Systems and methods for controlling autonomous functions

Abstract

A system (10) for neuromodulation and / or neurostimulation for treating a mammal, comprising at least: ‑ at least one control unit (12) configured and arranged to provide stimulation data; ‑ at least one stimulation unit (14) configured and arranged to provide stimulation pulses; ‑ at least one real-time monitoring unit (18); ‑ at least one signal processing unit (16); wherein the system (10) is configured and arranged for controlling blood pressure, wherein the stimulation unit (14) is constructed to include a wire (20), and wherein the wire (20) is capable of and is configured to provide stimulation to the spinal cord at location T9-L1.

Description

Technical Field

[0001] The present invention relates to the field of spinal cord neuroprostheses, in particular for restoration of autonomic function.

[0002] In particular, it refers to a system for spinal cord stimulation, more particularly for restoration of autonomic function, particularly blood pressure, in mammals suffering from spinal cord injury or other diseases (such as stroke, multiple sclerosis, autonomic failure, neuropathy or cancer of the nervous tissue, which impairs the functioning of the descending sympathetic pathways that normally contribute to the control of autonomic function). Background Art

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

[0004] Autonomic dysfunction after SCI is a potentially life-threatening condition that leads to unstable blood pressure and subsequent chronic dysfunction of the cardiac and vascular distribution. Most SCI patients experience severe blood pressure fluctuations multiple times a day and list this as a top priority for health insurance.

[0005] Blood pressure is the force of circulating blood against the walls of blood vessels. Unless otherwise specified, the term "blood pressure" generally refers to the pressure in the systemic arteries. Blood pressure can often be expressed as systolic pressure, the maximum pressure during a heartbeat, and / or diastolic pressure, the minimum pressure between heartbeats, and / or mean arterial 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.

[0006] Blood pressure monitoring may include monitoring parameter values ​​such as diastolic blood pressure, systolic blood pressure, diastolic and systolic blood pressure, mean arterial pressure, mixed blood pressure values, and the like.

[0007] Furthermore, perfusion pressure, i.e. 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 or in the lumbar cistern of an injured mammal.

[0008] When blood pressure, especially arterial blood pressure, decreases or increases as a result of SCI, the spinal cord neurons responsible for blood pressure control no longer have the ability to maintain blood pressure at normal physiological levels. This shutdown of sympathetic control can lead to a situation where blood vessels are unable to maintain appropriate tone (e.g., blood vessels may dilate). A large amount of blood may pool in the lower body of the subject, for example, in the legs and intestines. As a result, subjects affected by SCI may suffer from extremely low blood pressure, i.e., hypotension. Individuals with SCI are generally unable to regulate their blood pressure. These individuals typically experience very low arterial blood pressure at rest, during exercise, and / or when sitting or standing. This low blood pressure may lead to dizziness, disorientation, decreased cognitive function, loss of consciousness, and a predisposition to stroke and heart disease. In addition, a dangerous increase in blood pressure, i.e., hypertension, may also be caused by SCI. Hypertension may lead to heart disease, stroke, and subclinical vascular consequences. As mentioned above, autonomic cardiovascular dysfunction after SCI is a top health priority. A major autonomic problem after high-level SCI (i.e., above thoracic segment 6) is orthostatic hypotension, clinically defined as a decrease in systolic blood pressure ≥20 mmHg and / or a decrease in diastolic blood pressure of 10 mmHg when assuming an upright position. Another key autonomic problem after SCI is autonomic dysreflexia, which is associated with potentially life-threatening increases in blood pressure due to afferent input activating sympathetic circuits located in the spinal cord caudal to the site of SCI. Clinically, autonomic dysreflexia is defined as an increase in systolic blood pressure of 20 mmHg or more (WO2018148844A1).

[0009] WO2018148844A1 discloses a device and algorithm for controlling the autonomic function of an individual. In particular, a controller device is disclosed that uses physiological measurements (such as blood pressure) to regulate spinal cord stimulation to stabilize blood pressure. A control interface and algorithm for controlling the autonomic function of a subject. In particular, an algorithm that uses physiological measurements (such as blood pressure) to regulate spinal cord stimulation to stabilize blood pressure is disclosed. For example, the neuronal structures involved can be located within the T1 to S5 segments of the spinal cord. The stimulation can be configured to control a specific function by selecting electrodes and / or the properties of the stimulation.

[0010] US2007156200A1 discloses an apparatus and method for controlling blood pressure by stimulating cardiac afferent sympathetic nerves. The present invention can be implemented in a medical device having a pressure sensor for sensing blood pressure, electrodes for providing electrical signals to the cardiac afferent sympathetic nerves, and a controller for providing signals to the electrodes that vary in response to the blood pressure signal received from the pressure sensor.

[0011] US2011082515A1 discloses a neurostimulation device comprising an external neurostimulator worn by a patient, the external neurostimulator using a support element that supports a portion of the patient's body. The external neurostimulator delivers neurostimulation to modulate the patient's cardiovascular function. Preferably, the external stimulator delivers neurostimulation transcutaneously to a stimulation target within the patient's body using surface stimulation electrodes placed on the body approximately above the stimulation target.

[0012] US2011 / 0202107A1 relates to an electrical stimulation device and method for treating hypotension in patients with SCI. The electrical stimulation device comprises: a blood pressure measuring device for continuously measuring a subject's blood pressure; a current applying device for intermittently applying an electric current to the subject's skin; and a control device for controlling the current applying device so that the blood pressure is maintained at a predetermined target blood pressure value by activating the current applying device when the subject's blood pressure is equal to or less than the target blood pressure value.

[0013] US2013 / 0289650A1 relates to neuromodulation for controlling hypertension and other cardiorenal disorders in patients with SCI. A neuromodulatory device is delivered to the patient's body to apply electrical activation based on the patient's monitored blood pressure to reduce renal sympathetic nerve hyperactivity, without substantially thermally energizing the patient's body. The electrical activation can also be dependent on the patient's monitored blood volume. A feedback control module can be used to provide feedback control information for adjusting the electrical activation based on the patient's monitored blood pressure and blood volume.

[0014] US3650277A discloses a system for lowering and controlling the blood pressure of a hypertensive patient 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, and the patient's arterial blood pressure is controlled in such a way that the number of stimulation pulses in each cardiac cycle is determined by the mean arterial blood pressure, and the distribution of the stimulation pulses throughout the cardiac cycle varies with the arterial pulse waveform, with the pulse frequency being greater in the first part of the cardiac cycle.

[0015] US6058331 discloses technology for therapeutically treating peripheral vascular disease. Sensors are implemented to sense the level of blood flow or ischemic pain in a patient's limbs and generate corresponding sensor signals. The signals are processed to determine the level of spinal cord stimulation or peripheral nerve stimulation to be applied. This information is provided to a signal generator, which provides electrical stimulation energy to one or more stimulation leads. Stimulation of the spinal cord, peripheral nerves, or ganglia of neural tissue thereby improves blood flow, helps restore tissue health, and reduces the level of ischemic pain in the limbs or other organs of patients with peripheral vascular disease. The present invention thus allows for automatic adjustment of stimulation to take into account changes in the patient's condition throughout the day.

[0016] US2007027495A1 relates to an implantable bladder sensor that can be attached to the outer surface of the urinary bladder to sense bladder status or incontinence, or the inability to control urination. The sensor includes strain gauges that detect mechanical deformation of the bladder. Mechanical deformation may indicate gradual bladder filling or a transient contraction indicating an impending urination event. Wireless telemetry circuitry within the sensor transmits this information to an implanted electrical stimulator, which delivers electrical stimulation to relieve incontinence, or to an external programmer that controls the implanted stimulator.

[0017] New therapies are needed to better control and / or manage autonomic dysfunction in subjects after SCI. Understanding the sympathetic nervous system connectome after SCI is crucial for the development of such new therapies. Summary of the Invention

[0018] Therefore, the purpose of the present invention is to provide a system and method solution that can better manage autonomic dysfunction after SCI. A key limitation in the development of such therapies, namely that the sympathetic nervous system connectome after SCI is not well understood, must be overcome. In particular, rationally targeted stimulation electrodes must be designed in such a way that they specifically target the sympathetic nervous system structures responsible for blood pressure control, and a stimulation paradigm must be provided to achieve precise and biomimetic control of blood pressure after SCI.

[0019] This object is solved by a system according to claim 1. According thereto, a system for neuromodulation and / or neurostimulation for treating a mammal comprises at least:

[0020] - at least one control unit configured and arranged to provide stimulation data;

[0021] - at least one stimulation unit configured and arranged to provide stimulation pulses;

[0022] - at least one real-time monitoring unit;

[0023] - at least one signal processing unit;

[0024] wherein the system is configured and arranged for controlling blood pressure, wherein the stimulation unit is constructed to include a lead, and

[0025] The lead is capable of and configured to provide stimulation to the spinal cord at location T9-L1.

[0026] The present invention is based on the basic idea that it is necessary to provide a stimulation system that specifically targets and modulates the sympathetic preganglionic and postganglionic neurons responsible for blood pressure control in a manner that enables precise control of blood pressure after SCI. In particular, a unique electrode design is provided, specifically configured and arranged to be implanted at a specific location in the spinal cord to target the posterior roots, combined with a new stimulation paradigm and a closed-loop controller that specifically targets and modulates the sympathetic preganglionic and postganglionic neurons responsible for controlling blood pressure by modulating the posterior roots in a manner that enables precise control of blood pressure after SCI.

[0027] The real-time monitoring unit may comprise at least one sensor unit. In particular, the real-time monitoring unit may comprise at least one sensor unit, which is configured and arranged to measure and / or monitor the blood pressure and / or perfusion pressure of a mammal. The sensor unit may generally measure and / or monitor the systolic blood pressure and / or diastolic blood pressure and / or mean arterial pressure and / or cerebrospinal fluid pressure (and / or also spinal cord perfusion pressure) of a mammal. It is also possible that the sensor unit may also report the pulse rate. The at least one sensor unit may be invasive or non-invasive. In other words, the at least one sensor unit may be at least partially implantable and / or implantable. Alternatively, the at least one sensor unit may be non-implantable and / or non-implantable.

[0028] Generally speaking, the sensor unit may comprise at least one sensor and / or at least one sensor base station. The at least one sensor may be a digital or analog sensor system.

[0029] Generally speaking, it is possible for at least two sensors to form a sensor network. A sensor network can generally comprise at least one at least partially implanted and / or implantable sensor and at least one non-implantable and / or non-implanted sensor.

[0030] The implanted and / or implantable sensor and / or the non-implantable and / or non-implantable sensor may be, but is not limited to, an upper arm blood pressure monitoring system, a wrist blood pressure monitoring system, or a finger blood pressure monitoring system. The sensor may measure and / or monitor a blood pressure signal indicative of a blood pressure measurement. Generally, at least one sensor may provide continuous monitoring of blood pressure and / or occasional monitoring of blood pressure and / or measurement or monitoring of blood pressure at predetermined time intervals.

[0031] In particular, the blood pressure sensor may be an invasive arterial line. In particular, an invasive arterial line may monitor blood pressure directly and in real time.

[0032] The signal processing device can compare a blood pressure signal indicative of blood pressure and / or a signal and / or value and / or marker related to spinal cord oxygenation of the mammal with a predetermined blood pressure and / or oxygenation target value and / or a predetermined blood pressure and / or oxygenation target range stored in the control unit. If the comparison indicates that the blood pressure measurement deviates from the predetermined blood pressure target value by a predetermined degree or is not within the predetermined target blood pressure range, the system, in particular the control unit, adjusts the stimulation parameters to restore the blood pressure in a manner such that the blood pressure is within the predetermined target blood pressure range and / or approaches the predetermined target blood pressure value. This means that if the measured blood pressure value is below the predetermined target blood pressure value and / or range, the method increases the level of the stimulation control signal until the blood pressure measurement is within the target blood pressure range and / or matches the predetermined blood pressure value. If the comparison indicates that the blood pressure measurement is above the predetermined target blood pressure range, the method decreases the stimulation level until the blood pressure measurement matches the predetermined target blood pressure value and / or blood pressure range. In other words, the system can be a closed-loop system.

[0033] Furthermore, there may be at least one other sensor. In particular, the system may comprise at least one sensor configured and arranged to measure and / or monitor the patient's blood pressure and / or perfusion pressure, in particular the spinal cord perfusion pressure. The sensor may generally measure and / or monitor the 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 that the sensor may also report the 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. The at least one sensor unit may be invasive or non-invasive. In other words, the at least one sensor may be at least partially implantable and / or implantable. Alternatively, the at least one sensor may be non-implantable and / or non-implantable.

[0034] In principle, the target blood pressure value and / or target blood pressure range can be determined by the patient and / or a medical professional (e.g., a therapist, nurse, physical therapist, physician, pharmacist, physician assistant, or any other trained operator). It is also possible that the target blood pressure and / or oxygenation value and / or target blood pressure and / or oxygenation range can be changed and / or reset at any point in time. The system can be configured and arranged so that different target blood pressure values ​​and / or target blood pressure ranges exist, for example, adjusted to the patient's circadian rhythm.

[0035] Alternatively, the system may be an open loop system.

[0036] Generally speaking, stimulation can be delivered to the dorsal side of the mammalian spinal cord. The stimulation may affect the dorsal roots, dorsal afferent fibers, and / or intraspinal structures that are directly or indirectly connected to sympathetic preganglionic neurons that affect the function being controlled.

[0037] Stimulation can be provided by electrical stimulation. In particular, stimulation can be provided by a lead comprising one or more electrodes. The lead can be implanted. Alternatively and / or additionally, transcutaneous stimulation via a lead is also generally possible.

[0038] Stimulation can be delivered epidurally (via epidural electrical stimulation, EES) and / or subdurally.

[0039] The stimulation unit may be configured to include leads.

[0040] Because of the complexity of the spinal cord, delivering epidural and / or subdural stimulation with implanted multi-electrode arrays (leads) is quite challenging.

[0041] The guidewire can be designed and / or constructed to target cardiovascular and / or blood pressure hotspots in the spinal segment. The cardiovascular and / or blood pressure hotspots can be identified through functional mapping.

[0042] Functional mapping can be understood as follows: To identify the optimal location on the spinal cord to elicit a blood pressure response, a functional mapping procedure can be performed, wherein individual spinal cord segments from T5 to L2 can be stimulated by targeting the protruding posterior roots of the T5 to L2 segments, and the blood pressure response to stimulation can be recorded. Mapping can be performed in animal models, such as a rat model of spinal cord injury. By doing so, it is possible to identify the optimal spinal segment for blood pressure control. The results obtained in animal models can then be transferred to humans. Mapping can also be performed in humans during surgical intervention using percutaneous guidewires.

[0043] Furthermore, the density of sympathetic preganglionic neurons in the spinal cord, which project to key visceral ganglia in the abdomen responsible for blood pressure control, can be determined to identify optimal stimulation sites.

[0044] Based on the results of the mapping and / or determination of the density of sympathetic preganglionic neurons in the spinal cord, the size, configuration, and / or shape of the lead can be designed and / or constructed.

[0045] In particular, the lead may be designed and / or constructed to specifically target the posterior root of the T9-L1 spinal segment.

[0046] In particular, the lead can be and is configured to provide stimulation to the spinal cord at the site T9-T12. In other words, the lead can be designed and constructed to specifically target the posterior root of the T9-T12 spinal segment.

[0047] As described above, a guide wire can be implanted. The guide wire can be and is configured to be positioned subdurally and / or epidurally at least partially at and / or between the vertebrae T9-L1, in particular at least partially below the vertebrae T9-L1. For epidural stimulation, the guide wire can be positioned in the epidural space above the spinal cord. For subdural stimulation, the guide wire can be positioned in the subdural space. In other words, the shape and / or size and / or configuration of the guide wire can be constructed in such a way that the guide wire can be positioned subdurally and / or epidurally at least partially at and / or between the vertebrae T9-L1, in particular at least partially below the vertebrae T9-L1. In particular, specific markers can be placed on the guide wire to align the guide wire with these specific vertebral locations. It is generally possible to use diagnostic tools, such as computed tomography (CT), X-rays, and / or magnetic resonance imaging (MRI) scans, to align the guide wire position with specific vertebral locations.

[0048] The stimulation unit may comprise at least one of a neurostimulator, a neuroregulator and a pulse generator, in particular an implantable pulse generator (IPG).The neurostimulator may be connected to the lead.

[0049] The stimulation data may include at least frequency, amplitude, and pulse width. The frequency may be 10 Hz-10 kHz, the amplitude may be 0-1 V or 0-15 V, and the pulse width may be 1-500 μs.

[0050] Further, the stimulation unit may be configured and arranged to provide at least one burst of stimulation pulses.

[0051] It is generally possible for the stimulation unit to provide two or more bursts.

[0052] A train of stimulation pulses called a burst of stimulation pulses may be preferred to increase specificity and comfort.A burst of stimulation may comprise a series of several pulses being delivered.

[0053] In particular, the stimulation unit may be configured and arranged to provide at least a group of several pulse bursts, preferably 2 to 5 pulses.

[0054] In particular, burst stimulation may comprise a series of 3 to 5 (or even more) pulses delivered at, for example, 200 Hz to 700 Hz, repeated at a frequency of, for example, 10-120 Hz.

[0055] Further, the control unit may comprise an oscillation control module, wherein the oscillation control module may be configured and arranged to provide an input of a low frequency oscillation of 0.01 Hz-0.2 Hz in amplitude and / or frequency.

[0056] In particular, the oscillation control module may be configured and arranged to provide an input of a 0.1 Hz low frequency oscillation in amplitude and / or frequency.

[0057] In particular, the oscillation control module can simulate the natural state of an intact sympathetic nervous system. Specifically, by inputting low-frequency oscillations in the amplitude or frequency control of the aforementioned stimuli, it is possible to optimize the superposition of low-frequency oscillations originating from supraspinal structures (i.e., the anterior ventrolateral medulla oblongata) responsible for blood pressure and / or oxygenation control.

[0058] Further, the control unit may comprise a time control module, wherein the time control module may be configured and arranged to provide a time delay.

[0059] In particular, the time delay provided by the time control module may be a time delay of 1-50 ms.

[0060] In particular, the time delay provided by the time control module may be a time delay of 1-4 ms, in particular a time delay of 2 ms.

[0061] Action potentials originate in the anteroventrolateral medulla and propagate with time delays between key thoracic segments. In rats, these segments may be T11-T12 and T12-T13. In humans, these segments may vary slightly, such as T9-T10, T10-T11, T11-T12, or T12-L1.

[0062] In particular, the time delay may depend on the segment length.

[0063] In particular, time delays can be longer for large mammals compared to small mammals.

[0064] In particular, time delays can be longer in humans compared to rats or mice.

[0065] The time delay can be 1-50ms,

[0066] However, other scales of time delay are generally possible.

[0067] For rats, the time delay may be 1-4 ms, preferably 2 ms.

[0068] In other words, the temporal control module can reproduce natural supraspinal sympathetic drive with the goal of delivering a biomimetic stimulation pattern. When coupled with standard stimulation parameters, this can achieve optimal control of blood pressure after spinal cord injury.

[0069] Alternatively and / or additionally, the stimulation unit may provide stimulation by optical signals, magnetic signals, optogenetic manipulation, chemogenetic manipulation, stimulation by chemical or pharmaceutical agents, thermal signals or the like.

[0070] According to the present invention, there is disclosed the use of a system for neuromodulation and / or neurostimulation according to any one of claims 1 to 10 for treating a mammal.

[0071] According to the present invention, a method is disclosed, which is characterized in that the method is performed using the system of any one of claims 1-10.

[0072] In particular, the method may be a method for neuromodulation, in particular a method for neuromodulation and / or neurostimulation of a mammalian nervous system, comprising at least the following steps:

[0073] - Positioning wire 20;

[0074] - providing neuromodulation and / or neurostimulation to the spinal cord via the lead 20;

[0075] -Monitor blood pressure;

[0076] - Compare the measured blood pressure value with the preset blood pressure target range;

[0077] - if the comparison indicates that the measured blood pressure deviates from the target blood pressure range, adjusting the neural stimulation until the blood pressure of the mammal is within the target blood pressure range;

[0078] Wherein the method is configured and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at spinal regions T9-L1.

[0079] The system and method can be used in a closed-loop manner, taking into account parameters, in particular parameters indicative of the patient's blood pressure and / or oxygenation (in particular spinal cord oxygenation) and / or perfusion pressure, in particular spinal cord perfusion pressure. Furthermore, instead of monitoring blood pressure, oxygenation can additionally or alternatively be monitored and compared to a target value.

[0080] It is generally possible to use the system and method in an open-loop manner as well.

[0081] Alternatively and / or additionally, the system may be used to restore any other type of autonomic dysfunction, such as digestion, bladder and bowel control, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Further details and advantages of the present invention will now be disclosed with reference to the accompanying drawings.

[0083] It is shown in

[0084] Figure 1 Schematic overview of an embodiment of a system according to the invention for neuromodulation and / or neurostimulation, with which the method according to the invention can be performed;

[0085] Figure 2 Equipped with Figure 1 An example of a patient showing the system;

[0086] Figure 3a Figure 1 An example of a lead of the system is shown, along with an embodiment of the implant side of the lead;

[0087] Figure 3b Figure 3a Further examples of implanted sides (rat model);

[0088] Figure 3c Figure 3a Further examples of implanted sides (non-human primate / monkey model);

[0089] Figure 3d Figure 3a Further examples of implanted sides (human patients);

[0090] Figure 4a Example of functional mapping results - heat map showing preferential increases in SBP, DBP, and MAP at T12 as the injury progresses from acute to chronic injury;

[0091] Figure 4b Example of functional mapping results - quantification of responses at intermediate stages, showing preference for T11-T13 in all measurements;

[0092] Figure 4c Example of functional mapping results - quantification of response over time at T12, showing increase over time after injury;

[0093] Figure 4d functional mapping in nonhuman primates;

[0094] Figure 5 Activation of natural frequencies in systolic blood pressure signals during orthostatic stimulation in uninjured and spinal cord-injured rats;

[0095] Figure 6 activation of natural frequency aspects of the systolic blood pressure signal using biologically relevant stimuli;

[0096] Figure 7a A schematic overview of sympathetic neuron activation according to the present invention; and

[0097] Figure 7b Schematic overview of the mechanisms by which EES stabilizes hemodynamics. DETAILED DESCRIPTION

[0098] Figure 1A schematic overview of an embodiment of a system 10 for neuromodulation and / or neurostimulation for treating a mammal according to the invention is shown, with which system the method according to the invention can be performed.

[0099] The system 10 includes a control unit 12 .

[0100] The control unit 12 is configured and arranged to provide stimulation data.

[0101] Furthermore, the system 10 comprises a stimulation unit 14 .

[0102] The stimulation unit 14 is configured and arranged to provide stimulation pulses.

[0103] The stimulation unit 14 is configured to include a lead 20 .

[0104] In this embodiment, the lead is capable of and configured to provide stimulation to the spinal cord at location T9-L1.

[0105] The system 10 also includes a signal processing unit 16 .

[0106] The system 10 also includes a real-time monitoring unit 18 .

[0107] In this embodiment, the real-time monitoring unit 18 is configured and arranged to monitor blood pressure.

[0108] In this embodiment, the real-time monitoring unit 18 comprises a sensor unit 18a.

[0109] The sensor unit 18a is configured and arranged to measure and / or monitor the blood pressure of the patient P.

[0110] In alternative embodiments, the system 10 may include more than one control unit 12 and / or more than one stimulation unit 14 and / or more than one signal processing unit 16 and / or more than one real-time monitoring unit 18 .

[0111] In this embodiment, the control unit 12 is connected to a stimulation unit 14 , a signal processing unit 16 and a real-time monitoring unit 18 .

[0112] In this embodiment, the connection between the control unit 12 and the stimulation unit 14, the connection between the control unit 12 and the processing unit 16, and the connection between the control unit 12 and the real-time monitoring unit 18 are direct and bidirectional connections.

[0113] In this embodiment, the connection between the control unit 12 and the stimulation unit 14, the connection between the control unit 12 and the processing unit 16, and the connection between the control unit 12 and the real-time monitoring unit 18 are established via wireless links WL.

[0114] However, alternatively, cable binding and / or unidirectional and / or indirect connection between the control unit 12 and the stimulation unit 14, cable binding and / or unidirectional and / or indirect connection between the control unit 12 and the processing unit 16, and cable binding and / or unidirectional and / or indirect connection between the control unit 12 and the real-time monitoring unit 18 are generally possible.

[0115] In this embodiment, the stimulation unit 14 is connected to a signal processing unit 16 .

[0116] The connection between the stimulation unit 14 and the signal processing unit 16 is a direct and bidirectional connection.

[0117] The connection between the stimulation unit 14 and the signal processing unit 16 is established via a wireless link WL.

[0118] Alternatively, however, a cable bond and / or a unidirectional and / or indirect connection between the stimulation unit 14 and the signal processing unit 16 is generally possible.

[0119] In this embodiment, the signal processing unit 16 is connected to a real-time monitoring unit 18 .

[0120] The connection between the signal processing unit 16 and the real-time monitoring unit 18 is a direct and bidirectional connection.

[0121] In this embodiment, the connection between the signal processing unit 16 and the real-time monitoring unit 18 is established via a wireless link WL.

[0122] However, alternatively, a cable bond and / or a unidirectional and / or indirect connection between the signal processing unit 16 and the real-time monitoring unit 18 would generally also be possible.

[0123] The real-time monitoring unit 18 , in particular the sensor unit 18 a of the real-time monitoring unit 18 , measures the blood pressure of the patient P.

[0124] Not shown in this embodiment, the sensor unit 18a may generally measure and / or monitor the systolic and / or diastolic and / or mean arterial pressure.

[0125] Not shown in this embodiment, sensor unit 18a may also report pulse rate.

[0126] Not shown in this embodiment, the at least one sensor unit 18a may be an invasive or a non-invasive sensor unit 18a.

[0127] Not shown in this embodiment, the sensor unit 18a may be at least partially implantable and / or implanted.

[0128] Alternatively, the at least one sensor unit 18a may be non-implantable and / or non-implanted.

[0129] The measured blood pressure is transmitted from the real-time monitoring unit 18 to the signal processing unit 16 .

[0130] In this embodiment, the measured blood pressure is transmitted from the real-time monitoring unit 18 to the signal processing unit 16 in real time.

[0131] In alternative embodiments, the measured blood pressure may be transmitted from the real-time monitoring unit 18 to the signal processing unit 16 in near real-time or with a time delay.

[0132] The signal processing unit 16 compares the measured blood pressure value with a predetermined blood pressure value and / or a predetermined blood pressure target range.

[0133] If the comparison result indicates that the measured blood pressure deviates from the predetermined target blood pressure range, the control unit 12 may adjust the stimulation data.

[0134] The stimulation unit 14 provides stimulation via the line 20 in accordance with the stimulation data provided by the control unit 12 .

[0135] Not shown in this embodiment, the sensor unit 18 a can additionally and / or alternatively measure and / or monitor the perfusion pressure, in particular the spinal cord perfusion pressure.

[0136] Not shown in this embodiment, the measured spinal cord perfusion pressure may be transmitted from the real-time monitoring unit 18 to the signal processing unit 16 .

[0137] Not shown in this embodiment, the measured spinal cord perfusion pressure may be transmitted from the real-time monitoring unit 18 to the signal processing unit 16 in real time.

[0138] Not shown in this embodiment, the measured spinal cord perfusion pressure may be transmitted from the real-time monitoring unit 18 to the signal processing unit 16 in near real time or with a time delay.

[0139] Not shown in this embodiment, the signal processing unit 16 may compare the measured spinal cord perfusion pressure value with a predetermined spinal cord perfusion pressure target value and / or a predetermined spinal cord perfusion pressure target range.

[0140] Not shown in this embodiment, the control unit 12 may adjust the stimulation data if the comparison indicates that the measured spinal cord perfusion pressure deviates from a predetermined spinal cord perfusion pressure target value and / or from a predetermined spinal cord perfusion pressure target range.

[0141] In this embodiment, the stimulation data comprises at least frequency, amplitude, and pulse width.

[0142] In this embodiment, the frequency may be 10 Hz-10 kHz, the amplitude may be 0-1 V or 0-15 V, and the pulse width may be 1-500 μs.

[0143] Not shown in this embodiment, the stimulation unit 14 may be configured and arranged to provide at least one burst of stimulation pulses.

[0144] Figure 1 What is not shown in FIG. 1 is that it is generally possible for the stimulation unit 14 to provide two or more bursts.

[0145] In particular, the stimulation unit 14 may be configured and arranged to provide at least a group of several pulse bursts, preferably 2 to 5 pulses.

[0146] Figure 1 Not shown in FIG, a train of stimulation pulses called a burst of stimulation pulses may be preferred to increase specificity and comfort.

[0147] Figure 1 Not shown in FIG. 3 , burst stimulation may comprise, in particular, a series of 3 to 5 (or even more) pulses delivered at, for example, 200 Hz to 700 Hz, repeated at, for example, a frequency of 10-120 Hz.

[0148] Not shown in this embodiment, lead 20 is capable of and configured to provide stimulation to the spinal cord at locations T9-T12.

[0149] Not shown in this embodiment, the guidewire 20 can be and is configured to be positioned subdurally and / or epidurally at least partially at and / or between vertebrae T9-L1, and in particular at least partially beneath vertebrae T9-L1 of the patient.

[0150] Figure 1 What is not shown is that the control unit 12 may include an oscillation control module.

[0151] Generally speaking, the oscillation control module may provide an input of a low frequency oscillation of 0.01 Hz-0.2 Hz in amplitude.

[0152] In particular, the oscillation control module may provide an input of a low frequency oscillation of 0.1 Hz in amplitude.

[0153] Alternatively and / or additionally, the oscillation control module may provide an input of a low frequency oscillation in the frequency range of 0.01 Hz-0.2 Hz.

[0154] In particular, the oscillation control module may alternatively and / or additionally provide an input of a low frequency oscillation in frequency of 0.1 Hz.

[0155] Figure 1What is not shown is that the control unit 12 may include a time control module.

[0156] Generally speaking, a time control module can provide a time delay.

[0157] In general, the time delay may depend on the segment length.

[0158] In general, time delays can be longer for large mammals than for small mammals.

[0159] In general, time delays can be longer in humans compared to rats or mice.

[0160] Generally speaking, the time delay provided by the time control module may be a time delay of 1-50 ms.

[0161] Generally speaking, the time delay provided by the time control module may be a time delay of 1-4 ms, particularly a time delay of 2 ms.

[0162] However, every other time delay provided by the time control module will generally be possible.

[0163] In accordance with the present invention, a system 10 or use of neuromodulation is disclosed.

[0164] The use of system 10 and the functionality of system 10 can be described as follows:

[0165] Use of a system 10 for neuromodulation and / or neurostimulation according to any one of claims 1 to 10 for treating a mammal.

[0166] The method performed by the system 10 and the functionality of the system 10 can be described as follows:

[0167] A method for neuromodulation and / or neurostimulation of a mammalian nervous system, comprising at least the following steps:

[0168] - Positioning wire 20;

[0169] - providing neuromodulation and / or neurostimulation to the spinal cord via the lead 20;

[0170] -Monitor blood pressure;

[0171] - Compare the measured blood pressure value with the preset blood pressure target range;

[0172] - if the comparison indicates that the measured blood pressure deviates from the target blood pressure range, adjusting the neural stimulation until the blood pressure of the mammal is within the target blood pressure range;

[0173] Wherein the method is configured and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at spinal regions T9-L1.

[0174] In particular, the method may be arranged for positioning the lead subdurally and / or epidurally at least partially at and / or between vertebrae T9-L1, in particular at least partially beneath vertebrae T9-L1.

[0175] In particular, the method may be configured and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at least at spinal regions T9-T12.

[0176] The method can provide neuromodulation and / or neurostimulation to the spinal cord with a frequency of 10 Hz-10 kHz, an amplitude of 0-1 V or 0-15 V, and a pulse width of 1-500 μs.

[0177] Generally speaking, stimulation may be provided to the spinal cord via at least one burst of stimulation pulses.

[0178] Generally speaking, stimulation may be provided to the spinal cord with at least a burst of several pulses, preferably 2 to 5 pulses.

[0179] Generally speaking, stimulation may be provided with a control input of low frequency oscillations of 0.01 Hz-0.2 Hz in amplitude and / or frequency.

[0180] In particular, stimulation may be provided with a control input of a 0.1 Hz low frequency oscillation in amplitude and / or frequency.

[0181] Furthermore, stimulation may be provided using control inputs that include time delays.

[0182] In general, time delays can be longer in humans compared to rats or mice.

[0183] In general, the time delay may depend on the segment length.

[0184] In particular, stimulation may be provided with a control input comprising a time delay of 1-50 ms.

[0185] In particular, stimulation may be provided with control inputs comprising a time delay of 1-4 ms.

[0186] In particular, stimulation may be provided with a control input comprising a time delay of 2 ms.

[0187] It is noted that the present system 10 and methods may also be applied to treat mammals suffering from neurological disorders other than SCI, including but not limited to stroke, multiple sclerosis, autonomic failure, autonomic neuropathy, and cancers of the nervous tissue that impair the functioning of the descending sympathetic pathways that normally contribute to the control of autonomic function.

[0188] Figure 1 Not shown, the present systems and methods may also be applied to treat any other autonomic dysfunction besides impaired blood pressure control, including but not limited to heart rate, digestive function, bladder control, and / or bowel control.

[0189] Figure 2 Shown is equipped with Figure 1 An example of a patient of the system 10 is shown.

[0190] Patient P is equipped with Figure 1 The system 10 disclosed in .

[0191] In this embodiment, the real-time monitoring unit 18 comprises a sensor unit 18a.

[0192] In this embodiment, the sensor unit 18a includes a sensor.

[0193] The sensor monitors the blood pressure of patient P.

[0194] In this embodiment, sensors monitor patient P's systolic and diastolic blood pressure.

[0195] In this embodiment, the sensor is a non-invasive sensor.

[0196] In this embodiment, the sensor is a wrist blood pressure monitoring system.

[0197] In this embodiment, the sensor is a digital blood pressure monitoring system.

[0198] In an alternative embodiment, the sensor may be an analog blood pressure monitoring system.

[0199] In this embodiment, the sensor continuously monitors blood pressure in real time and provides the blood pressure data to the signal processing unit 16 in real time.

[0200] However, it is generally possible for the sensor to measure the blood pressure at predefined time intervals.

[0201] In alternative embodiments, the sensor may be or may include other embodiments of a blood pressure monitoring system, including but not limited to a cuff, an arterial pressure sensor, an optical biometric sensor, an upper arm blood pressure monitoring system, a finger blood pressure monitoring system, or any other type of non-implanted blood pressure monitoring system, as well as any type of implantable and / or implanted blood pressure monitoring system.

[0202] In alternative embodiments, the sensor may additionally and / or alternatively measure and / or monitor other parameters indicative of perfusion pressure and / or blood pressure, including but not limited to arterial blood pressure.

[0203] In alternative embodiments, the sensor may additionally measure and / or monitor the patient P's pulse rate.

[0204] In an alternative embodiment, the sensor may be or may comprise an arterial line.

[0205] In an alternative embodiment, the sensor may be or may comprise an arterial line in a hospital.

[0206] In general, the sensor unit 18a may include more than one sensor and / or at least one sensor base station.

[0207] Figure 3a Shown in Figure 1 An example of a lead 20 of the system 10 is shown in FIG. 1 , and an embodiment of the implant side of the lead 20 according to the present invention.

[0208] In this embodiment, the lead 20 is sized to perfectly target the posterior root of the T9-L1 spinal segment.

[0209] To identify the optimal location on the spinal cord to elicit a blood pressure response, a functional mapping procedure can be performed, for example, in an animal model, for example, in an animal model of SCI.

[0210] In other words, to identify the optimal location for providing stimulation to the spinal cord, a functional mapping procedure can be performed, for example, in an animal model, for example, in an animal model of SCI.

[0211] In other words, to identify the optimal location for positioning lead 20 for providing stimulation to the spinal cord, a functional mapping procedure can be performed, for example, in an animal model, such as an animal model of SCI.

[0212] Implantation sites are so-called hotspots and are conserved across species and can be found in Figure 3b 、 Figure 3c and Figure 3d Further export:

[0213] Figure 3b Shown Figure 3aFurther illustration of the implantation side (rat model).

[0214] Figure 3c Shown Figure 3a Further example of the implant side (non-human primate / monkey model).

[0215] Figure 3d Shown Figure 3a Further example of the implant side (of a human patient).

[0216] In these examples, to identify the optimal location on the spinal cord to elicit a blood pressure response, a functional mapping procedure was performed in a rat model of SCI, as described herein:

[0217] In principle, various spinal cord segments from T5 to L2 in a rat model of SCI were stimulated, and the blood pressure response to monopolar, 50 Hz stimulation was recorded.

[0218] In this example, it has been found that T11-T13 is the optimal segment for stimulation in rodents, with peak responses occurring during stimulation at T12, see Figure 4a .

[0219] In particular, the systolic blood pressure SBP, the diastolic blood pressure DBP or the mean arterial blood pressure MAB have been measured.

[0220] Notably, this response was consistent at different time points after injury, including 1 hour (acute), 5 days (subacute), 2 weeks (intermediate), and 1 month (chronic).

[0221] Notably, a similar approach can be performed to facilitate obtaining a lead 20 designed to perfectly target the posterior root of the T9-L1 spinal segment in humans.

[0222] Notably, simulation parameters can be varied in a similar manner to that performed in humans.

[0223] Figure 4b The bar graph shown shows a quantification of the responses at the intermediate stages shown in FIG. 4A , showing a preference for T11-T13 in all measurements.

[0224] Figure 4c The bar graph shown shows quantification of the response at T12 over time after injury, including 1 hour (acute), 5 days (subacute), 2 weeks (intermediate), and 1 month (chronic), showing an increase over time after injury.

[0225] Not shown, in a next step, the density of sympathetic preganglionic neurons in the spinal cord that project to key visceral ganglia in the abdomen responsible for blood pressure control can be determined.

[0226] Not shown, the density of sympathetic preganglionic neurons projecting from these ganglia was also found to peak at T12, and there was a strong linear correlation between the density of sympathetic preganglionic neurons and the functional blood pressure response to stimulation.

[0227] Not shown, next, two converging lines of evidence have been used to confirm that this stimulation leads to activation of the visceral ganglia.

[0228] First, the spinal cord was stimulated at T12 for 30 minutes, and activated neurons within the visceral ganglia were identified using classical immunohistochemistry (using the current early gene Fos, Fos proto-oncogene, AP-1 transcription factor subunit).

[0229] Compared to unstimulated animals, the number of neurons expressing Fos was found to be significantly increased, and these neurons were synthesizing adrenaline (confirmed by the presence of protein tyrosine hydroxylase), confirming their role in blood pressure control.

[0230] Using optogenetic techniques, it has been found that inhibiting the depolarization of these same neurons blunts the response to stimulation.

[0231] With the knowledge that the T11-T13 segments preferentially activate sympathetic structures and that stimulation of these segments can regulate blood pressure, high-resolution CT and MRI scans were performed to precisely identify the relationship between spinal segments and vertebral locations.

[0232] Additionally, the exact length of the T11-T13 segment has been confirmed using ex vivo dissection.

[0233] A biocompatible electronic lead 20 spinal implant is then designed with the exact dimensions required to stimulate T11-T13, and the lead 20 is placed directly beneath the T9-T12 vertebrae, see FIG. 3 .

[0234] This design of lead 20 can thus be easily extended to any animal or human model using MRI techniques and computational modeling.

[0235] In other words, the design of the lead 20 is based on key anatomical features (using a rat model as an animal model)

[0236] - Identification of functional cardiovascular "hot spots" - see Figure 4A-C (T11-T13)

[0237] - These "cardiovascular hotspots" were found to match the segmental density of sympathetic preganglionic neurons;

[0238] -Complete CT and MRI scans of the same rat spinal cord in order to match the features of the lead 20 to the posterior root of the T11-T13 segment (see FIG3 for exact dimensions);

[0239] - placing specific markings on the guidewire 20 to align the guidewire 20 to a specific vertebral location;

[0240] Thus, the lead 20 dimensions (see FIG. 3 ) were designed to perfectly target the posterior roots of the rat T11-T13 spinal segments, which have been determined to be critical for maintaining blood pressure using epidural electrical stimulation.

[0241] In humans, this would correspond to the T9-T12 region.

[0242] Figure 4d Functional mapping in non-human primates is shown and the conservation of hotspots is demonstrated (see Figures 3a-3d ).

[0243] Figure 5 Shown are activations in natural frequencies in systolic blood pressure signals during orthostatic stimulation in uninjured and SCI rats.

[0244] The heat represents the frequency power at a given wavelet band.

[0245] The dashed line represents the onset of upright stimulation.

[0246] Data for 30 seconds are shown.

[0247] A power drop is observed in the range around 0.1 Hz.

[0248] A stimulation paradigm can be designed that mimics the natural state of an intact sympathetic nervous system.

[0249] Specifically, frequency oscillation superpositions can be optimized that originate from supraspinal / spinal structures responsible for blood pressure control (i.e., the anterior ventrolateral medulla oblongata / spinal cord) and trigger 0.1 Hz low-frequency oscillating sympathetic preganglionic neurons in a complete system.

[0250] Not shown, using electrophysiological experiments, it was determined that action potentials originating in the anteroventrolateral medulla propagate with a time delay of 2 ms between T11-T12 and T12-T13 in rats.

[0251] In humans, this would correspond to the T9-T11 and T11-T12 regions.

[0252] We describe a biomimetic stimulation paradigm that can reproduce natural supraspinal sympathetic drive and, when coupled with a range of standard parameters (frequency 10 Hz-10 kHz, amplitude 0-1 V or 0-15 V, pulse width 1-500 μs), achieves biologically relevant BIO control of blood pressure after spinal cord injury.

[0253] It has been confirmed that this BIO paradigm reproduces the natural dynamics of the autonomic nervous system using wavelet decomposition, where an increase in frequency power within the systolic blood pressure signal was observed upon stimulus activation.

[0254] Figure 6 Activation in terms of natural frequencies within the systolic blood pressure signal using biologically relevant BIO stimulation is shown.

[0255] The heat represents the frequency power at a given wavelet band.

[0256] The dashed line represents the onset of the stimulus.

[0257] Data for 30 seconds are shown.

[0258] An increase in power was observed in the range around 0.1 Hz, confirming that the natural rhythm found in the uninjured state was reproduced.

[0259] Figure 7a A schematic overview of sympathetic neuron activation according to the present invention is shown.

[0260] In particular, activation of sympathetic neural circuits in response to stimulation is shown.

[0261] In particular, activation of sympathetic neural circuits in response to stimulation with the system 10 and / or methods according to the present invention is shown.

[0262] Stimulation enters the dorsal root ganglion DRG and activates the sympathetic preganglionic neurons SPN, which then activate the splanchnic ganglia SG, which are responsible for blood pressure.

[0263] Figure 7b A schematic overview of the mechanism by which EES stabilizes hemodynamics is shown.

[0264] Part a shows the intraspinal density of neurons traced backward from the splanchnic ganglia, the amplitude of the pressor responses to TESS applied to each segment, and the agreement between the anatomical and functional datasets.

[0265] Part b shows a hypothetical circuit activated by TESS to cause vasoconstriction.

[0266] Panel c shows color-coded potentials after TESS application to the spinal cord, indicating exclusive activation of afferent fibers. Illustration illustrates posterior root rhizotomy. Bar graph reports pressor responses to targeted epidural spinal cord stimulation (TESS) before and after rhizotomy (n=5, paired sample one-tailed t-test; t=4.36; P=0.006).

[0267] Part d shows transsynaptic backward tracing, revealing interneurons connecting to the splanchnic ganglion.

[0268] Part e shows interneurons that express the excitatory marker Slc17a6 and receive vGlut1 synapses from large-diameter proprioceptive afferents.

[0269] Part f shows Fos expression in THON neurons in the visceral ganglion in control and after TESS. Barplot reports the percentage of FOSON neurons (n=5, independent sample one-tailed t-test; t=13.96; P=4.99e-05).

[0270] Panel g shows that ablation of visceral efferents attenuated the pressor response (n=4, independent samples one-tailed t-test; t=-4.54; P=0.0099).

[0271] Part h shows that blocking α1 receptors with prazosin attenuates the pressor response (n=5, independent sample one-tailed t-test; t=-5.59; P=0.0007).

[0272] refer to

[0273] 10 System

[0274] 12 Control Unit

[0275] 14 stimulation units

[0276] 16 signal processing units

[0277] 18 Real-time monitoring unit

[0278] 18a Sensor unit

[0279] 20 wires

[0280] BIO Biologically relevant stimulation

[0281] CT computed tomography

[0282] DRG dorsal root ganglion

[0283] MRI Magnetic Resonance Imaging

[0284] Patient P

[0285] SCI Spinal Cord Injury

[0286] SPN Sympathetic preganglionic neuron

[0287] SG visceral ganglion

[0288] WL Wireless Link

[0289] DBP diastolic blood pressure

[0290] MAP mean arterial pressure

[0291] SBP Systolic blood pressure

[0292] LX Lumbar vertebraeX

[0293] L1 Lumbar vertebra 1

[0294] TX Thoracic spine X or thoracic vertebra X

[0295] T6 Thoracic Segment 6 or Thoracic Vertebra 6

[0296] T7 Thoracic Segment 7 or Thoracic Vertebra 7

[0297] T8 thoracic spine segment 8 or thoracic vertebrae segment 8

[0298] T9 thoracic spine segment 9 or thoracic vertebrae segment 9

[0299] T10 thoracic spine segment 10 or thoracic vertebrae 10

[0300] T11 thoracic spine segment 11 or thoracic vertebrae segment 11

[0301] T12 thoracic spine segment 12 or thoracic vertebrae 12

[0302] T13 thoracic vertebrae 13 or thoracic vertebrae 12

Claims

1. A system (10) for neuromodulation and / or neurostimulation for treating a mammal, comprising at least: - at least one control unit (12) configured and arranged to provide stimulation data; - at least one stimulation unit (14) configured and arranged to provide stimulation pulses; - at least one real-time monitoring unit (18); - at least one signal processing unit (16); wherein the system (10) is configured and arranged for controlling blood pressure, wherein the stimulation unit (14) is constructed to include a lead (20), and wherein the lead (20) is capable of and configured to provide stimulation to the spinal cord at location T9-L1; and The control unit (12) comprises an oscillation control module, wherein the oscillation control module is configured and arranged to provide an input of a low frequency oscillation of 0.1 Hz in amplitude and / or frequency.

2. The system (10) according to claim 1, characterized in that The lead (20) is capable of and configured to provide stimulation to the spinal cord at locations T9-T12.

3. The system (10) according to claim 1 or claim 2, characterized in that The guidewire (20) is capable of and is configured to be positioned at least partially subdurally and / or epidurally at and / or between vertebrae T9-L1.

4. The system (10) according to claim 1, characterized in that The stimulation data includes at least frequency, amplitude, and pulse width, wherein the frequency of the stimulation data is 10 Hz-10 kHz, the amplitude of the stimulation data is 0 V-15 V, and the pulse width of the stimulation data is 1 μs-500 μs.

5. The system (10) according to claim 1, characterized in that The stimulation unit (14) is configured and arranged to provide at least one burst of stimulation pulses.

6. The system (10) according to claim 5, characterized in that The stimulation unit (14) is configured and arranged to provide at least one set of several pulse bursts.

7. The system (10) according to claim 1, characterized in that The control unit (12) comprises a time control module, wherein the time control module is configured and arranged to provide a time delay.

8. The system (10) according to claim 7, characterized in that The time delay provided by the time control module is a time delay of 1ms-50ms.

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