CN116115904A - Central nerve stimulation system - Google Patents

Abstract

The invention discloses a central nervous stimulation system, which comprises a control unit, a stimulation generating unit, a stimulation receiving unit and a stimulation receiving unit, wherein the stimulation receiving unit is implantable. The control unit comprises an executable program capable of programming central nerve stimulation wave, the stimulation generating unit is a programmable pulse generator/stimulation isolator, and the stimulation program edited by the stimulator can repeatedly apply transcranial magnetic stimulation to the motor cortex, so that the motor function of the forelimbs of the patient with spinal cord injury can be better recovered. Most spinal cord injury patients have injury sites at the cervical spine, and some nerve functions below the injury site survive. For these patients, their primary task is to restore the function of the arms and hands. Most spinal injuries keep some connection below the injury part, even those without standby functions, the recovery of the motor functions of the arms or fingers of a patient can be obviously improved through paired motor cortex stimulation, and the spinal injuries have important clinical guiding significance.

Description

Central nerve stimulation system

Technical Field

The present invention relates to the field of nerve electrical stimulation, and more particularly to a central nerve stimulation system for improving recovery after a neurological disorder such as Spinal Cord Injury (SCI) after a trauma.

Background

In the united states, approximately 28.8 tens of thousands of people suffer from spinal cord injury, almost half (47.2%) of which occurs at the cervical level and some neural function (NSCISC, 2018) is retained below the site of injury. For cervical spine injury patients, their primary task is restoration of arm and hand function (Anderson, 2004). Most spinal cord injuries retain some of the links below the site of injury, even in those without sparing function (Shermwood et al, 1992; dimitrijevic et al, 1984; dimitrijevic et al, 1983; bunge et al, 1993; kakulas and Kaelan, 2015). Our approach has been to electrically stimulate the downstream motor connections without damage to promote connectivity. Functional recovery for alternate cortical separation junctions may be performed by either phased electrical stimulation of the motor cortex (calmel and martin, 2014; calmel et al, 2010) or stimulation of the spinal cord (Gerasimenko et al, 2007). Stimulation of the spinal cord and brain in a coordinated manner may potentially selectively strengthen the link between them (Harel and Carmel, 2016).

In humans, the primary system controlling autonomous locomotion, the corticospinal system, is also the most prominent system that leads to loss of function upon injury. Because of its importance in health and disease, the corticospinal tract (CST), which directly connects the motor cortex and the spinal cord, has been the main target of injury and repair research.

The corticospinal system is the main way we turn our ideas into actions. CST is highly adapted to limb control, particularly hand and forelimb control, as the sole cortical-based motion path. The size of CST and its functional importance is highly correlated with forelimb or hand dexterity (Iwaniuk et al, 1999). As a downlink motor system derived from the cortex, CST can obtain sensory input and an internal framework of a motor plan.

Control signals are then sent to execute the plan. The massive loss of function associated with CST lesions underscores its importance. Stroke (Stinear et al 2007;Lindenberg et al, 2012) and spinal cord injury (Raineteau and Schwab, 2001), the extent of CST injury can be well predicted for the resulting motor injury.

Motor cortex stimulation of humans using electrical stimulation (carboel et al, 2010, 2013, 2014). This results in an increase in the activity of a well-defined motor system, the cortical separation system, which includes direct spinal cord projection and cortical projection to the brain stem (Carmel et al, 2013). The corticospinal motor system stimulation contrasts with the use of behavioral approaches such as forced induction motor therapy (CIMT), which may alter the activation patterns of multiple motor and somatosensory pathways and primary afferent fibers (Mark et al, 2006). At the same time, motor cortex stimulation produced a large increase (3-5 fold) in axonal density. Furthermore, a selective increase in the terminal density of cortical erythrocyte axons was also observed in the putative forelimb region of the contralateral large cell erythrocyte.

In the field of recovery after neurological diseases such as Spinal Cord Injury (SCI), such as after trauma, neurostimulation systems are improved, in particular neuromodulation or neurostimulation can be provided in an autonomously regulated manner, to accommodate patient needs and to provide assistance to the patient for the required training and daily life, and to adjust to the patient's progress in rehabilitation.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a central nervous stimulation system.

The invention is realized by the following technical scheme:

a central nervous system stimulation system comprising:

at least one control unit;

at least one stimulus generating unit;

at least one stimulus receiving unit;

wherein the stimulation unit is implantable.

The control unit comprises an executable program capable of programming the central nerve stimulation wave.

The control unit executable is c++ written using the Arduino development environment, with an Arduino compatible Stimjim library, allowing low level device control, writing registers in the DAC or ADC, or setting stimulus control modes.

The stimulus generating unit is a programmable pulse generator/stimulus isolator (similar to STG-4002 of a multi-channel system) and the pulse amplitude of the stimulus generating unit is controlled by a USB cable connected to the stimjim program.

The stimulation generating unit is a current and voltage stimulator for stimulating nerve tissues, and is a flexible, accurate and cheap open-source stimulator.

The stimulation generating unit is an electric isolation stimulation generator and is a microcontroller board based on Teensy 3.5, and a 32-bit Arm 55 Cortex-M4F processor is used, so that the operating frequency is 120 MHz.

The stimulation generating unit comprises a USB interface, two green indicator lamps, two BNC connectors for inputting 1 and 2 and two independently controllable electric stimulation output channels, wherein the USB interface is connected with the control unit; the two green indicator lamps flash for half a second when the control unit is connected with the stimulation generating unit, and the connection is successful; the BNC connectors of the two inputs 1 and 2 receive external electric stimulation input to form a closed loop system; the two independently controllable electrical stimulation output channels each having a current and voltage output mode.

The stimulation receiving unit is composed of two brain stimulation electrodes, one part of which is implanted into the sports cortex and the other part of which is exposed.

The stimulus receiving unit is anchored to the head by means of medical dental cement.

The stimulation receiving unit consists of a connector wiring socket of the connector, a connector wiring terminal of the connector, an electrode wire without an insulating layer and a screw with the diameter of 1.2 mm.

The control unit is capable of independently controlling and switching on and off the stimulus generating unit.

The invention can perform stimulation programming autonomously, and can generate complex stimulation waves compared with the traditional stimulator.

Compared with the traditional invasive stimulation method, the method has the advantages that firstly, the influence on the basic life of a patient is smaller, and secondly, the damage to the patient is smaller, and the used stimulation electrode consists of two stainless steel screws (with the diameter of 1.2mm and plastics). An insulated stainless steel wire connects the screw to the plastic connector, partially implanted into the athletic cortex and partially exposed. Initial studies used "L" shaped wire electrodes to stimulate the motor cortex, fixed with dental cement (Carmel et al, 2010, 2013;Carmel et al, 2014). This was altered in replication studies by using screw electrodes, which can be placed faster and with less likelihood of damaging underlying dural material (Garcia-Sandoval et al, 2018; mishra et al, 2017). Attempts were made to determine whether stimulating the cortex with a spiral electrode was similar to the physiological effects caused by an "L" shaped electrode. We have previously observed that the change in shape of the stimulation electrode has no effect on the stimulation effect (Carmel et al, 2010). The electric stimulator for central motor nerve is one kind of flexible, accurate and cheap open source stimulator with two independently controllable output channels, each with current and voltage output modes and total cost: 200. dollars. Output range in current mode: -3.33mA to +3.33mA. Output range in voltage mode: 15V to 15V. The compliance voltage in current mode with pulse width as low as 0.02 ms (using default firmware configuration) is + -13.7V (output may be +/-3.33uA for resistances up to 4k and + -137uA for resistances up to 100 k), powered by USB, channel and power supply and isolated from each other. The on-board ADC measures the actual output current or voltage.

The electrostimulator software for the central motor nerve was written in c++ using the Arduino development environment. We provide an Arduino compatible Stimjim library that allows low level device control (writing registers in the DAC or ADC, or setting stimulus control modes). Library functions enable a user to create new programs to run on Stimjim-e.g., to generate custom waveform outputs that are stored on an on-board SD card. We also provide a default program using the library that can generate a user-defined pulse sequence. The user sets the parameters of the pulse sequence and reads the measured pulse amplitude through a serial connection on the USB. Burst parameters-include the output mode (current or voltage), frequency, duration, and amplitude of each phase of the pulse itself. Stimjim can store definitions of 100 bursts simultaneously, and the user can select and initiate a particular burst.

Hu Na et al show that the unidirectional pulse acts more strongly than the bi-directional pulse in brain stimulation studies, but that unidirectional pulses may cause damage to nerve tissue, so that bi-directional pulses should be used for long-term high frequency stimulation therapy.

In view of this, the present invention employs intermittent θ pulse stimulation (irbs) at the forelimb region of the motor cortex, which is delivered through implanted cortical electrodes, providing stimulation for 5 periods (1630 seconds total). Each period was 360 seconds long, containing 20 repeated stimulations (200 seconds of stimulation total, 160 seconds of interstitial phase). Each repetition amounted to 10s, including 2s stimulation and 8s interstitial phase. Each 2 second stimulus included 10 stimuli. Each pulse train consisted of 3 pulses (200 mus, biphasic pulse, interstitial interval: 50 ms). The intensity was set at 75% of the motion threshold.

The invention has the advantages that: the invention applies transcranial magnetic stimulation repeated by the stimulation program edited by the stimulator to the sports cortex, so that the motor function of the forelimb of the patient with spinal cord injury can be better recovered. The invention can obviously improve the recovery of the movement function of the arms or fingers of a patient through paired movement cortex stimulation, and has important clinical guiding significance.

The present invention improves the neurostimulation system in the field of recovery after neurological diseases such as Spinal Cord Injury (SCI), such as after trauma, and in particular, can provide neuromodulation or neurostimulation in an autonomously regulated manner, adapt to the needs of the patient and assist in the training and daily life required by the patient, and adjust according to the patient's progress in rehabilitation.

Drawings

FIG. 1 is a block diagram of a minimally invasive central nerve stimulator system;

FIG. 2 is a flow chart of a method of minimally invasive central nerve stimulation;

FIG. 3 is a schematic diagram of a micro-invasive CNS stimulating electrode structure;

FIG. 4 is a schematic diagram of a stimulus wave of a micro-invasive CNS stimulator system;

FIG. 5 is a graph showing the effect of a micro-invasive CNS stimulator system (IBB behavioural task test in FIG. 5a, lateral ladder walking task in FIG. 5 b).

Detailed Description

As shown in fig. 1, a central nerve stimulation system includes:

at least one control unit 1;

at least one stimulus generating unit 2;

at least one stimulus receiving unit 3;

wherein the stimulus receiving unit 3 is implantable.

The control unit 1 comprises an executable program capable of programming the central nerve stimulation wave.

The executable program of the control unit 1 is written in c++ using the Arduino development environment, with a Stimjim library compatible with Arduino, allowing low-level device control, writing registers in DAC or ADC or setting stimulus control modes.

The stimulus generating unit 2 is a programmable pulse generator/stimulus isolator (similar to STG-4002 of a multi-channel system), the pulse amplitude of the stimulus generating unit 2 being controlled by a USB cable connection to the stinjim program.

The stimulation generating unit 2 is a current and voltage stimulator for stimulating nerve tissue, and is a flexible, accurate and inexpensive open source stimulator.

The stimulation generating unit 2 is an electric isolation stimulation generator and is a micro-controller board based on teensy 3.5, and a 32-bit Arm 55 Cortex-M4F processor is used, and the running frequency is 120 MHz.

The stimulation generating unit 2 comprises a USB interface 4, two green indicator lamps 5, two BNC connectors 6 for inputting 1 and 2 and two independently controllable electric stimulation output channels 7, wherein the USB interface 4 is connected with the control unit 1; the two green indicator lamps 5 flash for half a second when the control unit 1 is connected with the stimulation generating unit 2, and the connection is successful; the BNC connectors 6 of the two inputs 1 and 2 receive external electric stimulation input to form a closed loop system; the two independently controllable electrical stimulation output channels 7 each having a current and voltage output mode.

The stimulation receiving unit 3 is two brain stimulation electrodes, one part of which is implanted into the sports cortex and the other part of which is exposed.

The stimulus receiving unit 3 is anchored to the head by means of medical dental cement.

The stimulation receiving unit 3 consists of a connector wiring socket 8, a connector wiring terminal 9, an electrode wire 10 without an insulating layer and a screw with the diameter of 1.2 mm.

The control unit 1 is capable of independently controlling and switching on and off the stimulus generating unit 2.

Fig. 1 shows in schematic form a component according to the invention comprising: a control unit 1, a stimulation generation unit 2, a stimulation reception unit 3, wherein the stimulation reception unit 3 in a component of the central nervous stimulation system is implantable. The control unit 1 contains an executable program capable of central nerve stimulation wave programming, the stimulation generating unit 2 is a programmable pulser/stimulation isolator (similar to STG-4002 of a multi-channel system) whose pulse amplitude can be controlled by a program to which a USB cable is connected, named stinjim.

The control unit 1 is controlled by using a stimjim software, the stimulation generating unit 2 is a stimjim stimulator, a stimulation mode of combining software and hardware is adopted, a computer outputs a digital signal, the stimulator converts the digital signal into an electric signal, and the stimulator can output isolated constant current or constant voltage. Most extracellular stimuli use a constant current, since if the resistance of the stimulating electrode is for any reason, including electrode polarization, the delivered current will not theoretically change. StimJIm can output a biphasic current pulse with no gap period. Furthermore, the last phase of stimulation may be reduced in amplitude and extended in duration to ensure that the first phase of stimulation is the phase of stimulation of the axon. Importantly, stimJim will emit an output signal between pulses. This prevents leakage current between pulses, which may be a problem for stimulus isolators without this capability. This biphasic current pulse output plus the output ground between pulses eliminates electrode polarization and ensures reliable sustained stimulation.

Fig. 2 is a flow chart illustrating an embodiment of how to operate a neuromodulation or neurostimulation system according to the present invention.

In step S1, the screw electrode illustrated in fig. 3 is implanted into the cerebral motor cortex and fixed to the head using medical dental cement.

In step S2, the motor threshold, i.e. the minimum electrical intensity required to initiate movement of a particular contralateral forelimb, of each rat of the stimulation group is confirmed.

In step S3, the control unit 1 is debugged to stimulate the program, set the stimulation parameters, and the intensity is set to 75% of the exercise threshold.

In step S4, the obtained digital signal is transferred to a stimulation unit to convert the stimulator into an electrical signal.

In step S5, the electrical signals are transmitted to the two electrodes through two interfaces of the two independently controllable electrical stimulation output channels and the wires.

Fig. 3 is a schematic illustration of electrodes of a stimulus receiving unit, each electrode consisting of two stainless steel screws (diameter 1.2, mm, plastic). An insulated stainless steel wire connects the screw to the plastic connector, partially implanted into the athletic cortex and partially exposed. Initial studies used "L" shaped wire electrodes to stimulate the motor cortex, with cementation of the dental caps (Carmel et al, 2010, 2013;Carmel et al, 2014). We altered this by using screw electrodes in replication studies, which can be placed faster and with less likelihood of damaging underlying dural material (Garcia-Sandoval et al, 2018; mishra et al, 2017). We have attempted to determine if stimulating the cortex with a spiral electrode is similar to the physiological effects caused by an "L" shaped electrode. We have previously observed that the change in shape of the stimulation electrode has no effect on the stimulation effect (Carmel et al, 2010).

Fig. 4 shows the stimulus wave output from the control unit 1, using intermittent theta pulse stimulation (iTBS) which provides 5 periods of stimulation (1630 seconds total): plot D. Each period was 360 seconds long, containing 20 repeated stimulations (200 seconds total stimulation, 160 seconds interstitial phase). Each repetition was 10s total, including 2s stimulation and 8s interstitial phase, and 10 stimulations were included every 2 seconds of stimulation: panel B. Each pulse train consisted of 3 pulses, panel a (200 mus, biphasic, interstitial spacing: 50 ms). The intensity was set at 75% of the motion threshold.

Fig. 5 is a graph of intermittent theta pulse stimulation effect, and the left graph is an IBB behavioural task test. IBB scores of rats were averaged. At each time point, IBB score is the average of four grains. The red and blue thick lines are the average IBB scores for all stimulated and control groups, respectively. The light red and blue thin lines represent the individual stimulated and control rats, respectively. Score 9 before injury. On week 7, control rats had an average grip method that was different from baseline, where their forepaws were unable to conform to the grain shape, with only one finger contributing to handling, and therefore IBB scores of 5.2±2.6. In contrast, the average score of stimulated rats was 7.2±0.8, as their front paws could conform to the shape of the cereal and had a similar grip to that before injury. At the end of the evaluation, the stimulated group of rats performed significantly better in the food manipulation task than the control group of rats. The right graph is a horizontal ladder walking task, and we quantify the error rate of the horizontal ladder walking task before and 4-7 weeks after injury. 7 weeks after spinal cord injury, the stimulated rats showed significantly fewer errors than the control rats. Similar to food handling tasks, the stimulus is also very active in skilled walking tasks.

Claims (10)

1. A central nervous system stimulation system, characterized by: comprises the following steps:

at least one control unit;

at least one stimulus generating unit;

at least one stimulus receiving unit;

wherein the stimulation unit is implantable.

2. A central nerve stimulation system according to claim 1, wherein: the control unit comprises an executable program capable of programming the central nerve stimulation wave.

3. A central nerve stimulation system according to claim 2, wherein: the control unit executable is c++ written using the Arduino development environment, with an Arduino compatible Stimjim library, allowing low level device control, writing registers in the DAC or ADC, or setting stimulus control modes.

4. A central nerve stimulation system according to claim 1, wherein: the stimulation generating unit is a programmable pulse generator/stimulation isolator, and the pulse amplitude of the stimulation generating unit is controlled by connecting a USB cable to the stimjim program.

5. A central nerve stimulation system according to claim 1, wherein: the stimulation generating unit is a current and voltage stimulator for stimulating nerve tissue.

6. A central nerve stimulation system according to claim 1, wherein: the stimulation generating unit is an electric isolation stimulation generator and is a microcontroller board based on Teensy 3.5, and a 32-bit Arm 55 Cortex-M4F processor is used, so that the operating frequency is 120 MHz.

7. A central nerve stimulation system according to claim 1, wherein: the stimulation generating unit comprises a USB interface, two green indicator lamps, two BNC connectors for inputting 1 and 2 and two independently controllable electric stimulation output channels, wherein the USB interface is connected with the control unit; the two green indicator lamps flash for half a second when the control unit is connected with the stimulation generating unit, and the connection is successful; the BNC connectors of the two inputs 1 and 2 receive external electric stimulation input to form a closed loop system; the two independently controllable electrical stimulation output channels each having a current and voltage output mode.

8. A central nerve stimulation system according to claim 1, wherein: the stimulation receiving unit is composed of two brain stimulation electrodes, one part of which is implanted into the sports cortex and the other part of which is exposed.

9. A central nerve stimulation system according to claim 1, wherein: the stimulus receiving unit is anchored to the head by means of medical dental cement.

10. A central nerve stimulation system according to claim 1, wherein: the stimulation receiving unit consists of a connector wiring socket of the connector, a connector wiring terminal of the connector, an electrode wire without an insulating layer and a screw with the diameter of 1.2 mm.

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