SYSTEM AND METHOD FOR CLOSED LOOP CONTROL OF AUTONOMIC FUNCTION

Abstract

A neuromodulation system, especially a neurostimulation system, for treating a patient, especially for enhancing at least one autonomous function such as blood circulation and/or respiration, wherein the system comprises: at least one signal input module, which is configured to receive at least one or more signals being indicative for blood circulation, especially being indicative for pulse and/or blood pressure, at least one control module, wherein the control module is connected to the signal input module, wherein the control module is configured to adapt the neurostimulation provided by the neuromodulation system on the basis of the signal(s) received by the signal input module.

Claims

1. A neuromodulation system, including a neurostimulation system, for treating a patient, wherein the system comprises at least one signal input module, which is configured to receive at least one or more signals being indicative for blood circulation, at least one control module, wherein the control module is connected to the signal input module, wherein the control module is configured to adapt the neurostimulation provided by the neuromodulation system on the basis of the signal(s) received by the signal input module.

2. The neuromodulation system according to claim 1, wherein the neuromodulation system further comprises at least one stimulation unit and/or at least one real-time monitoring unit, wherein the at least one real-time monitoring unit comprises at least one sensor.

3. The neuromodulation system according to claim 1, wherein the signals being indicative for blood circulation are signals indicative for oxygenation and/or blood pressure and/or cumulative firing rates from at least one brainstem control area.

4. The neuromodulation system according to claim 1, wherein the at least one signal input module comprises an input switch module, wherein the input switch module is configured to switch between signals indicative for blood pressure and cumulative firing rates from at least one brainstem control area.

5. The neuromodulation system according to one of claim 1, wherein the signal input module is configured to receive baseline signals, wherein the baseline signals define at least one target value.

6. The neuromodulation system according to claim 1, wherein the control module is configured to detect differences between the at least one target value and at least one or more signals indicative for blood circulation, wherein the control module is further configured and arranged to adapt neurostimulation based on the differences between the at least one target value and at least one or more signals indicative for blood circulation.

7. The neuromodulation system according to claim 1, wherein the control module comprises a linear proportional control module, wherein the linear proportional control module is configured to modify at least one of amplitude and frequency of a stimulation paradigm in response to the at least one or more signals indicative for blood circulation with a coefficient β that controls the linear proportion with which the amplitude or frequency changes.

8. The neuromodulation system according to claim 1, wherein the control module comprises a forward module, wherein the forward module is configured and arranged to take into account at least one predictive effect of stimulation to adjust coefficient β with a specified time window.

9. The neuromodulation system according to claim 1, wherein the control module is configured to comprise stimulation paradigm control parameters, including minimal or maximal bounds on the stimulation paradigm.

10. The neuromodulation system according to claim 1, wherein the signal input module is or comprises at least one sensing element configured to sense a signal indicative for a physiological parameter of a patient, at least one spatial mapping module configured to link spatial electrode stimulation configurations (Config) targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect, at least one parameter mapping module configured to prepare stimulation parameters for the control module based on input received from the sensing element and/or the spatial mapping module.

11. The system according to claim 10, wherein the system comprises at least one stimulation element comprising at least one electrode array A comprising multiple electrodes E.

12. The system according to claim 10, wherein the system comprises at least one temporal mapping module configured to link temporal electrode stimulation configurations to at least one physiological effect.

13. The system according to claim 11, wherein the control module is configured to identify a target value for autonomic function based on a signal provided by the sensing element.

14. The neuromodulation system according to claim 11, wherein the spatial mapping module isolates key electrodes E based on anatomical location of the afferent fibers in the dorsal roots and a learning procedure initiated at these electrodes E to optimize the configuration of the surrounding electrodes E.

15. The neuromodulation system according to claim 10, wherein the stimulation parameters comprise at least frequency, amplitude and pulse width, wherein the frequency is 10 Hz-10 kHz, the amplitude is 0-1 A or 0-15V and the pulse width is 1-500 μs.

16. The neuromodulation system according to claim 10, wherein the spatial mapping module is configured to perform a reinforcement learning procedure, wherein the reinforcement learning procedure is part of the process to link spatial electrode stimulation configurations (Config) targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect.

17. The neuromodulation system according to claim 10, wherein the spatial mapping module is configured to perform a spatial mapping phase for identifying a suitable electrode configuration (Config) in terms of selected electrodes E and their spatial arrangement in a first step and a parameter mapping phase for adjusting stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

18. The neuromodulation system according to claim 10, wherein the physiological parameter is at least one of oxygenation, blood pressure of the patient, spinal cord perfusion pressure of the patient, posture of the patient and/or position of the patient.

19. Use of a neurostimulation system according to claim 1 for treating a patient, including for enhancing at least one autonomous function such a blood circulation and/or respiration.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0101] Further details of the present disclosure shall now be disclosed in connection with the drawings.

[0102] It is shown in

[0103] FIG. 1 a schematical overview of an embodiment of the system for neuromodulation and/or neurostimulation according to the present disclosure, with which the method according to the present disclosure can be performed;

[0104] FIG. 2 a schematical overview of a further embodiment of the system 110 for neuromodulation and/or neurostimulation, for the treatment of a patient, according to the present disclosure, with which the method according to the present disclosure can be performed;

[0105] FIG. 3 an example of the bottom up understanding of the sympathetic circuitry within the spinal cord;

[0106] FIG. 4a a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation;

[0107] FIG. 4b a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation in a non-human primate;

[0108] FIG. 4c a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation in a human patient;

[0109] FIG. 5a an example of closed-loop control of blood pressure according to the present disclosure;

[0110] FIG. 5b an example of closed-loop control of blood pressure according to the present disclosure as shown FIG. 5a, here with Acute and Chronic SCI;

[0111] FIG. 5c an example of closed-loop control of blood pressure according to the present disclosure in non-human primates;

[0112] FIG. 5d an example of closed-loop control of blood pressure according to the present disclosure in a human patient;

[0113] FIG. 6a a schematical overview of the activation of sympathetic neurons;

[0114] FIG. 6b a schematical overview of mechanisms, by which EES stabilizes hemodynamics;

[0115] FIG. 7 a schematical overview of an embodiment of the system for neuromodulation and/or neurostimulation according to the present disclosure, with which the method according to the present disclosure can be performed;

[0116] FIG. 8a a graph with a series of 24 spatial electrode configurations Config and the immediate blood pressure response of a patient equipped with the system disclosed in FIG. 7;

[0117] FIG. 8b a graph of two selected spatial electrode configurations Config disclosed in FIG. 8a and the immediate blood pressure response of a patient equipped with the system 10 disclosed in FIG. 7;

[0118] FIG. 8c a schematical overview of electrode arrays A with electrode configurations Config according to FIG. 8b;

[0119] FIG. 8d a further overview of the stimulation effect on blood pressure;

[0120] FIG. 9 shows embodiments, where the stimulus changing blood pressure is constant or variable;

[0121] FIG. 10 shows a blood pressure collapse, which is treated and rescued by the system according to the present disclosure.

DETAILED DESCRIPTION

[0122] FIG. 1 shows a schematical overview of an embodiment of the system 10 for neuromodulation and/or neurostimulation, for the treatment of a patient, according to the present disclosure, with which the method according to the present disclosure can be performed.

[0123] In this embodiment, the system 10 is configured or treating a patient, especially for enhancing at least one autonomous function such as blood circulation and/or respiration.

[0124] In this embodiment, the system 10 is configured for treating a patient, especially for enhancing blood pressure function.

[0125] Alternatively, and/or additionally, the system 10 could be configured for treating a patient, especially for enhancing any type of autonomous function.

[0126] In this embodiment, the system 10 comprises a signal input module 12.

[0127] It is generally possible that the signal input module is configured to receive at least one or more signals being indicative for blood circulation, especially being indicative for pulse and/or blood pressure and/or oxygenation.

[0128] In this embodiment, the signal input module 12 is configured to receive at least one or more signals being indicative for blood pressure.

[0129] It is generally possible that the signal input module 12 is configured to receive additionally and/or alternatively at least one or more signals being indicative for pulse.

[0130] In this embodiment, the system 10 further comprises a control module 14.

[0131] The control module 14 is connected to the signal input module 12.

[0132] In this embodiment, the connection between the control module 14 and the signal input module 12 is a direct and bidirectional connection.

[0133] In general, also an indirect and/or unidirectional connection would be generally possible.

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

[0135] In general, also cable-bound connection would be generally possible.

[0136] In this embodiment, the control module 12 is configured to adapt neurostimulation provided by the neurostimulation system 10 on the basis of the signals received by the signal input module 12.

[0137] Not shown in FIG. 1 is that the at least one or more signals being indicative for blood pressure could comprise at least one of diastolic blood pressure, systolic blood pressure, diastolic blood pressure and a systolic blood pressure, mean arterial pressure, blended blood pressure value or the like.

[0138] Not shown in FIG. 1 is that the at least one or more signals being indicative for blood circulation could comprise 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 of importance. Further, also the signal can be related to or indicative for oxygenation.

[0139] FIG. 2 shows a schematical overview of a further embodiment of the system 110 for neuromodulation and/or neurostimulation, for the treatment of a patient, according to the present disclosure, with which the method according to the present disclosure can be performed.

[0140] The system 110 comprises the structural and functional features as disclosed for neuromodulation system 10 in FIG. 1.

[0141] The corresponding references are indicated as 100+x (e.g. input module 112).

[0142] In this embodiment, the system 110 is configured or treating a patient, especially for enhancing at least one autonomous function of a patient.

[0143] In this embodiment, the system 110 is configured for treating a patient, especially for enhancing blood circulation function of a patient.

[0144] In this embodiment, the system 110 is configured for treating a patient, especially for enhancing blood pressure function of a patient.

[0145] Alternatively, and/or additionally, the system 110 could be configured for treating a patient, especially for enhancing any type of autonomous function of a patient.

[0146] The system 110 comprises a control unit 116.

[0147] In this embodiment, the control unit 116 comprises a signal input module 112 and a control module 114, cf. signal input module 12 and control module 14 as disclosed in FIG. 1.

[0148] The system 110 also comprises a real-time monitoring unit 118.

[0149] In this embodiment, the real-time monitoring unit 118 is configured and arranged to monitor blood pressure.

[0150] Not shown in this embodiment is that the real-time monitoring unit 118 comprises a sensor.

[0151] Not shown in this embodiment is that the sensor is configured and arranged to measure and/or monitor blood pressure of a patient P.

[0152] Further, the system 110 comprises a stimulation unit 120.

[0153] The stimulation unit 120 is configured and arranged to provide stimulation.

[0154] Not shown in FIG. 2 is that stimulation is provided by electrical stimulation.

[0155] Not shown in FIG. 2 is that the stimulation unit 120 is constructed to comprise a lead.

[0156] In particular, stimulation is provided by a lead comprising one or multiple electrodes.

[0157] Not shown in FIG. 2 is that the lead is implanted.

[0158] Not shown in FIG. 2 is that alternatively, and/or additionally, transcutaneous stimulation by a lead could generally also be possible.

[0159] Not shown in FIG. 2 is that autonomic-optimized stimulation could be generally possible.

[0160] Not shown in FIG. 2 is that stimulation could be delivered epidurally (by epidural electrical stimulation, EES) and/or subdurally.

[0161] Not shown in FIG. 2 is that the stimulation unit 120 comprises a pulse generator, in particular an implantable pulse generator (IPG).

[0162] Not shown in FIG. 2 is that the IPG is connected to the lead.

[0163] Not shown in FIG. 2 is that in general, stimulation could be delivered to the dorsal aspect of the spinal cord of a mammal.

[0164] Not shown in FIG. 2 is that in general, stimulation could be applied with stimulation parameters comprising at least frequency, amplitude and pulse width, wherein the frequency could be 10 Hz-10 kHz, the amplitude could be 0-1 A or 0-15V and the pulse width could be 1-500 μs.

[0165] Not shown in FIG. 2 is that in general, stimulation could be applied by burst train stimulation.

[0166] Pulse trains called burst train stimulation could be used to increase the specificity and comfort.

[0167] Burst train stimulation could comprise a series of several pulses, e.g. 3 to 5 pulses delivered at 200 Hz to 700 Hz, repeated at the frequency 10-120 Hz.

[0168] In this embodiment, the real-time monitoring unit 118 is configured and arranged to monitor blood pressure.

[0169] In this embodiment, the real-time monitoring unit 118 comprises a single sensor.

[0170] In an alternative embodiment, the real-time monitoring unit 118 could comprise more than one sensor.

[0171] In an alternative embodiment, the real-time monitoring unit 118 could comprise a sensor network.

[0172] The sensor is configured and arranged to measure and/or monitor blood pressure of a patient.

[0173] In an alternative embodiment, the system 110 may comprise more than one control unit 116 and/or more than one stimulation unit 120 and/or more than one real-time monitoring unit 180.

[0174] In this embodiment, the control unit 116 is connected to the stimulation unit 120 and the real-time monitoring unit 118.

[0175] In this embodiment, the connection between the control unit 116 and the stimulation unit 120 and the control unit 116 and the real-time monitoring unit 118 is a direct and bidirectional connection.

[0176] In this embodiment, the connection between the control unit 116 and the stimulation unit 120, the control unit 116 and the real-time monitoring unit 118 is established by a wireless link.

[0177] However, alternatively, also a cable bound and/or unidirectional and/or indirect connection between the control unit 116 and the stimulation unit 120 and the control unit 116 and the real-time monitoring unit 118 could be generally possible.

[0178] In this embodiment, the stimulation unit 120 is connected to the real-time monitoring unit 118.

[0179] The connection between the stimulation unit 120 and the real-time monitoring unit 118 is a direct and bidirectional connection.

[0180] The connection between the stimulation unit 120 and the real-time monitoring unit 118 is established by a wireless link.

[0181] However, alternatively, also a cable bound and/or unidirectional and/or indirect connection between the stimulation unit 120 and the real-time monitoring unit 118 could be generally possible.

[0182] The real-time monitoring unit 118, in particular the sensor of the real-time monitoring unit 180 measures blood pressure of the patient.

[0183] Not shown in this embodiment is that the sensor could generally measure and/or monitor systolic and/or diastolic and/or mean arterial pressure.

[0184] Not shown in this embodiment is that a further sensor could additionally and/or alternatively measure cumulative firing rates from a brainstem control area.

[0185] Not shown in this embodiment is that a further sensor could additionally and/or alternatively measure cumulative firing rates from the ventrolateral medulla.

[0186] In other words, the signals indicative for blood circulation could be signals indicative for blood pressure and/or cumulative firing rates from at least one brainstem control area, especially but. Not limited to firing rates from the rostral ventrolateral medulla.

[0187] Not shown in this embodiment is that the sensor could also report pulse rate.

[0188] Not shown in this embodiment is that the at least one sensor may be an invasive or non-invasive sensor.

[0189] Not shown in this embodiment is that the sensor could be at least partially implantable and/or implanted.

[0190] Alternatively, the at least one sensor could be not implantable and/or not implanted.

[0191] The measured blood pressure is communicated from the real-time monitoring unit 118 to the signal input module 112.

[0192] Not shown in FIG. 2 is that the signal input module 112 could comprise an input switch module, wherein the input switch module could be configured to switch between signals indicative for blood pressure and cumulative firing rates from at least one brainstem control area, especially but not limited to firing rates from the rostral ventrolateral medulla.

[0193] Not shown in FIG. 2 is that the signal input module 112 could be configured to receive baseline signals, wherein the baseline signals define at least one target value.

[0194] Not shown in FIG. 2 is that the control module 114 could be configured to detect differences between the at least one target value and at least one or more signals indicative for blood circulation, wherein the control module 114 could be further configured and arranged to adapt neurostimulation based on the differences between the at least one target value and at least one or more signals indicative for blood circulation.

[0195] Not shown in FIG. 2 is that after recording a baseline, i.e., a target pressure, i.e. a target value, a perturbation signal could be provided to the patient.

[0196] The perturbation signal could be provided in the form of negative pressure, a drug, or a tilt-test.

[0197] However, any other form of perturbation signal could be generally possible.

[0198] In this embodiment, the control module 114 could detect the change in blood pressure.

[0199] In particular, the control module 114 could detect the change in blood pressure using a moveable parameter to increase or decrease sensitivity.

[0200] In this embodiment, the control module 114 could implement a controlled increase in stimulation to the stimulation unit 120 in order to increase blood pressure.

[0201] Not shown in this embodiment is that the control module 114 could comprise a linear proportional control module, wherein the linear proportional control module could be configured to modify at least one of amplitude and frequency of a stimulation paradigm in response to the at least one or more signals indicative for blood circulation with a coefficient β that controls the linear proportion with which the amplitude or frequency changes.

[0202] Further not shown in FIG. 2 is that the control module could comprise a forward module, wherein the forward module is configured and arranged to take into account at least one predictive effect of stimulation to adjust coefficient β with a specified time window.

[0203] Not shown in FIG. 2 is that it is generally possible that blood pressure responds linearly or almost linearly to changes in the amplitude of stimulation.

[0204] Also not shown in FIG. 2 is that the control module 114 could be configured to comprise stimulation paradigm control parameters, especially minimal or maximal bounds on the stimulation paradigm.

[0205] Not shown in FIG. 2 is that it is generally possible that the system 110 is applied to any mammal suffering from SCI.

[0206] According to the present disclosure the use of a system 10, 110 for neuromodulation is disclosed.

[0207] The use of the system 10, 110 and functionality of the system 10, f110 can be described as follows:

[0208] Use of a neurostimulation system 10, 110 for treating a patient, especially for enhancing at least one autonomous function such a blood circulation and/or respiration.

[0209] In other words, according to the present disclosure, the use of a neurostimulation system 10, 110 according to the system 10, 110 for treating a patient, especially for enhancing at least one autonomous function such a blood circulation and/or respiration is disclosed.

[0210] According to the present disclosure a method is disclosed, the method characterized in that the method is performed with the system of any of claims 1-9.

[0211] The method performed with the system 10,110 and functionality of the system 10,110 can be described as follows:

[0212] A method for neuromodulation, especially for neurostimulation, for treating a patient, especially for enhancing at least one autonomous function such a blood circulation and/or respiration, comprising the steps of

[0213] receiving at least one or more signals being indicative for blood circulation, especially being indicative for pulse and/or blood pressure and/or oxygenation,

[0214] adapting neurostimulation on the basis of the signal(s) received.

[0215] In particular, the method could further comprise the steps of providing neurostimulation and monitoring signals indicative for blood circulation in real-time, especially signals being indicative for pulse and/or blood pressure.

[0216] In particular, the signals being indicative for blood circulation could be signals indicative for blood pressure and/or cumulative firing rates from at least one brainstem control area, especially but not limited to firing rates from the rostral ventrolateral medulla.

[0217] In particular, the method could comprise switching between signals indicative for blood pressure and cumulative firing rates from at least one brainstem control area, especially but not limited to firing rates from the rostral ventrolateral medulla.

[0218] In particular, the method could comprise receiving baseline signals, wherein the baseline signals define at least one target value.

[0219] Further, the method could be configured for detecting differences between the at least one target value and at least one or more signals indicative for blood circulation, wherein the method could be further configured and arranged to adapt neurostimulation based on the differences between the at least one target value and at least one or more signals indicative for blood circulation and/or oxygenation.

[0220] Further, the method could be configured to modify at least one of amplitude and frequency of a stimulation paradigm in response to the at least one or more signals indicative for blood circulation with a coefficient β that controls the linear proportion with which the amplitude or frequency changes.

[0221] Further, the method could be configured to take into account a predictive effect of stimulation to adjust coefficient β with a specified time window.

[0222] Further, the method could be configured to comprise stimulation paradigm control parameters, especially minimal or maximal bounds on the stimulation paradigm.

[0223] Of note, the present system 10 and method could also be applied for the treatment of a mammal suffering from neurological conditions other than SCI, including but not limited to stroke, multiple sclerosis, autonomic failure, autonomic neuropathy, as well as cancer of the neurological tissue which impair operation of descending sympathetic pathways that normally facilitate control of autonomic functions.

[0224] Not shown in FIG. 1 is that the present system and method could also be applied for the treatment of any other autonomic dysfunction than impaired blood pressure control, including but not limited to heart rate, digestive function, bladder control and/or bowel control.

[0225] FIG. 3 shows an example of bottom up understanding of the sympathetic circuitry within the spinal cord.

[0226] Deep learning reveals disrupted dynamics between critical control centers, i.e. rostral ventrolateral medulla RVLM, integrated sympathetic nerve activity iSNA, systolic blood pressure SBP, after spinal cord injury SCI.

[0227] On the left the specific interaction being studied is described.

[0228] The normalized real response (real) to a perturbation that lowers blood pressure, and the predicted response based on machine learning (predicted) was observed.

[0229] For uninjured panels a good prediction across each control node in the system exists.

[0230] After SCI there is a disruption in the relationship between all aspects and the spinal cord, showing disrupted control.

[0231] The system 10, 110 seeks to replace this disrupted control.

[0232] The mean absolute error MAE from the deep learning predictions is indicated.

[0233] Beta β of a linear regression model is indicated.

[0234] FIG. 4a shows a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation.

[0235] In particular, the linear relationship between blood pressure and amplitude of epidural electrical stimulation EES provides the basis for a linear proportional control mechanism.

[0236] FIG. 4b (like FIG. 4a) shows a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation in a non-human primate.

[0237] FIG. 4c shows a general layout of the linear relationship between blood pressure and amplitude of epidural electrical stimulation in a human patient;

[0238] FIG. 5a shows an example of closed-loop control of blood pressure according to the present disclosure.

[0239] In this embodiment a patient suffering from SCI is equipped with the system 10, 110 as disclosed in FIG. 1 and/or FIG. 2.

[0240] Resting blood pressure was identified (baseline).

[0241] Baseline blood pressure was identified as target pressure.

[0242] An orthostatic challenge stimulus was identified which continued for 10 minutes (bottom trace for the pressure inside the chamber).

[0243] Closed-loop epidural electrical stimulation EES was turned on, consistently reaching the target pressure.

[0244] The following parameters were used for stimulation: amplitude control; 50 Hz stimulation; beta=10; pulse width=100 micro seconds.

[0245] Note that every other parameter could be generally used for stimulation.

[0246] In general, the frequency may be 10 Hz-10 kHz, the amplitude may be 0-1 A or 0-15V, and the pulse width may be 1-500 μs.

[0247] FIG. 5b (similar to FIG. 5a) shows an example of closed-loop control of blood pressure according to the present disclosure as shown FIG. 5a, here with Acute and Chronic SCI;

[0248] FIG. 5c (similar to FIG. 5a) shows an example of closed-loop control of blood pressure according to the present disclosure in non-human primates;

[0249] FIG. 5d (similar to FIG. 5a) shows an example of closed-loop control of blood pressure according to the present disclosure in a human patient;

[0250] FIG. 6a shows a schematical overview of the activation of sympathetic neurons according to the present disclosure.

[0251] In particular, the activation of the sympathetic circuitry in response to stimulation is shown.

[0252] In particular, the activation of the sympathetic circuitry in response to stimulation with the system 10, 110 and/or the method according to the present disclosure is shown.

[0253] Stimulation enters through the posterior roots of the dorsal root ganglion DRG and activates sympathetic pre-ganglionic neurons SPN, which then activate splanchic ganglia SG and blood vessels responsible for blood pressure.

[0254] FIG. 6b shows a schematical overview of mechanisms, by which EES stabilizes hemodynamics.

[0255] Part a shows the intraspinal density of neurons retrogradely traced from the splanchnic ganglia, amplitude of pressor responses to TESS applied to each segment, and concordance between anatomical and functional datasets.

[0256] Part b shows hypothetical circuits activated by TESS to elicit blood vessel constriction.

[0257] Part c shows color-coded electrical potentials following TESS applied to the spinal cord suggesting the exclusive activation of afferent fibres. Scheme illustrating rhizotomy of posterior roots. Barplots report pressor responses to Targeted Epidural Spinal Stimulation (TESS) before and after rhizotomy (n=5, paired samples one-tailed t-test; t=4.36; P=0.006).

[0258] Part d shows trans-synaptic retrograde tracing revealing interneurons connected to splanchnic ganglia.

[0259] Part e shows interneurons. These interneurons express the excitatory marker Slc17a6, and receive vGlut 1 synapses from large-diameter proprioceptive afferents.

[0260] Part f shows Fos expression in THON neurons in the splanchnic ganglia in control and after TESS. Barplot reports percentage of FOSON neurons (n=5, independent samples one-tailed t-test; t=13.96; P=4.99e-05).

[0261] Part g shows ablation of splanchnic efferents blunted the pressor response (n=4, independent samples one-tailed t-test; t=−4.54; P=0.0099).

[0262] Part h shows alpha1 receptor blockade with prazosin blunted pressor responses (n=5, independent samples one-tailed t-test; t=−5.59; P=0.0007).

[0263] FIG. 7 shows a schematical overview of a further embodiment of the system 210 for neuromodulation and/or neurostimulation, for the treatment of a patient, according to the present disclosure, with which the method according to the present disclosure can be performed.

[0264] The system 210 is neurostimulation system 210 for treating a patient, especially for enhancing at least one autonomous function such as blood circulation and/or respiration.

[0265] In this embodiment, the system 210 is a neurostimulation system 210 for treating a patient, especially for enhancing blood pressure function.

[0266] The system 210 comprises a sensing element 212.

[0267] In general, the sensing element 212 is configured to sense a signal indicative for a physiological parameter of a patient.

[0268] The system 210 further comprises a control module 214.

[0269] In this embodiment, the control module is configured to identify a target value for autonomic function based on a signal provided by the sensing element 212.

[0270] The system 210 further comprises a spatial mapping module 216.

[0271] In general, the spatial mapping module 216 is configured to link spatial electrode stimulation configurations Config targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect.

[0272] The system 210 further comprises a parameter mapping module 218.

[0273] In general, the parameter mapping module 218 is configured to prepare stimulation parameters for the control module 214 based on input received from the sensing element 212 and/or the spatial mapping module 216.

[0274] In an alternative embodiment, the system 210 comprises more than one sensing element 212 and/or more than one control module 214 and/or more than one spatial mapping module 216 and/or more than one parameter mapping module 218.

[0275] Not shown in FIG. 7 is that the system 210 further comprises at least one stimulation element.

[0276] Not shown in FIG. 7 is that the at least one stimulation element comprises at least one electrode array A comprising multiple electrodes E.

[0277] Not shown in FIG. 1 is that the electrode array A comprises in this embodiment 216 electrodes E.

[0278] In another embodiment, the electrode array A comprises 8-32 electrodes E.

[0279] However, any other number of electrodes E is generally possible.

[0280] In this embodiment, the control module 214 is connected to the sensing element 212.

[0281] The connection between the control module 214 and the sensing element 212 is a direct and bidirectional connection.

[0282] However, also an indirect and/or unidirectional connection would be generally possible.

[0283] In this embodiment, the connection between the control module 214 and the sensing element 212 is a wireless connection.

[0284] However, also a cable-bound connection would be generally possible.

[0285] In this embodiment, the control module 214 is connected to the spatial mapping module 216 and the parameter mapping module 218.

[0286] The connection between the control module 214 and the spatial mapping module 216 and the parameter mapping module 218 is a direct and bidirectional connection.

[0287] However, also an indirect and/or unidirectional connection would be generally possible.

[0288] In this embodiment, the connection between control module 214 and the spatial mapping module 216 and the parameter mapping module 218 is a wireless connection.

[0289] However, also a cable-bound connection would be generally possible.

[0290] It is generally possible that the sensing element 212, the spatial mapping module 216 and/or the parameter mapping module 218 are directly connected.

[0291] It is generally possible that the sensing element 212, the spatial mapping module 216 and/or the parameter mapping module 218 are directly connected by a unidirectional connection.

[0292] It is generally possible that the sensing element 212, the spatial mapping module 216 and/or the parameter mapping module 218 are directly connected by a bidrectional connection.

[0293] It is generally possible that the sensing element 212, the spatial mapping module 216 and/or the parameter mapping module 218 are directly connected by a wireless connection.

[0294] It is generally possible that the sensing element 212, the spatial mapping module 216 and/or the parameter mapping module 218 are directly connected by a cable-bound connection.

[0295] The sensing element 212 senses a signal indicative for a physiological parameter of a patient.

[0296] In this embodiment, the sensing element 212 is a sensor configured to sense a signal indicative for a physiological parameter of a patient.

[0297] In this embodiment, the sensing element 212 is a sensor configured to sense a signal indicative for blood pressure of a patient.

[0298] In this embodiment, the sensing element 212 is a sensor configured to sense systolic blood pressure SBP.

[0299] However, in an alternative embodiment, the sensing element 212 could be alternatively and/or additionally be configured to sense oxygenation and/or diastolic and/or mean arterial pressure and/or cerebrospinal fluid pressure and/or perfusion pressure, in particular spinal cord perfusion pressure.

[0300] In other words, the sensing element 212 could generally sense blood pressure and/or perfusion pressure.

[0301] However, in an alternative embodiment, the sensing element 212 could be alternatively and/or additionally be configured to sense posture and/or position.

[0302] In other words, the physiological parameter could be at least one of blood pressure of the patient, spinal cord perfusion pressure of the patient, posture of the patient and/or position of the patient.

[0303] In this embodiment, the sensing element 212 is an invasive arterial line.

[0304] In particular, the invasive arterial line senses blood pressure directly and in real-time.

[0305] In this embodiment the sensing element 212 senses blood pressure continuously.

[0306] However, it could be generally possible that the sensing element 212 provides sporadic monitoring of blood pressure and/or monitoring blood pressure in preset time intervals.

[0307] Not shown in FIG. 7 is that it could be generally possible that the sensing element 212 could be an implanted and/or implantable sensor and/or a non-implantable and/or non-implanted sensor.

[0308] Not shown in FIG. 7 is that could be generally possible that the sensing element 212 could be an external beat-by beat blood pressure monitor, intrathecal catheter and/or a standard brachial blood pressure cuff and/or any type of upper arm blood pressure monitor system and/or any type of wrist blood pressure monitor system and/or any type of finger blood pressure monitor system.

[0309] Not shown in FIG. 7 is that the system 210 could comprise at least one temporal mapping module configured to link temporal electrode stimulation configurations to at least one physiological effect.

[0310] In this embodiment, the control module 214 identifies a target value for autonomic function based on a signal provided by the sensing element 212.

[0311] In this embodiment, the spatial mapping module links spatial electrode stimulation configurations Config to blood pressure, in particular systolic blood pressure SBP.

[0312] It is generally possible that the spatial mapping module links spatial electrode stimulation configurations Config to at least one physiological effect.

[0313] In this embodiment, the parameter mapping module 218 prepares stimulation parameters for the control module 214 based on input received from the sensing element 212 and/or the spatial mapping module 216.

[0314] Not shown in FIG. 7 is that the spatial mapping module 216 could isolate key electrodes E based on anatomical location and a learning procedure initiated at these electrodes E to optimize the configuration of the surrounding electrodes E.

[0315] Not shown in FIG. 7 is that the spatial mapping module 216 could be configured to perform a reinforcement learning procedure, wherein the reinforcement learning procedure is part of the process to link spatial electrode stimulation configurations Config targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect.

[0316] Not shown in FIG. 7 is that the spatial mapping module 216 could be configured to perform a spatial mapping phase for identifying a suitable electrode configuration Config in terms of selected electrodes E and their spatial arrangement in a first step and a parameter mapping phase for adjusting stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

[0317] Not shown in FIG. 7 is that the stimulation parameters could comprise at least frequency, amplitude and pulse width, wherein the frequency is 10 Hz-10 kHz, the amplitude is 0-1 A or 0-15V and the pulse width is 1-500 μs.

[0318] Not shown in FIG. 7 is that in general, stimulation could be applied by burst train stimulation.

[0319] Pulse trains called burst train stimulation could be used to increase the specificity and comfort.

[0320] Burst train stimulation could comprise a series of several pulses, e.g. 3 to 5 pulses delivered at 200 Hz to 700 Hz, repeated at the frequency 10-120 Hz.

[0321] According to the present disclosure the use of a system 210 for neuromodulation is disclosed.

[0322] The use of the system 210 and functionality of the system 210 can be described as follows:

[0323] Use of a neuromodulation system 210 according to the neuromodulation system 210 for treating a patient, especially for enhancing at least one autonomous function such as blood circulation and/or respiration.

[0324] Thus, according to the present disclosure, the use of a neurostimulation system 210 according to the system 210 for treating a patient, especially for enhancing at least one autonomous function such a blood circulation and/or respiration is disclosed.

[0325] According to the present disclosure a method is disclosed, the method characterized in that the method is performed with the system 10, 110 and 210.

[0326] The method performed with the system 210 and functionality of the system 210 can be described as follows:

[0327] The method is a neuromodulation method, especially a neurostimulation method for treating a patient, especially for enhancing at least one autonomous function such a blood circulation and/or respiration, wherein the method comprises at least the following steps:

[0328] Performing a sensing procedure for sensing a signal indicative for a physiological parameter of a patient,

[0329] Performing a spatial mapping procedure to link spatial electrode stimulation configurations Config targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect,

[0330] Performing a parameter mapping procedure to prepare stimulation parameters based on input received from the sensing and/or the spatial mapping procedure.

[0331] In particular, the method could comprise the step of providing stimulation.

[0332] Further, the method could comprise the step of linking temporal electrode stimulation configurations to at least one physiological effect.

[0333] Further, the method could comprise the step of identifying a target value for autonomic function based on a signal indicative for a physiological parameter of a patient.

[0334] Further, the method may comprise the step of isolating key electrodes E based on anatomical location and a learning procedure initiated at these electrodes E to optimize the configuration Config of the surrounding electrodes E.

[0335] In general, stimulation parameters could comprise at least frequency, amplitude and pulse width, wherein the frequency could be 10 Hz-10 kHz, the amplitude could be 0-1 A or 0-15V and the pulse width could be 1-500 μs.

[0336] Further, the method could comprise the step of performing a reinforcement learning procedure, wherein the reinforcement learning procedure is part of the process to link spatial electrode stimulation configurations Config targeting the afferent fibers in the dorsal/posterior roots to at least one physiological effect.

[0337] It is generally possible that the method further comprises the step of performing a spatial mapping phase for identifying a suitable electrode configuration Config in terms of selected electrodes E and their spatial arrangement in a first step and a parameter mapping phase for adjusting stimulation parameters for the stimulation provided by the selected electrodes E in the first step.

[0338] It is generally possible that the physiological parameter could be at least one of oxygenation (including but not limited to spinal cord oxygenation), blood pressure of the patient, spinal cord perfusion pressure of the patient, posture of the patient and/or position of the patient.

[0339] Of note, the present system 10 and method could also be applied for the treatment of a mammal suffering from neurological conditions other than SCI, including but not limited to stroke, multiple sclerosis, autonomic failure, autonomic neuropathy, as well as cancer of the neurological tissue which impair operation of descending sympathetic pathways that normally facilitate control of autonomic functions.

[0340] Not shown in FIG. 7 is that the present system and method could be applied for the treatment of any type of autonomic dysfunction including but not limited to heart rate, digestive function, bladder control and/or bowel control.

[0341] FIG. 8a-d shows exemplary data from a patient equipped with the system 210 according to FIG. 7.

[0342] In particular, a patient suffering from spinal cord injury SCI was equipped with the system 210 disclosed in FIG. 7.

[0343] In particular, a series of spatial electrode configurations Config is shown, and the immediate blood pressure response, i.e. systolic blood pressure SBP, of the patient was measured, cf. FIG. 8a.

[0344] In this embodiment, a series of 24 spatial configurations was assessed.

[0345] In particular, the optimal spatial electrode configuration Config was selected, based on both the immediate increase in blood pressure and the absence of significant muscle contractions, cf. FIG. 8b.

[0346] In this embodiment, the optimal spatial electrode configuration Config selected was configuration Config 20.

[0347] In this embodiment, a suboptimal spatial electrode configuration Config would be e.g. spatial configuration Config 17.

[0348] In this example, the rostral four electrodes were identified most optimal to control blood pressure in the patient, cf. FIG. 8c.

[0349] The system enabled the identification of this optimized parameters.

[0350] Not shown is here that it is generally possible to visualize the electrode array comprising multiple electrodes using a CT or MRI or X-Ray scan to confirm the location of the electrode array.

[0351] FIG. 8d shows a further overview of the stimulation effect on blood pressure.

[0352] FIG. 9 shows embodiments, where the stimulus changing blood pressure is constant or variable.

[0353] On the left side, there is pressure in the chamber, blood pressure and TESS amplitude while the neuroprosthetic baroreflex is turned on and off sequentially. On the right side, there are the same variables as in left shown for cyclical changes in the pressure of the chamber.

[0354] FIG. 10 shows a blood pressure collapse, which is treated and rescued by the system according to the present disclosure.

REFERENCES

[0355] 10, 110 system

[0356] 12, 112 signal input module

[0357] 14, 114 control module

[0358] 116 control unit

[0359] 118 real-time monitoring unit

[0360] 120 stimulation unit

[0361] 210 system

[0362] 212 control module

[0363] 214 sensing element

[0364] 216 spatial mapping module

[0365] 218 parameter mapping module

[0366] β coefficient

[0367] A electrode array

[0368] E electrode

[0369] Config spatial electrode configuration

[0370] DRG dorsal root ganglion

[0371] EES epidural electrical stimulation

[0372] iSNA integrated sympathetic nerve activity

[0373] MAE mean absolute error

[0374] RVLM rostral ventrolateral medulla

[0375] SBP systolic blood pressure

[0376] SCI spinal cord injury

[0377] SPN sympathetic pre-ganglionic neurons

[0378] SG splanchic ganglia