SYSTEM AND METHOD FOR CONTROL OF AUTONOMIC FUNCTION

Abstract

A system for neuromodulation and/or neurostimulation, for the treatment of a mammal, at least comprising: at least one control unit configured and arranged to provide stimulation data; at least one stimulation unit configured and arranged to provide a stimulation pulse; at least one real-time monitoring unit; at least one signal-processing unit;

wherein the system is configured and arranged for control of blood pressure,

wherein the stimulation unit is constructed to comprise a lead, and wherein the lead is capable and configured to provide stimulation to the spinal cord at level T9-L1.

Claims

1. A system for neuromodulation and/or neurostimulation, for treatment of a mammal, at least comprising: at least one control unit configured and arranged to provide stimulation data; at least one stimulation unit configured and arranged to provide a stimulation pulse; at least one real-time monitoring unit; at least one signal-processing unit; wherein the system is configured and arranged for control of blood pressure, wherein the stimulation unit is constructed to comprise a lead, and wherein the lead is capable and configured to provide stimulation to a spinal cord at level T9-L1.

2. The system according to claim 1, wherein the lead (20) is capable and configured to provide stimulation to the spinal cord at level T9-T12.

3. The system according to claim 1, wherein the lead is capable and configured to be positioned subdurally and/or epidurally at least partially at and/or between the level of vertebrae T9-L1.

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

5. The system according to claim 4, wherein the control unit comprises an oscillation control module, wherein the oscillation control module is configured and arranged to provide an input of 0.01 Hz-0.2 Hz low frequency oscillation in the amplitude and/or frequency.

6. The system according to claim 1, wherein the stimulation unit is configured and arranged to provide at least one burst train stimulation pulse.

7. The system according to claim 6, wherein the stimulation unit is configured and arranged to provide at least one burst of several pulses.

8. The system according to claim 5, wherein the oscillation control module is configured and arranged to provide an input of 0.1 Hz low frequency oscillation in the amplitude and/or frequency.

9. The system according to claim 1, wherein the control unit comprises a time control module, wherein the time control module is configured and arranged to provide a time delay.

10. The system according to claim 9, wherein the time delay provided by the time control module is a time delay of 1-50 ms.

11. A method of operating a system for neuromodulation and/or neurostimulation according to the system of claim 1 for treating a mammal.

12. The system according to claim 3, wherein the lead is positioned subdurally and/or epidurally at least partially under vertebrae T9-L1.

13. The system according to claim 7, wherein the stimulation unit provides 2 to 5 pulses.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0082] Further details of the present disclosure shall now be disclosed in connection with the drawings.

[0083] 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;

[0084] FIG. 2 an example of a patient equipped with the system shown in FIG. 1;

[0085] FIG. 3a an example of a lead of the system shown FIG. 1, and an embodiment for the implantation side of said lead;

[0086] FIG. 3b a further example to the implantation side to FIG. 3a (rat model);

[0087] FIG. 3c a further example to the implantation side to FIG. 3a (non-human primate/monkey model);

[0088] FIG. 3d a further example to the implantation side to FIG. 3a (human patient);

[0089] FIG. 4a an example for functional mapping results—heatmaps demonstrating preferential increases in SBP, DBP, and MAP at T12, going from acute to chronic injuries;

[0090] FIG. 4b an example for functional mapping results—quantification of responses at the intermediate stage, showing preference for T11-T13 across all measures;

[0091] FIG. 4c an example for functional mapping results—quantification of the responses at T12 over time, showing an increase with time post-injury;

[0092] FIG. 4d functional mapping in a non-human primate;

[0093] FIG. 5 activation of natural frequency aspects within the systolic blood pressure signal during an orthostatic stimulus in uninjured and spinal cord injury rats;

[0094] FIG. 6 activation of natural frequency aspects within the systolic blood pressure signal using biologically relevant stimulation;

[0095] FIG. 7a a schematical overview of the activation of sympathetic neurons according to the present disclosure; and

[0096] FIG. 7b a schematical overview of mechanisms, by which EES stabilizes hemodynamics.

DETAILED DESCRIPTION

[0097] FIG. 1 shows a schematical overview of an embodiment of the system 10 for neuromodulation and/or neurostimulation, for the treatment of a mammal, according to the present disclosure, with which the method according to the present disclosure can be performed.

[0098] The system 10 comprises a control unit 12.

[0099] The control unit 12 is configured and arranged to provide stimulation data.

[0100] Further, the system 10 comprises a stimulation unit 14.

[0101] The stimulation unit 14 is configured and arranged to provide a stimulation pulse.

[0102] The stimulation unit 14 is constructed to comprise a lead 20.

[0103] In this embodiment the lead is capable and configured to provide stimulation to the spinal cord at level T9-L1.

[0104] The system 10 also comprises a signal processing unit 16.

[0105] The system 10 also comprises a real-time monitoring unit 18.

[0106] In this embodiment, the real-time monitoring unit 18 is configured and arranged to monitor blood pressure.

[0107] In this embodiment, the real-time monitoring unit 18 comprises a sensor unit 18a.

[0108] The sensor unit 18a is configured and arranged to measure and/or monitor blood pressure of a patient P.

[0109] In an alternative embodiment, the system 10 may comprise more than one control unit 12 and/or more than one stimulation unit 14 and/or more than one signal processing unit 16 and/or more than one real-time monitoring unit 18.

[0110] In this embodiment, the control unit 12 is connected to the stimulation unit 14, the signal processing unit 16 and the real-time monitoring unit 18.

[0111] In this embodiment, the connection between the control unit 12 and the stimulation unit 14, the control unit 12 and the processing unit 16 and the control unit 12 and the real-time monitoring unit 18 is a direct and bidirectional connection.

[0112] In this embodiment, the connection between the control unit 12 and the stimulation unit 14, the control unit 12 and the processing unit 16 and the control unit 12 and the real-time monitoring unit 18 is established by a wireless link WL.

[0113] However, alternatively, also a cable bound and/or unidirectional and/or indirect connection between the control unit 12 and the stimulation unit 14, the control unit 12 and the processing unit 16 and the control unit 12 and the real-time monitoring unit 18 could be generally possible.

[0114] In this embodiment, the stimulation unit 14 is connected to the signal processing unit 16.

[0115] The connection between the stimulation unit 14 and the signal processing unit 16 is a direct and bidirectional connection.

[0116] The connection between the stimulation unit 14 and the signal processing unit 16 is established by a wireless link WL.

[0117] However, alternatively, also a cable bound and/or unidirectional and/or indirect connection between the stimulation unit 14 and the signal processing unit 16 could be generally possible.

[0118] In this embodiment, the signal processing unit 16 is connected to the real-time monitoring unit 18.

[0119] The connection between the signal processing unit 16 and the real-time monitoring unit 18 is a direct and bidirectional connection.

[0120] In this embodiment, the connection between the signal processing unit 16 and the real-time monitoring unit 18 are established by a wireless link WL.

[0121] However, alternatively, also a cable bound and/or unidirectional and/or indirect connection between the signal processing unit 16 and the real-time monitoring unit 18 unit could be generally possible.

[0122] The real-time monitoring unit 18, in particular the sensor unit 18a of the real-time monitoring unit 18 measures blood pressure of the patient P.

[0123] Not shown in this embodiment is that the sensor unit 18a could generally measure and/or monitor systolic and/or diastolic and/or mean arterial pressure.

[0124] Not shown in this embodiment is that the sensor unit 18a could also reports pulse rate.

[0125] Not shown in this embodiment is that the at least one sensor unit 18a may be an invasive or non-invasive sensor unit 18a.

[0126] Not shown in this embodiment is that the sensor unit 18a could be at least partially implantable and/or implanted.

[0127] Alternatively, the at least one sensor unit 18a could be not implantable and/or not implanted.

[0128] The measured blood pressure is communicated from the real-time monitoring unit 18 to the signal processing unit 16.

[0129] 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.

[0130] In an alternative embodiment, the measured blood pressure could communicate from the real-time monitoring unit 18 to the signal processing unit 16 closed to real-time or with time delay.

[0131] The signal processing unit 16 compares the measured blood pressure value to a predetermined blood pressure value and/or to a predetermined blood pressure target range.

[0132] If the comparison indicates that the measured blood pressure deviates from the predetermined target blood pressure range, the control unit 12 could adapt stimulation data.

[0133] The stimulation unit 14 provides stimulation via the lead 20 according to the stimulation data provided by the control unit 12.

[0134] Not shown in this embodiment is that additionally and/or alternatively, a sensor unit 18a could measure and/or monitor perfusion pressure, in particular spinal cord perfusion pressure.

[0135] Not shown in this embodiment is that the measured spinal cord perfusion pressure could be communicated from the real-time monitoring unit 18 to the signal processing unit 16.

[0136] Not shown in this embodiment is that the measured spinal cord perfusion pressure could be communicated from the real-time monitoring unit 18 to the signal processing unit 16 in real-time.

[0137] Not shown in this embodiment is that the measured spinal cord perfusion pressure could be communicated from the real-time monitoring unit 18 to the signal processing unit 16 closed to real-time or with time delay.

[0138] Not shown in this embodiment is that the signal processing unit 16 could compare the measured spinal cord perfusion pressure value to a predetermined spinal cord perfusion pressure target value and/or to a predetermined spinal cord perfusion pressure target range.

[0139] Not shown in this embodiment is that if the comparison indicates that the measured spinal cord perfusion pressure deviates from the predetermined spinal cord perfusion pressure target value and/or from the predetermined spinal cord perfusion pressure target range, the control unit 12 could adapt stimulation data.

[0140] In this embodiment, the stimulation data comprises at least frequency, amplitude and pulse width.

[0141] In this embodiment, the frequency may be 10 Hz-10 kHz, the amplitude may be 0-1A or 0-15V, and the pulse width may be 1-500 μs.

[0142] Not shown in this embodiment that the stimulation unit 14 may be configured and arranged to provide at least one burst train stimulation pulse.

[0143] Not shown in FIG. 1 is that it could be generally possible that the stimulation unit 14 may provide two or more bursts.

[0144] In particular, the stimulation unit 14 could be configured and arranged to provide at least one burst of several pulses, or of 2 to 5 pulses.

[0145] Not shown in FIG. 1 is that stimulation pulse trains called burst train stimulation could be used to increase the specificity and comfort.

[0146] Not shown in FIG. 1 is that in particular, burst train stimulation could comprise a series of 3 to 5 (or even more) pulses delivered at e.g. 200 Hz to 700 Hz, repeated at a frequency of e.g. 10-120 Hz.

[0147] Not shown in this embodiment is that the lead 20 is capable and configured to provide stimulation to the spinal cord at level T9-T12.

[0148] Not shown in this embodiment is that the lead 20 is capable and configured to be positioned subdurally and/or epidurally at least partially at and/or between the level of vertebrae T9-L1, in particular at least partially under vertebrae T9-L1 of the patient P.

[0149] Not shown in FIG. 1 is that the control unit 12 could comprise an oscillation control module.

[0150] In general, the oscillation control module could provide an input of 0.01 Hz-0.2 Hz low frequency oscillation in the amplitude.

[0151] In particular, the oscillation control module could provide an input of 0.1 Hz low frequency oscillation in the amplitude.

[0152] Alternatively, and/or additionally, the oscillation control module could provide an input of 0.01 Hz-0.2 Hz low frequency oscillation in the frequency.

[0153] In particular, alternatively and/or additionally, the oscillation control module could provide an input of 0.1 Hz low frequency oscillation in the frequency.

[0154] Not shown in FIG. 1 is that the control unit 12 could comprise a time control module.

[0155] In general, the time control module could provide a time delay.

[0156] In general, the time delay could depend on segment length.

[0157] In general, the time delay could be longer for large mammals compared to small mammals.

[0158] In general, the time delay could be longer in humans compared to rats or mice.

[0159] In general, the time delay provided by the time control module could be a time delay of 1-50 ms.

[0160] In general, the time delay provided by the time control module could be a time delay of 1-4 ms, in particular a time delay of 2 ms.

[0161] However, every other time delay provided by the time control module could be generally possible.

[0162] According to the present disclosure the use of a system 10 or neuromodulation is disclosed.

[0163] The use of the system 10 and functionality of the system 10 can be described as follows:

[0164] Use of a system 10 for neuromodulation and/or neurostimulation according to the system 10 for treating a mammal.

[0165] The method performed with the system 10 and functionality of the system 10 can be described as follows:

[0166] A method for neuromodulation and/or neurostimulation to the nervous system of a mammal, at least comprising the steps of

[0167] positioning a lead 20;

[0168] providing neuromodulation and/or neurostimulation to the spinal cord via said lead 20;

[0169] monitoring blood pressure;

[0170] comparing a measured blood pressure value to a pre-set blood pressure target range;

[0171] if the comparison indicates that the measured blood pressure deviates from the target blood pressure range modulating neurostimulation until the blood pressure of the mammal is in the target blood pressure range;

[0172] wherein the method is configured and arranged to provide neuromodulation and/or neurostimulation to the spinal cord at spinal level T9-L1.

[0173] In particular, the method could be arranged for positioning the lead subdurally and/or epidurally at least partially at and/or between the level of vertebrae T9-L1, in particular at least partially under vertebrae T9-L1.

[0174] In particular, the method may be configured and arranged to provide neuromodulation and/or neurostimulation to the spinal cord at least at spinal level T9-T12.

[0175] The method could provide neuromodulation and/or neurostimulation to the spinal cord with a frequency of 10 Hz-10 kHz, an amplitude of 0-1A or 0-15V, and the pulse width of 1-500 μs.

[0176] In general, stimulation could be provided to the spinal cord by at least one burst train stimulation pulse.

[0177] In general, stimulation could be provided to the spinal cord with at least one burst of several pulses, or of 2 to 5 pulses.

[0178] In general, stimulation could be provided with a control input of 0.01 Hz-0.2 Hz low frequency oscillation in the amplitude and/or frequency.

[0179] In particular, stimulation could be provided with a control input of 0.1 Hz low frequency oscillation in the amplitude and/or frequency.

[0180] Further, stimulation could be provided with a control input comprising a time delay.

[0181] In general, the time delay could be longer in humans compared to rats or mice.

[0182] In general, the time delay could depend on segment length.

[0183] In particular, the stimulation could be provided with a control input comprising a time delay of 1-50 ms.

[0184] In particular, the stimulation could be provided with a control input comprising a time delay of 1-4 ms.

[0185] In particular, the stimulation could be provided with a control input comprising a time delay of 2 ms.

[0186] 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.

[0187] 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.

[0188] FIG. 2 shows an example of a patient equipped with the system 10 shown in FIG. 1.

[0189] The patient P is equipped with the system 10 as disclosed in FIG. 1.

[0190] In this embodiment, the real-time monitoring unit 18 comprises a sensor unit 18a.

[0191] In this embodiment, the sensor unit 18a comprises a sensor.

[0192] The sensor monitors blood pressure of the patient P.

[0193] In this embodiment, the sensor monitors systolic diastolic blood pressure of the patient P.

[0194] In this embodiment, the sensor is a non-invasive sensor.

[0195] In this embodiment, the sensor is wrist blood pressure monitor system.

[0196] In this embodiment, the sensor is a digital blood pressure monitor system.

[0197] In an alternative embodiment, the sensor could be an analog blood pressure monitor system.

[0198] In this embodiment, the sensor monitors blood pressure continuously in real-time and provides blood pressure data in real-time to the signal processing unit 16.

[0199] However, it is generally possible that the sensor measures blood pressure in predefined time-intervals.

[0200] In an alternative embodiment, the sensor may be or may comprise other embodiments of blood pressure monitor systems, 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-implanted blood pressure monitor system and any type of implantable and/or implanted blood pressure monitor system.

[0201] In an alternative embodiment, the sensor could measure and/or monitor additionally and/or alternatively other parameters indicating perfusion pressure and/or blood pressure, including but not limited to arterial blood pressure.

[0202] In an alternative embodiment, the sensor could measure and/or monitor additionally the pulse rate of the patient P.

[0203] In an alternative embodiment, the sensor could be or could comprise an arterial line.

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

[0205] In general, the sensor unit 18a could comprise more than one sensor and/or at least one sensor base station.

[0206] FIG. 3a shows an example of a lead 20 of the system 10 shown in FIG. 1, and an embodiment for the implantation side of said lead 20 according to the present disclosure.

[0207] In this embodiment, the dimensions of the lead 20 are designed to perfectly target the posterior roots of the T9-L1 spinal segments.

[0208] To identify the optimal location on the spinal cord to elicit blood pressure responses, a functional mapping procedure could be performed, e.g. in an animal model, e.g. in an animal model of SCI.

[0209] In other words, to identify the optimal location for providing stimulation to the spinal cord, a functional mapping procedure could be performed, e.g. in an animal model, e.g. in an animal model of SCI.

[0210] In other words, to identify the optimal location for positioning a lead 20 for providing stimulation to the spinal cord, a functional mapping procedure could be performed, e.g. in an animal model, e.g. in an animal model of SCI.

[0211] The implantation site is a so-called hotspot and preserved across species, as can be further derived from FIG. 3b, FIG. 3c and FIG. 3d:

[0212] FIG. 3b shows a further example to the implantation side to FIG. 3a (rat model).

[0213] FIG. 3c shows a further example to the implantation side to FIG. 3a (non-human primate/monkey model).

[0214] FIG. 3d shows a further example to the implantation side to FIG. 3a (human patient).

[0215] In these examples, to identify the optimal location on the spinal cord to elicit blood pressure responses, a functional mapping procedure was performed in a rat model of SCI as described here:

[0216] In principle, each segment of the spinal cord from T5 to L2 in a rat model of SCI was stimulated and blood pressure responses to monopolar, 50 Hz stimulation were recorded.

[0217] In this example, it has been found that T11-T13 are the optimal segments to stimulate in rodents, with the peak response occurring during stimulation of T12, cf. FIG. 4a.

[0218] In particular, systolic blood pressure SBP, diastolic blood pressure DBP or mean arterial blood pressure MAB has been measured.

[0219] In particular, this response was consistent across different time-points post injury, including 1 hour (acute), 5 days (subacute), 2 weeks (intermediate), and 1 month (chronic).

[0220] Note that a similar approach can be performed in order to obtain a lead 20 designed to perfectly target the posterior roots of the T9-L1 spinal segments of a human.

[0221] Note that simulation parameters could vary in a similar approach performed in a human.

[0222] FIG. 4b shows bar diagrams showing quantification of responses at the intermediate stage shown in FIG. 4a, showing preference for T11-T13 across all measures.

[0223] FIG. 4c shows bar diagrams showing quantification of the responses at T12 over time post injury, including 1 hour (acute), 5 days (subacute), 2 weeks (intermediate), and 1 month (chronic), showing an increase with time post-injury.

[0224] Not shown is that in a next step, the density of sympathetic pre-ganglionic neurons in the spinal cord projecting to key splanchnic ganglia in the abdomen was determined, which is responsible for blood pressure control.

[0225] Not shown is that it has also been found that the density of these ganglionic-projecting sympathetic pre-ganglionic neurons peaked in T12, and that there is a strong linear correlation between the density of sympathetic pre-ganglionic neurons and the functional blood pressure response to stimulation.

[0226] Not shown is that next, it has been confirmed that this stimulation led to activation of the splanchnic ganglia using two converging lines of evidence.

[0227] First, the spinal cord was stimulated at T12 for 30 minutes and classic immunohistochemistry was used to identify active neurons (using the immediate early gene Fos, Fos Proto-Oncogene, AP-1 Transcription Factor Subunit) within the splanchnic ganglia.

[0228] Compared to non-stimulated animals, a significant increase in the number of neurons expressing Fos was found, and these neurons were adrenalin-synthesizing (confirmed by the presence of the protein Tyrosine Hydroxylase), confirming their role in blood pressure control.

[0229] Using optogenetic techniques, it has been found that inhibiting the depolarization of these same neurons blunted the response to stimulation.

[0230] With the knowledge that the T11-T13 segments preferentially activate sympathetic structures and stimulation of these segments can modulate blood pressure, high resolution CT and MRI scans were performed to accurately identify the relationship between spinal segments and vertebral levels.

[0231] Additionally, the exact length of the T11-T13 segments using ex-vivo dissections has been confirmed.

[0232] Then, biocompatible electronic lead 20 spinal implants were designed with the exact dimensions required to stimulate T11-T13, with the lead 20 placed immediately under the T9-T12 vertebra, cf. FIG. 3.

[0233] This design of a lead 20 could thus be easily scaled to any animal or human model using MRI technology and computational modelling.

[0234] In other words, the design of the lead 20 is based off key anatomical features (using a rat model as an animal model).

[0235] The identification of functional cardiovascular ‘hotspots’—cf. FIGS. 4a-c (T11-T13).

[0236] The finding that these ‘cardiovascular hotspots’ are aligned with the segmental density of sympathetic pre-ganglionic neurons;

[0237] Completing of CT and MRI scans of the same rat spinal cord in order to align the features of the lead 20 to the posterior roots of the T11-T13 segments (cf. FIG. 3 for exact dimensions);

[0238] Placing specific markers on the lead 20 to align the lead 20 to the specific vertebral locations;

[0239] Thus, the lead 20 dimensions (c.f. FIG. 3) are designed to perfectly target the posterior roots of the T11-T13 spinal segments of rats, which have determined are critical for the maintenance of blood pressure using epidural electrical stimulation.

[0240] In a human being, this would correspond to the region of T9-T12.

[0241] FIG. 4d shows the functional mapping in a non-human primate and demonstrates the conservation of the hotspot (please cf. also FIGS. 3a-3d).

[0242] FIG. 5 shows activation of natural frequency aspects within the systolic blood pressure signal during an orthostatic stimulus in uninjured and SCI rats.

[0243] Heat represents the frequency power at a given wavelet band.

[0244] The dotted line represents the onset of the orthostatic stimulus.

[0245] 30 s of data are shown.

[0246] A decrease in the power within the range around 0.1 Hz is observed.

[0247] A stimulation paradigm could be designed that mimics the natural state of the intact sympathetic nervous system.

[0248] Specifically, frequency oscillation overlays could be optimized, which in an intact system originate in supraspinal/spinal structures responsible for blood pressure control (i.e., the rostral ventrolateral medulla/spinal cord), and elicit a 0.1 Hz low frequency oscillation sympathetic pre-ganglionic neurons.

[0249] Not shown is that, using electrophysiological experiments, it was determined that action potentials originating in the rostral ventrolateral medulla travel with a time delay of 2 ms between T11-T12 and T12-T13 in a rat.

[0250] In a human being, this would correspond to the region of T9-T11 and T11-T12.

[0251] A biomimetic stimulation paradigm is described that reproduces the natural supraspinal sympathetic drive and when coupled with a range of standard parameters (frequency of 10 Hz-10 kHz, amplitude of 0-1A or 0-15V, pulse width of 1-500 μs), achieves biologically relevant BIO control over blood pressure after spinal cord injury.

[0252] It was confirmed that this BIO paradigm recapitulates natural dynamics of the autonomic nervous system using wavelet decomposition, where an increase in the frequency power within the systolic blood pressure signal upon activation of the stimulation is observed.

[0253] FIG. 6 shows activation of natural frequency aspects within the systolic blood pressure signal using biologically relevant BIO stimulation.

[0254] Heat represents the frequency power at a given wavelet band.

[0255] The dotted line represents the onset of the stimulation.

[0256] 30 s of data are shown.

[0257] An increase in the power within the range around 0.1 Hz was observed, confirming that the natural rhythm found in the uninjured state was recapitulated.

[0258] FIG. 7a shows a schematical overview of the activation of sympathetic neurons according to the present disclosure.

[0259] In particular, the activation of the sympathetic circuitry in response to stimulation is shown.

[0260] In particular, the activation of the sympathetic circuitry in response to stimulation with the system 10 and/or the method according to the present disclosure is shown.

[0261] 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 responsible for blood pressure.

[0262] FIG. 7b shows a schematical overview of mechanisms, by which EES stabilizes hemodynamics.

[0263] 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.

[0264] Part b shows hypothetical circuits activated by TESS to elicit blood vessel constriction.

[0265] 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).

[0266] Part d shows trans-synaptic retrograde tracing revealing interneurons connected to splanchnic ganglia.

[0267] Part e shows interneurons. These interneurons express the excitatory marker Slc17a6, and receive vGlut1 synapses from large-diameter proprioceptive afferents.

[0268] 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).

[0269] 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).

[0270] 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).

REFERENCES

[0271] 10 system [0272] 12 control unit [0273] 14 stimulation unit [0274] 16 signal processing unit [0275] 18 real-time monitoring unit [0276] 18a sensor unit [0277] 20 lead [0278] BIO biologically relevant stimulation [0279] CT computer tomography [0280] DRG dorsal root ganglion [0281] MRI magnetic resonance imaging [0282] P patient [0283] SCI spinal cord injury [0284] SPN sympathetic pre-ganglionic neurons [0285] SG splanchic ganglia [0286] WL wireless link [0287] DBP diastolic blood pressure [0288] MAP mean arterial pressure [0289] SBP systolic blood pressure [0290] LX lumbar vertebra level X [0291] L1 lumbar vertebra level 1 [0292] TX thoracic spinal segmental level X or thoracic vertebra level X [0293] T6 thoracic spinal segmental level 6 or thoracic vertebra level 6 [0294] T7 thoracic spinal segmental level 7 or thoracic vertebra level 7 [0295] T8 thoracic spinal segmental level 8 or thoracic vertebra level 8 [0296] T9 thoracic spinal segmental level 9 or thoracic vertebra level 9 [0297] T10 thoracic spinal segmental level 10 or thoracic vertebra level 10 [0298] T11 thoracic spinal segmental level 11 or thoracic vertebra level 11 [0299] T12 thoracic spinal segmental level 12 or thoracic vertebra level 12 [0300] T13 thoracic spinal segmental level 13 or thoracic vertebra level 12