CN117982795A - Brain nerve regulation and control system for improving memory function by regulating and controlling brain electric oscillation characteristics - Google Patents
Brain nerve regulation and control system for improving memory function by regulating and controlling brain electric oscillation characteristics Download PDFInfo
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Abstract
The invention discloses a brain nerve regulating system for improving memory function by regulating and controlling brain electric oscillation characteristics. The system comprises: the model building unit is used for building a transcranial electric stimulation model and performing intracranial gamma electric stimulation on the target in a preset stimulation mode by using the set stimulation electrode; the electroencephalogram detection unit is used for collecting brain waves of a measuring electrode area in the electric stimulation process by using the arranged measuring electrode; the regulation and control unit is used for measuring the change of gamma oscillation energy before and after the electric stimulation by analyzing brain waves in real time so as to screen out optimized electric stimulation parameters; a behavioural assessment unit: and respectively carrying out water maze behavioural evaluation on the target receiving the optimized electric stimulation parameters and the target not receiving the electric stimulation to obtain the association relation between the stimulation frequency and the target learning and memory function. The invention can be used for carrying out sine alternating current stimulation with specific frequency, realizing the instant regulation and control of abnormal brain gamma waves and effectively improving the learning and memory functions.
Description
Technical Field
The invention relates to the technical field of biomedical engineering, in particular to a brain nerve regulating system for improving memory function by regulating and controlling brain electric oscillation characteristics.
Background
Central nerve degenerative diseases, cerebral ischemia, brain trauma and the like cause damage to central nerve functions, especially learning and memory functions, and even cause cognitive impairment. Along with such nerve function impairment, an electroencephalogram abnormality often occurs. The existing treatment methods for learning and memory function injury and cognitive dysfunction mainly adopt administration of neurotrophic drugs and compounds. However, due to the presence of the blood brain barrier, the effect of drug treatment is poor. Moreover, the neuroprotection and the nutraceutical treatment have no obvious effect on correcting the electroencephalogram abnormality. Therefore, aiming at enhancing and improving the learning and memory functions, development and establishment of immediate and effective innovative treatment technologies are urgently needed.
At present, the electric stimulation treatment based on the technical principle of electrophysiological regulation brings new treatment means and hope for treating various degenerative diseases of the central nervous system including brain AD. The Turnbull team reported the first cases in the world to treat AD senile dementia with deep brain electrical stimulation (DBS) in 1985. Post-operative PET/CT shows that there is a difference between stimulating different brain regions on the side compared to the opposite side. In 2008, lozano team found that hypothalamic/vault deep brain electrical stimulation of morbid obese patients could significantly enhance the patient's attention, language learning ability, and spatial memory function. Electroencephalogram traceability analysis of the patient suggests that the medial temporal lobe structure mainly comprising hippocampus and parahippocampal gyrus is activated, which indicates that hypothalamus/dome-electric stimulation can regulate the marginal system activity of the patient and improve the memory function. The existing brain electrical stimulation mainly adopts direct current, alternating current and pulse wave electrical stimulation, however, the association relation between the stimulation parameters and the treatment effect is not clear.
The gamma wave oscillation (gamma oscillation) in electroencephalogram belongs to high-frequency wave band in electroencephalogram, the frequency is 25-100Hz, and the gamma wave oscillation (gamma oscillation) exists in most important functional areas of brain, such as olfactory bulb, thalamus, hippocampus, various sensory and motor cortex parts and the like, and is a basic form of neural network activity. The generation of gamma oscillations is derived from the excitation of pyramidal cells caused by external stimuli or excitatory inputs, and by excitatory transmitters such as AMPA, the excitation of basket cells containing GABA, capable of rapid discharge and expression of microalbumin (Parvalbumin), which form an intermediate neuronal network generating 25-100Hz rhythmicity by gap junctions and GABA synapses, and the cone cells are also regulated by this rhythm, thus forming gamma oscillations. Several clinical and animal experiments prove that gamma oscillation is involved in the learning and memory functions of brain. The brain wave of AD patient is analyzed, and the gamma oscillation activity energy in brain wave is obviously reduced in synchronization with learning and memory function decline. It follows that gamma oscillatory reparative enhancement with specific frequency electrical stimulation (25-100 Hz) is a potential therapeutic new technological approach to AD treatment.
In the prior art, research based on animal experiments shows that the 40Hz flash stimulation of transgenic AD mice (5 xFAD) can cause the enhancement of the recovery of gamma oscillation in a plurality of areas in the brain, reduce the deposition of amyloid plaques and improve the AD cognitive function. Although this study was quite remarkable, the application of flash stimulation to clinical patients resulted in severe visual and emotional stimuli with very poor patient compliance.
A recent clinical study demonstrated that 40Hz transcranial electrical stimulation to the temporal lobe-hippocampal region can produce significant efficacy in AD patients. The study recruited 50 AD patients for a total of thirty treatments for six weeks, five days a week. Cognitive assessment was performed before and after intervention and changes in serum amyloid were detected. The results show that transcranial electrical stimulation treatment of bilateral temporal lobe-hippocampal regions significantly improves cognitive function in AD patients; the improvement in cognitive function is accompanied by a significant decrease in amyloid markers in serum. The conditions of therapeutic parameters of the electrical stimulation therapy are caused by unknown targeted molecules and cellular mechanisms of the electrical stimulation therapy: stimulation frequency, intensity (amplitude), stimulation time, etc. are not quantitatively defined.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a brain nerve regulating system for improving memory function by regulating and controlling the characteristics of brain electric oscillation. The system comprises:
Model building unit: the method comprises the steps of establishing a transcranial electric stimulation model, and performing intracranial gamma electric stimulation on a target in a preset stimulation mode by using a set stimulation electrode;
An electroencephalogram detection unit: the device is used for collecting brain waves of a measuring electrode area in the electric stimulation process by using the arranged measuring electrode;
Regulation and control unit: the method is used for measuring the gamma oscillation energy change before and after the electrical stimulation by analyzing brain waves in real time so as to screen out optimized electrical stimulation parameters;
A behavioural assessment unit: and respectively carrying out water maze behavioural evaluation on the target receiving the optimized electric stimulation parameters and the target not receiving the electric stimulation to obtain the association relation between the stimulation frequency and the target learning and memory function.
Compared with the prior art, the invention has the advantages that aiming at the weakening of the oscillation energy of the brain gamma wave accompanied by the damage of the learning and memory functions, for example, the mouse with Alzheimer disease is used as a model to carry out the minimally invasive sinusoidal alternating current stimulation with specific frequency, thereby realizing the instant regulation and control of abnormal brain gamma wave and further realizing the effective improvement of the learning and memory functions of the mouse.
Other features of the present invention and its advantages will become apparent from the following detailed description of exemplary embodiments of the invention, which proceeds with reference to the accompanying drawings.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description, serve to explain the principles of the invention.
FIG. 1 is a schematic diagram of a brain neuromodulation system for improving memory function by modulating an electrical brain oscillation characteristic, in accordance with one embodiment of the present invention;
FIG. 2 is a schematic representation of transcranial electrical stimulation according to one embodiment of the present invention;
FIG. 3 is a schematic representation of the effect of 40Hz transcranial electrical stimulation on Alzheimer's disease mouse brain electrical and gamma oscillations in accordance with one embodiment of the present invention;
FIG. 4 is a schematic representation of the effect of 40Hz transcranial electrical stimulation on learning and memory function in Alzheimer's disease mice according to one embodiment of the present invention.
Detailed Description
Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that: the relative arrangement of the components and steps, numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless it is specifically stated otherwise.
The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
Techniques, methods, and apparatus known to one of ordinary skill in the relevant art may not be discussed in detail, but are intended to be part of the specification where appropriate.
In all examples shown and discussed herein, any specific values should be construed as merely illustrative, and not a limitation. Thus, other examples of exemplary embodiments may have different values.
It should be noted that: like reference numerals and letters denote like items in the following figures, and thus once an item is defined in one figure, no further discussion thereof is necessary in subsequent figures.
The invention adopts minimally invasive gamma sine alternating current stimulation with specific frequency (40 Hz), specifically corrects pathological brain electrical gamma oscillation of the Alzheimer disease mouse model, and improves learning and memory functions. Minimally invasive and tested tolerance of electrical stimulation is achieved through the subcutaneous electrode; by electroencephalogram monitoring, effective stimulation parameters (alternating electrical waveforms, frequencies, stimulation intensities, etc.) for gamma oscillations are clarified. Provides an executable new technology for targeting the electric stimulation treatment in real time aiming at experimental animals and clinical treatment.
Referring to fig. 1, there is provided a brain nerve modulation system for improving a memory function by modulating an electroencephalogram oscillation characteristic, comprising: a model creation unit 110 for creating a transcranial electrical stimulation model and performing intracranial gamma electrical stimulation on the target in a predetermined stimulation mode using the set stimulation electrodes; an electroencephalogram detection unit 120 for collecting brain waves of a measurement electrode region during the electric stimulation using the set measurement electrode; the adjusting and controlling unit 130 is used for measuring the change of the gamma oscillation energy before and after the electric stimulation by analyzing the brain wave in real time so as to screen out the optimized electric stimulation parameters; and a behavioural evaluation unit 140, configured to perform a water maze behavioural evaluation on the target that receives the optimized electrical stimulation parameter and the target that does not receive the electrical stimulation, respectively, to obtain an association relationship between the stimulation frequency and the target learning and memory function.
Hereinafter, a mouse model will be specifically described.
1) Establishing 5xFAD mice transcranial electric stimulation model
FIG. 2 is a schematic of a process of transcranial electrical stimulation for a mouse, wherein FIG. 2 (a) is a schematic of transcranial electrical stimulation for a mouse; FIG. 2 (b) is the placement of transcranial electrical stimulation electrodes on the head of a mouse; FIG. 2 (c) is a schematic mouse model.
Specifically, 5xFAD mice were obtained by purchase, inhaled anesthetized with 2% (v/v) isoflurane oxygen, placed in prone position on a stereotactic apparatus, and after scalp shaved for sterilization, two autoclaved transcranial electrodes (1.6 mm diameter) were implanted subcutaneously. After electrode implantation, the scalp is sutured. After 24 hours of electrode implantation, an intracranial gamma electrical stimulation treatment course was performed. The stimulation mode includes: direct current, sinusoidal alternating current; frequency: 0-130 Hz; stimulation intensity: 50-250 microamps; stimulation time: 1 hour/day, 7 days of continuous stimulation.
In this step, a model mouse (5 xFAD) for Alzheimer's disease obtained by purchasing is used to build a model of transcranial electrical stimulation of the mouse by embedding electrodes under the scalp.
2) Electroencephalogram monitoring
Four (two pairs) measuring electrodes are embedded under the scalp in the above anesthesia step. And (3) the path electric stimulation is transmitted to the stimulation electrodes, and brain waves of the two pairs of measurement electrode areas are respectively collected.
In this step, the electroencephalogram of the mice at the pre-, mid-, and post-stage 5xFAD th stage of transcranial electrical stimulation was monitored using a small animal electroencephalogram detection apparatus.
3) Transcranial electrical stimulation
In this step, specific waveforms, frequencies and stimulation intensities of the effective transcranial electrical stimulation are determined for the effective increase in gamma oscillation energy by electroencephalographic analysis.
Specifically, by brain wave real-time monitoring analysis, the change of gamma oscillation energy before and after the electric stimulation is measured, and the electric stimulation parameters capable of effectively enhancing the gamma oscillation energy of the brain wave of the 5xFAD mice are determined. For example, the determined electrical stimulation parameters are: 40 Hz sinusoidal alternating current, 100 microamps.
4) Water maze behavioural assessment
In the step, through a water maze behavioural evaluation experiment, the improvement effect of transcranial electrical stimulation with specific frequency on the learning and memory functions of 5xFAD is verified.
For example, receiving specific stimulation parameters: the 40 hz sinusoidal ac, 100 microamps of 5xFAD mice electrically stimulated (1 hour/day, 7 days of continuous stimulation) and the control group 5xFAD mice not receiving the electrical stimulation were respectively subjected to water maze behavioural evaluation to evaluate the effect of the specific stimulation frequency on the learning and memory functions of the mice.
Specifically, the mouse water maze behavioral assessment experiments include swimming training experiments and test experiments. For each training experiment, mice were placed in a pool of water and reached the escape platform within a specified time. Any mice that did not reach the platform within the prescribed time were guided to the platform by the experimenter and allowed to stay on the platform for 10 seconds. During the test experiment, the target quadrant swimming time was measured as an evaluation criterion for learning memory function.
FIG. 3 is the effect of 40Hz transcranial electrical stimulation on brain electrical and gamma oscillations in Alzheimer's disease mice (5 xFAD). It can be seen that a significant increase in gamma oscillation energy was produced in the stimulation compared to the gamma oscillation energy before stimulation, and the gamma oscillation energy in the brain of the 5xFAD mice after stimulation remained significantly higher than the level before stimulation.
FIG. 4 is the effect of 40Hz transcranial electrical stimulation on learning and memory function in Alzheimer's disease mice (5 xFAD). The statistical analysis of the swimming time data of the target quadrant shows that 40Hz transcranial electric stimulation can obviously improve the swimming time of a 5xFAD mouse in the target quadrant, and prompt the effective improvement of the learning and memory functions.
In conclusion, experiments prove that the transcranial sinusoidal alternating electrical stimulation with the frequency of 40 Hz can effectively correct the decrease of the gamma oscillation energy of brain waves of mice with Alzheimer's disease (5 xFAD); the transcranial sinusoidal alternating electrical stimulation with the frequency of 40 Hz can effectively improve the learning and memory functions of the mice with Alzheimer's disease (5 xFAD).
In summary, compared with the prior art, the invention has the following advantages:
1) The invention adopts transcranial electric stimulation, embeds an electrode under the skin, and adopts low-frequency stimulation of 40 Hz. The stimulation treatment process does not generate any visual, sensory, emotional and physiological stimulation or injury to mice or people, and is even not easy to be perceived. And has better feasibility compared with the current flash stimulation.
2) The existing transcranial electrical stimulation used clinically is mostly direct current and pulse electrical stimulation, and less attention is paid to electroencephalogram abnormality and corrective treatment when learning and memory dysfunction is caused by Alzheimer disease and the like. The specific low-frequency sinusoidal alternating current stimulation adopted by the invention has remarkable enhancement effect on the gamma oscillation attenuation closely related to the learning and memory functions in the electroencephalogram of the 5xFAD mice, thereby providing possible mechanism explanation and feasible stimulation parameter schemes for the treatment effect of receiving transcranial electric stimulation of AD patients.
3) Proved by verification, the transcranial sinusoidal alternating electrical stimulation with the frequency of 40Hz can be used as clinical transformation application, thereby providing a new treatment technology and a recommended scheme for improving patients with brain wave abnormality, learning and memory dysfunction caused by various diseases.
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described. The terminology used herein was chosen in order to best explain the principles of the embodiments, the practical application, or the technical improvements in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein. The scope of the invention is defined by the appended claims.
Claims (9)
1. A brain neuromodulation system for improving memory function by modulating brain electrical oscillation characteristics, comprising:
Model building unit: the method comprises the steps of establishing a transcranial electric stimulation model, and performing intracranial gamma electric stimulation on a target in a preset stimulation mode by using a set stimulation electrode;
An electroencephalogram detection unit: the device is used for collecting brain waves of a measuring electrode area in the electric stimulation process by using the arranged measuring electrode;
Regulation and control unit: the method is used for measuring the gamma oscillation energy change before and after the electrical stimulation by analyzing brain waves in real time so as to screen out optimized electrical stimulation parameters;
A behavioural assessment unit: and respectively carrying out water maze behavioural evaluation on the target receiving the optimized electric stimulation parameters and the target not receiving the electric stimulation to obtain the association relation between the stimulation frequency and the target learning and memory function.
2. The system of claim 1, wherein the stimulation pattern comprises direct current, sinusoidal alternating current; the frequency is set to be 0-130 Hz; the stimulation intensity is set to be 50-250 microamps; the stimulation time was set to 1 hour/day, and the stimulation was continued for 7 days.
3. The system of claim 1, wherein the transcranial electrical stimulation model is a 5xFAD mouse transcranial electrical stimulation model.
4. The system of claim 1, wherein the optimized electrical stimulation parameters are 40 hz sinusoidal ac current, 100 microamps current, stimulation time set to 1 hour/day and stimulation for 7 days continuously.
5. The system of claim 1, wherein the stimulation electrode is subcutaneously implanted in the subject and the intracranial gamma electrical stimulation therapy session is performed 24 hours after the electrode is placed in.
6. The system of claim 1, wherein the measuring electrodes are arranged in two pairs and are implanted under the scalp of the subject.
7. The system of claim 1, further comprising: and electrically stimulating the target by using the optimized electrical stimulation parameters so as to improve the electroencephalogram gamma oscillation energy and the learning and memory functions.
8. The system of claim 1, wherein the stimulating electrode has a diameter of 1.6 millimeters.
9. A system according to claim 3, wherein the behavioural assessment unit performs swimming training experiments and test experiments, for each training experiment, places the mice in a pool of water and reaches the escape platform within a prescribed time; for mice that did not reach the platform within a specified time, directing them to the platform and allowing for a set time to remain on the platform; during the test experiment, the target quadrant swimming time was measured as an evaluation criterion for learning memory function.
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