Systems and methods for autonomous function closed-loop control

Abstract

The present invention discloses a neuromodulation system (10, 110), particularly a neurostimulation system (10, 110), for treating a patient, particularly for enhancing at least one autonomic function, such as blood circulation and / or respiration, wherein the system comprises: - at least one signal input module (12, 112) configured to receive at least one or more signals indicating blood circulation, particularly indicating pulse and / or blood pressure; - at least one control module (14, 114) connected to the signal input module (12, 112), wherein the control module (14, 114) is configured to adjust the neurostimulation provided by the neuromodulation system (10, 110) based on the signals received by the signal input module (12, 112).

Description

Technical Field

[0001] This invention relates to the field of spinal cord prostheses, particularly for the restoration of autonomous function.

[0002] Specifically, it refers to a system for spinal cord stimulation, and more particularly for the restoration of autonomic function, especially blood pressure, in patients with spinal cord injury or other conditions such as stroke, multiple sclerosis, autonomic failure, neuropathy or cancer of the nerve tissue that impairs the normal functioning of the descending sympathetic pathways that help control autonomic function. Background Technology

[0003] The spinal cord is a component of the central nervous system (CNS). Spinal cord injury (SCI) causes motor and sensory deficits, but it can also cause autonomic dysfunction. SCI can cause the closure of some, most, or all of the descending sympathetic pathways, which carry signals responsible for regulating arterial blood pressure, heart rate, and / or bowel and bladder function.

[0004] SCI-related autonomic dysfunction is a potentially life-threatening condition that leads to unstable blood pressure and subsequently chronic dysfunction of the heart and blood vessel distribution. Most SCI patients experience multiple dramatic blood pressure fluctuations daily and list this as a top priority for health insurance.

[0005] Individuals with severe SCI may suffer from cardiovascular control disorders. In the acute phase following injury, this manifests as severe resting hypotension, requiring close hemodynamic monitoring by intensive care physicians and the use of pharmacological agents (e.g., norepinephrine, daminozide, dobutamine) to raise blood pressure. However, these medications are short-acting and cause a significant increase in blood pressure, forcing clinicians to reduce the dosage, often resulting in episodes of very low blood pressure (i.e., hypoperfusion). In the chronic phase following injury (i.e., after 6 months), individuals with these severe SCIs may experience severe orthostatic hypotension (a drop in blood pressure equal to or greater than 20 mmHg systolic pressure). These hypotensive episodes occur daily and cause typical presyncope symptoms, impairing quality of life.

[0006] Severe spinal cord injury (SCI) can disrupt the brainstem control center from the sympathetic circuits in the thoracic spinal cord responsible for blood pressure regulation. This loss of regulation leads to significant hypotension in both the acute phase following injury (immediately in the emergency room and intensive care unit) and the subacute / chronic phase (after discharge from intensive care). In both cases, epidural electrical stimulation (EES) of the spinal cord can help stabilize blood pressure.

[0007] Blood pressure is the pressure of circulating blood against the walls of blood vessels. Unless otherwise specified, "blood pressure" usually refers to the pressure in the systemic arteries. Blood pressure is typically expressed as systolic pressure, the maximum pressure during a single heartbeat and / or exceeding diastolic pressure, and as the minimum pressure between two heartbeats and / or exceeding mean arterial blood pressure, the average blood pressure of an individual during a single cardiac cycle, which can be measured in millimeters of mercury (mmHg, above ambient atmospheric pressure).

[0008] Blood pressure monitoring can include monitoring parameter values ​​such as diastolic blood pressure, systolic blood pressure, diastolic and systolic blood pressure, mean arterial pressure, and mixed blood pressure values.

[0009] Furthermore, perfusion pressure, or spinal cord perfusion pressure, which is defined as the difference between mean arterial blood pressure and cerebrospinal fluid pressure, may be important. The latter can be monitored using an intrathecal catheter placed, for example, near the site of injury in the injured subject / patient or in the lumbar cistern.

[0010] When blood pressure, especially arterial blood pressure, decreases or increases as a result of spinal cord injury (SCI), the spinal neurons responsible for blood pressure control lose their ability to maintain blood pressure at normal physiological levels. This disruption of sympathetic control leads to a situation where blood vessels cannot maintain proper tone (e.g., blood vessels may dilate). Large amounts of blood may pool in the lower body of the subject, such as the legs and intestines. Therefore, subjects affected by SCI may suffer from extremely low blood pressure, i.e., hypotension. Individuals with SCI are often unable to regulate their blood pressure. These individuals typically experience very low arterial blood pressure at rest, during exercise, and / or when adopting a sitting or standing posture. This hypotension can lead to dizziness, disorientation, cognitive decline, loss of consciousness, and a predisposition to stroke and heart disease. Additionally, the risk of increased blood pressure, i.e., hypertension, can also be caused by SCI. Hypertension can lead to heart disease, stroke, and subclinical vascular consequences. As mentioned above, autonomous cardiovascular dysfunction following SCI is a top priority health issue. A major autonomic problem following high-level spinal cord injury (SCI) (i.e., above the 6th thoracic segment) is orthostatic hypotension, clinically defined as a decrease in systolic blood pressure ≥20 mmHg and / or a decrease in diastolic blood pressure ≥10 mmHg when adopting an upright posture. Another key autonomic problem following SCI is abnormal autonomic reflexes, which are associated with potentially life-threatening hypertension due to afferent input activating sympathetic circuits located from the caudal spinal cord to the SCI site. Clinically, abnormal autonomic reflexes are defined as an increase in systolic blood pressure of 20 mmHg or more (WO2018148844A1).

[0011] WO2018148844A1 discloses a device and algorithm for controlling an individual's voluntary functions. Specifically, it discloses a controller device that uses physiological measurements (such as blood pressure) to modulate spinal cord electrical stimulation to stabilize blood pressure. A control interface and algorithm for controlling a subject's voluntary functions are also disclosed. Specifically, it discloses an algorithm for using physiological measurements (such as blood pressure) to modulate spinal cord electrical stimulation to stabilize blood pressure. For example, the neuronal structures involved may be located within the T1 to S5 segments of the spinal cord. The stimulation can be configured to control specific functions by selecting electrodes and / or the nature of the stimulation.

[0012] US2007156200A1 discloses an apparatus and method for controlling blood pressure by stimulating cardiac afferent sympathetic nerves. The invention can be implemented in a medical device having a pressure sensor for sensing blood pressure, electrodes for providing electrical signals to cardiac afferent sympathetic nerves, and a controller for providing signals to the electrodes, the signals changing in response to a blood pressure signal received from the pressure sensor.

[0013] US2011082515A1 discloses a neurostimulation device comprising an external neurostimulator worn by a patient, the external neurostimulator utilizing a support element that supports a portion of the patient's body. The external neurostimulator delivers neural stimulation to modulate the patient's cardiovascular function. Preferably, the external stimulator uses surface stimulation electrodes placed on the body approximately above the stimulation target to deliver neural stimulation percutaneously to the stimulation target within the patient's body.

[0014] US2011 / 0202107A1 relates to an electrical stimulation device for treating hypotension in patients with SCI and a method for treating hypotension. The electrical stimulation device includes: a blood pressure measuring device for continuously measuring the blood pressure of a subject; an electric current applying device for intermittently applying an electric current to the skin of the subject; and a control device for controlling the electric current applying device to maintain the blood pressure at a predetermined target blood pressure value by activating the electric current applying device when the subject's blood pressure is equal to or less than a target blood pressure value.

[0015] US2013 / 0289650A1 relates to neuromodulation for controlling hypertension and other cardiorenal diseases in patients with SCI. A neuromodulation device is delivered to the patient's body to apply electrical activation based on monitored patient blood pressure to reduce renal sympathetic hyperactivity, substantially without requiring thermal amplification of the patient's body. Electrical activation may also be dependent on monitored blood volume. A feedback control module may be used to provide feedback control information to adjust the electrical activation based on monitored patient blood pressure and blood volume.

[0016] US3650277A discloses a system for lowering and controlling blood pressure in hypertensive patients by providing electrical pulse stimulation of the carotid-sinus nerve, wherein the electrical pulse stimulation of the carotid-sinus nerve is controlled by the patient's arterial blood pressure, which is controlled in such a way that the number of stimulation pulses per cardiac cycle is determined by the mean arterial blood pressure, and the distribution of stimulation pulses throughout the cardiac cycle changes with the arterial pulse waveform, with a higher pulse frequency in the first part of the cardiac cycle.

[0017] US6058331 discloses a technique for the therapeutic treatment of peripheral vascular disease. A sensor is implemented to sense the degree of blood flow or ischemic pain in a patient's limb and generate a corresponding sensor signal. The signal is processed to determine the level of spinal cord or peripheral nerve stimulation to be applied. This information is provided to a signal generator, which then provides electrical stimulation energy to one or more stimulation leads. Stimulation of the spinal cord, peripheral nerves, or ganglia of nerve tissue improves blood flow, helps restore tissue health, and reduces the degree of ischemic pain in the limbs of patients with peripheral vascular disease or in other organs of other patients. This invention thus allows for automatic adjustment of stimulation to take into account the patient's changing condition throughout the day.

[0018] US2007027495A1 relates to an implantable bladder sensor that can be attached to the outer surface of the urobladder to sense bladder condition or urinary incontinence activity, or inability to control urination. The sensor includes a strain gauge that detects mechanical deformation of the bladder. Mechanical deformation may indicate gradual bladder filling or a momentary contraction indicating an impending urination event. Wireless telemetry circuitry within the sensor transmits information to an implanted electrostimulator that delivers electrical stimulation to relieve urinary incontinence, or to an external programmer that controls the implanted stimulator.

[0019] A new therapy is needed to better control and / or manage the autonomic dysfunction in subjects after SCI.

[0020] In the acute phase following injury, optimizing hemodynamics using EES can reduce the number of times patients experience hypoperfusion, and prior work is directly linked to the likelihood of subsequent neurological improvement. However, in typical clinical settings, manual hemodynamic monitoring 24 hours a day is impractical. Therefore, a closed-loop solution for managing blood pressure in both the acute and chronic phases following injury could not only improve patients' quality of life but may even increase the chances of positive neurological outcomes. Summary of the Invention

[0021] Therefore, the purpose of this invention is to provide a solution for a system and method that can better manage autonomous dysfunction after SCI.

[0022] This objective is achieved by the system according to claim 1. Accordingly, a neuromodulation system, particularly a neurostimulation system, is provided for treating a patient, especially for enhancing at least one autonomic function, such as blood circulation and / or respiration, wherein said system comprises

[0023] - At least one signal input module configured to receive at least one or more signals indicating blood circulation, particularly pulse and / or blood pressure.

[0024] - At least one control module, wherein the control module is connected to the signal input module.

[0025] The control module is configured to adjust the neural stimulation provided by the neural modulation system based on the signals received by the signal input module.

[0026] This invention is based on the fundamental idea that a stimulation system must be provided based on a bottom-up understanding of the sympathetic circuits within the spinal cord, particularly how the EES can target this circuit, the optimal sites of the EES for blood pressure regulation, and a deep understanding of the specific dynamics of the control of the entire sympathetic nervous system. Specifically, a stimulation paradigm based on functional and anatomical evidence for stimulating and controlling blood pressure after acute and chronic SCI is derived. Further, the dynamics of the sympathetic control system are investigated, including recordings from the main brainstem control center (rostral ventrolateral medulla), sympathetic outflow from the spinal cord (in the form of renal sympathetic recordings), and blood pressure dynamics. Specifically, deep learning methods were used to discover that these dynamics are completely dysregulated after SCI. Specifically, the system is configured and arranged to replace this dysregulation.

[0027] Furthermore, the system may include at least one stimulation unit and / or at least one real-time monitoring unit, wherein the at least one real-time monitoring unit includes at least one sensor.

[0028] The stimulation unit can provide stimulation. Stimulation can be provided by electrical stimulation. In particular, stimulation can be provided by a lead containing one or more electrodes. The lead can be implanted. Alternatively and / or additionally, percutaneous stimulation via a lead is generally also possible. Self-optimized stimulation is generally possible.

[0029] Stimulation can be delivered epidurally (via epidural electrical stimulation, EES) and / or subdurally.

[0030] The stimulation unit may include at least one of a neurostimulator, a neuromodulator, and a pulse generator, particularly an implantable pulse generator (IPG). The neurostimulator may be connected to a lead wire.

[0031] Generally, stimuli can be delivered to the dorsal aspect of the mammalian spinal cord. Stimuli can target the dorsal root, dorsal afferent fibers within the dorsal root, and / or intraspinal structures that are directly or indirectly connected to preganglionic sympathetic neurons that influence the controlled function.

[0032] Generally, stimulation parameters can be included at least in terms of frequency, amplitude, and pulse width to apply stimulation, where the frequency can be 10Hz-10kHz, the amplitude can be 0-1V or 0-15V, and the pulse width can be 1-500μs.

[0033] Additionally and / or alternatively, stimulation can be applied via burst tandem stimulation. A pulse tandem, referred to as burst tandem stimulation, may be preferred to increase specificity and comfort. Burst tandem stimulation may consist of a series of pulses, such as 3 to 5 pulses delivered at 200 Hz to 700 Hz and repeated at a frequency of 10–120 Hz.

[0034] The real-time monitoring unit may include at least one sensor. Specifically, the real-time monitoring unit may include at least one sensor configured and arranged to measure and / or monitor a patient's blood pressure and / or perfusion pressure, particularly spinal cord perfusion pressure. The sensor can generally measure and / or monitor a patient's systolic and / or diastolic blood pressure and / or mean arterial pressure and / or cerebrospinal fluid pressure (and / or also spinal cord perfusion pressure). It is also possible for the sensor to report pulse rate. Further, the sensor may be configured and arranged to measure and / or monitor signals and / or values ​​and / or markers related to spinal cord oxygenation. At least one sensor unit may be invasive or non-invasive. In other words, at least one sensor may be at least partially implantable and / or implantable. Alternatively, at least one sensor may be non-implantable and / or non-implantable.

[0035] Furthermore, the sensor can monitor the cumulative discharge rate from any brainstem control region, especially from the anterior ventrolateral medulla oblongata.

[0036] In particular, signals indicating blood circulation can be signals indicating blood pressure and / or cumulative discharge rate from at least one brainstem control area, especially but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0037] At least one sensor can be a digital or analog sensor system.

[0038] Generally, it is possible to form a sensor network with at least two sensors. A sensor network can generally include at least one sensor that is at least partially implanted and / or implantable, and at least one sensor that is not implantable and / or not implantable.

[0039] Implantable and / or implantable sensors and / or non-implantable and / or non-implantable sensors may be, but are not limited to, upper arm blood pressure monitoring systems, wrist blood pressure monitoring systems, or finger blood pressure monitoring systems. The sensors can measure and / or monitor blood pressure signals indicating blood pressure measurement. Generally, at least one sensor can provide continuous monitoring of blood pressure and / or occasional monitoring of blood pressure and / or measurement or monitoring of blood pressure at preset time intervals.

[0040] Specifically, the blood pressure sensor can be an invasive arterial line. In particular, invasive arterial lines can directly and in real-time monitor blood pressure.

[0041] In particular, the signal input module may include an input switch module, wherein the input switch module may be configured to switch between a signal indicating blood pressure and a signal indicating the cumulative discharge rate from at least one brainstem control region, particularly but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0042] Specifically, the signal input module can be configured to receive a baseline signal, wherein the baseline signal defines at least one target value.

[0043] The control module can be configured to detect the difference between at least one target value and at least one or more signals indicating blood circulation, wherein the control module can be further configured and arranged to adjust the neural stimulation based on the difference between at least one target value and at least one or more signals indicating blood circulation and / or signals and / or values ​​and / or markers related to spinal cord oxygenation.

[0044] Specifically, after recording the baseline, i.e., the target pressure, i.e., the target value, a perturbation signal can be provided to the patient. This perturbation signal can be provided in the form of negative pressure, medication, or a tilt test in human patients. However, other types of perturbation signals are generally possible.

[0045] Tilt test is a medical procedure commonly used to diagnose voluntary dysfunction or syncope.

[0046] Patients with symptoms of dizziness or mild headache, with or without loss of consciousness (syncope), or suspected involvement of decreased blood pressure or orthostatic tachycardia are suitable candidates for this test.

[0047] The procedure attempts to induce syncope by having the patient lie flat on a special table or bed, then monitoring with an ECG and a continuously measuring blood pressure monitor to determine the cause of the syncope. The table then creates a change in posture from lying down to standing.

[0048] Specifically, it can include negative pressure on the lower body.

[0049] The control module can detect changes in blood pressure. In particular, the control module can use adjustable parameters to increase or decrease the sensitivity of blood pressure detection.

[0050] Furthermore, the control module can apply controlled stimulation to the stimulation unit to increase blood pressure.

[0051] The control module may include a linear proportional control module, wherein the linear proportional control module may be configured to modify at least one of the amplitude and frequency of the stimulus paradigm in response to at least one or more signals indicating blood circulation, and with a coefficient β that controls the change in amplitude or frequency in a linear proportion.

[0052] In particular, blood pressure can respond linearly or almost linearly to changes in the amplitude of a stimulus.

[0053] Furthermore, the control module may include a forward module, wherein the forward module is configured and arranged to take into account at least one predictive effect of the stimulus to adjust the coefficient β within a specified time window.

[0054] Furthermore, the control module can be configured to include stimulus paradigm control parameters, particularly minimum or maximum limits on the stimulus paradigm.

[0055] Generally speaking, it is possible to control blood pressure in a closed-loop manner in response to negative pressure stimulation in the lower body.

[0056] In particular, the system can be applied to any mammal suffering from SCI.

[0057] Furthermore, a neuromodulation system is disclosed, particularly a neurostimulation system for treating patients, especially for enhancing at least one autonomic function, such as blood circulation and / or respiration, wherein said system comprises

[0058] - At least one sensing element configured to sense signals indicating physiological parameters of a patient.

[0059] - At least one control module, wherein the control module is connected to the sensing element.

[0060] - At least one spatial mapping module configured to link spatial electrode stimulation configurations targeting afferent fibers in the dorsal / posterior root to at least one physiological action.

[0061] - At least one parameter mapping module is configured to prepare stimulation parameters for the control module based on inputs received from the sensing element and / or the spatial mapping module.

[0062] This invention is based on the following fundamental idea: to provide a neurostimulation system that specifically targets and modulates preganglionic and postganglionic neurons of the sympathetic nervous system responsible for autonomic control. This targeting and modulation is performed in a manner that enables the system to achieve precise and optimized control of autonomic control after spontaneous involuntary coronary intervention (SCI). Specifically, the neurostimulation system optimizes neurostimulation by identifying target values ​​for autonomic function, identifying electrode configurations that have the optimal effect on autonomic function while minimizing the effect on other functions such as muscle function, optimizing the stimulation device and its location, and optimizing stimulation parameters.

[0063] The sensing element may include at least one sensor. In particular, the sensing element may include at least one sensor configured and arranged to measure and / or monitor a patient's blood pressure and / or perfusion pressure, especially the patient's spinal cord perfusion pressure and / or spinal cord oxygenation.

[0064] Sensors can typically measure and / or monitor a patient's systolic and / or diastolic blood pressure and / or mean arterial pressure and / or cerebrospinal fluid pressure (and / or spinal cord perfusion pressure) and / or spinal oxygenation. It is also possible for the sensor to report pulse rate. At least one sensor element can be invasive or non-invasive. In other words, at least one sensor can be at least partially implantable and / or implantable. Alternatively, at least one sensor can be non-implantable and / or non-implantable.

[0065] At least one sensor can be a digital or analog sensor system.

[0066] Generally, it is possible for at least two sensors to form a sensor network. A sensor network can generally include at least one sensor that is at least partially implanted and / or implantable, and at least one sensor that is not implantable and / or not implantable.

[0067] Implantable and / or implantable sensors and / or non-implantable and / or non-implantable sensors may be, but are not limited to, upper arm blood pressure monitoring systems, wrist blood pressure monitoring systems, or finger blood pressure monitoring systems. The sensors can measure and / or monitor blood pressure signals indicating blood pressure measurement. Generally, at least one sensor can provide continuous monitoring of blood pressure and / or occasional monitoring of blood pressure and / or measurement or monitoring of blood pressure at preset time intervals.

[0068] Specifically, the blood pressure sensor can be an invasive arterial line. In particular, invasive arterial lines can directly and in real-time monitor blood pressure.

[0069] Generally speaking, sensing elements can monitor physiological signals in real time or near real time.

[0070] Generally, the sensing element can be or may include an external pulsatile blood pressure monitor and / or an intrathecal catheter and / or a standard brachial blood pressure loop and / or any type of upper arm blood pressure monitoring system and / or any wrist blood pressure monitoring system and / or any type of finger blood pressure monitoring system and / or an oxygenation sensor.

[0071] In particular, the system may include at least one control module.

[0072] The parameter mapping module can optimize stimulus parameters. In particular, the parameter mapping module can optimize stimulus parameters using reinforcement learning models.

[0073] Generally, stimulation parameters can include at least one of frequency, amplitude and pulse width, where the frequency can be 10Hz-10kHz, the amplitude can be 0-1V or 0-15V, and the pulse width can be 1-500μs.

[0074] Additionally and / or alternatively, stimulation can be applied via burst tandem stimulation. A pulse tandem, referred to as burst tandem stimulation, may be preferred to increase specificity and comfort. Burst tandem stimulation may consist of a series of several pulses, for example, 3 to 5 pulses delivered at 200 Hz to 700 Hz and repeated at a frequency of 10–120 Hz.

[0075] In particular, the system may include at least one stimulating element, which includes at least one electrode array comprising multiple electrodes.

[0076] Electrode arrays can contain 8-32 electrodes, particularly 16 electrodes. However, it is generally possible to include various other numbers of electrodes in at least one electrode array.

[0077] Electrode arrays can be designed and / or configured to target cardiovascular and / or blood pressure hotspots in the spinal segment.

[0078] Specifically, stimulation can be provided via electrical stimulation. Electrode arrays can be implanted. Alternatively and / or additionally, percutaneous stimulation via electrode arrays is generally possible. Self-optimized stimulation is generally possible.

[0079] Stimulation can be delivered epidurally (via epidural electrical stimulation, EES) and / or subdurally.

[0080] Furthermore, the stimulation element may include at least one of a neurostimulator, a neuromodulator, and a pulse generator, particularly an implantable pulse generator (IPG). At least one of the neurostimulator, neuromodulator, and pulse generator, particularly the IPG, may be connected to an electrode array.

[0081] Generally, stimuli can be delivered to the dorsal aspect of the mammalian spinal cord. Stimuli can target posterior / dorsal roots, dorsal afferent fibers, and / or intraspinal structures directly or indirectly connected to preganglionic sympathetic neurons that influence the controlled function.

[0082] In particular, the system may include at least one time mapping module configured to link time electrode stimulation configurations to at least one physiological effect.

[0083] In particular, stimulation can be provided in the form of pulse trains, where different time intervals of the stimulation events can be arranged to provide pulse trains.

[0084] The control module can be configured to identify target values ​​for autonomous functions based on signals provided by sensing elements.

[0085] In particular, the target value can be the baseline value.

[0086] The spatial mapping module can isolate key electrodes based on anatomical locations and learning procedures initiated at these electrodes to optimize the configuration of surrounding electrodes.

[0087] The spatial mapping module can be configured to perform a reinforcement learning procedure, which is part of a process of linking spatial electrode stimulation configurations targeting afferent fibers in the dorsal / posterior root to at least one physiological effect.

[0088] The spatial mapping module can be configured to perform a spatial mapping phase to identify a suitable electrode configuration in the first step according to the selected electrodes and their spatial arrangement, and to perform a parameter mapping phase to adjust the stimulation parameters for the stimulation provided by the selected electrodes in the first step.

[0089] In particular, a suitable electrode configuration can depend on the exact location of the electrode array and / or the electrodes of the electrode array.

[0090] Specifically, key electrodes can be isolated based on anatomical location, and reinforcement learning programs can be initiated at these electrodes to optimize the configuration of surrounding electrodes. A brief stimulus can be provided, and pressure can be monitored, accompanied by a "reward" setting to increase the pressure. Thus, the model may be "punished" for failing to reliably alter the configuration for physiological purposes and rewarded for altering them. Alternatively, a punishment model can be selected if the patient finds the configuration uncomfortable or if other side effects (including but not limited to spasticity) are observed. By doing so, the system may be able to systematically and rapidly identify the optimal electrode configuration.

[0091] Specifically, the physiological parameters may be at least one of the patient's blood pressure, spinal cord perfusion pressure, posture and / or position and / or spinal cord oxygenation.

[0092] Specifically, blood pressure and spinal cord perfusion pressure can be expressed as at least one of systolic pressure and / or diastolic pressure and / or mean arterial pressure and / or cerebrospinal fluid pressure (and / or spinal cord perfusion pressure).

[0093] Furthermore, the patient's pulse rate can be monitored additionally and / or alternatively.

[0094] Furthermore, physiological parameters may additionally and / or alternatively be the firing rate from any brainstem control region, particularly from the anterior ventrolateral medulla oblongata.

[0095] In particular, the system can be applied to any mammal suffering from SCI.

[0096] In other words, the patient can be any mammal with SCI.

[0097] According to the present invention, the use of a neurostimulation system for treating patients according to the present invention is disclosed, particularly for enhancing at least one autonomic function, such as blood circulation and / or respiration.

[0098] According to the present invention, a method is disclosed, characterized in that the method is performed, in particular, by the system of the present invention.

[0099] Generally speaking, the system and method may also be used in an open-loop manner.

[0100] Specifically, the method can be a method for neuromodulation, particularly for nerve stimulation, for treating a patient, and especially for enhancing at least one autonomic function, such as blood circulation and / or respiration, and the method comprises the following steps:

[0101] - Receive at least one or more signals indicating blood circulation, especially signals indicating pulse and / or blood pressure and / or oxygenation.

[0102] - Adjust neural stimulation based on the received signals. Attached Figure Description

[0103] Further details and advantages of the invention will now be disclosed in conjunction with the accompanying drawings.

[0104] It is shown in

[0105] Figure 1 A schematic overview of embodiments of a system for neural modulation and / or neural stimulation according to the present invention, which enables the execution of methods according to the present invention;

[0106] Figure 2A schematic overview of further embodiments of the system 110 for treating patients according to the invention, which enables the execution of methods according to the invention;

[0107] Figure 3 An example of understanding the sympathetic circuitry in the spinal cord from the bottom up;

[0108] Figure 4a The general distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude;

[0109] Figure 4b General distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude in non-human primates;

[0110] Figure 4c The general distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude in human patients;

[0111] Figure 5a An example of blood pressure closed-loop control according to the present invention;

[0112] Figure 5b Examples of blood pressure closed-loop control according to the present invention, such as Figure 5a As shown here, this includes acute and chronic SCI.

[0113] Figure 5c Examples of closed-loop blood pressure control according to the invention in non-human primates;

[0114] Figure 5d Examples of closed-loop blood pressure control according to the invention in human patients;

[0115] Figure 6a A schematic overview of sympathetic neuron activation;

[0116] Figure 6b A schematic overview of the mechanism by which EES stabilizes hemodynamics;

[0117] Figure 7 A schematic overview of embodiments of a system for neural modulation and / or neural stimulation according to the present invention, which enables the execution of methods according to the present invention;

[0118] Figure 8a Featuring a series of 24 space electrode configurations and equipped with Figure 7 The publicly available chart shows the patient's real-time blood pressure response to the system.

[0119] Figure 8b Figure 8a The two selected space electrode configurations disclosed in the document are Config and equipped with Figure 7A chart showing the real-time blood pressure response of patients in the publicly disclosed system 10;

[0120] Figure 8c Based on Figure 8b A schematic overview of the electrode array A in the electrode configuration Config;

[0121] Figure 8d A further overview of its stimulating effect on blood pressure;

[0122] Figure 9 An implementation scheme is shown, wherein the stimulus that alters blood pressure is constant or variable;

[0123] Figure 10 A blood pressure collapse was demonstrated, which was treated and resuscitated using a system according to the invention. Detailed Implementation

[0124] Figure 1 A schematic overview of an embodiment of a system 10 for neural modulation and / or neural stimulation according to the present invention is shown, which enables the execution of methods according to the present invention.

[0125] In this embodiment, system 10 is configured to treat a patient, particularly to enhance at least one autonomous function, such as blood circulation and / or respiration.

[0126] In this embodiment, system 10 is configured to treat patients, particularly to enhance blood pressure function.

[0127] Alternatively and / or additionally, system 10 can be configured to treat patients, particularly to enhance any type of autonomous function.

[0128] In this embodiment, system 10 includes signal input module 12.

[0129] Generally, the signal input module is configured to receive at least one or more signals indicating blood circulation, particularly pulse and / or blood pressure and / or oxygenation.

[0130] In this embodiment, the signal input module 12 is configured to receive at least one or more signals indicating blood pressure.

[0131] Generally, it is possible that the signal input module 12 is configured to additionally and / or alternatively receive signals of at least one or more indicator pulses.

[0132] In this embodiment, system 10 further includes control module 14.

[0133] The control module 14 is connected to the signal input module 12.

[0134] In this embodiment, the connection between the control module 14 and the signal input module 12 is a direct and bidirectional connection.

[0135] In general, indirect and / or unidirectional connections will also be possible.

[0136] In this embodiment, the connection between the control module 14 and the signal input module 12 is a wireless connection.

[0137] Generally speaking, cable bonding connections will also be possible.

[0138] In this embodiment, the control module 14 is configured to adjust the neural stimulation provided by the neural stimulation system 10 based on the signal received by the signal input module 12.

[0139] Figure 1 The signals not shown may include at least one of the following: diastolic blood pressure, systolic blood pressure, diastolic and systolic blood pressure, mean arterial pressure, mixed blood pressure value, etc.

[0140] Figure 1 Not shown, at least one or more signals indicating blood circulation may include perfusion pressure, i.e., spinal cord perfusion pressure, which is defined as the difference between mean arterial blood pressure and cerebrospinal fluid pressure, and may be important. Furthermore, the signal may also be related to or indicate oxygenation.

[0141] Figure 2 A schematic overview of a further embodiment of a system 110 according to the invention for treating a patient with neuromodulation and / or neurostimulation is shown, which enables the execution of the methods according to the invention.

[0142] System 110 includes, for example Figure 1 The structural and functional characteristics of the neural regulatory system 10 disclosed in the text.

[0143] The corresponding reference indicator is 100+x (e.g., input module 112).

[0144] In this embodiment, system 110 is configured to treat a patient, particularly to enhance at least one of the patient's autonomous functions.

[0145] In this embodiment, system 110 is configured to treat a patient, particularly to enhance the patient's blood circulation.

[0146] In this embodiment, system 110 is configured to treat a patient, particularly to enhance the patient's blood pressure function.

[0147] Alternatively and / or additionally, system 110 may be configured to treat a patient, particularly to enhance any type of autonomous function in the patient.

[0148] System 110 includes control unit 116.

[0149] In this embodiment, the control unit 116 includes a signal input module 112 and a control module 114, see below. Figure 1 The disclosed signal input module 12 and control module 14.

[0150] System 110 also includes a real-time monitoring unit 118.

[0151] In this embodiment, the real-time monitoring unit 118 is configured and arranged to monitor blood pressure.

[0152] As not shown in this embodiment, the real-time monitoring unit 118 includes sensors.

[0153] Not shown in this embodiment, the sensor is configured and arranged to measure and / or monitor the blood pressure of patient P.

[0154] Furthermore, system 110 includes stimulation unit 120.

[0155] Stimulation unit 120 is configured and arranged to provide stimulation.

[0156] Figure 2 Not shown, stimulation is provided by electrical stimulation.

[0157] Figure 2 As not shown, the stimulation unit 120 is configured to include wires.

[0158] In particular, stimulation is provided by a wire containing one or more electrodes.

[0159] Figure 2 Not shown, a wire was implanted.

[0160] Figure 2 Not shown, alternatively and / or additionally, transcutaneous stimulation via a wire is generally also possible.

[0161] Figure 2 As not shown, self-optimizing stimuli are generally possible.

[0162] Figure 2 As not shown, stimulation can be delivered epidurally (by epidural electrical stimulation, EES) and / or subdurally.

[0163] Figure 2 As not shown, the stimulation unit 120 includes a pulse generator, particularly an implantable pulse generator (IPG).

[0164] Figure 2 Not shown, the IPG is connected to the wire.

[0165] Figure 2 As not shown, stimulation can generally be delivered to the dorsal side of the mammalian spinal cord.

[0166] Figure 2 As not shown, stimulation parameters can generally include at least frequency, amplitude, and pulse width to apply stimulation, where the frequency can be 10Hz-10kHz, the amplitude can be 0-1V or 0-15V, and the pulse width can be 1-500μs.

[0167] Figure 2 As not shown, stimulation can generally be applied through a burst of tandem stimulation.

[0168] A pulse cascade, known as a burst cascade stimulation, may be preferred to increase specificity and comfort.

[0169] Sudden tandem stimulation can consist of a series of several pulses, such as 3 to 5 pulses delivered at 200 Hz to 700 Hz and repeated at a frequency of 10 to 120 Hz.

[0170] In this embodiment, the real-time monitoring unit 118 is configured and arranged to monitor blood pressure.

[0171] In this embodiment, the real-time monitoring unit 118 includes a single sensor.

[0172] In an alternative implementation, the real-time monitoring unit 118 may include more than one sensor.

[0173] In an alternative implementation, the real-time monitoring unit 118 may include a sensor network.

[0174] The sensors are configured and arranged to measure and / or monitor the patient's blood pressure.

[0175] In an alternative implementation, system 110 may include more than one control unit 116 and / or more than one stimulation unit 120 and / or more than one real-time monitoring unit 180.

[0176] In this embodiment, the control unit 116 is connected to the stimulation unit 120 and the real-time monitoring unit 118.

[0177] In this embodiment, the connection between the control unit 116 and the stimulation unit 120, and the connection between the control unit 116 and the real-time monitoring unit 118, are direct and bidirectional.

[0178] In this embodiment, the connection between the control unit 116 and the stimulation unit 120, and the connection between the control unit 116 and the real-time monitoring unit 118, are established via wireless connection.

[0179] However, alternatively, cable bonding and / or one-way and / or indirect connection between control unit 116 and stimulation unit 120, and cable bonding and / or one-way and / or indirect connection between control unit 116 and real-time monitoring unit 118 are generally possible.

[0180] In this embodiment, the stimulation unit 120 is connected to the real-time monitoring unit 118.

[0181] The connection between the stimulation unit 120 and the real-time monitoring unit 118 is direct and bidirectional.

[0182] The connection between the stimulation unit 120 and the real-time monitoring unit 118 is established via a wireless link.

[0183] However, alternatively, cable bonding and / or unidirectional and / or indirect connection between the stimulation unit 120 and the real-time monitoring unit 118 is generally possible.

[0184] The sensors of the real-time monitoring unit 118, and especially the real-time monitoring unit 180, measure the patient's blood pressure.

[0185] As not shown in this embodiment, the sensor can generally measure and / or monitor systolic blood pressure and / or diastolic blood pressure and / or mean arterial pressure.

[0186] Not shown in this embodiment, further sensors may additionally and / or alternatively measure the cumulative discharge rate from the brainstem control region.

[0187] Not shown in this embodiment, further sensors may additionally and / or alternatively measure the cumulative discharge rate from the anterior ventrolateral medulla oblongata.

[0188] In other words, the signal indicating blood circulation can be a signal indicating blood pressure and / or cumulative discharge rate from at least one brainstem control area, especially but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0189] As not shown in this implementation, the sensor can also report the pulse rate.

[0190] As not shown in this embodiment, at least one sensor may be an invasive or non-invasive sensor.

[0191] As not shown in this embodiment, the sensor may be at least partially implantable and / or implantable.

[0192] Alternatively, at least one sensor may be non-implantable and / or not implantable.

[0193] The measured blood pressure is transmitted from the real-time monitoring unit 118 to the signal input module 112.

[0194] Figure 2 As not shown, the signal input module 112 may include an input switch module, wherein the input switch module may be configured to switch between a signal indicating blood pressure and a signal indicating the cumulative discharge rate from at least one brainstem control region, particularly but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0195] Figure 2 As not shown, the signal input module 112 can be configured to receive a baseline signal, wherein the baseline signal defines at least one target value.

[0196] Figure 2 As not shown, the control module 114 can be configured to detect the difference between at least one target value and at least one or more signals indicating blood circulation, wherein the control module 114 can be further configured and arranged to adjust the neural stimulation based on the difference between at least one target value and at least one or more signals indicating blood circulation.

[0197] Figure 2 What is not shown is that after the baseline, i.e. the target pressure, i.e. the target value, is recorded, a perturbation signal can be provided to the patient.

[0198] Disturbance signals can be provided in the form of negative pressure, drugs, or tilt tests.

[0199] However, any other form of disturbance signal is generally possible.

[0200] In this embodiment, the control module 114 can detect changes in blood pressure.

[0201] In particular, the control module 114 can use movable parameters to detect changes in blood pressure to increase or decrease sensitivity.

[0202] In this embodiment, the control module 114 can apply controlled stimulation to the stimulation unit 120 to increase blood pressure.

[0203] As not shown in this embodiment, the control module 114 may be configured to modify at least one of the amplitude and frequency of the stimulation paradigm in response to at least one or more signals indicating blood circulation, and with a coefficient β that controls the amplitude or frequency change in a linear proportion.

[0204] Figure 2What is not further shown is that the control module may include a forward module, wherein the forward module is configured and arranged to take into account at least one predictive action of the stimulus to adjust the coefficient β for a specified time window.

[0205] Figure 2 As not shown, it is generally possible that blood pressure responds linearly or almost linearly to changes in the amplitude of a stimulus.

[0206] Figure 2 As not shown, the control module 114 can be configured to include stimulus paradigm control parameters, particularly minimum or maximum limits on the stimulus paradigm.

[0207] Figure 2 As not shown, it is generally possible to apply System 110 to any mammal suffering from SCI.

[0208] According to the present invention, the use of systems 10 and 110 for neural modulation is disclosed.

[0209] The use of Systems 10 and 110 and the functions of Systems 10 and f110 can be described as follows:

[0210] The use of the neurostimulation system 10, 110 according to any one of claims 1 to 9 for treating a patient, particularly for enhancing at least one autonomic function, such as blood circulation and / or respiration.

[0211] In other words, according to the present invention, the use of the neurostimulation system 10, 110 of any one of claims 1 to 9 is disclosed for treating patients, especially for enhancing at least one autonomic function, such as blood circulation and / or respiration.

[0212] According to the present invention, a method is disclosed, characterized in that the method is performed using the system of any one of claims 1-9.

[0213] The methods and functions of systems 10 and 110 can be described as follows:

[0214] A method for neural modulation, particularly neural stimulation, for treating a patient, and especially for enhancing at least one autonomic function, such as blood circulation and / or respiration, comprises the following steps:

[0215] - Receive at least one or more signals indicating blood circulation, especially signals indicating pulse and / or blood pressure and / or oxygenation.

[0216] - Adjust neural stimulation based on the received signals.

[0217] In particular, the method may further include the steps of providing neural stimulation and real-time monitoring of signals indicating blood circulation, especially signals indicating pulse and / or blood pressure.

[0218] In particular, signals indicating blood circulation can be signals indicating blood pressure and / or cumulative discharge rate from at least one brainstem control area, especially but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0219] In particular, the method may include switching between a signal indicating blood pressure and a signal indicating the cumulative discharge rate from at least one brainstem control region, especially but not limited to the discharge rate from the anterior ventrolateral medulla oblongata.

[0220] Specifically, the method may include receiving a baseline signal, wherein the baseline signal defines at least one target value.

[0221] Furthermore, the method can be configured to detect the difference between at least one target value and at least one or more signals indicating blood circulation, wherein the method can be further configured and arranged to adjust neural stimulation based on the difference between at least one target value and at least one or more signals indicating blood circulation and / or oxygenation.

[0222] Furthermore, the method can be configured to modify at least one of the amplitude and frequency of the stimulation paradigm in response to at least one or more signals indicating blood circulation, and with a coefficient β that controls the amplitude or frequency change in a linear proportion.

[0223] Furthermore, the method can be configured to take into account the predictive effect of the stimulus to adjust the coefficient β within a specified time window.

[0224] Furthermore, the method can be configured to include stimulus paradigm control parameters, particularly minimum or maximum limits on the stimulus paradigm.

[0225] It is worth noting that the system 10 and method can also be applied to treat mammals with neurological diseases other than SCI, including but not limited to stroke, multiple sclerosis, autonomic failure, autonomic neuropathy, and cancer of neural tissue that impairs the normal functioning of descending sympathetic pathways that contribute to the control of autonomic functions.

[0226] Figure 1 As not shown, this system and method can also be used to treat any other autonomic dysfunctions other than impaired blood pressure control, including but not limited to heart rate, digestive function, bladder control and / or bowel control.

[0227] Figure 3 This illustrates an example of understanding the sympathetic neural circuits within the spinal cord from the bottom up.

[0228] Deep learning revealed the disruption dynamics between key control centers, namely the anterior ventrolateral medulla oblongata (RVLM), integrative sympathetic neural activity (iSNA), systolic blood pressure (SBP), and spinal cord injury (SCI).

[0229] The left side describes the specific interaction being studied.

[0230] We observed normalized true responses (true) and machine learning-based predicted responses (predicted) to perturbations that lower blood pressure.

[0231] For undamaged panels, there are good predictions across every control node in the system.

[0232] Following SCI, the relationship between various aspects and the spinal cord is interrupted, indicating the need for control of the interruption.

[0233] Systems 10 and 110 seek to replace control of this interruption.

[0234] It indicates the mean absolute error (MAE) of deep learning predictions.

[0235] This indicates the Betaβ of the linear regression model.

[0236] Figure 4a The general distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude is shown.

[0237] In particular, the linear relationship between blood pressure and the amplitude of epidural electrical stimulation (EES) provides a basis for a linear proportional control mechanism.

[0238] Figure 4b (similar to) Figure 4a This shows a general distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude in non-human primates.

[0239] Figure 4c The general distribution of the linear relationship between blood pressure and epidural electrical stimulation amplitude in human patients is shown;

[0240] Figure 5a An example of closed-loop blood pressure control according to the present invention is shown.

[0241] In this implementation plan, patients with SCI are equipped with, for example Figure 1 and / or Figure 2 The publicly disclosed systems are 10 and 110.

[0242] Identify resting blood pressure (baseline).

[0243] Baseline blood pressure is identified as target pressure.

[0244] Identify a 10-minute upright challenge stimulus (bottom tracking of intracavitary pressure).

[0245] Open the closed-loop epidural electrical stimulation (EES) to consistently achieve the target pressure.

[0246] The following parameters are used for stimulation: amplitude control; 50Hz stimulation; β = 10; pulse width = 100 microseconds.

[0247] It is worth noting that each of the other parameters can generally be used as a stimulus.

[0248] Generally speaking, the frequency can be 10Hz-10kHz, the amplitude can be 0-1V or 0-15V, and the pulse width can be 1-500μs.

[0249] Figure 5b (and Figure 5a (Similarly) An example of blood pressure closed-loop control according to the present invention is shown, such as Figure 5a As shown here, this includes acute and chronic SCI.

[0250] Figure 5c (and Figure 5a (Similar) An example of closed-loop blood pressure control according to the invention in non-human primates is shown;

[0251] Figure 5d (and Figure 5a (Similar) An example of closed-loop blood pressure control according to the present invention is shown in a human patient;

[0252] Figure 6a A schematic overview of sympathetic neuron activation according to the present invention is shown.

[0253] In particular, the activation of sympathetic neural circuits in response to stimuli is shown.

[0254] In particular, responsive stimuli are shown to activate sympathetic neural circuits in systems 10, 110 and / or according to the method of the invention.

[0255] Stimulation enters the dorsal root ganglion (DRG) and activates the preganglionic sympathetic neurons (SPN), which in turn activate the visceral ganglion (SG) and blood vessels responsible for blood pressure.

[0256] Figure 6b A schematic overview of the mechanism by which EES stabilizes hemodynamics is shown.

[0257] Part a shows the intraspinal density of neurons traced backward from the visceral ganglion, the amplitude of the pressure response to TESS applied to each segment, and the consistency between the anatomical and functional datasets.

[0258] Part b illustrates a hypothetical circuit activated by TESS to induce vasoconstriction.

[0259] Part c shows the color-coded potentials following TESS application to the spinal cord, representing specific activation of afferent fibers. The diagram illustrates radiculotomy of the posterior root. Bar graphs report the pressor response to targeted epidural spinal stimulation (TESS) before and after radiculotomy (n=5, paired-samples one-tailed t-test; t=4.36; P=0.006).

[0260] Part d shows a transsynaptic regression tracing, revealing intermediate neurons connected to the visceral ganglion.

[0261] Part e shows interneurons. These interneurons express the excitatory marker Slc17a6 and receive vGlut1 synapses from large-diameter proprioceptive afferents.

[0262] Part f shows Fos expression in THON neurons in the visceral ganglia after control and TESS. Barplot reports the percentage of FOSON neurons (n=5, independent samples one-tailed t-test; t=13.96; P=4.99e-05).

[0263] Part g shows the ablation-reduced pressurization response transmitted from the viscera (n=4, independent samples one-tailed t-test; t=-4.54; P=0.0099).

[0264] Part h showed that blocking α1 receptors with prazosin attenuates the pressor response (n=5, independent samples one-tailed t-test; t=-5.59; P=0.0007).

[0265] Figure 7 A schematic overview of a further embodiment of a system 210 according to the invention for treating a patient with neuromodulation and / or neurostimulation is shown, which enables the execution of the method according to the invention.

[0266] System 210 is a neurostimulation system 210 for treating patients, particularly for enhancing at least one autonomic function, such as blood circulation and / or respiration.

[0267] In this embodiment, system 210 is a neurostimulation system 210 for treating patients, particularly for enhancing blood pressure function.

[0268] System 210 includes sensing element 212.

[0269] Generally, the sensing element 212 is configured to sense signals indicating the patient's physiological parameters.

[0270] System 210 further includes control module 214.

[0271] In this embodiment, the control module is configured to identify target values ​​for autonomous functions based on signals provided by sensing element 212.

[0272] System 210 further includes a space mapping module 216.

[0273] Generally, the spatial mapping module 216 is configured to link a spatial electrode stimulation configuration Config targeting afferent fibers in the dorsal / posterior root to at least one physiological action.

[0274] System 210 further includes a parameter mapping module 218.

[0275] Generally, the parameter mapping module 218 is configured to prepare stimulation parameters for the control module 214 based on inputs received from the sensing element 212 and / or the spatial mapping module 216.

[0276] In an alternative implementation, system 210 includes more than one sensing element 212 and / or more than one control module 214 and / or more than one spatial mapping module 216 and / or more than one parameter mapping module 218.

[0277] Figure 7 As not shown, system 210 further includes at least one stimulating element.

[0278] Figure 7 As not shown, at least one stimulation element comprises at least one electrode array A containing a plurality of electrodes E.

[0279] Figure 1 As not shown, in this embodiment, electrode array A comprises 216 electrodes E.

[0280] In another embodiment, electrode array A comprises 8-32 electrodes E.

[0281] However, any other number of electrodes E is generally possible.

[0282] In this embodiment, the control module 214 is connected to the sensing element 212.

[0283] The connection between the control module 214 and the sensing element 212 is direct and bidirectional.

[0284] However, indirect and / or unidirectional connections will generally also be possible.

[0285] In this embodiment, the connection between the control module 214 and the sensing element 212 is a wireless connection.

[0286] However, cable bonding connections will generally also be possible.

[0287] In this embodiment, the control module 214 is connected to the space mapping module 216 and the parameter mapping module 218.

[0288] The connection between the control module 214, the space mapping module 216, and the parameter mapping module 218 is a direct and bidirectional connection.

[0289] However, indirect and / or unidirectional connections will generally also be possible.

[0290] In this embodiment, the connection between the control module 214, the space mapping module 216, and the parameter mapping module 218 is a wireless connection.

[0291] However, cable-bonded connections will generally also be possible.

[0292] Generally, it is possible to directly connect the sensing element 212, the spatial mapping module 216, and / or the parameter mapping module 218.

[0293] Generally, it is possible to directly connect the sensing element 212, the spatial mapping module 216, and / or the parameter mapping module 218 via a one-way connection.

[0294] Generally, it is possible to directly connect the sensing element 212, the spatial mapping module 216, and / or the parameter mapping module 218 via a bidirectional connection.

[0295] Generally, it is possible to directly connect the sensing element 212, the spatial mapping module 216, and / or the parameter mapping module 218 via a wireless connection.

[0296] Generally, it is possible to directly connect the sensing element 212, the spatial mapping module 216, and / or the parameter mapping module 218 via cable bonding.

[0297] The sensing element 212 senses signals that indicate the patient's physiological parameters.

[0298] In this embodiment, the sensing element 212 is a sensor configured to sense signals indicating physiological parameters of the patient.

[0299] In this embodiment, the sensing element 212 is a sensor configured to sense a signal indicating a patient's blood pressure.

[0300] In this embodiment, the sensing element 212 is a sensor configured to sense systolic blood pressure (SBP).

[0301] However, in alternative embodiments, sensing element 212 may alternatively and / or additionally be configured to sense oxygenation and / or diastolic pressure and / or mean arterial pressure and / or cerebrospinal fluid pressure and / or perfusion pressure, particularly spinal perfusion pressure.

[0302] In other words, the sensing element 212 can generally sense blood pressure and / or perfusion pressure.

[0303] However, in alternative embodiments, sensing element 212 may alternatively and / or additionally be configured to sense gesture and / or position.

[0304] In other words, physiological parameters can be at least one of the patient's blood pressure, spinal cord perfusion pressure, posture, and / or position.

[0305] In this embodiment, the sensing element 212 is an invasive arterial line.

[0306] In particular, invasive arterial lines can directly and in real time sense blood pressure.

[0307] In this embodiment, the sensing element 212 continuously senses blood pressure.

[0308] However, it is generally possible that the sensing element 212 provides occasional monitoring of blood pressure and / or monitoring of blood pressure at preset time intervals.

[0309] Figure 7 As not shown, it is generally possible that the sensing element 212 may be an implanted and / or implantable sensor and / or a non-implantable and / or non-implantable sensor.

[0310] Figure 7 As not shown, it is generally possible that the sensing element 212 can be an external pulse-by-pulse blood pressure monitor, an intrathecal catheter and / or a standard brachial blood pressure loop and / or any type of upper arm blood pressure monitoring system and / or any wrist blood pressure monitoring system and / or any type of finger blood pressure monitoring system.

[0311] Figure 7 As not shown, system 210 may include at least one time mapping module configured to link time electrode stimulation configuration to at least one physiological effect.

[0312] In this embodiment, the control module 214 identifies the target value of the autonomous function based on the signal provided by the sensing element 212.

[0313] In this implementation, the spatial mapping module links the spatial electrode stimulation configuration Config to blood pressure, specifically systolic blood pressure SBP.

[0314] Generally, it is possible that the spatial mapping module links the spatial electrode stimulation configuration (Config) to at least one physiological action.

[0315] In this embodiment, the parameter mapping module 218 prepares stimulation parameters for the control module 214 based on inputs received from the sensing element 212 and / or the spatial mapping module 216.

[0316] Figure 7 As not shown, the spatial mapping module 216 can isolate the critical electrodes E based on the anatomical location and a learning program initiated at these electrodes E to optimize the configuration of the surrounding electrodes E.

[0317] Figure 7 As not shown, the spatial mapping module 216 can be configured to execute a reinforcement learning procedure, wherein the reinforcement learning procedure is part of a process of linking a spatial electrode stimulation configuration Config to at least one physiological action, the spatial electrode stimulation configuration Config targeting afferent fibers in the dorsal / posterior root.

[0318] exist Figure 7 As not shown, the spatial mapping module 216 can be configured to perform a spatial mapping phase to identify a suitable electrode configuration Config in the first step according to the selected electrodes E and their spatial arrangement, and to perform a parameter mapping phase to adjust the stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

[0319] Figure 7 As not shown, the stimulation parameters may include at least one of frequency, amplitude and pulse width, wherein the frequency is 10Hz-10kHz, the amplitude is 0-1V or 0-15V, and the pulse width is 1-500μs.

[0320] Figure 7 As not shown, stimulation can generally be applied through a burst of tandem stimulation.

[0321] A pulse cascade, known as a burst cascade stimulus, may be preferred to increase specificity and comfort.

[0322] Sudden tandem stimulation can consist of a series of several pulses, such as 3 to 5 pulses delivered at 200 Hz to 700 Hz and repeated at a frequency of 10 to 120 Hz.

[0323] According to the present invention, the use of the system 210 for neural modulation is disclosed.

[0324] The purpose and functions of system 210 can be described as follows:

[0325] Depending on the intended use of the neuromodulation system 210 for treating patients, it is particularly used to enhance at least one autonomous function, such as blood circulation and / or respiration.

[0326] Therefore, according to the present invention, the use of a neurostimulation system 210 for treating a patient is disclosed, particularly for enhancing at least one autonomic function, such as blood circulation and / or respiration.

[0327] According to the present invention, a method is disclosed, characterized in that the method is performed by systems 10, 110 and 210 and as defined in the claims.

[0328] The method executed by system 210 and the functions of system 210 can be described as follows:

[0329] The method is a neuromodulation method, particularly a neurostimulation method for treating patients, especially for enhancing at least one autonomic function, such as blood circulation and / or respiration, wherein the method includes at least the following steps:

[0330] -Execute a sensing procedure to detect signals that indicate the patient's physiological parameters.

[0331] - Perform a spatial mapping procedure to link a spatial electrode stimulation configuration Config to at least one physiological action, said spatial electrode stimulation configuration Config targeting afferent fibers in the dorsal / posterior root.

[0332] - Execute a parameter mapping procedure to prepare stimulation parameters based on input received from a sensing and / or spatial mapping procedure.

[0333] In particular, the method may include a step of providing stimulation.

[0334] Furthermore, the method may include the step of linking time electrode stimulation configuration to at least one physiological effect.

[0335] Furthermore, the method may include a step of identifying target values ​​for autonomous function based on signals indicative of the patient's physiological parameters.

[0336] Furthermore, the method may include the step of isolating critical electrodes E based on anatomical location and a learning process initiated at these electrodes E to optimize the configuration of surrounding electrodes E.

[0337] Generally, stimulation parameters can include at least frequency, amplitude, and pulse width, where the frequency can be 10Hz-10kHz, the amplitude can be 0-1V or 0-15V, and the pulse width can be 1-500μs.

[0338] Furthermore, the method may include the step of performing a reinforcement learning procedure, wherein the reinforcement learning procedure is part of a process of linking a spatial electrode stimulation configuration Config to at least one physiological action, the spatial electrode stimulation configuration Config targeting afferent fibers in the dorsal / posterior root.

[0339] Generally, the method may further include a step of performing a spatial mapping phase to identify a suitable electrode configuration Config in the first step according to the selected electrodes E and their spatial arrangement, and performing a parameter mapping phase to adjust the stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

[0340] Generally, physiological parameters may include at least one of oxygenation (including but not limited to spinal oxygenation), patient blood pressure, patient spinal cord perfusion pressure, patient posture, and / or patient position.

[0341] It is worth noting that the system 10 and method can also be applied to treat mammals with neurological diseases other than SCI, including but not limited to stroke, multiple sclerosis, autonomic failure, autonomic neuropathy, and cancer of neural tissue that impairs the normal functioning of descending sympathetic pathways that contribute to the control of autonomic functions.

[0342] Figure 7 As not shown, this system and method can also be used to treat any type of voluntary dysfunction, including but not limited to heart rate, digestive function, bladder control and / or bowel control.

[0343] Figure 8a -d indicates the source equipped with according to Figure 7 Exemplary patient data from system 210.

[0344] In particular, patients with spinal cord injury (SCI) are equipped with... Figure 7 The publicly available system is 210.

[0345] Specifically, a series of spatial electrode configurations (Config) are shown, and the patient's immediate blood pressure response, i.e., systolic blood pressure (SBP), is measured. See [link to relevant documentation]. Figure 8a .

[0346] In this implementation plan, a series of 24 spatial configurations were evaluated.

[0347] Specifically, based on the immediate rise in blood pressure and the absence of significant muscle contraction, the optimal spatial electrode configuration (Config) was selected; see [link to relevant documentation]. Figure 8b .

[0348] In this implementation, the selected optimal space electrode configuration Config is configuration Config20.

[0349] In this implementation, the suboptimal space electrode configuration Config would be, for example, space configuration Config17.

[0350] In this example, the four electrodes at the front end were identified as the optimal choice for controlling the patient's blood pressure. See [link to relevant documentation]. Figure 8c .

[0351] The system is able to identify this optimization parameter.

[0352] Not shown here, it is generally possible to use CT, MRI, or X-ray scans to visualize the electrode array containing multiple electrodes in order to confirm the location of the electrode array.

[0353] Figure 8d A further overview of its stimulating effect on blood pressure is shown.

[0354] Figure 9 An implementation scheme is shown in which the stimulus that changes blood pressure is constant or variable.

[0355] On the left, as the prosthetic baroreflex sequentially opens and closes, there are changes in intracavitary pressure, blood pressure, and TESS amplitude. On the right, for periodic changes in intracavitary pressure, there are the same changes as shown on the left.

[0356] Figure 10 A blood pressure collapse was demonstrated, which was treated and resuscitated using a system according to the invention.

[0357] refer to

[0358] 10, 110 system

[0359] 12, 112 signal input modules

[0360] 14, 114 Control Module

[0361] 116 Control Unit

[0362] 118 Real-time Monitoring Unit

[0363] 120 stimulation units

[0364] 210 System

[0365] 212 Control Module

[0366] 214 Sensing Element

[0367] 216 Spatial Mapping Module

[0368] 218 Parameter Mapping Module

[0369] β coefficient

[0370] A electrode array

[0371] E electrode

[0372] Config Space Electrode Configuration

[0373] DRG dorsal root ganglion

[0374] EES epidural electrical stimulation

[0375] iSNA integrated sympathetic nervous system activity

[0376] MAE (Mean Absolute Error)

[0377] RVLM (Anterior Ventral Lateral Medulla Oblongata)

[0378] SBP (systolic blood pressure)

[0379] SCI spinal cord injury

[0380] SPN (preganglionic sympathetic neurons)

[0381] SG visceral ganglion

Claims

1. A neuromodulation system for providing epidural stimulation to treat a patient, characterized in that, The system includes: - At least one signal input module (12, 112) is configured to receive at least one or more signals indicating blood circulation. - At least one control module, wherein the control module is connected to the signal input module (12, 112). The control module is configured to adjust the epidural electrical stimulation provided by the neuromodulation system based on the signals received by the signal input module (12, 112). The control module includes a linear proportional control module, and The linear proportional control module is configured to respond to the at least one or more signals indicating blood circulation and to modify at least one of the amplitude and frequency of the stimulation paradigm by a coefficient β that controls the linear proportionality of the amplitude or frequency change.

2. The neural modulation system according to claim 1, characterized in that, The neural modulation system further includes at least one stimulation unit (120) and / or at least one real-time monitoring unit (118), wherein the at least one real-time monitoring unit (118) includes at least one sensor.

3. The neural modulation system according to claim 1 or 2, characterized in that, The signal indicating blood circulation is a signal indicating oxygenation and / or blood pressure and / or cumulative discharge rate from at least one brainstem control area.

4. The neural modulation system according to claim 1, characterized in that, The at least one signal input module (12, 112) includes an input switch module, wherein the input switch module is configured to switch between a signal indicating blood pressure and a signal indicating the cumulative discharge rate from at least one brainstem control region.

5. The neural modulation system according to claim 1, characterized in that, The signal input module (12, 112) is configured to receive a baseline signal, wherein the baseline signal defines at least one target value.

6. The neural modulation system according to claim 5, characterized in that, The control module is configured to detect the difference between the at least one target value and at least one or more signals indicating blood circulation, wherein the control module is further configured and arranged to adjust the neural stimulation based on the difference between the at least one target value and at least one or more signals indicating blood circulation.

7. The neural modulation system according to claim 1, characterized in that, The control module includes a forward module, wherein the forward module is configured and arranged to take into account at least one predictive effect of the stimulus to adjust the coefficient β within a specified time window.

8. The neural modulation system according to claim 1, characterized in that, The control module is configured to include stimulus paradigm control parameters.

9. The neural modulation system according to claim 1, characterized in that... - The signal input module is or includes at least one sensing element configured to sense signals indicating physiological parameters of the patient. - At least one spatial mapping module configured to link a spatial electrode stimulation configuration (Config) targeting afferent fibers in the dorsal / posterior root to at least one physiological action. - At least one parameter mapping module (218) is configured to prepare stimulation parameters for the control module based on inputs received from the sensing element and / or the spatial mapping module.

10. The neural modulation system according to claim 9, characterized in that, The system includes at least one stimulating element, which includes at least one electrode array A containing a plurality of electrodes E.

11. The neural modulation system according to claim 10, characterized in that, The system includes at least one time mapping module configured to link time electrode stimulation configurations to at least one physiological effect.

12. The neural modulation system according to claim 10 or 11, characterized in that, The control module is configured to identify target values ​​for autonomous functions based on signals provided by the sensing elements.

13. The neural modulation system according to claim 10, characterized in that, The spatial mapping module isolates key electrodes E to optimize the configuration of surrounding electrodes E based on the anatomical location of the afferent fibers in the dorsal / posterior root and the learning program initiated at these electrodes E.

14. The neural modulation system according to claim 9, characterized in that, The stimulation parameters include at least frequency, amplitude, and pulse width, wherein the frequency is 10 Hz-10 kHz, the amplitude is 0-1 V or 0-15 V, and the pulse width is 1-500 μs.

15. The neural modulation system according to claim 9, characterized in that, The spatial mapping module is configured to perform a reinforcement learning procedure, which is part of a process of linking a spatial electrode stimulation configuration (Config) targeting afferent fibers in the dorsal / posterior root to at least one physiological effect.

16. The neural modulation system according to claim 10, characterized in that, The spatial mapping module is configured to perform a spatial mapping phase to identify a suitable electrode configuration (Config) in the first step according to the selected electrodes E and their spatial arrangement, and to perform a parameter mapping phase to adjust the stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

17. The neural modulation system according to claim 9, characterized in that, The physiological parameters are at least one of oxygenation, patient's blood pressure, patient's spinal cord perfusion pressure, patient's posture, and / or patient's position.

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