CN113244530A - Electrical stimulation device for brain substantia nigra reticulata and application thereof - Google Patents
Electrical stimulation device for brain substantia nigra reticulata and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
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Abstract
The invention discloses an electrical stimulation device for a brain substantia nigra reticular part and application thereof, wherein the electrical stimulation device comprises a pulse generator and a stimulation electrode, wherein the pulse generator is used for generating a pulse stimulation signal; the stimulation electrode is electrically connected to the pulse generator and is adapted to be embedded in the substantia nigra reticulata to apply the pulsed stimulation signal to the substantia nigra reticulata. The electrical stimulation device can perform deep brain electrical stimulation on the substantia nigra reticulata part, can obviously reduce the foraging behavior of methamphetamine addicts while not generating anxiety-like behavior, has the advantages of controllability and reversibility, and has great application value for treating methamphetamine addiction.
Description
Technical Field
The invention relates to the technical field of electrical stimulators, in particular to an electrical stimulation device for brain Substantia Nigra reticulata (SNr) and application of the electrical stimulation device in elimination of drug foraging caused by methamphetamine addiction.
Background
Drug addiction is a complex group of brain diseases and also an important global public health problem. About 2.69 million people worldwide used addictive drugs in the past year in 2018 at least once, with 13.2% of users eventually developing drug addiction. While the nervous system, the immune system, the cardiovascular system and the cerebrovascular system of a human body are damaged by drug addiction, the behaviors of attack, robbery, suicide and the like can be caused by the mental abnormality of an addict. Therefore, drug addiction not only imposes a heavy economic burden on the patient's family, but also seriously affects social stability. In recent years, the abuse situation of methamphetamine (also called methamphetamine) is increasingly severe, so that the research on an addiction mechanism of methamphetamine and the development of a new treatment means are reluctant, and the method has important scientific significance and clinical value.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide an electrical stimulation device for a brain substantia nigra reticular part and application thereof.
To achieve the above object, in one aspect, an electrical stimulation device for a brain substantia nigra reticulata according to an embodiment of the present invention is adapted to apply electrical stimulation to the brain substantia nigra reticulata to eliminate foraging behavior of methamphetamine, the electrical stimulation device including:
a pulse generator for generating a pulsed stimulation signal;
a stimulation electrode electrically connected with the pulse generator and adapted to be embedded in the substantia nigra reticulata to apply the pulsed stimulation signal to the substantia nigra reticulata.
According to one embodiment of the invention, the frequency of the pulsed stimulation signal is 80 to 150Hz or 10 to 40Hz, the pulse amplitude is 120 to 180 μ A and the pulse width is 80 to 120 μ s.
According to one embodiment of the invention, the pulse generator further comprises a controller, wherein the controller is electrically connected with the pulse generator and is used for performing pulse parameter control adjustment on the pulse generator.
In another aspect, embodiments of the present invention also provide an application of the electrical stimulation device for the brain substantia nigra reticulata as described above in elimination of methamphetamine foraging.
According to the electrical stimulation device for the brain substantia nigra reticular part and the application thereof, the foraging behavior of the rat methamphetamine can be reduced by deep electrical stimulation of the mesencephalon SNr. The method for electrically stimulating the midbrain SNr in a deep part can obviously reduce the drug foraging behavior of a methamphetamine addict while generating no anxiety-like behavior, and has great application value for treating the methamphetamine addiction.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the structures shown in the drawings without creative efforts.
FIG. 1 is a schematic view of the structure of an electrical stimulation apparatus for the substantia nigra reticulata of the brain;
FIG. 2 is a schematic structural view of a mouse in which a stimulation electrode is implanted in an electrical stimulation apparatus for the substantia nigra reticulata of the brain;
FIG. 3 is another schematic structural view of a mouse with stimulation electrodes implanted therein, in an electrical stimulation apparatus for substantia nigra reticulata of the brain;
FIG. 4 is a flowchart of an experiment investigating the effect of SNr DBS on methamphetamine foraging behavior;
FIG. 5 is a graph of the results of rat SNr pseudo-stimulation and high frequency DBS effects on rat foraging behavior;
FIG. 6 is a graph of the results of rat SNr pseudo-stimulation and low frequency DBS effects on rat foraging behavior;
FIG. 7 is a graph of the results of rat SNr pseudo-stimulation, high frequency and low frequency DBS effects on rat motor and anxiety-like behavior;
FIG. 8 is a graph of the results of rat SNr pseudo-stimulation and high frequency DBS on rat methamphetamine conditioned place preference.
The implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are exemplary and intended to be illustrative of the present invention and should not be construed as limiting the present invention, and all other embodiments that can be obtained by one skilled in the art based on the embodiments of the present invention without inventive efforts shall fall within the scope of protection of the present invention.
The present invention has been completed based on the following studies and findings of the inventors:
at present, the treatment means of methamphetamine addiction mainly adopts drug treatment, but still has the characteristics of difficult cure, easy relapse and the like, so that the search for a safe, effective and convenient new treatment means is a hotspot of the current research. With the development of neurosurgery, Deep Brain Stimulation (DBS) technology is becoming favored. DBS is based on brain stereotactic technology, the stimulation electrode is accurately implanted into a target brain area related to diseases, stimulation parameters are set according to the types of the diseases and the characteristics of a patient, and the pulse generator regulates the activity of the brain area according to pulse current with specific frequency to control the disease symptoms. Compared with the traditional cerebral neurosurgery, the DBS technology has the characteristics of reversibility, controllability and the like, and is considered as one of the replacement therapies of the stereotactic brain area damage operation. The currently known research targets for DBS are mainly the brain regions associated with addiction, i.e. nucleus accumbens, subthalamic nucleus, dorsal striatum, lateral reins, prefrontal cortex and lateral hypothalamic region, and the effect on SNr is not clear.
Referring to fig. 1, an electrical stimulation device for a brain substantia nigra reticulate part, according to an embodiment of the present invention, is adapted to apply electrical stimulation to the brain substantia nigra reticulate part to eliminate the foraging behavior of methamphetamine, and includes a pulse generator 10 and a stimulation electrode 20, wherein the pulse generator 10 is configured to generate a pulse stimulation signal; a stimulation electrode 20 is electrically connected to the pulse generator 10 and is adapted to be embedded in the substantia nigra reticulata to apply the pulsed stimulation signal thereto.
Preferably, the frequency of the pulsed stimulation signal is 80 to 150Hz (high frequency) or 10 to 40Hz (low frequency), the pulse amplitude is 120 to 180 μ A, and the pulse width is 80 to 120 μ s.
In one embodiment of the present invention, a controller 30 is further included, wherein the controller 30 is electrically connected to the pulse generator 10 for performing pulse parameter control adjustment on the pulse generator 10, so as to adjust pulse parameters of the pulse stimulation signal, such as frequency, pulse amplitude, pulse width, and the like, by using the controller 30.
The embodiment of the invention also provides application of the electrical stimulation device for the brain substantia nigra reticulata in elimination of methamphetamine foraging.
The following experimental methods are all conventional methods unless otherwise specified, and the experimental materials used are readily available from commercial companies unless otherwise specified.
The experimental animal was Sprague-Dawley (SD) male rat (purchased from Beijing Wintolite laboratory animal technology, Inc., animal production license number SYXK (Jing) 2019-.
The method of the nuclear mass stereotaxic surgery comprises the following steps: after anesthetizing the rat with an R550IP small animal anesthesia machine (rewarded, china), the rat was placed on a brain stereotaxic apparatus in a prone position and fixed with an ear stick in a horizontal direction. Removing hair on the cranium, and fixing on a brain stereotaxic apparatus; the surgical field was disinfected with iodophor and 75% alcohol. The connective tissue of the skull at the top of the rat head was cleaned, and the skull was exposed with an arterial clamp, and the pre-and post-halogens were adjusted to the same level. 4 shallow holes are drilled on the surface of the skull by using a skull drill, and small stainless steel screws are fixed. The stimulation electrode 20 is embedded in the target brain region (substantia nigra reticulata), and according to the rat brain stereotaxic map, the coordinates of the substantia nigra reticulata are: AP, -5.3 mm; ML, ± 2.3 mm; DV, -8.2mm, where AP and ML are in bregma, and DV is in reference to the surface of the skull. The electrodes and screws were fixed to the skull with dental cement. After the cement is dried, the rats are taken down from the positioning instrument and are raised in a single cage, the recovery time is 5-7 days, the behavioral training is carried out after the body weight of the rats recovers the preoperative level, and penicillin (20 ten thousand IU, intraperitoneal injection) is given every day during the period to prevent infection.
Deep brain electrical stimulation: a monophasic square pulse (pulse stimulation signal) is input to the substantia nigra reticulata using a current-based pulse generator 10 through a wire connected to a stimulation electrode 20. The stimulation parameters were 130 or 20Hz pulse frequency, 150 μ A pulse amplitude, 100 μ s pulse width. In the sham group, the rats were connected to an external wire, but did not receive electrical stimulation.
Conditional Place Preference (CPP): the experiment was conducted using an unbiased design. The conditional place preference box (developed by the institute of medicine, medical sciences institute) is a PVC three-box system, controlled by a computer, with both side boxes (LxWxH: 27.9cm x 21.0cm x 20.9cm) and the middle box (12.1cm x 21.0cm x 20.9cm) made of black organic plastic. The bottom plates of the two side boxes are different, the bottom plates are respectively a latticed wire netting and parallel stainless steel rods, the box on one side is provided with light, the box on one side is not provided with light, the bottom plate of the middle box is made of smooth black organic plastic, and the three boxes are separated by a movable partition plate. The infrared sensing device is arranged on the side wall of the three boxes, and can detect the movement of the rat and automatically record the staying time of the rat in each box. The baseline test was first conducted by opening the movable partition between the three chambers, placing the SD rats in the middle chamber, allowing them to freely shuttle in the three chambers for 15min, and recording their residence time in each chamber simultaneously by a computer. The majority of rats remained for a period of time that was not significantly different between the chambers, approximately 1/3 for the total time, and a minority of rats showed significant natural preference (residence time in either chamber exceeded 540s), which was rejected from the experiment. Then carrying out CPP training on animals, wherein on days 1, 3, 5 and 7, the rats receive methamphetamine administration (1mg/kg, intraperitoneal injection) and then are placed in a medicine accompanying box for staying for 45 min; on days 2,4, 6 and 8, the mixture is injected with normal saline (1ml/kg, i.e. intraperitoneal injection) and then placed in a non-accompanied medicine box for 45 min. After training, the rats were returned to the cage. The CPP acquisition test was performed on the ninth day in the same manner as the basal value test, and the conditional site-preferred preference score (CPP score) was defined as the difference between the residence time of the rat in the concomitant box and the residence time of the rat in the non-concomitant box.
CPP regression: DBS was performed 60min before washout training, and the high and low frequency stimulation groups were performed 6 and 9 washout training sessions, respectively. During training, rats can be shuttled freely for 15min in three boxes. On the last day, rats were given an intraperitoneal injection of 1mg/kg methamphetamine without DBS, and were tested immediately after dosing.
Testing in a mine field: the open field test box is 75cm long, 75cm wide and 45cm high, and has brown plywood on four walls and wood board on the bottom. The bottom surface was divided into 25 identical squares of 15cm by 15cm with black strokes. There is the infrared camera above the test box of open field, records the activity of rat in open field. The rats were moved to the open field test room 30min in advance and allowed to adapt to the test environment. The test was performed in dark light and the remaining odor was removed by wiping the field with a cloth stained with 75% alcohol. Rats were placed in the center of the open field, allowed to explore freely for 5min, and then placed in rearing cages. The total distance traveled by the rats in the open field and the time spent in the central area were counted as indicators for evaluating their anxiety-like behavior.
Elevated plus maze test: the elevated cross-shaped maze consists of two black iron open arms and closed arms, wherein the arms are 50cm long, 10cm wide and 70cm high, and the depth of the closed arms is 40 cm. An infrared camera is arranged above the elevated cross-shaped maze and used for recording the movement of the rat in the elevated cross-shaped maze. The rats are moved to the elevated plus maze test room 30min in advance to adapt to the test environment. The test was performed in a dark light environment. The device was wiped with a cloth stained with 75% alcohol to remove residual odors. The rats are placed in the central area of the elevated plus maze, are freely explored for 5min, and the times of entering the open arms and the time of staying in the open arms of the rats are counted to be used as indexes for evaluating the anxiety-like behaviors of the rats.
Perfusion fixation: rats were anesthetized by intraperitoneal injection of chloral hydrate (0.1g/ml in physiological saline) and then fixed by cardiac perfusion. The method comprises the steps of clamping the xiphoid process by using a hemostatic forceps, lifting upwards, cutting skin along costal arches on two sides, opening an abdominal cavity, cutting diaphragm muscle, cutting ribs, turning up the hemostatic forceps clamping the xiphoid process towards the head of a rat, fully exposing the heart, inserting a puncture needle into the heart until the aorta, quickly perfusing 0.01mol/L phosphate buffer solution, cutting the right auricle, enabling blood to smoothly flow out, and fixing the puncture needle by using the hemostatic forceps. Approximately 200-300ml of 0.01mol/L phosphate buffer was perfused into each rat until blood was flushed out completely, there was no bleeding in the right atrial appendage, and the liver became white. Then, 200-300ml of 4% paraformaldehyde solution was injected until the limb became hard. Taking brain, placing in EP tube filled with 4% paraformaldehyde solution, freezing at 4 deg.C, fixing for 12-18 hr, and dewatering by changing to 30% sucrose. Putting dry ice in a heat-preserving barrel, pouring a proper amount of absolute ethyl alcohol, stirring into a pasty mixture, putting a small beaker filled with n-hexane in the dry ice, putting the completely dehydrated brain tissue into the n-hexane for quick freezing for about 18s when the temperature is reduced to-60 ℃, taking out, and storing in a refrigerator at-80 ℃.
Taking brain slices: the box temperature of the frozen slicer and the temperature of the sample head are adjusted to-20 ℃ in advance for precooling, required tools such as a blade, a slice picking needle, a writing brush and the like are put into the slicer for precooling, and the slice thickness is set to be 20 mu m. The brain tissue was taken out from a freezer at-80 ℃ and equilibrated in a temperature-adjusted microtome, and the brain tissue was fixed with an embedding material for tissue (OCT) and then sectioned. The slice thickness is 20 μ M, and brain slices of the target brain area are taken according to the map and put into 0.01M phosphate buffer solution.
And (3) Nie dyeing: mounting brain slices on a glass slide, drying for 36-48h on a baking sheet machine at the temperature of not higher than 40 ℃, rinsing with distilled water, and dip-dyeing with Nissen dyeing liquor on a shaking table at room temperature for 15-30 min. The color separation process comprises soaking in 90% ethanol for 1min, soaking in 95% ethanol for 5min, taking out, soaking in another 95% ethanol for 5min, soaking in 100% ethanol for 1min, and soaking in another 100% ethanol for 1 min. After dewaxing the xylene for 5min twice, the wafer was mounted with neutral resin and scanned down with an optical microscope to confirm the electrode position.
Data processing: all experimental results are expressed as mean ± SEM, analyzed using One-way analysis of variance (One-way ANOVA) or Repeated measures analysis of variance (Repeated-measures ANOVA). All post hoc comparisons were statistically significant using the LSD test with p < 0.05.
Example 1
High-frequency DBS (dodecyl benzene sulfonic acid) can reduce drug foraging behavior of methamphetamine addicted rats
The experimental procedure is shown in FIG. 4. After 8 days of CPP training, rats developed significant methamphetamine-induced CPP behavior (sham-stimulated group: t7 ═ 3.308, p < 0.05; HF-DBS: t7 ═ 2.868, p < 0.05). Rats were given withdrawal training with 60min of high frequency DBS before each training, i.e. 130Hz, and observed for CPP scores, and the withdrawal test scores for the high frequency DBS group rats were found to be significantly lower than those for the sham-stimulated group rats (DBS: F (1,14) ═ 5.122, p < 0.05; withdrawal training: F (3.112,43.57) ═ 3.089, p < 0.05; interactive effect: F (5,70) ═ 0.4994, p ═ 0.7756). 24h after completion of the regression, rats were given an intraperitoneal injection of 1mg/kg methamphetamine without DBS and tested immediately after dosing, and rats with high frequency DBS were found to have significantly lower CPP scores than those with sham-stimulated rats (t14 ═ 2.178, p <0.05) (fig. 5). Experimental results show that the high-frequency DBS can promote the elimination training of the rat methamphetamine CPP and eliminate the foraging behavior induced by the ignition of the methamphetamine drug.
In order to verify whether the low frequency DBS has similar effect, the above experimental steps are also implemented in the low frequency DBS group, and the experimental flow is the same as that in fig. 4. After 8 days of CPP training, rats developed significant methamphetamine-induced CPP behavior (sham-stimulated group: t6 ═ 4.003, p < 0.01; low frequency DBS group: t5 ═ 11.17, p < 0.0001). Rats were given withdrawal training with 60min of low frequency DBS before each training, i.e. 20Hz, and observed for CPP scores, and the withdrawal test scores for the low frequency DBS group rats were found to be significantly higher than those for the sham-stimulated group rats (DBS: F (1,11) ═ 6.473, p < 0.05; withdrawal training: F (3.737,41.11) ═ 5.041, p < 0.01; interactive effect: F (8,88) ═ 0.5160, p ═ 0.8415). 24h after completion of the regression, rats were given an intraperitoneal injection of 1mg/kg methamphetamine without DBS and tested immediately after administration, and rats in both the sham-stimulated and low frequency DBS groups were found to exhibit significant CPP behavior (t11 ═ 1.374, p ═ 0.1969) (fig. 6). Experimental results show that the low-frequency DBS can inhibit the regression training of the methamphetamine CPP of rats and cannot reduce the foraging behavior of the rats addicted to methamphetamine.
After all experiments are finished, perfusion fixation, brain slice drawing and Nie's staining are carried out on the rat, and whether the electrode position is accurate or not is verified.
Example 2
DBS does not affect the motor ability of rats and does not produce anxiety-like behavior
Rats were subjected to high frequency or low frequency DBS for 60min before the elevated plus maze test and the open field test, and there was no significant difference in the distance of movement between the sham-stimulated, low frequency DBS and high frequency DBS groups (F (2,15) ═ 0.1107, p ═ 0.8959), nor in the time to arm entry (F (2,15) ═ 0.04105, p ═ 0.9599) and the number of times to arm opening (F (2,15) ═ 0.2453, p ═ 0.7856) between the three groups of rats in the elevated plus test (fig. 7), indicating that SNr DBS did not affect the motor ability of the rats nor cause anxiety-like behavior of the rats.
Example 3
DBS does not influence establishment of rat methamphetamine CPP
During the CPP training process, rats are subjected to pseudo-stimulation or high-frequency DBS for 60min before methamphetamine injection each time, and the rats in the pseudo-stimulation group and the high-frequency DBS group can generate obvious methamphetamine-induced CPP behaviors (the pseudo-stimulation group is t 7-3.494, p is less than 0.05, the high-frequency DBS group is t 7-4.859, and p is less than 0.01) (figure 8), which indicates that the DBS does not influence the establishment of the rat methamphetamine CPP.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications and equivalents of the present invention, which are made by the contents of the present specification and the accompanying drawings, or directly/indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (4)
1. An electrical stimulation device for the substantia nigra reticulata suitable for applying electrical stimulation to the substantia nigra reticulata to eliminate the foraging behavior of methamphetamine, the electrical stimulation device comprising:
a pulse generator for generating a pulsed stimulation signal;
a stimulation electrode electrically connected with the pulse generator and adapted to be embedded in the substantia nigra reticulata to apply the pulsed stimulation signal to the substantia nigra reticulata.
2. The electrical stimulation apparatus for the reticular portion of the brain substantia nigra of claim 1, wherein the frequency of the pulse stimulation signal is 80 to 150Hz or 10 to 40Hz, the pulse amplitude is 120 to 180 μ A, and the pulse width is 80 to 120 μ s.
3. The electrical stimulation apparatus for the substantia nigra reticulata of claim 1, further comprising a controller electrically connected to the pulse generator for pulse parameter controlled adjustment of the pulse generator.
4. Use of an electrical stimulation apparatus as claimed in any one of claims 1 to 3 for the substantia nigra reticulata of the brain to counteract methamphetamine foraging.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020151939A1 (en) * | 2000-02-24 | 2002-10-17 | Rezai Ali R. | Modulation of the brain to affect psychiatric disorders |
| CN1833490A (en) * | 2005-12-31 | 2006-09-20 | 山东科技大学 | Virtul positive reinforcing method of intelligent animals |
| US20070250119A1 (en) * | 2005-01-11 | 2007-10-25 | Wicab, Inc. | Systems and methods for altering brain and body functions and for treating conditions and diseases of the same |
| CN111529924A (en) * | 2020-04-13 | 2020-08-14 | 清华大学深圳国际研究生院 | Deep brain stimulation electrode device |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020151939A1 (en) * | 2000-02-24 | 2002-10-17 | Rezai Ali R. | Modulation of the brain to affect psychiatric disorders |
| US20070250119A1 (en) * | 2005-01-11 | 2007-10-25 | Wicab, Inc. | Systems and methods for altering brain and body functions and for treating conditions and diseases of the same |
| CN1833490A (en) * | 2005-12-31 | 2006-09-20 | 山东科技大学 | Virtul positive reinforcing method of intelligent animals |
| CN111529924A (en) * | 2020-04-13 | 2020-08-14 | 清华大学深圳国际研究生院 | Deep brain stimulation electrode device |
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