CN107858283A - A kind of neuromodulation method and device - Google Patents
A kind of neuromodulation method and device Download PDFInfo
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- CN107858283A CN107858283A CN201710947799.9A CN201710947799A CN107858283A CN 107858283 A CN107858283 A CN 107858283A CN 201710947799 A CN201710947799 A CN 201710947799A CN 107858283 A CN107858283 A CN 107858283A
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Abstract
The application provides a kind of neuromodulation method and device, is related to technical field of medical instruments, to solve the deficiency of neuromodulation device in the prior art, including：Brain piece fixing device, in vitro brain piece living, the cerebrospinal fluid for meeting preset temperature filled with circulation in the brain piece fixing device are fixed with the brain piece fixing device, and cerebrospinal fluid loop is formed in the brain piece fixing device；Wherein, after the in vitro brain piece living is transfected by brain region interested in acceptor, and obtained according to predetermined manner；Electrical stimulation device, the electrical stimulation device are connected with the brain piece fixing device, implement to stimulate for the in vitro brain piece living into the brain piece fixing device；Harvester, used in implementing stimulating course to the in vitro brain piece living in the electrical stimulation device, the cell behavior of real-time exhibition slow-virus transfection mark and morphologic change, or the change of intracellular organelle and cytoplasm intermediate ion.
Description
Technical field
The application is related to technical field of medical instruments, more particularly to a kind of neuromodulation method and device.
Background technology
Gradually it is proved with the validity and security of physical factor treatment central nervous system disease, on this aspect
The breadth and depth of research constantly extends, wherein being the noninvasive neuromodulation technology of representative in base using electro photoluminescence and Neural stem cell
Progress is all achieved in plinth research and clinical research.But due to the limitation of research method, basic research focuses primarily upon biology
The computer simulation of effect or the signaling pathway molecule using the means research neuromodulations such as molecular biology correlation, but
The research of this form is on the one hand because the brain structure specificity of bion is so large that the result of analogue simulation in life
It is difficult to reproduce in thing individual, on the other hand noninvasive neuromodulation technology is to play neuromodulation by extra electric field or magnetic field to make
With, if microcosmic regulating and controlling effect can be played in molecular level and be still not clear, but lacked again suitable for the grand of basic research at this stage
See research meanses and seriously constrain the further investigation of the technology.Although in clinical studies can by functional magnetic resonance,
The research neuromodulation mechanism of the mode such as near infrared imaging and electroencephalogram macroscopic view, but the inadequate system of result of study, the essence of observation
Degree and spatial resolution are significantly insufficient.Thus it is badly in need of a kind of new research method at this stage to solve clinical macro -examination and basis
The deficiency of microexamination, to promote noninvasive neuromodulation to swash further investigation of the technology to brain regulatory mechanism.
The content of the invention
The application provides a kind of neuromodulation method and device, and to solve in the prior art, neuromodulation device is not
Foot.
In a first aspect, the embodiment of the present invention provides a kind of neuromodulation device, including：Brain piece fixing device, the brain piece
In vitro brain piece living, the brain ridge for meeting preset temperature filled with circulation in the brain piece fixing device are fixed with fixing device
Liquid, and cerebrospinal fluid loop is formed in the brain piece fixing device；Wherein, the in vitro brain piece living passes through interested in acceptor
After brain region is transfected, and obtained according to predetermined manner；Electrical stimulation device, the electrical stimulation device are consolidated with the brain piece
Determine device to be connected, implement to stimulate for the in vitro brain piece living into the brain piece fixing device；Harvester, in the electricity
Stimulating apparatus is implemented in stimulating course to the in vitro brain piece living, the cell behavior and shape of real-time exhibition slow-virus transfection mark
The change of state, or the change of intracellular organelle and cytoplasm intermediate ion.
With reference in a first aspect, in the first possible implementation of first aspect, brain piece fixing device includes
Primary Ioops, and the first entrance and first outlet being arranged on the first loop, wherein, first loop is described for accommodating
Cerebrospinal fluid, to form the cerebrospinal fluid loop, first loop communicates with the first entrance, the first outlet with it is described
First loop communicates, and the first entrance is used to input the cerebrospinal fluid to first loop, and the first outlet is used for will
Cerebrospinal fluid output in first loop, to cause cerebrospinal fluid to be circulated in first loop.
With reference to the possible implementation of the first of first aspect or first aspect, second in first aspect is possible
In implementation, the corner of brain piece fixing device is respectively arranged with stimulating electrode, is arranged on the stimulation of brain piece fixing device corner
The stimulating electrode of any two corners in electrode is connected with the electrical stimulation device, for the electric current exported in the electrical stimulation device
In the presence of export different types of electric field.
With reference to second of possible implementation of first aspect, in the third possible implementation of first aspect
In, electrical stimulation device has following at least one stimulus modality：Stimulus of direct current pattern, impulse stimulation pattern, sinusoidal stimulus modality
And pseudo- stimulus modality (electric current not being produced, equivalent to unpowered state).Wherein, under stimulus of direct current pattern, voltage adjustable extent：
0-18V, current adjustment scope 0-5A, the minimum μ A of precision 1；The adjustable frequency scope of sinusoidal stimulus modality is：0.01-250Hz；Arteries and veins
The adjustable pulse cycle 100-2000ms of spurt energizing mode, adjustable pulse width scope is 100-2000ms.
With reference to the possible implementation of the third of first aspect or first aspect, the 4th kind in first aspect is possible
In implementation, stimulating electrode is calutron, has magnet inner core in the calutron, and the calutron is used in institute
State electrical stimulation device output electric current in the presence of produce induced field.
Any one of the 4th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In five kinds of possible implementations, the device that the application provides also includes：Objective table, the harvester are arranged on by support
On the objective table, the objective table is used to fix the brain piece fixing device, and the brain piece fixing device is located at the collection
The underface of device.
Any one of the 5th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In six kinds of possible implementations, the harvester in the application is fluorescence microscope.
Any one of the 6th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In seven kinds of possible implementations, the thickness of in vitro brain piece living is 300 μm.
Any one of the 7th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In eight kinds of possible implementations, first entrance is connected with peristaltic pump, and peristaltic pump is used for by first entrance into the first loop
Input meets the oxygenation cerebrospinal fluid of preset temperature.
Any one of the 8th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In nine kinds of possible implementations, first outlet is connected with collection device by pipeline, and the collection device is used to collect from institute
State the cerebrospinal fluid of first outlet output.
Any one of the 9th kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In ten kinds of possible implementations, the brain from first entrance input is more than or equal to from the speed of the cerebrospinal fluid of first outlet output
The speed of spinal fluid.
Any one of the tenth kind of possible implementation with reference to first aspect to first aspect, the of first aspect
In a kind of ten possible implementations, the device that the application provides also includes：Control unit, for controlling the brain piece to fix dress
Put and be moved in the acquisition range of the harvester.
Any one of the tenth a kind of possible implementation with reference to first aspect to first aspect, in first aspect
In 12nd kind of possible implementation, control unit, it is connected, described control unit, is additionally operable to the electrical stimulation device
When the brain piece fixing device is moved in the acquisition range of the harvester, the electrical stimulation device is triggered to the brain piece
In vitro brain piece living in fixing device implements electro photoluminescence.
Any one of the 12nd kind of possible implementation with reference to first aspect to first aspect, in first aspect
In 13rd kind of possible implementation, control unit is also connected with peristaltic pump, described control unit, is additionally operable to control described compacted
Dynamic pump inputs the cerebrospinal fluid into first loop according to pre-set velocity, and the peristaltic pump is used to provide cerebrospinal fluid.
Any one of the 13rd kind of possible implementation with reference to first aspect to first aspect, in first aspect
In 14th kind of possible implementation, device also includes：Clamping device, the clamping device are fixed for clamping the brain piece
Device, described control unit are connected with the clamping device, and the clamping device is additionally operable under the triggering of described control unit,
The brain piece fixing device is controlled to be moved in the acquisition range of the harvester.
Any one of the 14th kind of possible implementation with reference to first aspect to first aspect, in first aspect
In 15th kind of possible implementation, control unit is used to obtain the electrical stimulation device to the in vitro brain piece implementation thorn living
During swashing, the cell behavior for the slow-virus transfection mark that the harvester collects and morphologic change, Huo Zhexi
The change of intracellular organelle and cytoplasm intermediate ion；
Described control unit is additionally operable to, will be under equal stimulation parameter, and the slow-virus transfection collected marks thin
Born of the same parents' behaviouristics and morphologic change, or the change of intracellular organelle and cytoplasm intermediate ion are joined with acceptor in equal stimulate
Several lower caused reactions contrast, to determine desired control mechanism.
Second aspect, the embodiment of the present invention provides a kind of method of neuromodulation, applied to first aspect to first aspect
Any one possible implementation described by neuromodulation device in, this method includes：The mobile dress of control unit control
Put and brain piece fixing device is moved in the acquisition range of harvester；In vitro brain living is fixed with the brain piece fixing device
Piece, the cerebrospinal fluid for meeting preset temperature filled with circulation in the brain piece fixing device, and in the brain piece fixing device
Middle formation cerebrospinal fluid loop；Described control unit is it is determined that the brain piece fixing device is moved in the acquisition range of harvester
Afterwards, the first control signal is sent to the electrical stimulation device, first control signal is used to indicate the electrical stimulation device pair
The in vitro brain piece living being fixed in the brain piece fixing device is implemented to stimulate；The electrical stimulation device is according to the described first control
Signal processed, the in vitro brain piece living is implemented to stimulate and sends the second control signal, second control to the harvester
Signal processed is used to trigger the harvester in the electrical stimulation device implements stimulating course to the in vitro brain piece living, in real time
Show the cell behavior of slow-virus transfection mark and morphologic change, or intracellular organelle and cytoplasm intermediate ion
Change；
The harvester is under the triggering of second control signal, in the electrical stimulation device to the in vitro brain living
Piece is implemented in stimulating course, the cell behavior of real-time exhibition slow-virus transfection mark and morphologic change, or into the cell
The change of organelle and cytoplasm intermediate ion.
With reference to second aspect, in the first possible implementation of second aspect, control unit, it is additionally operable to control compacted
Dynamic pump inputs the cerebrospinal fluid into first loop according to pre-set velocity, and the peristaltic pump is used to provide cerebrospinal fluid.
With reference to the possible implementation of the first of second aspect or second aspect, second in second aspect is possible
In implementation, the corner of brain piece fixing device is respectively arranged with stimulating electrode, is arranged on the brain piece fixing device corner
The stimulating electrode of any two corners in stimulating electrode is connected with the electrical stimulation device, for what is exported in the electrical stimulation device
Different types of electric field is exported in the presence of electric current, methods described also includes：
Described control unit controls the electrical stimulation device and is arranged on the stimulating electrode of the brain piece fixing device corner
In the stimulating electrodes of any two corners be connected, and control the electrical stimulation device by the stimulating electrodes of any two corners to it is described from
Body work brain piece is implemented to stimulate.
Any one of second of possible implementation with reference to second aspect to second aspect, the of second aspect
In three kinds of possible implementations, stimulating electrode is calutron, has magnet inner core, the electromagnetic installing in the calutron
Put for producing induced field in the presence of the electric current that is exported in the electrical stimulation device, methods described also includes：
Described control unit controls the electrical stimulation device to the magnet inner core input dc power, to produce magnetostatic field,
Or described control unit controls the electrical stimulation device to the magnet inner core input pulse electric current to produce pulsed magnetic field；Or
Person's described control unit controls the electrical stimulation device to magnet inner core input AC electricity, to produce alternating magnetic field.
Any one of the third possible implementation with reference to second aspect to second aspect, the of second aspect
In four kinds of possible implementations, control unit be additionally operable to control input to the cerebrospinal fluid in first loop flow velocity with from institute
The flow velocity for stating the cerebrospinal fluid exported in the first loop is equal.
Any one of the 4th kind of possible implementation with reference to second aspect to second aspect, the of second aspect
In five kinds of possible implementations, neuromodulation device also includes：Clamping device, the clamping device are used to clamp the brain piece
Fixing device, methods described also include：
Control unit moves the brain piece fixing device under the triggering of the 3rd control signal, by the clamping device
To the acquisition range of the harvester.
Any one of the 5th kind of possible implementation with reference to second aspect to second aspect, the of second aspect
In six kinds of possible implementations, the method that the application provides also includes：Described control unit, it is additionally operable to obtain the electro photoluminescence
Device is implemented in stimulating course to the in vitro brain piece living, the cell row for the slow-virus transfection mark that the harvester collects
To learn and morphologic change, or the change of intracellular organelle and cytoplasm intermediate ion；
Described control unit, it is additionally operable under equal stimulation parameter, the slow-virus transfection collected marks thin
Born of the same parents' behaviouristics and morphologic change, or the change of intracellular organelle and cytoplasm intermediate ion are joined with acceptor in equal stimulate
Several lower caused reactions contrast, to determine desired control mechanism.
Brief description of the drawings
Fig. 1 is a kind of structural representation of neuromodulation device provided in an embodiment of the present invention；
Fig. 2 is the modular construction schematic diagram of neuromodulation device provided in an embodiment of the present invention；
Fig. 3 is the structural representation of magnet inner core provided in an embodiment of the present invention；
Fig. 4 is the structural representation of another neuromodulation device provided in an embodiment of the present invention；
Fig. 5 is a kind of labeling process schematic diagram provided in an embodiment of the present invention.
Embodiment
As shown in figure 1, Fig. 1 shows a kind of structural representation for neuromodulation device that the application provides, such as Fig. 1 institutes
Show, the device includes：Brain piece fixing device 101, in vitro brain piece living is fixed with the brain piece fixing device 101, in the brain
The cerebrospinal fluid for meeting preset temperature filled with circulation in piece fixing device 101, and formed in the brain piece fixing device 101
Cerebrospinal fluid loop；Wherein, after brain piece living is transfected by brain region interested in acceptor in vitro, and according to predetermined manner
Obtain；Electrical stimulation device 102, electrical stimulation device 102 are connected with brain piece fixing device 101, are filled for being fixed to the brain piece
The in vitro brain piece living put in 101 is implemented to stimulate.
Harvester 103, it is real used in implementing stimulating course to the in vitro brain piece living in the electrical stimulation device 102
When gather the cell behavior of slow-virus transfection mark and morphologic change, or intracellular organelle and cytoplasm intermediate ion
Change.
Optionally, brain piece fixing device uses isolation material, for example, plastics, can so avoid electrical stimulation device to
In vitro brain piece living in the brain piece fixing device 101 is implemented to produce interference in stimulating course, meanwhile, set in brain piece fixing device
The fixed component of insulation is equipped with, for fixed in vitro brain piece living, it is ensured that harvester is gathering the in vitro work during changing
The stability of brain piece, further, since cerebrospinal fluid is the formation loop in brain piece fixing device, therefore fixed component can also be kept away
Exempt from impact of the cerebrospinal fluid of circulation in vitro brain piece living, the fixed component is nylon fiber.
The acquisition of brain piece living can be in the following manner in vitro in the application：
Operation principle of the present invention is as follows：
1. specific nerve cell (such as NSC, nerve can be marked by way of locating injection before experiment
Member, spongiocyte etc.), the slow virus of the organelle (mitochondria) of cell interior or cytoplasm intermediate ion (Ca2+) etc. it is (interested
Brain area be to be determined by researcher, different brain areas cerebral function regulation in role it is also different, researcher determine grind
Which kind of cerebral function studied carefully, brain area corresponding to this function is exactly brain area interested；The main purpose of slow-virus transfection is by spy
Fixed nerve cell makes marks in order to which later observations are studied, because being difficult that differentiation is different types of in not having markd brain
Nerve cell, specific cell will show different colors under fluorescence microscope after being marked by slow virus, such as to god
The red fluorescent protein through meta-tag, then the cell that feux rouges is sent under fluorescence microscope is exactly neuron, do not have markd
Cell does not send fluorescence under fluorescence microscope, so can more accurately study specific cells and be played under neuromodulation technology
Effect.Certainly the method marked has many kinds, and viral species is also a lot, and conventional has slow virus, adenovirus, and both make
With all popularizing very much, functionally without what difference；The method of another kind mark is by transgenic animals, in specific nerve carefully
The genetic fragment of certain fluorescin is added in born of the same parents, so this kind of nerve cell just all expresses fluorescin, but turns base
Because animal cost is high, cycle length, filial generation genetic stability is difficult to ensure that) (transfection is transfected to brain region interested
As a result it is exactly the gene that viral carrying has been gone up in specific nerve cell transfection, and these gene integrations have arrived these cells
In DNA, the can gene that is transferred to of expression and fluorescin is synthesized afterwards, under the microscope can be with so transfecting successful cell
Show the color of this fluorescin, it may also be said to which show this color is exactly this cell, and both are of equal value)；
2. broken end takes brain after the laboratory animal anesthesia after pair slow-virus transfection mark, afterwards using shaking slicer in advance
It is oxygenated and is cooled in advance and the brain slice in vitro of 300 μ m thicks is cut into 0 DEG C of artificial cerebrospinal fluid (artificial cerebrospinal fluid of precooling can reduce
The accretion rate of brain tissue, delays cell death；Oxygenation is in order to preferably simulate in body environment, preferably in artificial cerebrospinal fluid
Maintain the existing state of cell in brain slice in vitro)；
3. the in vitro living brain piece cut is transferred in 37 DEG C of aeration, artificial cerebrospinal fluid rewarming 30min (in low temperature during section
Metabolism is reduced in environment can improve brain cell survival rate, but carry out needing cell to be in just when electric field or magnetic stimulation observation
Normal physiological status, so needing to brain piece in 37 DEG C of rewarmings)；
4. the in vitro living brain piece after a rewarming is shifted and is fixed in brain piece fixing device, and by 37 DEG C of aeration, artificial brain
Spinal fluid forms cerebrospinal fluid loop by peristaltic pump in brain piece fixing device, with simulation in body cerebrospinal fluid circulation process, preferably
Maintain the existing state of brain slice in vitro.
By the specific nerve cell (such as NSC, neuron, spongiocyte) to brain area interested, (nerve is thin
Base unit of the born of the same parents as cerebral function, in noninvasive neuromodulation technology, i.e. electro photoluminescence, Neural stem cell performance neuromodulation effect
A series of changes may occur in morphosis, behavior state, electro physiology, ion concentration etc., so research is specific
Nerve cell can preferably understand the regulatory mechanism of these control techniques), the organelle (mitochondria) or cell of cell interior
Matter intermediate ion (Ca2+) etc. carry out slow-virus transfection mark after, isolated condition (refer to by specific nerve cell mark after
In vitro builds brain tissue viability environment in vivo, so that it is guaranteed that in vitro brain tissue can survive and carry out follow-up machine
System research；Isolated condition：37 DEG C of temperature；Artificial cerebrospinal fluid formula：NaCl 124mM,KCl 2.5mM,NaHCO3 26mM,
NaH2PO4 1.25mM,MgCl2 1mM,CaCl2 2mM,C6H12O6 10mM,PH 7.3-7.4；Inputted in artificial cerebrospinal fluid
95%O2 and 5%CO2 mixed gas) under build brain tissue (brain tissue refers to quickly remove complete brain after Animal Anesthesia,
Complete brain is cut into thickness in 0 DEG C of artificial cerebrospinal fluid using vibratome afterwards (to cut for 300 μm of brain tissue slices
Cell in piece is living)；In the numerous brain tissue slices being cut into, according to the anatomical structure of brain, it can be determined which brain
The brain area interested of specific nerve cell is marked before containing oneself in histotomy) viability environment in vivo, and then
Success culture of ex vivo is lived, and (brain is complete to brain piece after Animal Anesthesia quickly takes brain, passes through mechanical brains of the vibratome at 0 DEG C
It is 300 μm of brain tissue slices that complete brain is cut into thickness in spinal fluid, the nerve cell at this moment in vitro brain tissue slice
All it is survival, and the nerve cell in these brain slice in vitro can survive for a long time in artificial cerebrospinal fluid, it is 3-5 small
When, in vitro living brain piece, mainly nerve cell is living in brain slice in vitro) to carry out Mechanism Study.
Optionally, as shown in Fig. 2 brain piece fixing device 101 includes the first loop 1011, and it is arranged on the first loop
First entrance 1012 and first outlet 1013 on 011, wherein, first loop 1011 is used to accommodate the cerebrospinal fluid, with
Form the cerebrospinal fluid loop, first loop 1011 communicates with the first entrance 1012, the first outlet 1013 with
First loop 1011 communicates, and the first entrance 1012 is used to input the cerebrospinal fluid, institute to first loop 1011
State first outlet 1013 to be used to export in the cerebrospinal fluid in first loop 1011, to cause cerebrospinal fluid in first loop
Circulated in 1011.
Optionally, as shown in figure 1, the first outlet is connected by conduit with waste collecting device 104, the first outlet with
Conduit connection is provided with the first valve, and first valve is connected with the control unit of neuromodulation device, and the control unit is used
In the unlatching or opening that control first valve, in addition, control unit can also control the flow of the first valve, with control from
The flow velocity of the cerebrospinal fluid of first outlet outflow.The first entrance is connected by conduit with peristaltic pump 105, the peristaltic pump 105 with
The container 106 for accommodating cerebrospinal fluid is connected, and the container 106 is also connected with oxygen producer 107, and the oxygen producer 107 is used
In inputting oxygen to container 106, to simulate environment of the cerebrospinal fluid in acceptor.The peristaltic pump 105 is connected with control unit, the control
Unit processed is additionally operable to control peristaltic pump 105 to input cerebrospinal fluid into the first loop according to pre-set velocity.Specifically, the control device
Peristaltic pump can also be controlled to stop inputting cerebrospinal fluid into the first loop, or by adjusting the parameter of peristaltic pump, with change to
The speed of cerebrospinal fluid is inputted in first loop.
Optionally, as shown in Fig. 2 the corner of brain piece fixing device 101 is respectively arranged with stimulating electrode 1014, it is arranged on brain
The stimulating electrode of any two corners in the stimulating electrode 1014 that 101 4 jiaos of piece fixing device is connected with the electrical stimulation device 102,
For exporting different types of electric field in the presence of the electric current that is exported in the electrical stimulation device 102.Electro photoluminescence fills in the application
It is different to put connected stimulating electrode, horizontal, longitudinal, oblique electric field can be produced.Specifically, any two stimulating electrode
1014 are connected by electrode jointing 1015 with electrical stimulation device 102.
Wherein, the stimulating electrode is detachably secured in brain piece fixing device.
Specifically, electrical stimulation device has following at least one stimulus modality：Stimulus of direct current pattern, impulse stimulation pattern,
Sinusoidal stimulus modality and pseudo- stimulus modality.Wherein, under stimulus of direct current pattern, voltage adjustable extent：0-18V, current adjustment model
Enclose 0-5A, the minimum μ A of precision 1；The adjustable frequency scope of sinusoidal stimulus modality is：0.01-250Hz；Impulse stimulation pattern it is adjustable
Pulse period 100-2000ms, adjustable pulse width scope are 100-2000ms.
Include specifically, electrical stimulation device can pass through connected stimulating electrode to the electric field of in vitro brain piece output living：
DC electric field, impulse electric field, AC field, the electric field of sinusoidal variations.
Optionally, as shown in Fig. 2 stimulating electrode is calutron, there is magnet inner core 108, institute in the calutron
Calutron is stated to be used to produce induced field in the presence of the electric current of electrical stimulation device output.When the stimulating electrode is
During calutron, the stimulating electrode is connected by binding post 1016 with the electrical stimulation device 102.
Specifically, the magnet inner core 108 is the helix tube of U-shaped magnet inner core.The structure of the magnet inner core 108 such as Fig. 3 institutes
Show.
By externally-applied magnetic field it is that input current is changed into by magnetic field by solenoid in the application, that is to say, that input
Electric current produces magnetostatic field when being direct current, input pulse electric current produces pulsed magnetic field, and input AC electricity produces alternating magnetic field etc..
Optionally, the device that the application provides also includes：Objective table, the harvester 103 are arranged on institute by support
State on objective table, the objective table is used to fix the brain piece fixing device, and the brain piece fixing device fills positioned at the collection
Put 103 underface.
Optionally, be provided with the neck for holding brain piece fixing device on the objective table, the shape of the neck with it is described
The form fit of brain piece fixing device.
The harvester 103 is fluorescence microscope.
Electric field or magnetic field are applied to the brain piece fixing device for being fixed with vitro brain piece living by electrical stimulation device in the application,
With the cell behavior in the stimulating course of electric field or magnetic field and morphologic real-time change, or intracellular organelle and cell
The real-time change of matter intermediate ion, so as to by fluorescence microscope in real time, visualization method study noninvasive god in brain piece living
Regulatory mechanism of the regulated technology to brain.(visualization is referred mainly to observe under the microscope and is labeled in vitro brain piece living
Specific nerve cell, realizing visualization can, to observe under extra electric field or magnetic fields these in real time labeled
The change of cell)
Optionally, the thickness of brain piece living is 300 μm in vitro.
Specifically, it is more than or equal to from the speed of the cerebrospinal fluid of first outlet output from the cerebrospinal fluid of first entrance input
Speed.
As shown in figure 4, this application provides the structural representation of above-mentioned neuromodulation device, as shown in figure 4, electro photoluminescence fills
Put including:Power management module, the power management module are connected with power supply for producing module and display module as a trial to waveform
Operating voltage is provided, the waveform generating module is used for waveform during in vitro brain piece implementation electro photoluminescence living, specific waveform life
Include time generation module into module, time parameter during for setting electro photoluminescence, stimulus of direct current module, in vitro brain living
It is DC waveform that piece, which implements output current wave during electro photoluminescence,；Impulse stimulation module, for implementing electro photoluminescence in vitro brain piece living
When output current wave be impulse waveform；Sinusoidal stimulating module, for the electric current for implementing to export during electro photoluminescence in vitro brain piece living
Waveform is sinusoidal waveform, when display module is used to show the various waveforms exported during electro photoluminescence by waveform generating module and stimulated
Between parameter.Specifically, waveform generating module is also connected with D/A modular converters, the D/A modular converters are used for waveform generating module
The electric current of the various waveforms of generation is converted to analog signal and exported to stimulating electrode.
The embodiment of the present invention provides a kind of method of neuromodulation, applied to such as Fig. 1 or as described in Figure 2 neuromodulations
In device, this method includes：
Brain piece fixing device is moved in the acquisition range of harvester by S101, control unit control mobile device；Institute
State and in vitro brain piece living is fixed with brain piece fixing device, meet preset temperature filled with circulation in the brain piece fixing device
Cerebrospinal fluid, and cerebrospinal fluid loop is formed in the brain piece fixing device.
S102, control unit are after it is determined that the brain piece fixing device is moved in the acquisition range of harvester, to institute
State electrical stimulation device and send the first control signal, first control signal is used to indicate the electrical stimulation device to being fixed on
The in vitro brain piece living stated in brain piece fixing device is implemented to stimulate.
S103, electrical stimulation device are implemented to stimulate and to institute according to first control signal to the in vitro brain piece living
State harvester and send the second control signal, second control signal fills for triggering the harvester in the electro photoluminescence
Put and the in vitro living brain piece implemented in stimulating course, the cell behavior of real-time exhibition slow-virus transfection mark with it is morphologic
Change, or the change of intracellular organelle and cytoplasm intermediate ion.
S104, harvester are under the triggering of second control signal, in the electrical stimulation device to described in vitro living
Brain piece is implemented in stimulating course, the cell behavior of real-time exhibition slow-virus transfection mark and morphologic change, or cell
The change of inner cell organ and cytoplasm intermediate ion.
Optionally, control unit controls peristaltic pump to input the cerebrospinal fluid according to pre-set velocity into first loop,
The peristaltic pump is used to provide cerebrospinal fluid.
Optionally, the corner of brain piece fixing device is respectively arranged with stimulating electrode, is arranged on the brain piece fixing device four
The stimulating electrode of any two corners in the stimulating electrode at angle is connected with the electrical stimulation device, for defeated in the electrical stimulation device
Different types of electric field is exported in the presence of the electric current gone out, the method that the application provides also includes：
S105, control unit control the electrical stimulation device and are arranged on the stimulating electrode of the brain piece fixing device corner
In the stimulating electrodes of any two corners be connected, and control the electrical stimulation device by the stimulating electrodes of any two corners to it is described from
Body work brain piece is implemented to stimulate.
Optionally, stimulating electrode is calutron, has magnet inner core in the calutron, the calutron is used for
Induced field is produced in the presence of the electric current of electrical stimulation device output, the method that the application provides also includes：
S106, control unit control the electrical stimulation device to the magnet inner core input dc power, to produce magnetostatic field,
Or described control unit controls the electrical stimulation device to the magnet inner core input pulse electric current to produce pulsed magnetic field；Or
Person's described control unit controls the electrical stimulation device to magnet inner core input AC electricity, to produce alternating magnetic field.
Optionally, control unit be additionally operable to control input to the cerebrospinal fluid in first loop flow velocity with from described first
The flow velocity of the cerebrospinal fluid exported in loop is equal.
Optionally, neuromodulation device also includes：Clamping device, the clamping device are used to clamp the brain piece fixation dress
Put, methods described also includes：
The brain piece is fixed and filled under the triggering of the 3rd control signal by S107, control unit by the clamping device
Put and be moved in the acquisition range of the harvester.
Optionally, the method that the application provides also includes：
S108, control unit obtain the electrical stimulation device and the in vitro brain piece living are implemented in stimulating course, described to adopt
The cell behavior for the slow-virus transfection mark that acquisition means collect and morphologic change, or intracellular organelle and cell
The change of matter intermediate ion；
S109, control unit will be under equal stimulation parameters, the cell behavior of the slow-virus transfection mark collected
Learn change and the acceptor institute under equal stimulation parameter with morphologic change, or intracellular organelle and cytoplasm intermediate ion
Caused reaction contrasts, to determine desired control mechanism.
As shown in figure 5, Fig. 5 shows the idiographic flow for the in vitro brain piece living of mark that the application provides：Specifically testing
The preceding specific nerve cell (such as NSC, neuron, spongiocyte), thin of being marked by way of locating injection
(brain area interested is determined by researcher for the organelle (mitochondria) in intracellular portion or the slow virus of cytoplasm intermediate ion (Ca2+) etc.
Fixed, the different brain area role in cerebral function regulation is also different, and researcher determines which kind of cerebral function studied, this
Brain area corresponding to function is exactly brain area interested；The main purpose of slow-virus transfection be by specific nerve cell make marks with
It is easy to later observations to study, because being difficult to distinguish different types of nerve cell in not having markd brain, passes through slow virus
Specific cell will show different colors under fluorescence microscope after mark, for example red fluorescence egg is marked to neuron
In vain, then the cell that feux rouges is sent under fluorescence microscope is exactly neuron, do not have markd cell under fluorescence microscope not
Fluorescence is sent, so can more accurately study the effect that specific cells play under neuromodulation technology.Certainly the side marked
Method has many kinds, and viral species is also a lot, and conventional has slow virus, adenovirus, and both are not had functionally using all popularizing very much
There is any difference；The method of another kind mark is by transgenic animals, and certain fluorescence egg is added in specific nerve cell
White genetic fragment, so this kind of nerve cell just all express fluorescin, but transgenic animals cost is high, the cycle
Long, filial generation genetic stability is difficult to ensure that) transfected that (purpose of transfection is to mark green portion above to brain region interested
Point；The result of transfection is exactly the gene that viral carrying has been gone up in specific nerve cell transfection, and these gene integrations have arrived this
In the DNA of a little cells, can expresses the gene being transferred to and synthesizes fluorescin afterwards, so transfecting successful cell micro-
The color of this fluorescin can be shown under mirror, it may also be said to which show this color is exactly this cell, and both are
Valency).
Claims (10)
- A kind of 1. neuromodulation device, it is characterised in that including：Brain piece fixing device, in vitro brain piece living is fixed with the brain piece fixing device, is filled in the brain piece fixing device There is the cerebrospinal fluid for meeting preset temperature of circulation, and cerebrospinal fluid loop is formed in the brain piece fixing device；Wherein, after the in vitro brain piece living is transfected by brain region interested in acceptor, and obtained according to predetermined manner Arrive；Electrical stimulation device, the electrical stimulation device are connected with the brain piece fixing device, for into the brain piece fixing device In vitro living brain piece implement to stimulate；Harvester, used in implementing stimulating course to the in vitro brain piece living in the electrical stimulation device, real-time exhibition is sick slowly The cell behavior of malicious transfection markers and morphologic change, or the change of intracellular organelle and cytoplasm intermediate ion.
- 2. device according to claim 1, it is characterised in that the brain piece fixing device includes the first loop, and The first entrance and first outlet being arranged on the first loop, wherein, first loop is used to accommodate the cerebrospinal fluid, with shape Into the cerebrospinal fluid loop, first loop communicates with the first entrance, the first outlet and first loop phase Logical, the first entrance is used to input the cerebrospinal fluid to first loop, and the first outlet is used for described first time Cerebrospinal fluid output in road, to cause cerebrospinal fluid to be circulated in first loop.
- 3. device according to claim 1 or 2, it is characterised in that the corner of the brain piece fixing device is respectively arranged with Stimulating electrode, the stimulating electrode for any two corners being arranged in the stimulating electrode of the brain piece fixing device corner pierce with the electricity Excitation device is connected, for exporting different types of electric field in the presence of the electric current that is exported in the electrical stimulation device.
- 4. according to the device described in claim any one of 1-3, it is characterised in that stimulating electrode is calutron, the electromagnetism There is magnet inner core, the calutron is used to produce sensing in the presence of the electric current of electrical stimulation device output in device Magnetic field.
- A kind of 5. method of neuromodulation, it is characterised in that applied to the neuromodulation dress as described in claim any one of 1-4 In putting, methods described includes：Brain piece fixing device is moved in the acquisition range of harvester by control unit control mobile device；The brain piece is fixed In vitro brain piece living is fixed with device, the cerebrospinal fluid for meeting preset temperature of circulation is filled with the brain piece fixing device, And cerebrospinal fluid loop is formed in the brain piece fixing device；Described control unit is pierced after it is determined that the brain piece fixing device is moved in the acquisition range of harvester to the electricity Excitation device sends the first control signal, and first control signal is used to indicate the electrical stimulation device to being fixed on the brain piece The in vitro brain piece living in fixing device is implemented to stimulate；The electrical stimulation device is implemented to stimulate and to the collection according to first control signal to the in vitro brain piece living Device sends the second control signal, and second control signal is used to trigger the harvester in the electrical stimulation device to institute State in vitro brain piece living to implement in stimulating course, the cell behavior of real-time exhibition slow-virus transfection mark and morphologic change, Or the change of intracellular organelle and cytoplasm intermediate ion；The harvester is real to the in vitro brain piece living in the electrical stimulation device under the triggering of second control signal Apply in stimulating course, the cell behavior of real-time exhibition slow-virus transfection mark and morphologic change, or cell within a cell The change of device and cytoplasm intermediate ion.
- 6. according to the method for claim 5, it is characterised in that the corner of the brain piece fixing device is respectively arranged with stimulation Electrode, stimulating electrode and the electro photoluminescence of any two corners being arranged in the stimulating electrode of the brain piece fixing device corner fill To put connected, any two stimulating electrode exports different types of electric field in the presence of the electric current that the electrical stimulation device exports, Methods described also includes：Described control unit controls the electrical stimulation device and is arranged in the stimulating electrode of the brain piece fixing device corner The stimulating electrode of any two corners is connected, and controls the electrical stimulation device to be lived in vitro to described by the stimulating electrode of any two corners Brain piece is implemented to stimulate.
- 7. the method according to claim 5 or 6, it is characterised in that stimulating electrode is calutron, in the calutron With magnet inner core, the calutron produces induced field in the presence of the electric current that the electrical stimulation device exports, described Method also includes：Described control unit controls the electrical stimulation device to the magnet inner core input dc power, to produce magnetostatic field, or Described control unit controls the electrical stimulation device to the magnet inner core input pulse electric current to produce pulsed magnetic field；Or institute State control unit and control the electrical stimulation device to magnet inner core input AC electricity, to produce alternating magnetic field.
- 8. according to the method for claim 5, it is characterised in that methods described also includes：What described control unit control input exported to the flow velocity of the cerebrospinal fluid in first loop and from first loop The flow velocity of cerebrospinal fluid is equal.
- 9. according to the method for claim 5, it is characterised in that the neuromodulation device also includes：Clamping device, it is described Clamping device is used to clamp the brain piece fixing device, and methods described also includes：Described control unit moves the brain piece fixing device under the triggering of the 3rd control signal, by the clamping device To the acquisition range of the harvester.
- 10. according to the method for claim 5, it is characterised in that methods described also includes：Described control unit obtains the electrical stimulation device and the in vitro brain piece living is implemented in stimulating course, the harvester In cell behavior and the morphologic change, or intracellular organelle and cytoplasm of the slow-virus transfection mark collected from The change of son；Described control unit will be under equal stimulation parameter, the cell behavior and shape of the slow-virus transfection mark collected The change of state, or the change of intracellular organelle and cytoplasm intermediate ion and acceptor are caused by under equal stimulation parameter Reaction contrasts, to determine desired control mechanism.
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| WO2021012178A1 (en) * | 2019-07-23 | 2021-01-28 | 深圳先进技术研究院 | Nerve regulation device and method |
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