WO2025039037A1

WO2025039037A1 - Autonomic nervous system neuromodulation

Info

Publication number: WO2025039037A1
Application number: PCT/AU2024/050894
Authority: WO
Inventors: Vahid MOHABBATI; Parsa MOHABBATI
Original assignee: Vahid MOHABBATI
Priority date: 2023-08-24
Filing date: 2024-08-22
Publication date: 2025-02-27
Also published as: WO2025039024A1

Abstract

Autonomic Nervous System Neuromodulation represents a pioneering endeavour in neuromodulation technology. By selectively interfacing with the autonomic nervous system, this new technology offers a prospective avenue for ameliorating conditions characterised by autonomic dysregulation including but not limited to pain of head and neck, upper limb, chest, abdomen, pelvis, and lower limb, post-traumatic stress disorder (PTSD), acute and chronic heart failure, gastrointestinal and genitourinary system dysmotility, and peripheral vascular disease. By employing targeted stimulation of intricate autonomic neural pathways, it aspires to reinstate equilibrium with autonomic functions. This innovation bears the potential to significantly enhance the quality of life for individuals grappling with a spectrum of autonomic disorders, ushering in a paradigm shift in neurological therapies.

Description

Autonomic Nervous System Neuromodulation

TECHNICAL FIELD

This invention bridges neuroscience, medical technology, and biomedical engineering to potentially address conditions related to autonomic dysregulation. The autonomic nervous system (ANS) is a subcomponent of the peripheral nervous system (PNS) that regulates involuntary physiologic processes, including blood pressure, heart rate, respiration, digestion, and sexual arousal. It comprises sympathetic, parasympathetic, and enteric nervous systems, which are three anatomically distinct divisions.

BACKGROUND OF THE INVENTION

The autonomic nervous system (ANS) plays a pivotal role in maintaining internal homeostasis, regulating vital functions such as heart rate, blood pressure, digestion, and respiratory rate. However, disruptions in autonomic balance can lead to a range of debilitating conditions collectively referred to as autonomic dysregulation. These conditions encompass disorders like orthostatic hypotension, vasovagal syncope, and cardiac arrhythmias, which profoundly impact patients' quality of life and pose significant challenges for traditional therapeutic approaches. The ANS is also involved in our fight-flight response and subsequently in many painful conditions involving different body parts or organs, including but not limited to cluster or migraine headaches, Complex Regional Pain Syndrome (CRPS), visceral pain of chest, abdomen and or pelvis, and ischemic pain due to peripheral vascular disease.

Conventional treatment modalities for autonomic dysregulation often target symptoms rather than addressing underlying neural imbalances. Medications can be limited by side effects and have a temporary and partial effect. Chemical blocks using needle techniques may have temporary benefits. Surgical sympathectomies may carry significant risks. This calls for innovative interventions capable of recalibrating autonomic function while minimising invasiveness and adverse effects. Stimulation of Dorsal Root Ganglion (DRG-S) has been employed and postulated to be a useful technique in recruiting sympathetic chain in literature. DRG-S uses implantable electrodes over DRG of the spinal nerve roots (consisting of sensory/motor and sympathetic fibres) to achieve this. DRG-S is a technically challenging and a high-risk procedure. Stimulating DRG has its limitations such as unwanted motor stimulation, sensory stimulation (induction of paraesthesia) that can be intolerable for some patients and lead migration and fracture.

Autonomic Nervous System Neuromodulation emerges as a promising solution to these challenges. By combining principles from neuroengineering, neuromodulation, and biomedical technology, this novel approach aims to restore autonomic equilibrium through targeted modulation of the sympathetic chain. This innovation holds the potential to revolutionise the treatment landscape in several ways:

In conclusion, Autonomic Nervous System Neuromodulation represents an innovation poised to redefine the management of autonomic dysregulation-related disorders. By leveraging the synergy of neuroengineering, neuromodulation, and biomedical technology, this approach holds the promise of providing patients with more effective, personalised, and minimally invasive treatment options. As ongoing research and clinical trials unfold, the potential advantages of this technology could lead to a paradigm shift in addressing autonomic dysregulation and enhancing the well-being of countless individuals.

There are several challenges in applying autonomic nervous system neuromodulation to particular situations and conditions. These challenges include:

• Risk of Direct Damage: invasive methods typically carry a risk of direct tissue damage.

• Complexity and Variability: The ANS is highly complex and its interactions with various physiological systems can be difficult to predict. This complexity can make it challenging to achieve consistent and predictable outcomes.

• Limited Standardization: There is often a lack of standardized protocols for stimulation parameters (e.g., frequency, duration), which can lead to variable results and difficulties in comparing studies.

• Potential for Systemic Side Effects: Modulating the ANS can lead to unintended systemic effects due to its widespread influence on various organ systems.

In summary, the advantages of autonomic nervous system stimulation span multiple domains, from cardiovascular and neurological health to pain management and immune function. The ongoing development and refinement of stimulation techniques continue to enhance their therapeutic potential. ANS neuromodulation provides broader systemic effects and versatility in treating various conditions, but it also grapples with complexity and potential systemic side effects. The method disclosed in the present invention aims overcomes those challenges.

PRIOR ART

In the recent past, neuromodulation has witnessed significant advances with regard to the science, mechanisms, clinical applications, and technology development. Some of these developments are disclosed in the following patent literature.

US 2009/0270935 discloses various system embodiments comprising an implantable lead, an implantable housing, a neural stimulation circuit in the housing, and a controller in the housing and connected to the neural stimulation circuit. The lead has a proximal end and a distal end. The distal end is adapted to deliver neural stimulation pulses to the ventral nerve root and the dorsal nerve root. The proximal end of the lead is adapted to connect to the housing. The neural stimulation circuit is adapted to generate neural stimulation pulses to stimulate the ventral nerve root or the dorsal nerve root using the implantable lead. The controller is adapted to control the neural stimulation circuit to deliver a neural stimulation treatment.

US 2010/0228310 discloses various embodiments of a method for modulating autonomic neural activity in a body having a spinal cord, a subclavian vein and thoracic lymphatic vessels that include a thoracic duct and a right lymphatic duct, at least one programmed therapy is implemented using an implanted medical device to modulate autonomic neural activity. Implementing the therapy includes increasing or decreasing sympathetic activity in sympathetic nerves branching from a first region of the spinal cord using a first electrode in the thoracic duct, and further includes increasing or decreasing parasympathetic activity in parasympathetic nerves adjacent to the desired thoracic lymphatic vessel or sympathetic activity in sympathetic nerves branching from a second region of the spinal cord using a second electrode in the desired thoracic lymphatic vessel.

US 2015/0039058 discloses a method of treating autonomic imbalance in a patient includes energizing a first therapeutic element disposed to deliver therapy to a parasympathetic nerve fiber and energizing a second therapeutic element to deliver therapy to a sympathetic cardiac nerve fiber. At least one of the therapeutic elements is disposed in the vasculature superior to the heart. The therapy decreases the patient's heart rate and elevates or maintains the blood pressure of the patient.

US 2021/0069511 discloses modulation of neural activity of a cardiac-related nerve at an interganglionic nerve branch in the sympathetic chain results in preferential reduction of sympathetic signals to the heart, thereby providing ways of treating and preventing cardiac dysfunction such as arrhythmias.

However, none of these documents discloses a method and apparatus as defined in the present application for autonomic nervous system neuromodulation targeting different areas of the ANS depending on the patient condition.

SUMMARY OF THE INVENTION

The Autonomic Nervous System Neuromodulation is an innovative breakthrough in neuroengineering and neuromodulation technology designed to address autonomic dysregulation-related disorders. This device operates on the fundamental principle of targeted neural modulation, interfacing with the autonomic nervous system through precise stimulation of the sympathetic chain based on the patient's symptoms and organ involvement. By offering a minimally invasive, patient-centric approach, this invention holds the potential to revolutionize the treatment landscape for conditions including but not limited to pain of head, neck, upper limb, chest, abdomen, pelvis and lower limb as well as acute and chronic heart failure, post-traumatic stress disorder (PTSD), gastrointestinal and genitourinary system disorders and dysfunctions including pain and dysmotility syndromes, and peripheral vascular disease and ischemic pain. The novel method disclosed in the present invention has several features. These include:

Precise Modulation of Autonomic Pathways: Unlike broader systemic interventions, the stimulator employs targeted electrode placement and stimulation techniques to selectively target specific ANS neural pathways responsible for autonomic regulation. This precision enables tailored modulation and potential restoration of autonomic balance. Minimally Invasive Approach: Surgical interventions for autonomic dysregulation can carry substantial risks. In our cadaveric studies of targeted ANS stimulation it was proven to be technically easier and need less skills compared to surgical sympathectomies or even DRG- Stim. Risk of lead migration and lead fracture will also be minimised. The ANS stimulator offers a less invasive alternative, utilising minimally invasive implantation techniques to minimize surgical complications and patient discomfort.

Holistic Impact on Autonomic Functions: By directly influencing the autonomic nervous system, this approach has the potential to impact multiple physiological processes simultaneously. This approach addresses the root causes of autonomic dysregulation in a more profound and direct way, potentially leading to more comprehensive and enduring therapeutic outcomes.

Patient- Centric Care: The stimulator's customisable parameters allow for individualised treatment, catering to the unique autonomic profiles of each patient. This patient-centric approach acknowledges the variability in autonomic dysfunction presentation and optimises treatment efficacy. Stimulators parameters such as mAmp, frequency, pulse width etc can be tailored to patients needs to achieve best outcomes.

Reduced Dependence on Pharmaceuticals: Patients with autonomic dysregulation often rely on a cocktail of medications with varying degrees of effectiveness. The stimulator offers the prospect of reducing or even eliminating dependence on pharmaceutical agents, thereby alleviating concerns about side effects and drug interactions.

The stimulator employed in the present invention includes biocompatible electrodes strategically positioned along the sympathetic chain, capitalizing on our understanding of autonomic pathways. It harnesses the intricate interplay between neural networks to selectively modulate autonomic functions. This principle is rooted in the concept of restoring equilibrium within the autonomic nervous system by stimulating key nodes associated with sympathetic nervous system function for example heart rate variability, vasomotor tone, sudomotor function and respiratory rhythm.

The invention is intended for individuals grappling with autonomic dysregulation-related conditions, where conventional treatments have proven inadequate or fraught with failure or side effects. It finds application in both clinical and research settings. Clinically, it offers a novel therapeutic avenue for patients seeking relief from autonomic malfunctions. In research, it serves as a platform for further understanding of autonomic neurophysiology, it’s relationship to modulation of pain and other symptoms and refining stimulation techniques.

The stimulator's operation revolves around its ability to deliver precise electrical pulses to targeted regions of the autonomic nervous system from Tito T3 (Stellate Ganglion) to Splanchnic nerves (T10/T11/T12) to Lumbar sympathetic plexus (L2/L3/L4) to Superior Hypogastric Plexus (L5/S1) to Ganglion Impar (Sacro-coccygeal plexus). Through a minimally invasive surgical procedure, the electrodes are implanted in proximity to autonomic neural pathways. These electrodes are then connected to a control unit (Impulse Generator- IPG) that allows for customisation of stimulation parameters. By manipulating pulse frequency, amplitude, pulse width and duty cycles, clinicians can tailor the stimulation to address specific autonomic imbalances. The device's ability to interface with the autonomic nervous system at a neural level enables real-time adjustment and optimisation.

DETAILED DESCRIPTION OF EMBODIMENTS

Autonomic Nervous System Neuromodulation (ANSNM) functions on principles like traditional spinal cord stimulators, DRG-Stimulattor used in pain medicine, but with a distinct focus on modulating autonomic functions rather than dorsal spinal column or DRG. Just as traditional stimulators involve electrode implantation on nerve sites to influence pain perception, the ANSNM employs a similar concept to target autonomic pathways for the regulation of physiological functions.

Electrode Placement: In the case of an ANSNM, electrodes are placed near specific autonomic nerve pathways along the vertebral bodies using a Touhey needle under direct fluoroscopy. These pathways are identified based on the patient's history, examination, advanced neuroimaging, and neurophysiological techniques, ensuring accurate targeting of autonomic nodes responsible for symptoms and organs involved. For example, a patient with lower limb CRPS, will receive ANSNM at L2/L3/L4 on the affected side or a person with chronic congestive heart failure will receive a T2 sympathetic ANSNM on the left side.

Neural Modulation: Both types of stimulators deliver controlled electrical pulses to the nerve via the implanted electrodes. In traditional stimulators, these pulses interfere with pain signals, creating a tingling sensation that "overrides" pain perception. In the ANSNM, the electrical pulses modulate autonomic nerve activity. By precisely stimulating or inhibiting certain autonomic pathways, the ANSNM aims to restore balance within the autonomic nervous system, improving its regulation of bodily functions.

Stimulation Parameters: The parameters of stimulation are crucial for both stimulator types. In traditional stimulators, factors such as pulse frequency, amplitude, and pulse width are adjusted to achieve optimal pain relief for the individual. Similarly, in the ANSNM, these parameters are customized to address specific autonomic dysregulation patterns. For example, altering the frequency and amplitude of electrical pulses can influence heart rate variability, while adjusting pulse width can impact vasomotor tone.

Individualized Treatment: Both stimulator types emphasize individualized treatment. Traditional stimulators allow patients to adjust stimulation settings based on their pain levels and preferences. Similarly, the ANSNM permits tailored modulation of autonomic functions, recognizing the variability in autonomic dysfunction presentations among individuals.

Minimally Invasive Implantation: The implantation procedure for both stimulator types is minimally invasive, involving the placement of electrodes through a surgical procedure. This approach reduces risks and promotes quicker recovery times for patients.

Neuromodulation of the autonomic nervous system (ANS) comes with its own set of advantages and challenges. The stimulation of the autonomic nervous system (ANS) offers several advantages across various medical conditions, leveraging both sympathetic and parasympathetic pathways to modulate physiological functions. These include:

• Targeting Systemic Effects: ANS neuromodulation can impact a range of physiological functions such as heart rate, blood pressure, and digestive processes, which are crucial for managing systemic conditions like hypertension, heart failure, and chronic pain.

• Potential for Broad Impact: By modulating the ANS, it’ s possible to influence multiple organ systems simultaneously, potentially offering therapeutic benefits for complex conditions where ANS dysfunction is a factor, such as PTSD or chronic pain. The method disclosed in the present invention has applications in several areas. The following examples illustrate the application of this novel method to different conditions.

Cardiovascular Health:

• Arrhythmia Management: Modulation of the ANS, including methods to reduce autonomic innervation, has shown promise in decreasing the incidence of arrhythmias such as atrial fibrillation.

• Heart Failure: Reduced vagal activity is associated with increased mortality in heart failure patients. Vagal nerve stimulation has potential therapeutic benefits, including improved survival and heart function.

• Hypertension: Alterations in autonomic balance, particularly increased sympathetic activity and reduced vagal tone, contribute to hypertension. Non-invasive techniques like vagus nerve stimulation can offer protective roles against high blood pressure and related complications.

Neurological and Mental Health:

• Parkinson's Disease: Subthalamic nucleus stimulation improves autonomic function by reducing the need for pharmacotherapy, leading to enhanced autonomic function in patients.

• PTSD: Vagus nerve stimulation has been shown to aid in heart repair post-myocardial infarction and restore autonomic balance, which could be beneficial in PTSD management.

Gastrointestinal Disorders:

• Irritable Bowel Syndrome: Modulation of the ANS, particularly by increasing sympathetic and decreasing parasympathetic activity, plays a crucial role in managing stress-related gastrointestinal disorders.

Pain and Immune Function:

• Pain Management: ANS stimulation, including techniques like spinal cord stimulation, can alter pain perception and provide relief in chronic pain conditions.

• Immunomodulation: The ANS's influence on immune function offers novel therapeutic approaches for diseases like cancer and inflammatory bowel diseases.

Autonomic Nervous System Balance:

• Heart Rate Variability: Stimulation of the parasympathetic nervous system has been associated with increased heart rate variability, indicating better autonomic responsiveness and potential cardiovascular benefits.

A major advantage of the present invention is it can be targeted for Pain and Physiological Regulation Across Various Conditions. Targeting specific nerves, such as the splanchnic and T2/T3 ganglia, allows for focused treatment of various conditions but requires careful consideration of potential risks and challenges. The below overview highlights the significance of specific ganglia and nerves in managing a range of medical conditions. Targeted interventions in these areas have shown promise in improving patient outcomes and managing complex pain syndromes.

Specific Nerves and Target Areas

1. Splanchnic Nerves (Stellate ganglion, C4-C6):

• Conditions Treated: o PTSD o Head and neck pain o Cluster headaches o Upper limb CRPS and pain o Chronic migraines o Menopausal symptoms

2. T2/T3 Ganglia:

• Conditions Treated: o Pulmonary function issues o Heart regulation

3. Splanchnic Nerves (Celiac Plexus, T10, Til, T12):

• Conditions Treated: o Visceral pain in the upper abdomen o Esophageal pain o Loin/upper uterine pain

The splanchnic nerves play a significant role in pain management and various physiological processes through their interaction with different ganglia. The following table summarizes the targeted ganglia, specific areas of intervention, associated conditions.

Use of the present invention to focus on specific ganglia and their application

(T10-T12) Celiac Plexus Targeted Conditions:

• Pancreatic pain, pancreatitis or Pancreatic Cancer: Effective in managing pain associated with pancreatitis or pancreatic cancer through splanchnic nerve blocks.

• Upper Abdominal pain, Cancer or non-cancer: Splanchnic nerve blocks provide significant pain relief in upper abdominal pain, malignant or non-malignant pain. T2/T3 Ganglion

Targeted Conditions:

• Pulmonary Function: Transcutaneous electrical acupoint stimulation (TEAS) and dexmedetomidine have shown benefits in improving lung function and postoperative recovery. • Heart Regulation: These ganglia influence heart rate and blood pressure, which can be critical post-heart surgery.

T10-T12 Splanchnic Nerves

Targeted Conditions:

Visceral Pain: Effective in managing pain from abdominal conditions, including esophageal and upper abdominal pain.

L2-L4 Splanchnic Nerves

Targeted Conditions:

• Lower Limb Peripheral Vascular Disease: Relevant in managing arteriole and venous diseases affecting the lower limbs.

Complex Regional Pain Syndrome (CRPS): Addresses pain and vascular issues in the CRPS. Sudomotor, vasomotor symptoms and signs are dominant features of CRPS. As indicated earlier in the specification, the parameters of stimulation are crucial for both stimulator types. In traditional stimulators, factors such as pulse frequency, amplitude, and pulse width are adjusted to achieve optimal pain relief for the individual. Similarly, in the ANSNM, these parameters are customized to address specific autonomic dysregulation patterns. For example, altering the frequency and amplitude of electrical pulses can influence heart rate variability, while adjusting pulse width can impact vasomotor tone.

According to the present invention, surprising results are obtained by using the programs that run at very low frequencies from 1-2 Hz, then 4 Hz, 6, 10, 20, 40 and 80 Hz, impedance from 0.1mA to 2 mA and pulse width from 100-1000 microseconds. These parameters are completely outside any known methods and provide surprising, positive results in treatment of PTSD, Head and neck pain, Cluster headaches, Upper limb CRPS and pain, Chronic migraines and Menopausal symptoms by focusing on targeted regions of the autonomic nervous system, Splanchnic Nerves (C4-C6). Similarly, above parameters provide surprising results in the treatment of pulmonary function issues and heart regulation when using delivering precise electrical pulses to targeted regions of the autonomic nervous system T2/T3 Ganglia. Similar positive results are also obtained for the treatment of visceral pain in the upper abdomen, esophageal pain and loin/upper uterine pain by targeting regions of the autonomic nervous system Splanchnic Nerves (T10, Til, T12).

Another aspect of the present invention is a system for stimulating autonomic nerves, using a stimulator employing biocompatible electrodes strategically positioned along the autonomic nervous system chain which comprises an electrode control unit that generates electrical pulses across the entire electromagnetic frequency spectrum and able to control stimulation parameters. The novel system further includes a neural pathway mapping system for identifying autonomic neural pathways associated with physiological functions and a stimulation customisation interface allowing adjustment of pulse frequency, amplitude, and pulse width.

The novel system of the present invention further includes:

• A closed-loop system to monitor autonomic responses and optimise stimulation settings depending on critical events;

• A biofeedback integration which can integrate biometrics including but not limited to heart rate and respiration for bi-directional communication

• An autonomic regulation algorithm that adapts stimulation patterns based on real-time autonomic feedback, including but not limited to machine learning and artificial intelligence;

• An anatomical imaging module to facilitate precise electrode placement along the spinal cord

• A multi-modal stimulation integrating other types of neuromodulation, including but not limited to transcranial magnetic stimulation or vagus nerve stimulation

• A patient- specific calibration module to tailor stimulation parameters to individual autonomic profiles;

• A data storage and analysis module integration for historical autonomic responses; and

• A remote wireless programming interface enabling remote adjustments of stimulation parameters.

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not by way of limitation. It will be apparent to a person skilled in the relevant art that various changes in form and details can be made therein to suit different situations without departing from the spirit and scope of the present invention. Thus, the present invention should not be limited by any of the abovedescribed exemplary embodiments.

Claims

The Claims defining the invention are as follows:

1. A method for the treatment of a patient suffering from autonomic dysregulation by neuromodulation which can specially stimulate autonomic nerves, through precise stimulation of the sympathetic and or parasympathetic chain based on the patient's symptoms and organ involvement, using a stimulator employing biocompatible electrodes strategically positioned along the sympathetic chain and harnessing intricate interplay between neural networks to selectively modulate autonomic functions by restoring equilibrium within the autonomic nervous system by stimulating nodes associated with sympathetic nervous system function.

2. The method as defined in claim 1 wherein said method uses a plurality of biocompatible electrodes configured for implantation along the autonomic nerves.

3. The method of claim 2 wherein the biocompatible electrodes are implanted in proximity to autonomic neural pathways using a minimally invasive surgical procedure.

4. The method of claim 3, wherein the electrodes are connected to a control unit (Impulse Generator- IPG) that allows for customisation of stimulation parameters.

5. The method of claim 4 wherein the stimulation parameters include specific pulse frequency, amplitude, pulse width and duty cycles which can be adjusted or optimized in real time, said method utilising programs that run at very low frequencies from 1-2 Hz, then 4 Hz, 6, 10, 20, 40 and 80 Hz, impedance from 0.1mA to 2 mA and Pulse width from 100-1000 microseconds.

6. The method as defined in claim 5 wherein said method includes delivery of precise electrical pulses to targeted regions of the autonomic nervous system, Splanchnic Nerves (C4-C6) to treat PTSD, Head and neck pain, Cluster headaches, Upper limb CRPS and pain, Chronic migraines and Menopausal symptoms.

7. The method as defined in claim 5 wherein said method includes delivery of precise electrical pulses to targeted regions of the autonomic nervous system T2/T3 Ganglia for the treatment of pulmonary function issues and heart regulation.

8. The method as defined in claim 5 wherein said method includes delivery of precise electrical pulses to targeted regions of the autonomic nervous system Splanchnic Nerves (T10, Ti l, T12) for the treatment of visceral pain in the upper abdomen, esophageal pain and loin/upper uterine pain.

9. The method of claim 6 to 8 wherein the electrodes are placed near specific autonomic nerve pathways along the vertebral bodies using a Touhey needle (or similar access needles) under direct fluoroscopy or ultrasound.

10. The method of claim 9 wherein the pathways are identified based on the patient's history, examination, advanced neuroimaging, and neurophysiological techniques, ensuring accurate targeting of autonomic nodes responsible for symptoms and organs involved.

11. The method of claim 10 wherein the key nodes associated with sympathetic nervous system function that includes heart rate variability, vasomotor tone, sudomotor function and respiratory rhythm and function.

12. A system for stimulating autonomic nerves as defined in claims 1 to 10, using a stimulator employing biocompatible electrodes strategically positioned along the autonomic nervous system chain which comprises an electrode control unit that generates electrical pulses across the specific electromagnetic frequency spectrum and able to control stimulation parameters in the range of very low frequencies from 1-2 Hz, then 4 Hz, 6, 10, 20, 40 and 80 Hz, impedance from 0.1mA to 2 mA and Pulse width from 100-1000 microseconds.

13. The system as defined in claim 12 wherein it further includes a neural pathway mapping system for identifying autonomic neural pathways associated with physiological functions.

14. The system as defined in claim 13 wherein it further includes a stimulation customisation interface allowing adjustment of pulse frequency, amplitude, and pulse width.

5. The system as defined in claim 14 that includes: a. A closed-loop system to monitor autonomic responses and optimise stimulation settings depending on critical events; b. A biofeedback integration which can integrate biometrics including but not limited to heart rate and respiration for bi-directional communication c. An autonomic regulation algorithm that adapts stimulation patterns based on real-time autonomic feedback, including but not limited to machine learning and artificial intelligence; d. An anatomical imaging module to facilitate precise electrode placement along the spinal cord e. A multi-modal stimulation integrating other types of neuromodulation, including but not limited to transcranial magnetic stimulation or vagus nerve stimulation f. A patient-specific calibration module to tailor stimulation parameters to individual autonomic profiles; g. A data storage and analysis module integration for historical autonomic responses; and h. A remote wireless programming interface enabling remote adjustments of stimulation parameters.