Systems and methods for control of autonomic nervous function

Abstract

A system (10) for neuromodulation and / or neurostimulation for the treatment of a mammal comprises at least at least one control unit (12) configured and arranged to provide stimulation data, at least one stimulator (14) configured and arranged to provide stimulation pulses, at least one real-time monitoring unit (18), and at least one signal processor (16), wherein the system (10) is configured and arranged for blood pressure control, and the stimulator (14) is configured with leads (20), and the leads (20) are capable of and configured to provide stimulation to the spinal cord at levels T9 to L1.

Description

[Technical field]

[0001] The invention particularly refers to the field of spinal nerve prostheses for the rehabilitation of autonomic function. [Background technology]

[0002] In particular, it refers to a system for stimulation of the spinal cord, and more specifically for the rehabilitation of autonomic function, especially blood pressure, in mammals with spinal cord injury or other disorders (e.g. stroke, multiple sclerosis, autonomic neuropathy, autonomic neuropathy or cancer of neurological tissue that impairs the operation of the descending sympathetic pathways that normally facilitate the control of autonomic function).

[0003] The spinal cord is an integral part of the central nervous system (CNS). Spinal cord injury (SCI) results in motor and sensory impairments as well as autonomic dysfunction. SCI results in partial, major or total interruption of the descending sympathetic pathways that carry signals responsible for regulating arterial blood pressure, heart rate and / or gastrointestinal and bladder function.

[0004] Autonomic dysfunction following SCI is a potentially life-threatening condition that leads to blood pressure instability and subsequent chronic dysfunction of the heart and vascular system. Most SCI patients experience multiple rapid fluctuations in blood pressure every day, making this problem a top health care priority.

[0005] Blood pressure is the pressure of circulating blood against the walls of blood vessels. Unless further specified, "blood pressure" often refers to the pressure within the arteries of the systemic circulation. Blood pressure is usually expressed in terms of systolic blood pressure, i.e. the maximum pressure during one heartbeat, and / or diastolic blood pressure, i.e. the minimum pressure between two heartbeats, and / or mean arterial pressure, i.e. the average blood pressure of an individual during one cardiac cycle, and may be measured in millimeters of mercury (mmHg, above the surrounding 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] Additionally, perfusion pressure can be important, i.e. spinal cord perfusion pressure defined as the difference between mean arterial pressure and cerebrospinal fluid pressure. The latter can be monitored, for example, using an intrathecal catheter placed near the injury site or in the lumbar cistern of the injured mammal.

[0008] When blood pressure, particularly arterial pressure, falls or rises as a result of SCI, spinal cord neurons responsible for blood pressure control no longer have the ability to maintain blood pressure at normal physiological levels. This blockage of sympathetic control can lead to a situation where blood vessels do not maintain proper tone (e.g., blood vessels may dilate). A large amount of blood can pool in the lower part of the subject's body, e.g., the legs and intestinal tract. Thus, subjects suffering from SCI can suffer from extremely low blood pressure, i.e., hypotension. Individuals with SCI are often unable to regulate their blood pressure. These individuals usually experience very low arterial pressure at rest, during exercise, and / or when seated or standing. This hypotension can cause dizziness, disorientation, reduced cognitive function, fainting, and a predisposition to strokes and heart attacks. In addition, a dangerous rise in blood pressure, i.e., hypertension, can also result from SCI. Hypertension can lead to heart attacks, strokes, and hidden vascular consequences. As mentioned above, autonomic cardiovascular dysfunction following SCI is a top health concern. One major autonomic problem after a high (i.e., 6th thoracic segment or higher) SCI is orthostatic hypotension, which is clinically defined as a decrease in systolic blood pressure of 20 mmHg or more and / or a decrease in diastolic blood pressure of 10 mmHg when assuming an upright position. Another significant autonomic problem after SCI is autonomic dysreflexia, which is associated with a potentially life-threatening rise in blood pressure due to afferent inputs that activate sympathetic circuits located caudal to the location of the SCI in the spinal cord. Clinically, autonomic dysreflexia is defined as an increase in systolic blood pressure of 20 mmHg or more (WO 2018 / 148844).

[0009] WO 2018 / 148844 discloses devices and algorithms for controlling autonomic functions in an individual. In particular, a controller device is disclosed that utilizes physiological measurements (such as blood pressure) to modulate spinal cord electrical stimulation to stabilize blood pressure. Control interfaces and algorithms for controlling autonomic functions in a subject. In particular, an algorithm is disclosed that utilizes physiological measurements (such as blood pressure) to modulate spinal cord electrical stimulation to stabilize blood pressure. The neuronal structures involved may be located, for example, within the T1-S5 segments of the spinal cord. Stimulation may be configured to control specific functions by selection of electrodes and / or nature of stimulation.

[0010] US 2007 / 156200 discloses an apparatus and method for controlling blood pressure by stimulating the cardiac afferent sympathetic nerves. The invention may be embodied 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 as a function of the blood pressure signal received from the pressure sensor.

[0011] US 2011 / 082515 discloses a neurostimulation device that includes an external neurostimulator worn by a patient using a brace element that immobilizes a portion of the patient's body. The external neurostimulator delivers neurostimulation to regulate the patient's cardiovascular function. Preferably, the external neurostimulator delivers neurostimulation percutaneously to a stimulation target within the patient's body using surface stimulation electrodes that are placed on the body over the stimulation target.

[0012] US 2011 / 0202107 A1 relates to an electrical stimulation device for treating hypotension in a patient suffering from SCI and a method for treating hypotension, the electrical stimulation device comprising blood pressure measuring means for continuously measuring the blood pressure of a subject, current applying means for intermittently applying a current to the skin of the subject, and control means for controlling the current applying means to maintain the blood pressure at a predetermined target blood pressure value by activating the current applying means when the blood pressure of the subject falls below a target blood pressure value.

[0013] US Patent Publication No. 2013 / 0289650 relates to neuromodulation for controlling hypertension and other cardiorenal disorders in patients with SCI. A neuromodulation device is delivered to the patient's body to apply electrical activation to reduce the patient's renal sympathetic hyperactivity based on the patient's monitored blood pressure, without substantially imparting thermal energy to the patient's body by applying the electrical activation. The electrical activation may also be dependent on the patient's monitored blood volume. A feedback control module may be used to provide feedback control information to adjust the electrical activation based on the patient's monitored blood pressure and blood volume.

[0014] U.S. Pat. No. 3,650,277 discloses a system for reducing and controlling blood pressure in hypertensive patients by providing electrical pulse stimulation of the carotid sinus nerve controlled by the patient's arterial pressure, in a manner in which the distribution of stimulation pulses over the cardiac cycle is a function of the arterial pulse waveform, the pulse frequency being higher during the first part of the cardiac cycle, while the number of stimulation pulses within each cardiac cycle is determined by the arterial mean blood pressure.

[0015] US6058331 discloses a technique for therapeutically treating peripheral vascular disease. A sensor is implemented to sense the blood flow or the degree of 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 delivers electrical stimulation energy to one or more stimulation leads. Stimulation of the spinal cord, peripheral nerves, or nerve tissue ganglia thereby improves blood flow, restores tissue health, and reduces the degree of ischemic pain in the limbs of a peripheral vascular disease patient or other patient organ. This invention thereby allows stimulation to be automatically adjusted to accommodate changes in the patient's condition throughout the day.

[0016] US 2007 / 027495 relates to an implantable bladder sensor that can be attached to the exterior surface of the bladder to sense bladder state or activity for urinary incontinence or loss of control of voiding function. The sensor includes a strain gauge that detects mechanical deformation of the bladder. The mechanical deformation may indicate a gradual filling of the bladder or a momentary contraction indicating an impending voiding event. Wireless telemetry circuitry within the sensor transmits the information to an implantable electrical stimulator that delivers electrical stimulation to relieve urinary incontinence or to an external programmer that controls the implantable stimulator. Summary of the Invention

[0017] There is a need for new therapies to control and / or manage autonomic dysfunction in subjects after SCI. Understanding the connectome of the sympathetic nervous system after SCI is crucial for the development of such new therapies.

[0018] Therefore, it is an objective of the present invention to provide a solution for a system and method that can better manage autonomic dysfunction after SCI. A fundamental limitation to the development of such a treatment needs to be overcome, namely that the connectome of the sympathetic nervous system after SCI is poorly understood. In particular, rationally targeted stimulation electrodes need to be designed in such a way that they specifically target the sympathetic nervous system structures responsible for blood pressure control, and precise and biomimetic controllable stimulation paradigms for blood pressure after SCI need to be provided.

[0019] This object is solved by the system according to claim 1. Thus, a system for neuromodulation and / or neurostimulation for the treatment of a mammal comprises: at least one control unit constructed and arranged to provide stimulation data; at least one stimulator constructed and arranged to deliver stimulation pulses; At least one real-time monitoring unit; at least one signal processing unit, At least The system is constructed and arranged for control of blood pressure, and the stimulator is configured with leads, the leads capable of and configured to provide stimulation to the spinal cord at levels T9-L1.

[0020] The present invention is based on the fundamental idea that a stimulation system must be provided that specifically targets and modulates the sympathetic pre- and post-ganglionic neurons responsible for blood pressure control in a manner that allows for precise control over blood pressure after SCI. In particular, a unique electrode design is provided, specifically configured and arranged for implantation at a specific location in the spinal cord that specifically targets the dorsal root, and combined with a novel stimulation paradigm and closed-loop controller that specifically targets and modulates the sympathetic pre- and post-ganglionic neurons responsible for blood pressure control via dorsal root modulation in a manner that allows for precise control over blood pressure after SCI.

[0021] 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 constructed and arranged to measure and / or monitor the blood pressure and / or perfusion pressure of the mammal. The sensor unit generally measures and / or monitors the systolic and / or diastolic and / or mean arterial pressure and / or cerebrospinal fluid pressure (and / or also spinal perfusion pressure) of the mammal. 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 implanted. Alternatively, the at least one sensor unit may be non-implantable and / or not implantable.

[0022] 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.

[0023] At least two sensors can generally constitute a sensor network. A sensor network may generally comprise both at least one at least partially implanted and / or implantable sensor and at least one non-implantable and / or non-implanted sensor.

[0024] The implanted and / or implantable sensor and / or the non-implantable and / or non-implanted sensor may be, but is not limited to, an upper arm blood pressure monitor system, a lumbar blood pressure monitor system, or a finger blood pressure monitor system. The sensor may measure and / or monitor a blood pressure signal indicative of a blood pressure measurement. In general, the at least one sensor may provide continuous monitoring of blood pressure, sporadic monitoring of blood pressure, and / or measuring or monitoring blood pressure at preset time intervals.

[0025] In particular, the blood pressure sensor can be an invasive arterial line, which can monitor blood pressure directly and in real time.

[0026] The signal processing device can compare the blood pressure signal, indicative of blood pressure, signals, values ​​and / or markers correlating to spinal 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 controller. If the comparison indicates that the blood pressure measurement is outside 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 controller, adapts the stimulation parameters to restore the blood pressure in a manner such that the blood pressure is within and / or near the predetermined target blood pressure value. This means that if the blood pressure measurement 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 and / or corresponds to the target blood pressure value. If the comparison indicates that the blood pressure measurement is above the predetermined target blood pressure range, the method reduces the stimulation level until the blood pressure measurement corresponds to the predetermined target blood pressure value and / or range. In other words, the system can be a closed loop system.

[0027] There may also 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 or mean arterial pressure and / or cerebrospinal fluid pressure (and / or also the spinal cord perfusion pressure). The sensor may also report the pulse rate. The sensor may also be configured and arranged to measure and / or monitor signals, values ​​and / or markers that correlate with spinal cord oxygenation. The at least one sensor portion may be invasive or non-invasive. In other words, the at least one sensor may be at least partially implantable and / or implanted. Alternatively, the at least one sensor may not be implanted and / or not implantable.

[0028] In principle, the target blood pressure values ​​and / or target blood pressure ranges can be predefined by the patient and / or by a medical professional (e.g., a therapist, nurse, physiotherapist, doctor, pharmacist, physician assistant or any other trained operator). It may also be possible that the target blood pressure and / or oxygenation values ​​and / or target blood pressure and / or oxygenation ranges can be changed and / or reset at any time. There may be various target blood pressure values ​​and / or target blood pressure ranges to configure and arrange the system, for example, to be adapted to the patient's circadian rhythm.

[0029] Alternatively, the system may be an open loop system.

[0030] Generally, stimulation may be delivered to the dorsal aspect of the mammalian spinal cord, and may affect dorsal roots, dorsal afferent fibers, and / or intraspinal structures that are directly or indirectly connected to sympathetic ganglion neurons that affect the function being controlled.

[0031] The stimulation may be provided by electrical stimulation. In particular, the stimulation may be provided by a lead comprising one or more electrodes. The lead may be implanted. Alternatively and / or additionally, percutaneous stimulation by the lead is generally also possible.

[0032] Stimulation may be delivered epidurally (by epidural electrical stimulation EES) and / or subdurally.

[0033] The stimulator may be configured to include a lead.

[0034] Due to the complexity of the spinal cord, it is very difficult to deliver epidural and / or subdural stimulation to implanted multi-electrode arrays (leads).

[0035] The leads may be designed and / or configured to allow for targeting of cardiovascular and / or spinal segmental blood pressure hotspots. Cardiovascular and / or blood pressure hotspots may be identified by functional mapping.

[0036] Functional mapping may be understood as follows: To identify the optimal location on the spinal cord that elicits a blood pressure response, a functional mapping procedure may be performed, where each segment of the spinal cord from T5 to L2 will be stimulated by targeting the dorsal roots projecting to these segments, and the blood pressure response to the stimulation may be recorded. Mapping may be performed in an animal model, for example a rat model of spinal cord injury. In doing so, those spinal segments that are optimal for blood pressure control may be identified. The results obtained by the animal model may later be transferred to humans. Mapping may also be performed on humans during surgical interventions using percutaneous leads.

[0037] Also, the density of sympathetic preganglionic neurons in the spinal cord that project to important splanchnic ganglia in the abdomen responsible for blood pressure regulation can be determined to identify optimal stimulation sites.

[0038] Based on the results of mapping and / or identifying the density of sympathetic preganglionic neurons in the spinal cord, the size, configuration and / or shape of the lead may be designed and / or configured.

[0039] In particular, the leads may be designed and / or configured to specifically target the dorsal roots of the T9-L1 spinal segments.

[0040] In particular, the lead may be capable of and configured to stimulate the spinal cord at levels T9-T12, or in other words, the lead may be designed and / or configured to specifically target the dorsal roots of the T9-T12 spinal segments.

[0041] As mentioned above, the leads may be implanted. The leads may be and may be configured to be subdurally and / or epidurally positioned at least partially at or between the levels of vertebrae T9-L1, in particular at least partially below vertebrae T9-L1. For epidural stimulation, the leads may be positioned in the epidural space above the spinal cord. For subdural stimulation, the leads may be positioned in the subdural space. In other words, the shape, dimensions and / or configuration of the leads may be configured in such a manner that the leads may be subdurally and / or epidurally positioned at least partially at or between the levels of vertebrae T9-L1, in particular at least partially below vertebrae T9-L1. In particular, specific markers may be placed on the leads to align the leads to their specific vertebral locations. Generally, diagnostic tools such as computed tomography (CT), x-ray and / or magnetic resonance imaging (MRI) scans may be used to align the positions of the leads to specific vertebral locations.

[0042] The stimulator 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 a lead.

[0043] The stimulation data may include at least a frequency, an amplitude, and a pulse width. The frequency may be 10 Hz to 10 kHz, the amplitude may be 0 to 1 A or 0 to 15 V, and the pulse width may be 1 to 500 μs.

[0044] The stimulator may also be constructed and arranged to deliver at least one burst train stimulation pulse.

[0045] In general, it is possible that a stimulator can deliver two or more bursts.

[0046] A stimulation pulse train, referred to as a burst train stimulation pulse, may be preferred to increase the specificity and comfort of the stimulation. Burst train stimulation may include a series of multiple delivered pulses.

[0047] In particular, the stimulator may be constructed and arranged to deliver at least one burst of a plurality of pulses, preferably between 2 and 5 pulses.

[0048] In particular, burst train stimulation may include a series of 3-5 (or more) pulses delivered at, for example, 200 Hz-700 Hz and repeated at a frequency of, for example, 10-120 Hz.

[0049] The control unit may also comprise an oscillation control module, which may be constructed and arranged to provide an input of low frequency oscillations, in amplitude and / or frequency, between 0.01 Hz and 0.2 Hz.

[0050] In particular, the oscillation control module may be constructed and arranged to provide an input of a low frequency oscillation of 0.1 Hz in amplitude and / or frequency.

[0051] In particular, the oscillation control module can mimic the natural state of an intact sympathetic nervous system: in particular, a low-frequency oscillation overlay is optimized, which originates from the supraspinal structures responsible for blood pressure and / or oxygenation control (i.e., the rostral ventrolateral medulla) by input of the aforementioned low-frequency oscillations in the amplitude or frequency control of the stimulation.

[0052] The control unit may also include a time control module, the time control module constructed and arranged to provide a time delay.

[0053] In particular, the time delay provided by the time control module may be a time delay of 1 to 50 ms.

[0054] In particular, the time delay provided by the time control module may be a time delay of 1 to 4 ms, in particular a time delay of 2 ms.

[0055] Action potentials originate from the rostral ventrolateral medulla and propagate with a specific time delay between the important thoracic segments. In rats, the important thoracic segments may be T11-T12 and T12-T13. In humans, the important thoracic segments may be slightly different, i.e. T9-T10, T10-T11 or T11-T12 or T12-L1.

[0056] In particular, the time delay may be dependent on the segment length.

[0057] In particular, the time delay may be longer for large mammals compared to small mammals.

[0058] In particular, the time delay may be longer in humans compared to rats or mice.

[0059] The time delay can be from 1 to 50 ms.

[0060] However, other measures of time delay are generally possible.

[0061] For rats, the time delay may be 1-4 ms, preferably 2 ms.

[0062] In other words, the time control module can replicate the natural supraspinal sympathetic drive in order to deliver biomimetic stimulation patterns. When coupled with standard stimulation parameters, this may allow for the best control over blood pressure following spinal cord injury to be achieved.

[0063] Alternatively and / or additionally, the stimulator may provide stimulation via optical signals, magnetic signals, optogenetic manipulation, chemogenetic manipulation, stimulation with chemical or pharmacological agents, thermal signals, and the like.

[0064] 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.

[0065] According to the present invention a method is disclosed, characterized in that the method is implemented in a system according to any one of claims 1 to 10.

[0066] In particular, the method may be a method for neuromodulation, in particular for neuromodulation and / or neurostimulation of a mammalian nervous system, comprising at least: - positioning the lead 20; - providing neuromodulation and / or neurostimulation to the spinal cord via said lead 20; - monitoring blood pressure; - comparing the measured blood pressure value with a pre-defined blood pressure target range; - if the comparison indicates that the measured blood pressure is outside of a target blood pressure range, adjusting the neural stimulation until the mammal's blood pressure is within the target blood pressure range; Equipped with The method is constructed and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at spinal levels T9-L1.

[0067] The systems and methods may be used in a closed loop manner taking into account parameters, in particular parameters indicative of the patient's blood pressure, oxygenation (in particular spinal cord oxygenation) and / or perfusion pressure, in particular spinal cord perfusion pressure, and instead of monitoring blood pressure, oxygenation may additionally or alternatively be monitored and compared to a target value.

[0068] It is generally possible that the systems and methods can also be used in an open-loop manner.

[0069] Alternatively and / or additionally, the system may be used to restore any other type of autonomic dysfunction, such as digestive, bladder and bowel control.

[0070] Further details and advantages of the invention are disclosed herein in connection with the drawings. [Brief description of the drawings]

[0071] [Figure 1]FIG. 1 is a schematic overview of an embodiment of a system for neuromodulation and / or neurostimulation according to the invention, in which the method according to the invention can be implemented. [Diagram 2] FIG. 2 shows an example of a patient fitted with the system shown in FIG. [Figure 3-1] FIG. 3a shows an example of a lead for the system shown in FIG. 1, illustrating an embodiment of the implant side of the lead. [Figure 3-2] Figure 3b shows a further example of a transplant side to Figure 3a (rat model) Figure 3c shows a further example of a transplant side to Figure 3a (non-human primate / monkey model). [Figure 3-3] FIG. 3d shows a further example of a transplant side relative to FIG. 3a (human patient). [Figure 4-1] FIG. 4a shows an example of functional mapping results—heat maps show preferential increases in SBP, DBP and MAP at T12 from acute to chronic injury. [Figure 4-2] FIG. 4b shows an example of functional mapping results—quantification of responses at intermediate stages shows a preference for T11-T13 in all measurements. [Figure 4-3] FIG. 4c shows an example of functional mapping results—quantification of the response at T12 over time, which increases with time after injury. [Figure 4-4] FIG. 4d shows functional mapping in non-human primates. [Diagram 5] FIG. 5 shows the activation of specific frequency aspects within the systolic blood pressure signal during orthostatic stimulation in intact and spinal cord injured rats. [Figure 6] FIG. 6 shows the activation of specific frequency aspects within the systolic blood pressure signal using biorelevant stimulation. [Figure 7-1] FIG. 7a is a schematic overview of the activation of sympathetic neurons according to the present invention. [Figure 7-2] Figure 7b is a schematic overview of the mechanism by which EES stabilizes hemodynamics. [Figure 7-3]Figure 7b is a schematic overview of the mechanism by which EES stabilizes hemodynamics. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] FIG. 1 shows a schematic overview of an embodiment of a system 10 for neuromodulation and / or neurostimulation for the treatment of a mammal, according to the present invention, with which the method according to the present invention may be performed.

[0073] The system 10 includes a control unit 12 .

[0074] The control unit 12 is constructed and arranged to provide stimulation data.

[0075] The system 10 further comprises a stimulator 14 .

[0076] The stimulator 14 is constructed and arranged to deliver stimulation pulses.

[0077] The stimulator 14 is configured with a lead 20 .

[0078] In this embodiment, the lead is capable of and configured to provide stimulation to the spinal cord from levels T9 to L1.

[0079] The system 10 also includes a signal processing section 16 .

[0080] The system 10 also includes a real-time monitoring component 18 .

[0081] In this embodiment, the real-time monitoring unit 18 is constructed and arranged to monitor blood pressure.

[0082] In this embodiment, the real-time monitoring unit 18 includes a sensor unit 18a.

[0083] The sensor portion 18a is constructed and arranged to measure and / or monitor the blood pressure of the patient P.

[0084] In alternative embodiments, the system 10 may include two or more control units 12, two or more stimulation units 14, two or more signal processing units 16, and / or two or more real-time monitoring units 18.

[0085] 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.

[0086] In this embodiment, the connections between the control unit 12 and the stimulation unit 14, between the control unit 12 and the processing unit 16, and between the control unit 12 and the real-time monitoring unit 18 are direct and bidirectional connections.

[0087] In this embodiment, the connections between the control unit 12 and the stimulation unit 14, between the control unit 12 and the processing unit 16, and between the control unit 12 and the real-time monitoring unit 18 are established by wireless links WL.

[0088] However, alternatively, cable connections and / or unidirectional and / or indirect connections between the control unit 12 and the stimulation unit 14, between the control unit 12 and the signal processing unit 16, and between the control unit 12 and the real-time monitoring unit 18 may generally also be possible.

[0089] In this embodiment, the stimulator 14 is connected to a signal processor 16 .

[0090] The connection between the stimulator 14 and the signal processor 16 is a direct and bidirectional connection.

[0091] The connection between the stimulator 14 and the signal processor 16 is established by a wireless link WL.

[0092] However, alternatively, cable coupling and / or unidirectional and / or indirect connections between the stimulator unit 14 and the signal processor 16 may generally also be possible.

[0093] In this embodiment, the signal processing unit 16 is connected to a real-time monitoring unit 18 .

[0094] The connection between the signal processing unit 16 and the real-time monitoring unit 18 is a direct and bidirectional connection.

[0095] In this embodiment, the connection between the signal processing unit 16 and the real-time monitoring unit 18 is established by a wireless link WL.

[0096] Alternatively, however, a cable coupling and / or a unidirectional and / or indirect connection between the signal processing unit 16 and the real-time monitoring unit 18 may also generally be possible.

[0097] The real-time monitoring unit 18, particularly the sensor unit 18a of the real-time monitoring unit 18, measures the blood pressure of the patient P.

[0098] Although not shown in the present embodiment, the sensor unit 18a can generally measure and / or monitor systolic and / or diastolic and / or mean arterial pressure.

[0099] Although not shown in the present embodiment, the sensor unit 18a can also report the pulse rate.

[0100] Although not shown in the present embodiment, the at least one sensor unit 18a may be an invasive or non-invasive sensor unit 18a.

[0101] Although not shown in this embodiment, the sensor portion 18a may be at least partially implantable and / or implanted.

[0102] Alternatively, at least one sensor portion 18a may not be implantable and / or may not be implanted.

[0103] The measured blood pressure is communicated from the real-time monitoring unit 18 to the signal processing unit 16 .

[0104] In this embodiment, the measured blood pressure is communicated from the real-time monitoring unit 18 to the signal processing unit 16 in real time.

[0105] In alternative embodiments, the measured blood pressure may be communicated from the real-time monitoring unit 18 to the signal processor 16 in near real-time or with a time delay.

[0106] The signal processor 16 compares the measured blood pressure value with a predetermined blood pressure value and / or a predetermined blood pressure target range.

[0107] If the comparison indicates that the measured blood pressure is outside a predetermined target blood pressure range, the control unit 12 may adapt the stimulation data.

[0108] The stimulator 14 applies stimulation via leads 20 in response to stimulation data provided by the controller 12 .

[0109] Although not shown in this embodiment, sensor portion 18a may additionally and / or alternatively measure and / or monitor perfusion pressure, in particular spinal cord perfusion pressure.

[0110] Although not shown in this embodiment, the measured spinal cord perfusion pressure can be communicated from the real-time monitoring unit 18 to the signal processing unit 16.

[0111] Although not shown in this embodiment, the measured spinal cord perfusion pressure can be communicated in real time from the real-time monitoring unit 18 to the signal processing unit 16.

[0112] Although not shown in this embodiment, the measured spinal cord perfusion pressure may be communicated from the real-time monitoring unit 18 to the signal processing unit 16 in near real-time or with a time delay.

[0113] Although not shown in this embodiment, the signal processor 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.

[0114] Although not shown in this embodiment, the control unit 12 may adapt the stimulation data if the comparison indicates that the measured spinal cord perfusion pressure is outside a predetermined spinal cord perfusion pressure target value and / or a predetermined spinal cord perfusion pressure target range.

[0115] In this embodiment, the stimulation data includes at least frequency, amplitude and pulse width.

[0116] In this embodiment, the frequency may be 10 Hz to 10 kHz, the amplitude may be 0 to 1 A or 0 to 15 V, and the pulse width may be 1 to 500 μs.

[0117] Although not shown in this embodiment, the stimulator 14 may be constructed and arranged to deliver at least one burst train stimulation pulse.

[0118] Although not shown in FIG. 1, it may generally be possible for stimulator 14 to deliver more than one burst.

[0119] In particular, the stimulator 14 may be constructed and arranged to deliver at least one burst of a plurality of pulses, preferably between 2 and 5 pulses.

[0120] Although not shown in FIG. 1, a train of stimulation pulses called burst train stimulation may be preferred for increased specificity and comfort.

[0121] In particular, although not shown in FIG. 1, burst train stimulation may comprise a series of 3-5 (or more) pulses delivered at, for example, 200 Hz-700 Hz and repeated at a frequency of, for example, 10-120 Hz.

[0122] Although not shown in the drawings, in this embodiment, the lead wire 20 is capable of providing stimulation to the spinal cord at levels T9 to T12 and is configured to do so.

[0123] Although not shown in this embodiment, the lead 20 is capable of and configured to be positioned at least partially at and / or between the levels of the vertebrae T9-L1 of the patient P, and in particular subdurally and / or extradurally at least partially below the vertebrae T9-L1.

[0124] Although not shown in FIG. 1, the control unit 12 may include an oscillation control module.

[0125] In general terms, the oscillation control module may provide an input of a low frequency oscillation between 0.01 Hz and 0.2 Hz in amplitude.

[0126] In particular, the oscillation control module may provide an input of a low frequency oscillation of 0.1 Hz in amplitude.

[0127] Alternatively and / or additionally, the oscillation control module may provide an input for a low frequency oscillation in the frequency range of 0.01 Hz to 0.2 Hz.

[0128] In particular, alternatively and / or additionally, the oscillation control module may provide an input of a low frequency oscillation at a frequency of 0.1 Hz.

[0129] Although not shown in FIG. 1, the control unit 12 may include a time control module.

[0130] Generally speaking, a time control module may provide a time delay.

[0131] Generally, the time delay may depend on the segment length.

[0132] Generally speaking, the time delay may be longer for large mammals compared to small mammals.

[0133] Generally speaking, the time delay may be longer in humans compared to rats or mice.

[0134] As an overview, the time delay provided by the time control module may be a time delay of 1 to 50 ms.

[0135] As an outline, the time delay provided by the time control module may be a time delay of 1 to 4 ms, in particular a time delay of 2 ms.

[0136] However, all other time delays provided by the time control module may generally be possible.

[0137] According to the present invention, the use of the system 10 or the use of neuromodulation is disclosed.

[0138] The use of and functionality of the system 10 may be described as follows: Use of a system 10 for neuromodulation and / or neurostimulation according to any one of claims 1 to 10 for treating a mammal.

[0139] The methods performed by and functions of system 10 may be described as follows: A method for neuromodulation and / or neurostimulation of a mammalian nervous system includes: - positioning the lead 20; - providing neuromodulation and / or neurostimulation to the spinal cord via a lead 20; - monitoring blood pressure; - comparing the measured blood pressure value with a pre-defined blood pressure target range; - if the comparison indicates that the measured blood pressure is outside of a target blood pressure range, adjusting the neural stimulation until the mammal's blood pressure is within the target blood pressure range. A method comprising at least The method is constructed and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at spinal levels T9-L1.

[0140] In particular, the method may be arranged to position the lead at least partially at and / or between the levels of vertebrae T9-L1, in particular subdurally and / or epidurally at least partially below vertebrae T9-L1.

[0141] In particular, the method may be constructed and arranged to provide neuromodulation and / or neurostimulation to the spinal cord at least at spinal levels T9-T12.

[0142] The method may provide neuromodulation and / or neurostimulation to the spinal cord at frequencies between 10 Hz and 10 kHz, amplitudes between 0 and 1 A or 0 and 15 V, and pulse widths between 1 and 500 μs.

[0143] Generally, stimulation may be provided to the spinal cord with at least one burst train stimulation pulse.

[0144] Generally, stimulation may be applied to the spinal cord in at least one burst of multiple pulses, preferably 2-5 pulses.

[0145] In summary, the stimulus may be provided with a control input that oscillates at low frequencies between 0.01 Hz and 0.2 Hz in amplitude and / or frequency.

[0146] In particular, the stimulus may be provided with a control input that oscillates at a low frequency of 0.1 Hz in amplitude and / or frequency.

[0147] Additionally, the stimulus may be provided with a control input that includes a time delay.

[0148] Generally speaking, the time delay may be longer in humans compared to rats or mice.

[0149] Generally, the time delay may depend on the segment length.

[0150] In particular, the stimulus may be presented with a control input that includes a time delay of 1-50 ms.

[0151] In particular, the stimulus may be presented with a control input that includes a time delay of 1-4 ms.

[0152] In particular, the stimulus may be presented with a control input that includes a time delay of 2 ms.

[0153] Of note, the present system 10 and methods may also be applied to the treatment of mammals suffering from neurological conditions other than SCI, including, but not limited to, stroke, multiple sclerosis, autonomic neuropathy, autonomic neuropathies, and cancers of neurological tissue that impair the operation of descending sympathetic pathways that normally facilitate control of autonomic function.

[0154] Although not shown in FIG. 1, the systems and methods may also be applied to the treatment of any autonomic dysfunction other than impaired blood pressure control, including, but not limited to, heart rate, digestive function, bladder control and / or bowel control.

[0155] FIG. 2 illustrates an example of a patient fitted with the system 10 shown in FIG.

[0156] A patient P is fitted with a system 10 as disclosed in FIG.

[0157] In this embodiment, the real-time monitoring unit 18 includes a sensor unit 18a.

[0158] In this embodiment, the sensor unit 18a includes a sensor.

[0159] The sensor monitors the patient P's blood pressure.

[0160] In this embodiment, the sensors monitor the patient P's systolic and diastolic blood pressure.

[0161] In this embodiment, the sensor is a non-invasive sensor.

[0162] In this embodiment, the sensor is a wrist blood pressure monitor system.

[0163] In this embodiment, the sensor is a digital blood pressure monitor system.

[0164] In an alternative embodiment, the sensor may be an analog blood pressure monitor system.

[0165] In this embodiment, the sensor continuously monitors blood pressure in real time and provides blood pressure data to the signal processor 16 in real time.

[0166] However, it is generally possible for the sensor to measure blood pressure at predefined time intervals.

[0167] In alternative embodiments, the sensor may be or comprise other embodiments of a blood pressure monitor system, including but not limited to a cuff, an arterial pressure sensor, an optical biometric sensor, an upper arm blood pressure monitor system, a finger blood pressure monitor system, or any other type of non-implantable blood pressure monitor system, as well as any type of implantable and / or implantable blood pressure monitor system.

[0168] 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.

[0169] In an alternative embodiment, the sensor may additionally measure and / or monitor the patient P's pulse rate.

[0170] In an alternative embodiment, the sensor may be or may include the arterial line.

[0171] In an alternative embodiment, the sensor may be or may include an arterial line in a hospital.

[0172] In general, the sensor unit 18a may include two or more sensors and / or at least one sensor base station.

[0173] FIG. 3a illustrates an example lead 20 of the system 10 shown in FIG. 1 and an embodiment of the implant side of the lead 20 according to the present invention.

[0174] In this embodiment, the dimensions of the lead 20 are designed to completely target the dorsal roots of the T9-L1 spinal segments.

[0175] To identify the optimal location on the spinal cord to elicit a blood pressure response, for example, a functional mapping procedure can be performed in an animal model, for example, an animal model of SCI.

[0176] In other words, functional mapping procedures can be performed, for example, in an animal model, for example an animal model of SCI, to identify optimal locations for providing stimulation to the spinal cord.

[0177] In other words, a functional mapping procedure may be performed, for example, in an animal model, for example an animal model of SCI, to identify optimal locations for positioning the lead 20 to provide stimulation to the spinal cord.

[0178] As can be further derived from Figures 3b, 3c and 3d, the implantation sites are so-called hot spots and are conserved across species. FIG. 3b shows a further example of the graft side relative to FIG. 3a (rat model). FIG. 3c shows a further example of a transplanted side to FIG. 3a (non-human primate / monkey model). FIG. 3d shows a further example of a transplant side relative to FIG. 3a (human patient).

[0179] In these instances, a functional mapping procedure was performed in a rat model of SCI, as described here, to identify the optimal spinal location for eliciting a blood pressure response. In principle, in a rat model of SCI, each spinal cord segment from T5 to L2 was stimulated and blood pressure responses to unipolar 50 Hz stimulation were recorded.

[0180] In this example, T11–T13 were found to be the optimal segments to stimulate in rodents, with the peak response occurring during stimulation of T12 (see Figure 4a).

[0181] In particular, the systolic blood pressure SBP, the diastolic blood pressure DBP or the mean arterial blood pressure MAB were measured.

[0182] Notably, this response was consistent across different time points after injury, including 1 hour (acute phase), 5 days (subacute phase), 2 weeks (intermediate phase) and 1 month (chronic phase).

[0183] It should be noted that a similar approach can be implemented to obtain a lead 20 that is designed to completely target the dorsal roots of human spinal segments T9-L1.

[0184] However, in a similar approach performed in humans, stimulation parameters may vary.

[0185] FIG. 4b shows a bar graph diagram illustrating the quantification of responses at the intermediate stages shown in FIG. 4a, showing a preference for T11-T13 across all measurements.

[0186] FIG. 4c shows a bar graph diagram illustrating quantification of the response at T12 over time after injury, including 1 hour (acute phase), 5 days (subacute phase), 2 weeks (intermediate phase) and 1 month (chronic phase), demonstrating an increase with time after injury.

[0187] In a next step, not shown, we identified the density of sympathetic preganglionic neurons in the spinal cord that project to important abdominal splanchnic ganglia responsible for blood pressure regulation.

[0188] Although not shown, we also found that the density of these ganglion-projecting sympathetic preganglionic neurons peaked at T12, and that there was a strong linear correlation between the density of sympathetic preganglionic neurons and the functional blood pressure response to stimulation.

[0189] Although not shown, two converging lines of evidence were then used to confirm that this stimulation results in activation of the visceral ganglia.

[0190] First, the spinal cord was stimulated at T12 for 30 min and active neurons were identified within the splanchnic ganglia using classical immunohistochemistry (using the immediate early gene Fos, the Fos proto-oncogene, and the AP-1 transcription factor subunit).

[0191] Compared with unstimulated animals, there was a significant increase in the number of Fos-expressing neurons, and these neurons synthesized adrenaline (as confirmed by the presence of protein tyrosine hydroxylase), confirming their role in blood pressure regulation.

[0192] Using optogenetic techniques, they found that inhibiting the depolarization of these same neurons blunted their response to stimulation.

[0193] 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 levels.

[0194] Additionally, the exact length of the T11-T13 segments was confirmed using ex-vivo anatomical specimens.

[0195] A spinal implant of a biocompatible electronic lead 20 was then designed with the precise dimensions required to stimulate T11-T13, and the lead 20 was placed just below the T9-T12 vertebrae (see FIG. 3).

[0196] Therefore, this design of lead 20 can be easily scaled to any animal or human model using MRI techniques and computer modeling.

[0197] In other words, the design of the lead 20 is based on important anatomical features (using the rat model as the animal model). -Identification of functional cardiovascular "hot spots" - see Figure 4a-c (T11-T13) -the discovery that these "cardiovascular hot spots" are localized by the segmental density of sympathetic preganglionic neurons; - Completion of CT and MRI scans of the spinal cord of the same rat to align the features of lead 20 to the dorsal root of the T11-T13 segments (see Figure 3 for exact dimensions); - Placing specific markers on the lead 20 to align the lead 20 to a particular vertebra; Therefore, the dimensions of lead 20 (see Figure 3) are designed to perfectly target the dorsal roots of the T11-T13 spinal segments of the rat, which have been identified as critical for the maintenance of blood pressure using epidural electrical stimulation.

[0198] In humans, this may correspond to the region T9-T12.

[0199] FIG. 4d shows functional mapping in non-human primates, demonstrating conservation of the hotspots (see also FIGS. 3a-3d).

[0200] FIG. 5 shows the activation of specific frequency aspects within the systolic blood pressure signal during orthostatic stimulation in intact and SCI rats.

[0201] The heat indicates the frequency power in a given wavelet band.

[0202] The dotted line indicates the onset of the orthostatic stimulus.

[0203] 30 seconds of data is shown.

[0204] A drop in power is observed within a range of about 0.1 Hz.

[0205] Stimulation paradigms can be designed that mimic the natural state of an intact sympathetic nervous system.

[0206] Specifically, in the intact system, a frequency oscillation overlay was optimized that could elicit a low-frequency oscillation of 0.1 Hz from supraspinal / spinal structures responsible for blood pressure control (i.e., rostral ventrolateral medulla / spinal cord).

[0207] Although not shown, using electrophysiological experiments, we determined that action potentials originating from the rostral ventrolateral medulla propagated with a time delay of 2 ms between T11-T12 and T12-T13 in rats.

[0208] In humans, this may correspond to the areas T9-T11 and T11-T12.

[0209] A biomimetic stimulation paradigm is described that recapitulates the natural supraspinal sympathetic drive and, when coupled with a range of standard parameters (frequency from 10 Hz to 10 kHz, amplitude from 0 to 1 A or 0 to 15 V, pulse width from 1 to 500 μs), achieves a biologically relevant BIO for blood pressure control after spinal cord injury.

[0210] It is confirmed that this BIO paradigm recapitulates the natural dynamics of the autonomic nervous system using wavelet decomposition, and an increase in frequency power within the systolic blood pressure signal in response to stimulus activation is observed.

[0211] FIG. 6 shows the activation of intrinsic frequency aspects within the systolic blood pressure signal using biorelevant BIO-stimulation.

[0212] The heat indicates the frequency power in a given wavelet band.

[0213] The dotted line indicates the onset of stimulation.

[0214] 30 seconds of data is shown.

[0215] A power increase was observed within a range of approximately 0.1 Hz, confirming the repetition of the natural rhythm seen in the intact state.

[0216] FIG. 7a shows a schematic overview of sympathetic activation according to the present invention.

[0217] In particular, it shows activation of sympathetic neural circuits in response to stimulation.

[0218] In particular, activation of sympathetic neural circuits in response to stimulation by the system 10 and / or methods of the present invention is shown.

[0219] The impulse enters through the dorsal root of the dorsal root ganglion DRG and activates the sympathetic preganglionic neurons SPN, which then activate the splanchnic ganglion SG, which controls blood pressure.

[0220] Figure 7b shows a schematic overview of the mechanism by which EES stabilizes hemodynamics.

[0221] Part a shows the intraspinal density of neurons traced retrogradely from the splanchnic ganglion, the amplitude of the blood pressure pressor response to TESS applied to each segment, and the agreement between the anatomical and functional data sets. Part b shows a hypothetical circuit that is activated by TESS and causes vascular constriction. Part c shows color-coded potentials following TESS applied to the spinal cord, suggesting exclusive activation of afferent fibers. The scheme illustrates dorsal root rhizotomy. The bar plot shows blood pressure pressor responses to targeted epidural spinal cord stimulation (TESS) before and after rhizotomy (n = 5, paired one-tailed t-test, t = 4.36, P = 0.006). Part d shows transsynaptic retrograde tracing revealing interneurons connected to the visceral ganglion. Part e shows interneurons that express the excitatory marker Slc17a6 and receive vGlut1 synapses from large diameter proprioceptive afferents. Part f shows Fos expression in THON neurons of the splanchnic ganglion after control and TESS. Bar plots show the percentage of FOSON neurons (n=5, unpaired one-tailed t-test; t=13.96, P=4.99e-05). Part g shows that ablation of splanchnic efferent nerves blunted the blood pressure pressor response (n=4, unpaired one-tailed t-test; t=-4.54, P=0.0099). Part h shows that blockade of α1 receptors with prazosin blunted the blood pressure pressor response (n=5, unpaired one-tailed t-test; t=-5.59, P=0.0007). [Explanation of symbols]

[0222] 10. System 12 Control section 14 Stimulation part 16 Signal Processing Section 18 Real-time Monitoring Department 18a Sensor section 20 Lead Wire BIO Biological related stimulation CT Computed Tomography DRG Dorsal root ganglion MRI Magnetic Resonance Imaging P patient SCI Spinal Cord Injury SPN Sympathetic preganglionic neurons SG splanchnic ganglion WL Radio Link DBP Diastolic Blood Pressure MAP Mean Arterial Pressure SBP Systolic blood pressure LX Lumbar level X L1 Lumbar level 1 TX Thoracic spinal segment level X or thoracic level X T6 Thoracic spinal segment level 6 or thoracic level 6 T7 Thoracic spinal level 7 or thoracic level 7 T8 Thoracic spinal segment level 8 or thoracic level 8 T9 Thoracic spinal segment level 9 or thoracic level 9 T10 Thoracic spinal segment level 10 or thoracic level 10 T11 Thoracic spinal segment level 11 or thoracic level 11 T12 Thoracic spinal segment level 12 or thoracic level 12 T13 Thoracic spinal level 13 or thoracic level 12

Claims

1. A system (10) for neuromodulation and / or neurostimulation for the treatment of a mammal, comprising: At least one control unit (12) constructed and arranged to provide stimulation data; At least one stimulator (14) constructed and arranged to deliver stimulation pulses; At least one real-time monitoring unit (18); At least one signal processing unit (16); At least The system (10) is constructed and arranged for control of blood pressure, and the stimulation unit (14) is configured with a lead (20) that is sized and designed to provide stimulation to a specific location of the spinal cord at levels T9-T12.

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

3. 3. The system (10) of claim 1 or 2, characterized in that the stimulation data includes at least a frequency, an amplitude and a pulse width, the frequency being between 10 Hz and 10 kHz, the amplitude being between 0 and 1 A or between 0 and 15 V, and the pulse width being between 1 and 500 μs.

4. The system (10) according to any one of claims 1 to 3, characterized in that the control unit (12) comprises an oscillation control module, the oscillation control module constructed and arranged to provide an input of a low frequency oscillation in amplitude and / or frequency between 0.01 Hz and 0.2 Hz.

5. The system (10) according to any one of claims 1 to 4, characterized in that the stimulator (14) is constructed and arranged to deliver at least one burst train stimulation pulse.

6. The system (10) of claim 5, wherein the stimulator (14) is constructed and arranged to deliver at least one burst of a plurality of pulses, preferably 2 to 5 pulses.

7. The system (10) of claim 4, characterized in that the oscillation control module is constructed and arranged to provide an input of a low frequency oscillation of 0.1 Hz in amplitude and / or frequency.

8. The system (10) of any one of claims 1 to 7, wherein the control unit (12) comprises a time control module, the time control module constructed and arranged to provide a time delay.

9. The system (10) of claim 8, wherein the time delay provided by the time control module is a time delay between 1 and 50 ms.

Images