Transnasal ramp brainstem ventral epidural electrostimulation system

Abstract

Disclosed is a transnasal ramp brainstem ventral epidural electrical stimulation system, which comprises: (1) a navigation unit for collecting structural magnetic resonance imaging images and craniofacial CT images of a subject, fusing the structural magnetic resonance imaging images and the craniofacial CT images to establish a brain model of the subject, and determining a ramp bone opening window position and local ramp bone thickness in the brain model of the subject through registration; (2) an implantation unit in communication with the navigation unit, for establishing bilateral posterior nasal cavity channels so as to establish a bone window at the skull base ramp, guide an electrode through the bone window and fix the electrode to the brainstem ventral epidural; and (3) an electrode comprising a discharging end, a fixer and an electrode lead wire, the discharging end being fixed opposite to the fixer, and the electrode lead wire being used for being connected to a stimulation current generator. The system provides a safe and stable implementation scheme for transnasal ramp electrical stimulation of the brainstem reticular formation, can effectively induce behavioral arousal signs, and improve the level of consciousness disorders.

Description

Technical Field

[0001] This application belongs to the field of neuromodulation technology, specifically relating to a transnasal clivus ventral brainstem epidural electrical stimulation system. Background Technology

[0002] Patients with disorders of consciousness (DOC) lose normal perception of themselves and their environment, exhibiting conditions such as coma, vegetative state, unresponsive wakefulness syndrome, or even minimal state of consciousness. The ascending reticular activating system (ARAS) in the brain plays an indispensable role in maintaining consciousness. Originating from the brainstem reticular formation (BRF), it projects extensively to the thalamus, basal forebrain, hypothalamus, and neocortex to maintain cortical arousal, facilitate attentional processing, and sustain the neural basis required for conscious experience. Within the ARAS, the BRF, as a heterogeneous neural network distributed in the midbrain, pons, and medulla oblongata, is the central hub for maintaining consciousness.

[0003] Current treatment strategies for DOC work by targeting different nodes within the ARAS (Advanced Arthrolateral Asthenospermia Syndrome). Given the limited effectiveness of traditional drug treatments, neuromodulation strategies have become highly promising treatment approaches. For example, deep thalamic stimulation (DBS) can improve arousal and goal-oriented behavior in some patients, but the response rate remains moderate. Spinal cord stimulation (SCS) has gained attention as an alternative neuromodulation strategy for DOC; clinical studies show that approximately 30%–40% of patients experience behavioral or electrophysiological improvements after receiving chronic cervical SCS treatment. However, the response rates of these invasive therapies are only low to moderate and unstable. In the realm of non-invasive stimulation, repetitive transcranial magnetic stimulation (rTMS) via the dorsolateral prefrontal cortex can temporarily enhance cortical excitability and network connectivity. Similarly, transcranial direct current stimulation (tDCS) targeting the prefrontal cortex shows promise, but these non-invasive therapies typically only provide transient improvements, and inter-individual efficacy varies significantly.

[0004] Therefore, there is a need for an effective electrical stimulation system that provides stable therapeutic feedback and targets specific points. Summary of the Invention

[0005] To address the problems existing in the prior art, the purpose of this application is to provide a transnasal clivus ventral brainstem epidural electrical stimulation system. Its navigation unit acquires and determines the target point of the implanted electrode based on the subject's structural MRI and CT images. The implantation unit communicates with the navigation unit to establish an implanted electrode access pathway from outside the body to the target point of electrical stimulation, and cooperates with the navigation unit to guide the implanted electrode to the target point of electrical stimulation to perform discharge, providing stable and safe electrical stimulation for BRF and improving DOC symptoms.

[0006] Specifically, this application relates to the following aspects: A transnasal clival ventral brainstem epidural electrical stimulation system includes: a navigation unit that acquires structural magnetic resonance imaging (MRI) images and craniofacial CT images of the subject, fuses the MRI images and craniofacial CT images to establish a brain model of the subject, and determines the location of the clival bone window and the local clival bone thickness in the subject's brain model through registration; an implantation unit that communicates with the navigation unit to establish bilateral posterior nasal passages to create a bone window in the clivus of the skull base, guides the electrode through the bone window and fixes it to the electrical stimulation area; and an electrode including a discharge end, a fixator and an electrode lead, wherein the discharge end is fixed relative to the fixator and the electrode lead is used to connect to a stimulation current generator; wherein the electrical stimulation area is the ventral epidural space of the brainstem.

[0007] According to some implementation schemes, the implantation unit establishes bilateral posterior nasal passages to create a bone window on the clivus of the skull base, including: the implantation unit grinding away the anterior and inferior walls of the sphenoid sinus to expose the clivus of the skull base; the implantation unit obtaining the location of the clivus bone window and the local clivus bone thickness from the navigation unit, and determining the grinding depth based on the local clivus bone thickness; the implantation unit thinning the clivus of the skull base based on the location of the clivus bone window and the grinding depth to form a bone window thereon; wherein, the location of the clivus bone window corresponds to the midbrain location.

[0008] According to some implementation schemes, the bone window created by the implanted unit at the clivus of the skull base is 1~2 cm × 1~2 cm in size.

[0009] According to some implementation schemes, the process of guiding the electrode through the bone window and fixing it to the electrical stimulation area includes: the navigation unit continuously monitoring the navigation coordinates of the fixator in the brain model through sensors and sending the navigation coordinates to the implantation unit; the implantation unit determining the actual position of the discharge end in the subject's brain based on the navigation coordinates, clamping the discharge end through the bone window, and fixing the discharge end to the electrical stimulation area.

[0010] According to some implementation schemes, the navigation unit continuously monitors the navigation coordinates of the fixator in the brain model through sensors, including: the navigation unit determines the relative position of the discharge end and the fixator and sends it to the implantation unit; the navigation unit uses sensors to continuously collect optical or electromagnetic information emitted by the fixator in order to continuously determine the navigation coordinates of the fixator.

[0011] According to some implementation schemes, fixing the discharge end to the electrical stimulation area by the implantation unit includes: after determining that the discharge end has reached the electrical stimulation area, the implantation unit uses gelatin sponge and / or fibrin glue to fix the discharge end to the electrical stimulation area.

[0012] According to some implementation schemes, the implantation unit establishes bilateral posterior nasal passages by: incising the posterior nasal septum mucosa with the implantation unit to establish bilateral posterior nasal passages.

[0013] According to some implementation schemes, the navigation unit determines the location of the clivus fenestration and the local clivus thickness in the subject's brain model through registration, including: the navigation unit performs spatial location registration based on the positioning marks of the scanned subject's craniofacial region; the navigation unit aligns the coordinates of the subject's brain model with the physical coordinates through registration, determines the actual location of the clivus fenestration through the tip of the navigation needle, and measures the local clivus thickness on the subject's craniofacial CT image.

[0014] According to some implementation schemes, the diameter of the electrode is 1 mm to 4 mm, the discharge end has multiple contacts with a contact spacing of 2 mm to 6 mm, the length of the electrode is not less than 15 mm, and the width is 4 mm to 8 mm.

[0015] According to some implementation schemes, the transnasal clival ventral epidural electrical stimulation system also includes a display unit; the display unit is used to display the subject's brain model and the location of the clival bone fenestration, the local clival bone thickness, and / or the location of the electrodes.

[0016] The technical advantages of the transnasal epidural brainstem ventral epidural electrical stimulation system provided in this application are as follows: the system targets specific stimulation response sites in the ventral brainstem via the transnasal epidural route to perform neuroelectrical stimulation modulation, which can improve the arousal state of DOC subjects, especially those with severe DOC, making the system an effective DOC implantation intervention. Furthermore, the system provides stable and advanced intraoperative guidance and optimized electrode design to avoid complications such as cerebrospinal fluid leakage or neurovascular damage. The electrical stimulation provided by the system can therefore stably induce arousal signs, ensuring the effectiveness and safety of the intervention treatment it provides. Attached Figure Description

[0017] Figure 1 The illustration shows a schematic diagram of the architecture of a transnasal ventral brainstem epidural electrical stimulation system according to an embodiment of this application.

[0018] Figure 2 The illustration shows a schematic diagram of the application of the transnasal ventral brainstem epidural electrical stimulation system according to an embodiment of this application.

[0019] Figure 3 The diagram illustrates the modulation results of the transnasal ventral epidural electrical stimulation system for the brainstem according to an embodiment of this application.

[0020] Figure 4 The figure illustrates the first result of the modulation effect of the transnasal brainstem ventral epidural electrical stimulation system according to an embodiment of this application.

[0021] Figure 5 The figure illustrates a second result of the modulation effect of the transnasal brainstem ventral epidural electrical stimulation system according to an embodiment of this application.

[0022] Figure 6 The figure illustrates the third result of the modulation effect of the transnasal brainstem ventral epidural electrical stimulation system according to an embodiment of this application.

[0023] Figure 7 The figure illustrates the fourth result of the modulation effect of the transnasal brainstem ventral epidural electrical stimulation system according to an embodiment of this application.

[0024] Figure 8 The figure illustrates the fifth result of the modulation effect of the transnasal brainstem ventral epidural electrical stimulation system according to an embodiment of this application. Detailed Implementation

[0025] The present application is further illustrated below with reference to embodiments. It should be understood that the embodiments are only used to further illustrate and explain the present application and are not intended to limit the present application.

[0026] Unless otherwise defined, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, materials and methods are described herein. In case of conflict, the definitions included herein shall prevail. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. The present application is further described below with reference to specific embodiments, but is not intended to limit the scope of the application.

[0027] Application Overview As mentioned above, a common feature of current invasive electrical stimulation protocols is that stimulation acts on areas indirectly projecting to the ARAS, rather than directly modulating the key ARAS hub, the BRF. This raises the question: would acting more directly on the BRF result in more effective and reliable improvements in consciousness? To address this issue, several animal studies have directly intervened in brainstem structures, such as the midbrain tegmentum and pontine reticular nucleus, and observed improvements in consciousness levels. However, deep localization of brainstem nuclei requires longer puncture paths, increasing procedural risks. Furthermore, the small size of these nuclei demands extremely high localization precision, and the dense surrounding structures make direct electrical stimulation prone to adverse reactions. These factors limit the clinical application of such puncture techniques.

[0028] The system described in this application provides a technical solution for epidural electrical stimulation of the ventral brainstem via a naso-clival approach. This solution restores inhibited behavioral responsiveness and cortical activity by applying epidural electrical stimulation to the brainstem reflex (BRF) via the naso-clival approach from the ventral side of the brainstem. Given that the BRF consists of a broad network of nuclei and interwoven nerve fibers running through the brainstem, stimulating the peripheral brainstem region can more broadly activate the BRF compared to precisely locating specific points within the brain parenchyma, while reducing the risk of direct puncture damage to specific brainstem nuclei. The system creates an access route for implanting electrodes on the ventral surface of the brainstem via the nose. The implantation unit, guided by a navigation unit, performs bone resection along the pathway and fixes the implanted electrodes in a broad area entering the ventral side of the brainstem to implement epidural electrical stimulation. This increases the effective area for modulating the BRF and promotes stable cortical arousal, thus providing a more effective neuromodulation scheme for the brainstem reflex (DOC).

[0029] After introducing the basic principles and advantages of this application, various non-limiting embodiments of this application will be described in detail below with reference to the accompanying drawings.

[0030] Exemplary System Figure 1 The illustration shows a schematic diagram of the architecture of a transnasal ventral brainstem epidural electrical stimulation system according to an embodiment of this application.

[0031] refer to Figure 1 The transnasal ventral epidural electrical stimulation system for the brainstem according to an embodiment of this application includes the following components.

[0032] The navigation unit acquires structural magnetic resonance imaging (MRI) images and craniofacial CT images of the subject, and fuses the structural MRI images and craniofacial CT images to establish a brain model of the subject, so as to determine the location of the clival bone fenestration and the local clival bone thickness in the subject's brain model through registration.

[0033] The implanted unit, communicating with the navigation unit, is used to establish bilateral posterior nasal passages to create bone windows at the clivus of the skull base, guiding electrodes through the bone windows and fixing them to the electrical stimulation area. In this application, the electrical stimulation area is the ventral epidural space of the brainstem.

[0034] The electrode includes a discharge end, a fixator, and an electrode wire. The discharge end is fixed relative to the fixator, and the electrode wire is used to connect to the stimulation current generator.

[0035] In this application, the implantation unit establishes bilateral posterior nasal passages to create a bone window on the clivus of the skull base, comprising: the implantation unit grinding away the anterior and inferior walls of the sphenoid sinus to expose the clivus; the implantation unit obtaining the location and local thickness of the clivus bone opening from a navigation unit, and determining the grinding depth based on the local thickness of the clivus bone; and the implantation unit thinning the clivus based on the location and grinding depth to form a bone window thereon. Since the upper part of the clivus is obscured by the sphenoid sinus, it is necessary to remove the anterior and inferior walls of the sphenoid sinus, which helps to expose the upper part of the clivus bone for bone window creation. Therefore, in one example, the implantation unit includes a navigation drill used to grind away the anterior and inferior walls of the sphenoid sinus to expose the clivus. The bone window is located in the midbrain, and electrodes can reach the area of ​​electrical stimulation through the bone window.

[0036] In this application, the bone window created by the implanted unit at the clivus of the skull base has a size of 1-2 cm × 1-2 cm. This size facilitates the smooth delivery of the electrode discharge end to the electrical stimulation area and its fixation.

[0037] In this application, the process of guiding the electrode through the bone window and fixing it to the electrical stimulation area by the implantation unit includes: a navigation unit continuously monitoring the navigation coordinates of the fixator in the brain model via sensors and sending the navigation coordinates to the implantation unit; the implantation unit determining the actual position of the discharge terminal in the subject's brain based on the navigation coordinates, clamping the discharge terminal through the bone window, and fixing the discharge terminal to the electrical stimulation area. In one example, the implantation unit also includes an endoscope, which can provide visual assistance in positioning throughout the entire process of establishing a stimulation channel through the ventral epidural space of the brainstem via the nasoclavicular region and / or throughout the entire electrode fixation process, or at least part of the process.

[0038] In this application, the navigation unit continuously monitors the navigation coordinates of the fixator in the brain model through sensors, including: the navigation unit determines the relative position of the discharge end and the fixator and sends it to the implantation unit; the navigation unit uses sensors to continuously collect optical or electromagnetic information emitted by the fixator in order to continuously determine the navigation coordinates of the fixator.

[0039] In this application, fixing the discharge end of the implanted unit to the electrical stimulation area includes: after determining that the discharge end has reached the electrical stimulation area, the implanted unit uses gelatin sponge and / or fibrin glue to fix the discharge end to the electrical stimulation area.

[0040] In this application, the implantation unit establishes bilateral posterior nasal cavity passages by incising the posterior nasal septum mucosa. In one example, the implantation unit further includes an electrocautery hook, which is used to incise the posterior nasal septum mucosa to establish bilateral posterior nasal cavity passages, facilitating subsequent drilling to create a bone window.

[0041] In this application, the navigation unit determines the location of the clivus fenestration and the local clivus thickness in the subject's brain model through registration, including: the navigation unit performs spatial location registration based on the positioning marks of the scanned subject's craniofacial region; the navigation unit aligns the coordinates of the subject's brain model with the physical coordinates through registration, so as to determine the actual location of the clivus fenestration through the tip of the navigation needle, and measures the local clivus thickness on the subject's craniofacial CT image.

[0042] In this application, the diameter of the electrode is 1 mm to 4 mm, the discharge end has multiple contacts, and the contact spacing is 2 mm to 6 mm; the length of the electrode is not less than 15 mm, and the width is 4 mm to 8 mm.

[0043] In this application, the transnasal brainstem ventral epidural electrical stimulation system further includes a display unit for displaying the subject's brain model and the location of the clival bone fenestration, the local clival bone thickness, and / or the location of the electrodes.

[0044] The following will describe, through exemplary embodiments, a specific implementation of the transnasal clivus ventral brainstem epidural electrical stimulation system of this application to perform epidural electrical stimulation on BRF in order to improve inhibited behavioral responsiveness and cortical activity.

[0045] like Figure 2 As shown, three sheep were used as experimental animals to test the intervention effect of the transnasal clivus ventral brainstem epidural electrical stimulation system on DOC according to the embodiments of this application. All procedures were approved by the Laboratory Animal Care Management Team of the Institutional Animal Care and Use Committee.

[0046] Specifically, structural magnetic resonance imaging (MRI) scans were performed on anesthetized experimental animals using a 3T scanner (Prisma, Siemens, Germany) equipped with a 64-channel head coil to aid in surgical planning and navigation. Three-dimensional T1-weighted images of the animals were acquired using MPRAGE sequences with the following parameters: TR = 2300 ms, TE = 2.32 ms, flip angle = 8°, slice thickness = 0.9 mm, field of view = 256 mm × 256 mm, voxel size = 0.9 mm. 3 × 0.9 mm 3 × 0.9mm 3 Images were acquired using a 3D T2-weighted SPACE dark liquid sequence with the following parameters: TR = 5000 ms, TE = 394 ms, flip angle = 120°, slice thickness = 1.0 mm, field of view = 256 mm × 240 mm, and voxel size = 1.0 mm. 3 × 1.0mm 3× 1.0 mm 3 .

[0047] On the day of surgery, five bone screws were percutaneously implanted into the craniofacial bones of each animal as positioning markers. The implantation process employed the same anesthesia protocol as the MRI acquisition. These positioning markers, used for image registration, were employed for intraoperative registration of the brain model based on image fusion with the actual physical brain model. Subsequently, each animal underwent a craniofacial CT scan. Preoperative MRI and CT images were imported into the NS1 surgical navigation system (Sinovation, Beijing, China) as navigation units for multimodal image fusion. After anesthesia and head fixation, spatial registration between the brain model and the physical brain model was achieved using the pre-implanted positioning markers, ensuring accurate intraoperative positioning. Following intravenous induction of anesthesia, endotracheal intubation was performed, and mechanical ventilation was initiated to maintain adequate respiration. An electrocardiogram monitor was connected to the animals, and a dual-spectral index (BIS) sensor was attached to the craniofacial region of each animal to monitor the depth of anesthesia in real time. Figure 3 As shown in section (A). Throughout the procedure, the animals were kept under anesthesia by passive inhalation of isoflurane at a concentration of 2.3% to 2.5% to simulate the coma symptoms of DOC.

[0048] After anesthesia, the animal was placed in a prone position with its head fixed to a head frame. Following successful navigation and positioning using the fused and registered brain model, the implanted unit's fixing electrodes were positioned at the designated locations. Specifically, a nasal endoscope was inserted into the right nasal cavity and advanced along the inferior turbinate to the posterior nasal cavity. Under endoscopic guidance, an electrocautery hook was used to incise the posterior nasal septum mucosa, establishing bilateral posterior nasal cavity passages. A high-speed drill was used to remove the anterior and inferior walls of the sphenoid sinus, exposing the clivus. The aforementioned brain model and positioning markers were used to locate the animal's ventral midbrain and pons, and the clivus bone thickness at the drill site was measured as a reference. Subsequently, the clivus was further thinned using a drill to create a bone window of approximately 1 cm × 2 cm to expose the ventral dura mater, such as... Figure 3 As shown in section (B). A separator can be used to carefully separate the adhesions between the dura mater and the clivus while maintaining the integrity of the dura mater. Guided by the brain model and localization markers, a strip electrode of appropriate size is selected: 1.5 mm in diameter, 5 mm in contact spacing, 20 mm in length, and 5 mm in width. Its discharge end is inserted into the epidural space. Insertion can be achieved by using forceps to hold the strip electrode through a bone window, with endoscopy as an aid. Figure 3 As shown in section (C). After the strip electrode reaches the epidural space, it is pressed with gelatin sponge and fibrin glue is sprayed around it. After the glue is applied, the strip electrode can be fixed in the epidural space.

[0049] After the strip electrode is fixed in place, the nasal mucosal flap can be repositioned to cover the electrode and gently packed into the nasal cavity. The electrode leads of the strip electrode are fixed through the nasal cavity and led out to a neurostimulator that generates a stimulating current. In one example, the neurostimulator includes a signal generator that generates a stimulation waveform and a constant current source that generates a stimulating current based on the stimulation waveform. The output of the constant current source is electrically connected to the electrode leads of the strip electrode.

[0050] Next, to evaluate the intervention effect of strip electrodes providing electrical stimulation to the epidural space on DOC coma symptoms in animals, scalp incisions were planned under the navigation guidance of a brain model and localization markers to implant bilateral cortical recording electrodes, and the animals' electroencephalographic activity was assessed. Specifically, burr holes were drilled in the bilateral frontal lobes of the animals using a craniotomy drill, and the bone windows were enlarged with a milling cutter to expose the dura mater. The dura mater was carefully incised, and two 2 × 8 subdural strip electrodes were placed on the surface of the bilateral frontoparietal cortex, as shown in the image. Figure 3 As shown in section (D), the electrode leads were fixed to the dura mater with sutures, the bone defect was filled with gelatin sponge, and then the scalp incision was sutured. The bilateral cortical recording electrodes were connected to the data acquisition system (NIM-ECLIPSE, model NS32, Medtronic).

[0051] Ten repetitive epidural electrical stimulation (ECoG) trials were conducted using the system. In each trial, continuous electrocorticography (ECoG) activity was recorded for 90 seconds prior to stimulation as a baseline, followed by 30 seconds of stimulation: the stimulation current was set to an amplitude of 5 mA, a single pulse duration of 100 μs, and a frequency of 100 Hz. Finally, EEG activity was recorded for 2 minutes after stimulation. An interval of approximately 4 minutes between stimulations was ensured to minimize the potential residual effects of the previous stimulation. In addition, a dedicated evaluator unaware of the research hypothesis was asked to rate the animals' arousal behaviors using a modified Animal Arousal Assessment Scale, including environmental exploration (0: none; 1: slight search for external cues; 2: full environmental survey), spontaneous movement (0: none; 1: slight trunk and / or limb movements; 2: large trunk and / or limb movements), shaking / touching (0: no response; 1: slight body movements; 2: large trunk movements), toe-clamping response (0: no response; 1: trunk movements or eyelid blinking or heart rate changes; 2: trunk movements with eyelid blinking or eye opening and heart rate changes), eye-opening response (0: no response; 1: slight blinking or eye movements; 2: full eye opening), and corneal reflex (0: absent; 1: present). To avoid interference with post-stimulation EEG recording, behavioral assessments were conducted only during 30-second stimulation periods, 10 times in total.

[0052] After acquiring experimental data from the recording electrodes, transient spikes were first detected and repaired by calculating a dynamic threshold of three times the standard deviation of the values ​​for each electrode channel. Signal segments exceeding this threshold were identified as artifacts and corrected using linear interpolation to mitigate electrode transients or amplifier saturation effects. Subsequently, a 6th-order Butterworth low-pass filter with a zero-phase bidirectional filter and a cutoff frequency of 250 Hz was applied to eliminate high-frequency noise while maintaining phase integrity. A 3rd-order Butterworth band-stop filter with a stopband of 48-52 Hz was then used to suppress 50 Hz power line interference. To handle non-stationary pulse noise induced by electrical stimulation, a sliding median filter with mirror-filled boundaries (15-point sliding window) was used to minimize edge artifacts. Finally, a bipolar lead reference scheme was implemented at all recording points, which suppressed common reference electrode interference and enhanced the spatial specificity of local signal variations.

[0053] Then, ECoG recordings were divided into time periods based on the stimulus initiation, with the zero point corresponding to the stimulus start time. A time window of -30 s to +150 s was extracted for each trial, covering the pre-stimulation baseline period (-30 s to 0), the stimulation period (0 to 30 s), and the post-stimulation recording period (30 s to 150 s). The absolute time-frequency power for each trial was obtained using a Short Time Fourier Transform (STFT) with a 2-s Hanning window and a 75% window overlap to minimize inter-frame information loss. The Fast Fourier Transform (FFT) points were set to the nearest power of 2 to ensure consistency in frequency binning during analysis. This analysis covered the 0 to 50 Hz frequency range to capture the dynamic characteristics of the animals' main neural oscillatory rhythms.

[0054] To quantify the relative power changes induced by electrical stimulation in the system, event-related spectrum (ERSP) analysis was further performed. First, the average power at each frequency was calculated during the baseline period (-30 s to 0). P baseline ( f Then, the power value at each time frequency point is... P ( t , f The following formula is used to convert the results to decibels relative to the baseline average power. Finally, the average of all test results is taken to obtain the average time-frequency spectrum for each cortical recording contact point. ERSP ( t , f ) (dB) : (Formula 1) To summarize the overall response pattern across all contact points and frequency bands, ERSP values ​​were averaged over a post-stimulus effect window of 30 to 60 seconds and divided into predefined frequency bands: delta band (0 Hz to 4 Hz), low theta band (4 Hz to 6 Hz), high theta band (6 Hz to 9 Hz), alpha band (9 Hz to 14 Hz), beta band (14 Hz to 35 Hz), low gamma band (35 Hz to 55 Hz), mid gamma band (55 Hz to 85 Hz), and high gamma band (85 Hz to 125 Hz).

[0055] Finally, to compare the power differences across frequency bands before and after electrical stimulation, the mean absolute power values ​​within a 30-second time window before and after each stimulation were extracted, followed by a paired-samples t-test. Given the locational differences in the contact points of the recording electrodes among different experimental animals, but considering that the first five rows of electrodes in all three animals were located in the frontal lobe and the last three rows in the parietal lobe, all cortical monitoring electrodes were divided into four anatomical regions: left frontal lobe, right frontal lobe, left parietal lobe, and right parietal lobe, for statistical analysis. The statistical significance threshold was set at p < 0.05.

[0056] The results showed that, guided by the navigation unit, the implantation of transnasal-clival epidural electrodes was successfully completed in all three experimental animals, with adequate exposure of the ventral brainstem dura mater and no cerebrospinal fluid leakage or vascular damage. Postoperative CT scans were performed. Figure 3 The reconstruction of the strip electrode's position in the brain model confirmed its correct implantation location at the sphenoid ridge and the reasonable positioning of the recording electrodes used for evaluation. Figure 3 As shown in sections (E), (F), (G), and (H), the first five rows of recording electrodes cover the surface of the frontal lobe, and the last three rows of recording electrodes cover the surface of the parietal lobe.

[0057] Following epidural ventral brainstem electrical stimulation, experimental animals showed a significant improvement in their arousal assessment scale scores. The scale scores exhibited an upward trend over 10 repetitions of stimulation, indicating a cumulative effect of electrical stimulation on improving coma. Figure 4 As shown, the score improvement was primarily attributed to spontaneous movements of the animal's trunk and limbs, as well as toe-pinching induced motor responses and eyelid blinking.

[0058] ERSP analysis results showed that, compared with the pre-stimulation baseline, the post-stimulation EEG signals in animals exhibited a stable pattern of significantly decreased low-frequency (δ, θ, α) power and significantly increased high-frequency (β, γ) power, such as... Figure 5 As shown. This power modulation induced by electrical stimulation is bilateral and widely distributed across multiple brain regions, with the most significant effect appearing in the bilateral frontal lobes, primarily manifested as a decrease in low-frequency (δ, θ) power, such as... Figure 6 , Figure 7 and Figure 8 As shown in the above evaluation results, the system can successfully induce measurable behavioral arousal responses in experimental animals through effective electrical stimulation, accompanied by cortical electrophysiological changes leading to a state of wakefulness. This indicates that the transnasal clivus epidural electrical stimulation provided by the system can directly modulate the brainstem-cortex DOC arousal circuit.

[0059] The transnasal clivus ventral brainstem epidural electrical stimulation system provided in this application delivers reliable epidural stimulation of the ventral brainstem via the nasal route. By meticulously removing local bone from the clivus and then applying epidural stimulation, it achieves close-range modulation of the brainstem BRF region, demonstrating an innovative modulation paradigm from the nasal cavity to the brain in this field. Through repetitive stimulation via this route, the system successfully induced measurable behavioral arousal responses, accompanied by cortical electrophysiological changes leading to a state of wakefulness. This demonstrates that the transnasal epidural stimulation of the ventral brainstem via the system can directly modulate the brainstem-cortical arousal circuit and improve DOC symptoms.

[0060] The basic principles of this application have been described above with reference to specific embodiments. However, it should be noted that the advantages, benefits, and effects mentioned in this application are merely examples and not limitations, and should not be considered as essential features of each embodiment of this application. Furthermore, the specific details disclosed above are for illustrative and facilitative purposes only, and are not limitations. These details do not limit the application to the necessity of employing the aforementioned specific details for implementation.

[0061] The block diagrams of devices, apparatuses, devices, and systems involved in this application are merely illustrative examples and are not intended to require or imply that they must be connected, arranged, or configured in the manner shown in the block diagrams. As those skilled in the art will recognize, these devices, apparatuses, devices, and systems can be connected, arranged, and configured in any manner. Words such as “comprising,” “including,” “having,” etc., are open-ended terms meaning “including but not limited to,” and are used interchangeably with them. The terms “or” and “and” as used herein refer to the terms “and / or,” and are used interchangeably with them unless the context clearly indicates otherwise. The term “such as” as used herein refers to the phrase “such as but not limited to,” and is used interchangeably with it.

[0062] It should also be noted that in the apparatus, equipment, and methods of this application, the components or steps can be disassembled and / or recombined. These disassemblies and / or recombinations should be considered as equivalent solutions of this application.

[0063] The above description of the disclosed aspects is provided to enable any person skilled in the art to make or use this application. Various modifications to these aspects will be readily apparent to those skilled in the art, and the general principles defined herein can be applied to other aspects without departing from the scope of this application. Therefore, this application is not intended to be limited to the aspects shown herein, but rather to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0064] The above description has been given for purposes of illustration and description. Furthermore, this description is not intended to limit the embodiments of this application to the forms disclosed herein. Although numerous exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain variations, modifications, alterations, additions, and sub-combinations thereof.

Claims

1. A transnasal clivus ventral brainstem epidural electrical stimulation system, characterized in that, include: The navigation unit acquires structural magnetic resonance imaging (MRI) images and craniofacial CT images of the subject, and fuses the structural MRI images and craniofacial CT images to establish a brain model of the subject, so as to determine the location of the clivus bone fenestration and the local clivus bone thickness in the subject's brain model through registration. The implanted unit communicates with the navigation unit and is used to establish bilateral posterior nasal passages in order to create a bone window at the clivus of the skull base, guide the electrode through the bone window and fix it to the electrical stimulation area; An electrode includes a discharge end, a fixator, and an electrode wire. The discharge end is fixed relative to the fixator, and the electrode wire is used to connect to a stimulation current generator. The area to be electrically stimulated is the epidural space on the ventral side of the brainstem.

2. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, wherein, The implanted unit establishes bilateral posterior nasal passages to facilitate the creation of a bone window at the clivus of the skull base, including: The implanted unit removes the anterior and inferior walls of the sphenoid sinus to expose the clivus of the skull base; The implantation unit obtains the location of the cleft bone opening and the local cleft bone thickness from the navigation unit, and determines the removal depth based on the local cleft bone thickness; The implantation unit thins the skull base slope to form a bone window thereon, based on the location and depth of the slope bone windowing. The location of the sloping bone fenestration corresponds to the midbrain location.

3. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 2, wherein, The bone window created by the implanted unit at the clivus of the skull base has a size of 1~2 cm × 1~2 cm.

4. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, wherein, The implanted unit guiding electrode passes through a bone window and is fixed to the electrical stimulation area, including: The navigation unit continuously monitors the navigation coordinates of the fixator in the brain model through sensors and sends the navigation coordinates to the implantation unit; The implanted unit determines the actual position of the discharge terminal in the subject's brain based on the navigation coordinates, so as to clamp the discharge terminal through the bone window and fix the discharge terminal to the electrical stimulation area.

5. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 4, wherein, The navigation unit continuously monitors the navigation coordinates of the fixation device in the brain model via sensors, including: The navigation unit determines the relative position of the discharge terminal and the fixator and sends it to the implantation unit; The navigation unit uses sensors to continuously collect optical or electromagnetic information emitted by the fixation device in order to continuously determine the navigation coordinates of the fixation device.

6. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 4, wherein, The implantation unit fixes the discharge end to the electrically stimulated region, including: After determining that the discharge end has reached the electrical stimulation area, the implanted unit uses gelatin sponge and / or fibrin glue to fix the discharge end to the electrical stimulation area.

7. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, wherein, The implanted unit establishes bilateral posterior nasal cavity passages, including: The implanted unit cuts the posterior nasal septum mucosa to create bilateral posterior nasal passages.

8. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, wherein, The navigation unit determines the location of the clival bone fenestration and the local clival bone thickness in the subject's brain model through registration, including: The navigation unit performs spatial location registration based on positioning markers scanned on the subject's craniofacial region; The navigation unit aligns the subject's brain model coordinates with physical coordinates through registration, determines the actual location of the clivus bone fenestration using the tip of the navigation needle, and measures the thickness of the local clivus bone on the subject's craniofacial CT image.

9. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, wherein, The diameter of the electrode is 1 mm to 4 mm, and the discharge end has multiple contacts with a contact spacing of 2 mm to 6 mm. The electrode is at least 15 mm long and 4 mm to 8 mm wide.

10. The transnasal clivus ventral brainstem epidural electrical stimulation system according to claim 1, further comprising a display unit; The display unit is used to display the subject's brain model and the location of the clival bone fenestration, the local clival bone thickness, and / or the location of the electrodes.

Images