable electrode within the subject.

37. The method of claim 34, wherein positioning the second implantable electrode on the second lateral side of the vertebral column of the subject at a position between the LI lumbar vertebral body and the SI sacral vertebral body comprises positioning the secondimplantable electrode at a position adjacent one or more of an L2 lumbar vertebral body, an L3 vertebral body and an L4 lumbar vertebral body.

38. The method of claim 37 further comprising positioning at least one electrode contact of the second implantable electrode at a position adjacent an anterior one-third portion of one of the L2 lumbar vertebral body, the L3 vertebral body and the L4 lumbar vertebral body.

39. The method of claim 34, further comprising positioning the second implantable electrode at a position adjacent an anterior one-third portion of a vertebra between the LI lumbar vertebral body and the SI sacral vertebral body.

40. The method of claim 34, wherein the second implantable electrode comprises an octrode including eight electrical contacts.

41. The method of claim 34, wherein the electrically stimulating using the second electrode is sufficient to cause vasodilation in an ipsilateral arm or leg corresponding to the second lateral side of the vertebral column.

42. The method of any one of claims 34 to 41, wherein the electrically stimulating using the first electrode and / or the second electrode is sufficient to cause vasodilation in the abdomen of the subject.

43. A system for treating a condition in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of the vertebral column of the subject; a third electrode contact configured to be positioned on a second lateral side of the vertebral column of the subject, the second lateral side opposite the first lateral side; and a fourth electrode contact configured to be positioned on the second lateral side of the vertebral column of the subject; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate a lumbar sympathetic chain on the second lateral side of the vertebral column, wherein the stimulator is configured to:send signals to the first electrode contact and the second electrode contact to cause vasodilation in at least one of a limb on the first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side of the subject; send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in at least one of the limb on the second lateral side of the subject or the limb on the first lateral side of the subject.

44. A system for treating a condition in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of the vertebral column of the subject; a third electrode contact configured to be positioned on a second lateral side of the vertebral column of the subject, the second lateral side opposite the first lateral side; and a fourth electrode contact configured to be positioned on the second lateral side of the vertebral column of the subject; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate a lumbar sympathetic chain on the second lateral side of the vertebral column, wherein the stimulator is configured to: send signals to the first electrode contact and the second electrode contact to cause vasodilation in at least one of a limb on a first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side; send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in at least one of the limb on the second lateral side of the subject or the limb on the first lateral side of the subject; andtoggle between sending the signals to the first electrode contact and the second electrode contact and sending the signals to the third electrode contact and the fourth electrode contact.

45. A system for treating a condition in a subject, the system comprising: a first implantable electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject at a position between an LI lumbar vertebral body and an SI sacral vertebral body; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column at a position between an LI lumbar vertebral body and an S 1 sacral vertebral body via the first electrode contact, wherein the stimulator is configured to: send signals to the first electrode contact to cause vasodilation in at least one of a limb on the first lateral side of the subject corresponding to the first lateral side of the vertebral column or a limb on a second lateral side of the subject opposite the first lateral side of the subject.

46. The system of claim 45, wherein the first implantable electrode comprises at least two spaced-apart electrode contacts.

47. The system of claim 45, wherein the first implantable electrode comprises an octrode including eight electrical contacts.

48. The system of claim 45, further comprising a second implantable electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject opposite the first lateral side at a position between an LI lumbar vertebral body and an SI sacral vertebral body; wherein the stimulator is further configured to send signals to the second electrode contact to cause vasodilation in one of a limb or abdomen of the subject.

49. The system of claim 48, wherein the second implantable electrode comprises at least two spaced-apart electrode contacts.

50. The system of any of claims 48 or 49, wherein the second implantable electrode comprises an octrode including eight electrical contacts51. A method of treating a condition in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a secondelectrode contact on the first lateral side, wherein electrically stimulating comprises at least one of: causing vasodilation in a leg on the first lateral side; or causing vasodilation in a leg on a second lateral side.

52. The method of Claim 51, further comprising positioning the first electrode contact and / or the second electrode contact on the first lateral side of the vertebral column corresponding to an anterior one-third portion of one or more of an LI vertebral body, L2 vertebral body, L3 vertebral body, L4 vertebral body, or L5 vertebral body.

53. The method of Claim 52, wherein the first electrode contact and / or the second electrode contact are disposed on an electrode lead configured to transition between a rigid, straightened configuration and a flexible implantation configuration, and wherein positioning the first electrode contact and or the second electrode contact comprises: percutaneously introducing the electrode lead in the straightened configuration into the subject via an introducer; navigating the electrode lead in the straightened configuration to the first lateral side of the vertebral column via the introducer; and decoupling the electrode lead from the introducer, wherein decoupling the electrode lead from the introducer causes the electrode lead to transition from the straightened configuration to the implantation configuration.

54. A system for electrically stimulating a lumbar sympathetic chain of a patient, the system comprising: an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain; one or more sensors configured to detect a physiological parameter or a condition of the patient; a processor configured to receive data from the one or more sensors; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain, the stimulator configured to receive an instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain based on the data received from the one or more sensors.

55. The system of Claim 54, wherein the stimulator is implantable.

56. The system of Claim 54, wherein the stimulator is wearable.

57. The system of any one of Claims 54 to 56, wherein the one or more sensors are configured to detect the physiological parameter.

58. The system of Claim 57, wherein the one or more sensors comprises an optical sensor or a ventilation sensor.

59. The system of Claim 57, wherein the physiological parameter comprises blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity.

60. The system of any one of Claims 54 to 59 wherein the one or more sensors are configured to detect the condition of the patient.

61. The system of Claim 60, wherein the one or more sensors comprises an electrical sensor, a gyrometer, or an accelerometer.

62. The system of Claim 60 or 61, wherein the condition of the patient is physical activity.

63. The system of Claim 60 or 61, wherein the condition of the patient is an uncomfortable sensation or pain.

64. The system of Claim 60 or 61 , wherein the condition of the patient is an efficacy of the electrical stimulation.

65. The system of any one of Claims 54 to 64, wherein the processor is configured to automatically receive the instruction in response to the one or more sensors detecting the physiological parameter of the condition of the patient.

66. The system of any one of Claims 54 to 65, further comprising an external device configured to receive instructions from the patient to send the instruction to the processor.

67. The system of any one of Claims 54 to 66, wherein the processor configured to: receive the data from the one or more sensors when the electrical stimulation is active and inactive; compare the data from when the electrical stimulation is active and the data from when the electrical stimulation is inactive; and adjust a stimulation parameter of the electrical stimulation based on an comparison between the data.

68. The system of any one of Claims 54 to 67, wherein the processor is on-board the stimulator.

69. The system of any one of Claims 54 to 68, wherein the processor is remote from the stimulator.

70. The system of any one of Claims 54 to 69, wherein the processor is configured to adjust a stimulation parameter of the instruction based on the data received from the one or more sensors.

71. The system of Claim 70, wherein the stimulation parameter comprises an amplitude, frequency, pulse width, duty cycle, and / or stimulation vector.

72. The system of any one Claim 70 or 71 , wherein the processor is configured to adjust the stimulation parameter without adjusting the implantable electrode contact.

73. The system of any one of Claims 54 to 71, wherein the processor is configured to continuously receive data from the one or more sensors.

74. The system of any one of Claims 54 to 72, wherein the processor is configured to receive data from the one or more sensors at pre-determined intervals or on demand.

75. The system of any one of Claims 54 to 74, wherein the one or more sensors are implantable.

76. The system of any one of Claims 54 to 75, wherein the one or more sensors are contained in an external monitoring device configured to wirelessly communicate with the stimulator.

77. A method of modulating a vasoactive property in a patient, the method comprising: detecting, by one or more sensors, a physiological parameter or condition of the patient; activating a stimulator to send a signal to an implantable electrode contact; and electrically stimulating a lumbar sympathetic chain via the implantable electrode contact based on the detected physiological parameter or condition.

78. The method of Claim 77, further comprising varying one or more of an amplitude, frequency, pulse width, or duty cycle of the electrical stimulation based on the detected physiological parameter or condition.

79. The method of Claim 77 or 78, further comprising varying electrical stimulation between wake and sleep.

80. The method of Claim 79, further comprising suspending or reducing electrical stimulation during sleep.

81. The method of Claim 79, further comprising increasing electrical stimulation during sleep if no side effects are detected.

82. The method of any one of Claims 77 to 81 , further comprising varying electrical stimulation based on a side effect of the electrical stimulation detected by the one or more sensors.

83. The method of Claim 82, further comprising detecting, by the one or more sensors, muscle stimulation or vibration.

84. The method of Claim 82, further comprising detecting, by the one or more sensors, measures of autonomic tone.

85. The method of any one of Claims 77 to 84, wherein the physiological parameter comprises blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity.

86. The method of any one of Claims 77 to 85, further comprising electrically stimulating after detecting physical exertion of the patient.

87. The method of any one of Claims 77 to 85, further comprising suspending or reducing electrical stimulation after detecting physical exertion of the patient.

88. The method of any one of Claims 77 to 87, further comprising varying electrical stimulation based on a posture of the patient.

89. The method of any one of Claims 77 to 87, further comprising varying electrical stimulation based on a time of day.

90. A method of modulating a vasoactive property in a patient, the method comprising: alternating electrically stimulation of a lumbar sympathetic chain via a first implantable electrode contact and electrical stimulation of baroreceptors via a second implantable electrode contact.

91. The method of Claim 90, further comprising preventing simultaneous stimulation between the electrical stimulation of the lumbar sympathetic chain and the baroreceptors.

92. A method of modulating a vasoactive property in a patient, the method comprising:electrically stimulating a lumbar sympathetic chain via an implantable electrode contact; and after electrically stimulating the lumbar sympathetic chain, defibrillating the patient’s heart.

93. The method of Claim 92, wherein electrical stimulation comprises causing a reduction in a defibrillation threshold.

94. A method of modulating a vasoactive property in a patient, the method comprising: electrically stimulating a lumbar sympathetic chain via an implantable electrode contact; and after electrically stimulating the lumbar sympathetic chain, delivering an electrical shock to the patient’s heart.

95. The method of Claim 94, wherein delivering the electrical shock to the patient’ s heart comprises defibrillating the patient’s heart.

96. The method of Claim 94, wherein electrical stimulation comprises causing a reduction in a defibrillation threshold.

97. The method of Claim 94, wherein delivering the electrical shock to the patient’ s heart comprises anti-tachycardia pacing.

98. A method of treating heart failure in a patient, the method comprising: electrically stimulating a lumbar sympathetic chain via an implantable electrode contact, wherein electrically stimulating comprises causing vasodilation in the musculoskeletal system of hands, legs, and abdomen and / or producing change in a biomarker that offload the patient’s heart and reduces cardiopulmonary congestion.

99. The method of Claim 98, wherein electrically stimulating comprises stimulating at pre-programmed periods of time.

100. The method of Claim 99, wherein the periods of time are at least at least one minute.

101. The method of Claim 98 or 99, wherein the periods of time are no more than two hours.

102. The method of any one of Claims 98 to 101, wherein electrically stimulating comprises stimulating at a fixed frequency.

103. The method of any one of Claims 98 to 102, wherein electrically stimulating improves ventilation.

104. The method of any one of Claims 98 to 103, wherein electrically stimulating comprises stimulating at pre-programmed intervals.

105. The method of any one of Claims 98 to 104, wherein electrically stimulating comprises causing vasodilation in a leg.

106. A system for electrically stimulating a lumbar sympathetic chain of a patient, the system comprising: an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain, the stimulator comprising a processor configured to receive a pre-programmed instruction to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain.

107. The system of Claim 106, wherein the stimulator is implantable.

108. The system of Claim 106, wherein the stimulator is wearable.

109. The system of any one of Claims 106 to 108, wherein the pre-programmed instruction comprises instructions to send the signal at pre-determined intervals during a day.

110. The system of any one of Claims 106 to 109, wherein the pre-programmed instruction comprises instructions to send the signal for pre-determined periods of time.

111. The system of any one of Claims 106 to 110, wherein the pre-programmed instruction comprises a fixed frequency.

112. A method of modulating a vasoactive property in a patient, the method comprising: receiving, by a controller from an external device, an instruction to electrically stimulate a lumbar sympathetic chain via an implantable electrode contact; activating a stimulator to send a signal to the implantable electrode contact; and electrically stimulating the lumbar sympathetic chain via the implantable electrode contact.

113. The method of Claim 112, wherein electrically stimulating a first side of the lumbar sympathetic chain at a first current or first voltage causes vasodilation in an ipsilateral arm, leg, and / or the entire abdomen.

114. The method of Claim 113, wherein electrically stimulating the first side of the lumbar sympathetic chain at a second current or second voltage causes vasodilation in a contralateral arm and / or leg.

115. The method of any one of Claims 112 to 114, wherein electrically stimulating the first side of the lumbar sympathetic chain at a third current or third voltage causes vasoconstriction in the ipsilateral arm and / or leg.

116. The method of any one of Claims 112 to 115, further comprising toggling electrical stimulation between different currents and / or voltages.

117. The method of any one of Claims 112 to 116, wherein electrically stimulating reduces pulmonary capillary wedge pressure.

118. The method of any one of Claims 112 to 117, further comprising detecting physical exertion using one or more sensors.

119. The method of Claim 118, further comprising electrically stimulating after detecting physical exertion of the patient.

120. The method of Claim 118, further comprising suspending or reducing electrical stimulation after detecting physical exertion of the patient.

121. The method of Claim 118, further comprising automatically electrically stimulating in response to detecting the physical exertion.

122. The method of Claim 118, further comprising prompting the patient to activate the stimulator in response to detecting the physical exertion.

123. The method of any one of Claims 118 to 122, wherein the one or more sensors comprises at least one of an electrical sensor, an accelerometer or a gyrometer.

124. The method of any one of Claims 118 to 123, further comprising detecting the physical exertion by measuring a physiological parameter using the one or more sensors.

125. The method of Claim 124, wherein the physiological parameter is blood pressure, respiratory rate, heart rate, heart rate variability, skin sympathetic nerve activity, heart rate recovery, heart rate turbulence, or baroreflex sensitivity.

126. The method of any one of Claims 1 18 to 125, further comprising deactivating the stimulator when the physical exertion is no longer detected.

127. The method of any one of Claims 112 to 126, wherein electrically stimulating comprises stimulating at a frequency of no more than 20 Hz.

128. The method of any one of Claims 112 to 127, wherein electrically stimulating comprises stimulating at a fixed frequency.

129. The method of any one of Claims 112 to 128, further comprising electrically stimulating after detecting a cold temperature.

130. The method of Claim 129, further comprising automatically electrically stimulating in response to detecting the cold temperature.

131. The method of Claim 129, further comprising prompting the patient to activate the stimulator in response to detecting the cold temperature.

132. The method of any one of Claims 129 to 131, further comprising detecting the cold temperature using one or more sensors.

133. The method of Claim 129, further comprising electrically stimulating so long as the cold temperature is detected.

134. A system for electrically stimulating a lumbar sympathetic chain of a patient, the system comprising: an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain, the stimulator comprising: a communication module configured to communicate with an external device; and a processor operably connected to the communication module, the processor configured to receive an instruction from the external device to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain.

135. The system of Claim 134, wherein the stimulator is implantable.

136. The system of Claim 134 or 135, further comprising one or more sensors configured to detect physical activity of the patient.

137. The system of any one of Claims 134 to 136, further comprising one or more sensors configured to measure a physiological parameter of the patient.

138. A system for electrically stimulating a lumbar sympathetic chain of a patient, the system comprising: an implantable electrode contact configured to be delivered into electrical communication with the lumbar sympathetic chain; and a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain, the stimulator comprising a processor configured to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain when activated by the patient.

139. The system of Claim 138, wherein the stimulator is configured to be activated by a wearable component.

140. The system of Claim 138 wherein the stimulator is configured to be activated by an external device.

141. The system of Claim 138, wherein the stimulator is configured to be activated when placed into electrical communication with the implantable electrode contact.

142. A method of treating diabetic vascular disease and neuropathy in a patient, the method comprising: receiving, by a controller from an external device, an instruction to electrically stimulate a lumbar sympathetic chain via an implantable electrode contact; activating a stimulator to send a signal to the implantable electrode contact; and electrically stimulating the lumbar sympathetic chain via the implantable electrode contact, wherein electrically stimulating comprises causing vasodilation in a leg.

143. The method of Claim 142, wherein electrically stimulating comprises accelerating wound healing.

144. The method of Claim 142 or 143 wherein the external device is a wearable device.

145. The method of any one of Claims 142 to 144, wherein electrically stimulating comprises stimulating at a fixed frequency.

146. A system for electrically stimulating a lumbar sympathetic chain of a patient, the system comprising: an implantable electrode contact configured to be delivered into contact with the lumbar sympathetic chain; a stimulator configured to send a signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain, the stimulator comprising a processor configured to receive an instruction from an external device to send the signal to the implantable electrode contact to electrically stimulate the lumbar sympathetic chain; and the external device configured to send the instruction to the processor.

147. The system of Claim 146, wherein the implantable electrode contact is an acute or sub-acute device.

148. The system of Claim 146 or 147, wherein the external device is a wearable device.

149. The system of any one of claims 146 to 148, wherein the stimulator is implantable.

150. A system for treating a condition in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of vertebral column of the subject; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein the stimulator is configured to send signals to the first electrode contact and the second electrode contact to: increase voltage until causing vasodilation in an ipsilateral leg; and increase voltage for longer than ipsilateral leg until causing vasodilation in a contralateral leg.

151. The system of Claim 150, wherein the condition is neuropathy, pain, exercise intolerance, heart failure, or hypertension.

152. The system of Claim 150 or 151, further comprising:a third electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; and a fourth electrode contact configured to be positioned on the second lateral side of vertebral column of the subject, wherein the stimulator is configured send second signals to the third electrode contact and the fourth electrode contact to: increase voltage until causing vasodilation in an ipsilateral leg; and increase voltage until causing vasodilation in a contralateral leg.

153. The system of Claim 152, wherein the stimulator is configured to toggle between sending the signals to the first electrode contact and the second electrode contact and sending the second signals to the third electrode contact and the fourth electrode contact.

154. The system of any one of Claims 150 to 153, wherein the signals comprise a fixed pulse width and a fixed frequency.

155. The system of Claim 154, wherein the fixed pulse width is between 0.1 ms and 10 ms.

156. The system of Claim 154 or 155, wherein the fixed frequency is between 0.1 Hz and 20 Hz.

157. A method of treating a condition in a subject, the method comprising: positioning a first electrode contact on a first lateral side of a vertebral column of the subject; positioning a second electrode contact on the first lateral side of the subject of vertebral column of the subject; and electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein electrically stimulating comprises: increasing voltage until causing vasodilation in an ipsilateral leg; and increasing voltage until causing vasodilation in a contralateral leg.

158. The method of Claim 157, wherein the condition is neuropathy, pain, exercise intolerance, heart failure, or hypertension.

159. The method of Claim 157 or 158, wherein electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact comprises: increasing voltage until causing vasoconstriction in the ipsilateral leg; and reducing voltage until causing vasodilation in the ipsilateral leg.

160. The method of any one of Claims 157 to 158, further comprising: positioning a third electrode contact on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; positioning a fourth electrode contact on the second lateral side of vertebral column of the subject; and electrically stimulating a lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact, wherein electronically stimulating comprises: increasing voltage until causing vasodilation in an ipsilateral leg; and increasing voltage until causing vasodilation in a contralateral leg.

161. The method of Claim 160, comprising toggling between electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact and electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact.

162. The method of Claim 161, wherein toggling comprises: electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact until reaching steady state; after reaching the steady state, electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact for a first duration; after the first duration, stopping electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact;after stopping electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact, electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact until reaching steady state; and after reaching the steady state, electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column via the third electrode contact and the fourth electrode contact for a second duration; after the second duration, stopping electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column via the third electrode contact and the fourth electrode contact.

163. The method of Claim 162, wherein the first duration and the second duration are a same duration.

164. The method of Claim 162 or 163, wherein the first duration is between 30 s and 5 min.

165. The method of any one of Claims 162 to 164, wherein toggling further comprises, after stopping electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column via the third electrode contact and the fourth electrode contact, electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column of the subject via the first electrode contact and the second electrode contact until reaching steady state.

166. The method of any one of Claims 157 to 165, wherein electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact comprises a fixed pulse width and a fixed frequency.

167. The method of Claim 166, wherein the fixed pulse width is between 0.1 ms and 10 ms.

168. The method of Claim 166 or 167, wherein the fixed frequency is between 0.1 Hz and 20 Hz.

169. The method of any one of Claims 157 to 168, wherein electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact comprises increasing a voltage from 1 V to 6 V.

170. The method of any one of Claims 157 to 169, wherein the first lateral side of vertebral column is a left side.

171. The method of Claim 170, wherein the method treats pain in a left leg of the subject.

172. The method of any one of Claims 157 to 169, wherein the first lateral side of vertebral column is a right side.

173. The method of Claim 172, wherein the method treats pain in a right leg of the subject.

174. The method of any one of Claims 157 to 173, further comprising instructing initiation of exercise after causing vasodilation in the contralateral leg.

175. A method of treating a subject, the method comprising: stimulating lumbar sympathetic nerve activity, wherein stimulating comprises causing vasodilation in hindlimb beds.

176. The method of Claim 175, wherein stimulating comprises unilaterally stimulating a lumbar sympathetic chain.

177. The method of Claim 175, wherein causing the vasodilation further comprises vasodilating renal beds.

178. The method of any one of Claims 175 to 177, wherein stimulating comprises electrically stimulating.

179. A method of treating a condition in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on one lateral side of vertebral column via an electrode contact on the one lateral side of the vertebral column of the subject, wherein electronically stimulating comprises applying electrical signals to the electrode contact to cause vasodilation in a contralateral leg.

180. The method of Claim 179, wherein the condition is neuropathy, pain, exercise intolerance, heart failure, or hypertension.

181. The method of Claim 179 or 180, comprising applying electrical signals to the electrode contact to cause vasodilation in an ipsilateral leg.

182. A method of treating pain in a subject, the method comprising: positioning a first electrode contact on a first lateral side of a vertebral column of the subject;positioning a second electrode contact on the first lateral side of the subject of vertebral column of the subject; electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein electrically stimulating comprises: increasing voltage until causing vasodilation in a leg on the first lateral side; and increasing voltage until causing vasodilation in a leg on a second lateral side; positioning a third electrode contact on the second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; positioning a fourth electrode contact on the second lateral side of vertebral column of the subject; electrically stimulating a lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact, wherein electronically stimulating comprises: increasing voltage until causing vasodilation in a leg on the second lateral side; and increasing voltage until causing vasodilation in a leg on the first lateral side; and toggling between electrically stimulating the lumbar sympathetic chain on the first lateral side of vertebral column via the first electrode contact and the second electrode contact and electrically stimulating the lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact.

183. A method of treating pain in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a second electrode contact on the first lateral side, wherein electrically stimulating comprises at least one of: causing vasodilation in a leg on the first lateral side; orcausing vasodilation in a leg on a second lateral side; and electrically stimulating a lumbar sympathetic chain on a second lateral side of a vertebral column opposite the first lateral side via a third electrode contact on the second lateral side and a second electrode contact on the second lateral side, wherein electrically stimulating comprises at least one of: causing vasodilation in a leg on the second lateral side; or causing vasodilation in a leg on the first lateral side.

184. A method of treating pain in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on one lateral side of a vertebral column via a first electrode contact on the one lateral side and a second electrode contact on the one lateral side, wherein electrically stimulating comprises causing vasodilation in a contralateral leg.

185. A system for treating pain in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of vertebral column of the subject; a third electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; and a fourth electrode contact configured to be positioned on the second lateral side of vertebral column of the subject; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate a lumbar sympathetic chain on the second lateral side of the vertebral column, wherein the stimulator is configured to: send signals to the first electrode contact and the second electrode contact to cause vasodilation in a leg on the first lateral side and vasodilation in a leg on the second lateral side;send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in the leg on the second lateral side and vasodilation in the leg on the first lateral side; and toggle between sending the signals to the first electrode contact and the second electrode contact and sending the signals to the third electrode contact and the fourth electrode contact.

186. A system for treating pain in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of vertebral column of the subject; a third electrode contact configured to be positioned on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; and a fourth electrode contact configured to be positioned on the second lateral side of vertebral column of the subject; and a stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact and to electrically stimulate a lumbar sympathetic chain on the second lateral side of the vertebral column, wherein the stimulator is configured to: send signals to the first electrode contact and the second electrode contact to cause vasodilation in at least one of a leg on the first lateral side or a leg on the second lateral side; send signals to the third electrode contact and the fourth electrode contact to cause vasodilation in at least one of the leg on the second lateral side or the leg on the first lateral side.

187. A system for treating pain in a subject, the system comprising: a first electrode contact configured to be positioned on a first lateral side of a vertebral column of a subject; a second electrode contact configured to be positioned on the first lateral side of the subject of vertebral column of the subject; anda stimulator configured to electrically stimulate a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein the stimulator is configured to send signals to the first electrode contact and the second electrode contact to cause vasodilation in a leg on a second lateral side.

188. A non-therapeutic diagnostic method of diagnosing vasodilation thresholds in a subject, the method comprising: positioning a first electrode contact on a first lateral side of a vertebral column of the subject; positioning a second electrode contact on the first lateral side of the subject of vertebral column of the subject; electrically stimulating a lumbar sympathetic chain on the first lateral side of the vertebral column via the first electrode contact and the second electrode contact, wherein electrically stimulating the lumbar sympathetic chain on the first lateral side comprises: increasing voltage until causing vasodilation in a leg on the first lateral side and having no effect on a leg on the second lateral side; recording as Vi-i the voltage that causes vasodilation in the leg on the first lateral side and has no effect on the leg on a second lateral side; further increasing voltage until causing vasodilation in the leg on the first lateral side and causing vasodilation in the leg on the second lateral side; recording as V1-2 the voltage that causes vasodilation in the leg on the first lateral side and vasodilation in the leg on the second lateral side; further increasing voltage until causing vasodilation in the leg on the second lateral side and causing vasoconstriction or having no effect in the leg on the first lateral side; recording as V1-3 the voltage that causes vasodilation in the leg on the second lateral side and causes vasoconstriction or has no effect in the leg on the first lateral side;further increasing voltage until causing vasoconstriction or having no effect in the leg on the first lateral side and causing vasoconstriction or having no effect in the leg on the second lateral side; and recording as Vi-4 the voltage that causes vasoconstriction or has no effect in the leg on the first lateral side and causes vasoconstriction or has no effect in the leg on the second lateral side; positioning a third electrode contact on a second lateral side of a vertebral column of the subject, the second lateral side opposite the first lateral side; positioning a fourth electrode contact on the second lateral side of vertebral column of the subject; and electrically stimulating a lumbar sympathetic chain on the second lateral side of vertebral column of the subject via the third electrode contact and the fourth electrode contact, wherein electronically stimulating the lumbar sympathetic chain on the second lateral side comprises: increasing voltage until causing vasodilation in a leg on the second lateral side and having no effect on a leg on the first lateral side; recording as V2-1 the voltage that causes vasodilation in the leg on the second lateral side and has no effect on the leg on the first lateral side; further increasing voltage until causing vasodilation in the leg on the second lateral side and causing vasodilation in the leg on the first lateral side; recording as V2-2 the voltage that causes vasodilation in the leg on the second lateral side and vasodilation in the leg on the first lateral side; further increasing voltage until causing vasodilation in the leg on the first lateral side and causing vasoconstriction or having no effect in the leg on the second lateral side; recording as V2-3 the voltage that causes vasodilation in the leg on the first lateral side and causes vasoconstriction or has no effect in the leg on the second lateral side; further increasing voltage until causing vasoconstriction or having no effect in the leg on the second lateral side and causing vasoconstriction or having no effect in the leg on the first lateral side; andrecording as V2-4 the voltage that causes vasoconstriction or has no effect in the leg on the second lateral side and causes vasoconstriction or has no effect in the leg on the first lateral side.

189. A non-therapeutic diagnostic method of diagnosing vasodilation thresholds in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a second electrode contact on the first lateral side, wherein electrically stimulating the lumbar sympathetic chain on the first lateral side comprises: increasing voltage until causing vasodilation in a leg on the first lateral side and having no effect on a leg on a second lateral side; recording as V1-1 the voltage that causes vasodilation in the leg on the first lateral side and has no effect on the leg on the second lateral side; further increasing voltage until causing vasodilation in the leg on the first lateral side and causing vasodilation in the leg on the second lateral side; recording as V1-2 the voltage that causes vasodilation in the leg on the first lateral side and vasodilation in the leg on the second lateral side; further increasing voltage until causing vasodilation in the leg on the second lateral side and causing vasoconstriction or having no effect in the leg on the first lateral side; recording as V1-3 the voltage that causes vasodilation in the leg on the second lateral side and causes vasoconstriction or has no effect in the leg on the first lateral side; further increasing voltage until causing vasoconstriction or having no effect in the leg on the first lateral side and causing vasoconstriction or having no effect in the leg on the second lateral side; and recording as V1-4 the voltage that causes vasoconstriction or has no effect in the leg on the first lateral side and causes vasoconstriction or has no effect in the leg on the second lateral side; and electrically stimulating a lumbar sympathetic chain on the second lateral side of the vertebral column via a third electrode contact on the second lateral side and a fourthelectrode contact on the second lateral side, wherein electrically stimulating the lumbar sympathetic chain on the second lateral side comprises: increasing voltage until causing vasodilation in a leg on the second lateral side and having no effect on a leg on the first lateral side; recording as V2-1 the voltage that causes vasodilation in the leg on the second lateral side and has no effect on the leg on the first lateral side; further increasing voltage until causing vasodilation in the leg on the second lateral side and causing vasodilation in the leg on the first lateral side; recording as V2-2 the voltage that causes vasodilation in the leg on the second lateral side and vasodilation in the leg on the first lateral side; further increasing voltage until causing vasodilation in the leg on the first lateral side and causing vasoconstriction or having no effect in the leg on the second lateral side; recording as V2-3 the voltage that causes vasodilation in the leg on the first lateral side and causes vasoconstriction or has no effect in the leg on the second lateral side; further increasing voltage until causing vasoconstriction or having no effect in the leg on the second lateral side and causing vasoconstriction or having no effect in the leg on the first lateral side; and recording as V2-4 the voltage that causes vasoconstriction or has no effect in the leg on the second lateral side and causes vasoconstriction or has no effect in the leg on the first lateral side.

190. A non-therapeutic diagnostic method of diagnosing vasodilation thresholds in a subject, the method comprising: electrically stimulating a lumbar sympathetic chain on a first lateral side of a vertebral column via a first electrode contact on the first lateral side and a second electrode contact on the first lateral side, wherein electrically stimulating comprises: increasing voltage until causing vasodilation in a leg on the first lateral side and having no effect on a leg on a second lateral side; recording as V1-1 the voltage that causes vasodilation in the leg on the first lateral side and has no effect on the leg on the second lateral side;further increasing voltage until causing vasodilation in the leg on the first lateral side and causing vasodilation in the leg on the second lateral side; recording as V1-2 the voltage that causes vasodilation in the leg on the first lateral side and vasodilation in the leg on the second lateral side; further increasing voltage until causing vasodilation in the leg on the second lateral side and causing vasoconstriction or having no effect in the leg on the first lateral side; recording as V1-3 the voltage that causes vasodilation in the leg on the second lateral side and causes vasoconstriction or has no effect in the leg on the first lateral side; further increasing voltage until causing vasoconstriction or having no effect in the leg on the first lateral side and causing vasoconstriction or having no effect in the leg on the second lateral side; and recording as V1-4 the voltage that causes vasoconstriction or has no effect in the leg on the first lateral side and causes vasoconstriction or has no effect in the leg on the second lateral side.

191. A method of inducing bilateral vasodilation from neurostimulation on one lateral side of a lumbar sympathetic chain of a subject, the method comprising: positioning a first electrode contact with the lumbar sympathetic chain on the one lateral side of a vertebral column of the subject; positioning a second electrode contact with the lumbar sympathetic chain on the one lateral side of vertebral column; electrically stimulating the lumbar sympathetic chain on the one lateral side of vertebral column via the first electrode contact and the second electrode contact; and causing vasodilation of both legs of the subject without increasing mean arterial pressure or heart rate, wherein the vasodilation treats at least one of neuropathy, pain, heart failure, or hypertension.

192. A method of treating hypertension, the method comprising: delivering an electrical signal to stimulate a lumbar sympathetic chain via a first electrode contact on a first lateral side of a vertebral column of a subject and a second electrode contact on the first lateral side of the vertebral column,the electrical signal comprising a constant frequency of 20 Hz, the electrical signal comprising a voltage between 1.5 V and 3.5 V, wherein after delivering the electrical signal, blood flow increases and vascular resistance decreases in both legs of the subject.

193. A method comprising: interfacing at least two electrode contacts with a lumbar sympathetic chain of a subject; and delivering an electrical signal to the lumbar sympathetic chain via the at least two electrode contacts to cause vasodilation in at least one of the subject’s legs, wherein the vasodilation occurs in the at least one of the subject’s legs ipsilateral or contralateral to the at least two electrode contacts.

194. A system comprising: a pulse generator configured to generate an electrical signal designed to stimulate a lumbar sympathetic chain of a subject; and at least two electrode contacts coupled to the pulse generator and configured to interface with the lumbar sympathetic chain to deliver the electrical signal, wherein stimulation of the lumbar sympathetic chain with the electrical signal causes vasodilation in at least one of a subject’s legs.

195. The use of any of the systems or methods of any of the preceding claims for the treatment of knee pain.

196. The use of any of the systems or methods of any of the preceding claims for the treatment of pelvic pain.

197. The use of any of the systems or methods of any of the preceding claims for the treatment of heart disease.

198. Apparatus and computer software products for performing the methods of any of the preceding method claims.

199. Methods and computer software products for performing functions of the systems of any of the preceding system claims.

200. The use of any of the systems or methods of any of the preceding claims for the treatment of knee pain through a surgical intervention.201 . The use of any of the systems or methods of any of the preceding claims for the treatment of pelvic pain through a surgical intervention.

202. The use of any of the systems or methods of any of the preceding claims for the treatment of pelvic pain through a surgical intervention.

203. The use of any of the systems or methods of any of the preceding claims for the treatment of heart disease through a surgical intervention.