JP2006094940A - Method and device for controlling local membrane potential in vivo and method and device for recovering nerve function - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method and a device for controlling a local membrane potential in vivo which use a conductive material to produce a transient reversible cell depolarization and a spreading depression intentionally by using a safe method, and a method and a device for recovering nerve functions. <P>SOLUTION: The device for controlling the local membrane potential in vivo includes a variable magnetic field generating means for generating a variable magnetic field by current supply, a current supply part for supplying a current to the variable magnetic field generating means, and a variation potential converting means for applying stimuli of the variation potential in vivo by converting the variable magnetic field generated by the variable magnetic field generating means to a variation potential. A local potential varying device in vivo is characterized with the variation potential converting means that converts the variable magnetic field generated by the variable magnetic field generating means by the current supply from the current supply part to the variation potential at local parts in vivo and applies the variation potential in vivo for producing a transient reversible cell depolarization and a spreading depression. The production of the transient reversible cell depolarization and the spreading depression is used for treating neurodegenerative diseases and the impairment of brain functions, for mitigating various damage and disorder of cerebral nerves, and for recovering and regenerating the functions of the damaged brain and organs. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to an in vivo local membrane potential control method, a control device, a nerve function recovery method, and a recovery device using a conductor.
An object of the present invention is to provide an in-vivo local membrane potential control method and control apparatus that can safely and intentionally change a local membrane (direct current) potential. Furthermore, by applying this technology, it causes continuous cell depolarization that has the property of activating endogenous stem cells, or long-term spread suppression, and as a result, suffers contusion due to cerebral infarction or trauma. Neurological function recovery method that is effective for the recovery of brain function or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, and other causes And providing a recovery device.

In the epithelium of the skin and gastrointestinal tract, stem (precursor) cells that can create new cells always exist after growth and development, and these stem (precursor) cells divide and proliferate to create new functional cell populations. Producing. On the other hand, in the adult brain, the presence of endogenous neural stem (progenitor) cells, which are thought to replenish the memory-related loss of hippocampus and olfactory bulb neurons, has been revealed. In some brains, it has been considered that there is no new means for supplementing nerve cells or means for promoting neurite extension.
Therefore, when brain cells are damaged for some reason, for example, due to cerebral infarction or trauma, or neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, etc. It is generally difficult to restore damaged brain and nerve function.

  On the other hand, there is a molecule called a neurotrophic factor that exhibits actions necessary for maintaining the survival of nerve cells, such as a nerve cell neurite extension promoting action, a nerve cell survival maintenance / viability enhancement action, and a differentiation induction action. In the process of neuronal development / differentiation, if a neurotrophic factor does not exist, the neuron causes apoptosis. Therefore, the presence of the neurotrophic factor is important for maintaining the survival of the neuron.

  It is thought that by supplying drugs that can stimulate the growth of nerve cells such as this neurotrophic factor to the brain, it is possible to treat neurodegenerative diseases and repair damaged brain cells, For example, Patent Document 1 describes a pharmaceutical composition containing 1,5-di (pyridin-4-yl) -penta-1,4-dien-3-one and a neurotrophic factor.

JP-T-2001-504470

In order to protect the brain from harmful substances, blood vessels in the brain and spinal cord have a mechanism called the blood-brain barrier that prevents substances from freely passing through and allows only selectively incorporated substances to enter the brain. .
Therefore, the pharmaceutical composition as described in Patent Document 1 administered into the body of a patient cannot reach the brain unless it passes through the blood-brain barrier, and exhibits a growth action of nerve cells. could not. In addition, endogenous neural stem (progenitor) cells that exist in the brain or other organs after growth and development are intentionally divided using safe means, and functional cells such as nerve cells are used using safe techniques. It was impossible to increase it intentionally.

  The present inventor has found a technique for controlling a biological (cell) membrane (direct current) potential reliably and safely. Furthermore, it has been found that application of the technology can promote cell division and proliferation of in vivo stem (progenitor) cells, and the present invention has been completed.

That is, the invention according to claim 1 relates to an in-vivo local membrane potential control method characterized by causing a potential fluctuation in a conductor placed in a living body, thereby controlling the membrane potential in the in-vivo region.
The invention according to claim 2 relates to a nerve function recovery method characterized by causing a potential fluctuation in a conductor placed in a living body, thereby controlling a membrane potential in a local area in the living body.
According to a third aspect of the present invention, there is provided a variable magnetic field generation unit that generates a variable magnetic field by supplying a current, a current supply unit that supplies a current to the variable magnetic field generation unit, and a variable magnetic field generated by the variable magnetic field generation unit. Fluctuating potential conversion means for converting the fluctuating potential to give a fluctuating potential stimulus to the living body, and the fluctuating potential converting means generates the fluctuating magnetic field generated by the fluctuating magnetic field generating means by supplying current from the current supplying section. The present invention relates to an in-vivo local membrane potential control device characterized in that it is converted into a variable potential locally in the body, and the variable potential is applied to a living body to cause reversible cell depolarization or propagation suppression.
The invention according to claim 4 relates to the in-vivo local membrane potential control apparatus according to claim 3, wherein the variable magnetic field generated by the variable magnetic field generating means is a pulsed magnetic field.
According to a fifth aspect of the present invention, the fluctuating magnetic field generated by the fluctuating magnetic field generating means has a frequency of 1 to 3000 Hz, a pulse width of 0.0001 to 10000 ms, and an average magnetic field strength of 0.1 to 100 T. The in-vivo local membrane potential control device according to claim 3 or 4, characterized in that
The invention according to claim 6 relates to the in-vivo local membrane potential control apparatus according to any one of claims 3 to 5, wherein the variable potential conversion means includes a conductor.
The invention according to claim 7 relates to the in-vivo local membrane potential control apparatus according to claim 6, wherein a part or the entire surface of the conductor is covered with an insulator.
According to an eighth aspect of the present invention, there is provided a variable magnetic field generation unit that generates a variable magnetic field by supplying a current, a current supply unit that supplies current to the variable magnetic field generation unit, and a variable magnetic field generated by the variable magnetic field generation unit. Fluctuating potential conversion means for converting the fluctuating potential to give a fluctuating potential stimulus to the living body, and the fluctuating potential converting means generates the fluctuating magnetic field generated by the fluctuating magnetic field generating means by supplying current from the current supplying section. The present invention relates to a nerve function recovery device characterized in that it is converted into a variable potential locally in the body, and the variable potential is applied to a living body to cause reversible cell depolarization or propagation suppression.
The invention according to claim 9 relates to the nerve function recovery device according to claim 8, wherein the fluctuation magnetic field generated by the fluctuation magnetic field generation means is a pulse magnetic field.
According to a tenth aspect of the present invention, the variable magnetic field generated by the variable magnetic field generating means has a frequency of 1 to 3000 Hz, a pulse width of 0.0001 to 10000 ms, and an average magnetic field strength of 0.1 to 100 T. The nerve function recovery apparatus according to 8 or 9.
The invention according to claim 11 relates to the nerve function recovery apparatus according to any one of claims 8 to 10, wherein the fluctuation potential converting means includes a conductor.
The invention according to claim 12 relates to the nerve function recovery apparatus according to claim 11, wherein a part or the whole of the surface of the conductor is covered with an insulator.

The in-vivo local membrane potential control method and control apparatus according to the present invention are a method and an apparatus capable of controlling a local membrane potential in the living body.
In vivo local membrane potential control method and control device enables treatment and prevention of various diseases by intentionally causing transient reversible cell depolarization or spreading suppression in a target cell population Method and apparatus. Transient reversible cell depolarization or spreading suppression continuously, endogenous neural stem (progenitor) cells, other stem cells, or other cells that can divide and proliferate, proliferative activity As a result, the target cell population can be intentionally divided and expanded.

Further, the neural function recovery method and device is a method and device that applies the in vivo local membrane potential control method and control device, and is intended for transient reversible cell depolarization or spreading suppression to a target cell population. Can be generated automatically. Transient reversible cell depolarization or spreading suppression continuously, endogenous neural stem (progenitor) cells, other stem cells, or other cells that can divide and proliferate, proliferative activity As a result, the target cell population can be intentionally divided and expanded.
The cells that can divide include cells that produce constituent cells such as peripheral nerves or central nerve cells and the heart, that is, stem (progenitor) cells that produce a cell population that has been considered non-renewable. By this nerve function recovery method and device, it is possible to regenerate an organ that has fallen in function by activating the division and proliferation of stem (progenitor) cells and further increasing the production of growth / nutrient factors. Therefore, the method and apparatus for recovering nerve function according to the present invention provides treatment of brain damaged by various diseases such as cerebral infarction or trauma, or Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar degeneration, muscle atrophic side. It can be used for the treatment of neurodegenerative diseases such as cord sclerosis, chronic pain, or decreased intelligence due to other causes, and the treatment of regional cerebral circulatory failure due to arteriosclerosis.
In the brain, it is possible to increase brain-derived neurotrophic factor by repeatedly causing spreading suppression, which is a transient, reversible depolarization phenomenon that is transmitted, and reduced brain function due to the neurite extension promoting action Can be used to improve or treat depression. On the other hand, when continuous depolarization stimulation using the in vivo local cell depolarization generation method is performed on organs other than the brain, regeneration is measured by dividing and proliferating endogenous stem (precursor) cells in the organ. It can also be used for various cell organ regeneration treatment purposes.

The in vivo local membrane potential control method according to the present invention will be described below.
The in vivo local membrane potential control method according to the present invention is characterized in that potential fluctuations having various levels and properties are intentionally generated in a local area of the living body.

When the direct-current potential in the living body is changed to a certain value or more, the polarization state observed as the difference between the direct-current potentials inside and outside the cell is tilted in a direction that temporarily decreases, that is, intracellular and extracellular depolarization occurs. In the brain, when the depolarization that occurs locally reaches a certain threshold value, the same depolarizing potential-varying wave that travels at a specific speed of about 2 to 5 mm / min around the depolarized region as a focal point. Spreads throughout the ipsilateral brain like a ripple. This phenomenon is called propagation suppression or spreading depression, that is, a transient reversible cell depolarization phenomenon that has the property of continuously propagating to surrounding cell populations. This phenomenon does not appear in the normal state of the mature brain, when migraine, epileptic seizures or cerebral infarction, extreme temperature stimulation to the brain or physical stimulation that damages the brain, or It is known to occur accompanying cerebral ischemia and the like. It is known that the spread suppression itself is harmless to the brain, and the significance of the spread suppression phenomenon in the living body is still unclear. As is evident from the fact that spreading suppression occurs in the brain associated with a normal migraine attack, only a single to several times of this spreading suppression phenomenon can cause any therapeutic or prevention in the brain. It is thought that it does not show an effective effect. This is also supported experimentally as follows.
The present inventor has found that induction of continuous spreading suppression over several days, not just hours, increases new neurons in the brain. That is, by causing spread suppression continuously for a certain period of time, the division activity of brain intrinsic neural stem (progenitor) cells is activated. On the other hand, this stimulation also increases brain-derived neurotrophic factor in the brain. This increase in brain-derived neurotrophic factor has the function of promoting neurite outgrowth or promoting the differentiation of the cell group produced by cell division of neural stem (progenitor) cells in the central nervous system into nerve cells. . In other words, the induction of continuous spread suppression over a long period of time promotes the neurogenesis that occurs slightly in the brain, usually in a limited range. Appropriate application of the in vivo local membrane potential control method provides therapeutic and preventive effects in vivo.
Therefore, the in vivo local membrane potential control method according to the present invention can be applied as a nerve function recovery method.

In order to cause transient reversible depolarization or spreading suppression having the property of promoting cell division activity, the local direct-current potential may be changed repeatedly and specifically, the cell may divide and proliferate. The local membrane potential may be changed so as to cause the activity.
The degree to which the local local direct-current potential is changed is not particularly limited, but regarding the fluctuation per time, the intracellular potential normally maintained (polarized) at about −5 to −100 mV by the fluctuation potential stimulation is changed to 5 to 5. What is necessary is just to change about 100 mV (depolarization). When this local depolarization reaches a certain threshold value, spread suppression (propagating potential fluctuation wave) occurs in the brain.

  In order to promote the cell division or proliferation of endogenous stem (progenitor) cells, it is necessary to cause reversible cell depolarization or spreading suppression continuously for a certain period or intermittently. The number of reversible cell depolarizations or the period for causing spread suppression is not particularly limited, but at least 2 to 10 times continuously for reversible cell depolarization and at least 1 for spread suppression. ˜6 hours must be continuously generated, preferably 10 times or more if reversible cell depolarization, 6 hours or more if spreadability is suppressed, and further repeated intermittently. You can do it.

Various parameter values of variable potential stimulation applied to living bodies such as brain and neural stem (progenitor) cells are not particularly limited, and reversible cell depolarization or spreading suppression occurs in living bodies such as brain and neural stem (precursor) cells. Any potential fluctuation can be used.
A method for applying a potential variation to a living body is not particularly limited. For example, a variation in which a living body can be subjected to a varying potential stimulus by being placed in a varying magnetic field (that is, a varying magnetic field can be converted into a varying potential). An example is a method in which the potential converting means is disposed locally in a living body such as the brain and a varying magnetic field is applied to the varying potential converting means from the outside.
In particular, in the present invention, it is preferable that the fluctuation magnetic field stimulation given to the fluctuation potential converting means is a pulse magnetic field stimulation. As an example of the pulse magnetic field, the frequency is 1 to 3000 Hz, preferably 1 to 50 Hz, the pulse width is 0.0001 to 10000 ms, preferably 0.1 to 3000 ms, and the average magnetic field strength is 0.1 to 100 T, preferably 0. The pulse magnetic field which is 5-10T can be illustrated.
The potential fluctuation that the fluctuation potential conversion means gives to the living body when the fluctuation magnetic field is given to the fluctuation potential conversion means is the magnitude of the fluctuation magnetic field stimulus given to the fluctuation potential conversion means, the apparatus that generates the fluctuation magnetic field, and the fluctuation potential conversion. It varies depending on the positional relationship with the means, the distance, the form of the fluctuation potential conversion means, and the like. Therefore, the parameter value of the above-mentioned variable magnetic field stimulation is an example, and the potential fluctuation given to the living body from the variable potential conversion means becomes a potential fluctuation that can cause reversible cell depolarization or spreading suppression in the living body. Fluctuating magnetic field stimulation may be applied to the varying potential conversion means.
There is no particular limitation on the period during which potential changes are applied to living bodies such as brain and neural stem (progenitor) cells, but continuous or intermittent stimulation for 1 to 24 hours per day may be applied for about 1 to 30 days.

The part of the brain that gives potential fluctuation is not particularly limited, and examples thereof include brain cortex, hippocampus, basal ganglia, midbrain, cerebellum, medulla and the like.
The potential fluctuation can also be applied to other organs that are expected to be regenerated by cell division.

Next, the in-vivo local membrane potential control apparatus according to the present invention will be described. An in-vivo local membrane potential control device (hereinafter sometimes simply referred to as a control device) can intentionally generate potential fluctuations having various levels and properties in a local region of the living body. FIG. 1 is a block diagram showing an outline of a control device according to the present invention.
The control device (10) according to the present invention includes a variable magnetic field generation unit (12) that can generate a variable magnetic field by supplying current, and a current supply unit (11) that supplies a current to the variable magnetic field generation unit (12). And a fluctuation potential conversion means (13) capable of converting the fluctuation magnetic field generated by the fluctuation magnetic field generation means (12) into a fluctuation potential to give a potential fluctuation to the living body.

The current supply unit (11) is provided to supply a current that can cause the variable magnetic field generation means (12) to generate a variable magnetic field. The current supply unit (11) in the illustrated example includes the power supply unit (11a). ), A control unit (11b), and an output unit (11c).
The power supply unit (11a) is provided to supply a required current. For example, an alkaline ion battery, a lithium ion battery, a 100V power supply, a 200V power supply, a battery, or the like is used.

The control unit (11b) includes a CPU (not shown), an oscillator (not shown), a voltage regulator (not shown) for adjusting the voltage of power supplied from the power supply unit (11a), and the like. ing. While receiving the power supply from the power supply unit (11a), the output unit (11c) is controlled so as to output a required current.
The output unit (11c) outputs a required current to the variable magnetic field generation means (12) under the control of the control unit (11b).
The output unit (11c) and the variable magnetic field generation means (12) are connected by a lead wire or the like.

  The variable magnetic field generation means (12) may be any means as long as it can generate a variable magnetic field by supplying current from the current supply unit (11). Specifically, a Helmholtz coil or the like can be exemplified. Further, the magnetic field may be generated by rotating the magnetic body by supplying current from the current supply unit (11).

FIG. 2 is a partial cross-sectional view showing a schematic configuration of the variable potential conversion means (13).
The fluctuation potential conversion means (13) can convert the fluctuation magnetic field generated by the fluctuation magnetic field generation means (12) into a fluctuation potential to give a fluctuation potential stimulus to the living body. In a normal case, the fluctuation potential conversion means (13) is arranged physically and spatially separated from the fluctuation magnetic field generation means (12).
The variable potential conversion means (13) may be any means as long as it can apply a variable potential stimulus to a living body by being placed in a variable magnetic field. For example, a conductor can be exemplified as one that can generate a variable potential by being placed in a variable magnetic field, and specifically, a metal such as stainless steel, iron, aluminum, copper, gold, silver, and the like. Alternatively, conductive polymers such as conductive polyacetylene, conductive polythiophene, and conductive polypyrrole can be exemplified.
The form of the variable potential conversion means (13) is not particularly limited, and examples thereof include a spherical shape, a screw shape, a plate shape, a membrane shape, or a shape obtained by combining these shapes.
The variable potential converting means (13) is a lead wire or a fixed portion of the variable potential converting means (13) as necessary so that the generated variable potential reaches the target biological (cell) membrane in the living body. Insulator covering is attached.
In the variable potential conversion means (13) shown in FIG. 2 (a), the other surface of the conductor (13a) is covered with an insulator (13b) so that only a part of the surface of the conductor (13a) is exposed. Has been. The variable potential conversion means (13) shown in FIG. 2 (a) is such that a part of the surface of the conductor (13a) that is not covered with the insulator (13b) is directly on or near the target site for applying the variable potential stimulus. Arranged to touch.
In the variable potential conversion means (13) shown in FIG. 2B, the entire surface of the conductor (13a) is covered with an insulator (13b), and a lead wire (13c) is provided. One end of the line (13c) is connected to the conductor (13a). The other end of the lead wire (13c) is arranged at or near the target site that gives potential fluctuations.

The number of the variable potential conversion means (13) to be arranged is not particularly limited, but a plurality of variable potential conversion means are provided at or near a target site (for example, cerebrum, cerebellum, blood vessel, nerve cell, etc.) to which the variable potential stimulation is to be applied. It is necessary to arrange so that the fluctuation potential stimulation from (13) is given. In FIG. 1, a total of four fluctuation potential conversion means (13) are arranged so as to be in contact with the cerebrum (B).
In the plurality of variable potential conversion means (13) arranged, all the variable potential conversion means (13) may have the same form or different forms. Moreover, the number is not specifically limited.

3 and 4 are views showing a state in which the variable potential conversion means (13) is arranged in the living body. 3 and 4, a is the scalp, b is the skull, c is the dura mater, d is the arachnoid membrane, e is the subarachnoid space, f is the pia mater, and g is the cerebrum. Cortex.
The fluctuation potential conversion means (13) is not particularly limited as long as it is arranged so that a fluctuation potential stimulation generated by receiving a fluctuation magnetic field can be given to a living body, and the fluctuation potential conversion means (13) is subcutaneously provided. It can be implanted or placed outside the body.
When the variable potential converting means (13) is implanted subcutaneously, the position where the variable potential converting means (13) is arranged is not particularly limited, but the arrival site of the variable potential stimulus is the brain cortex, hippocampus, basal ganglia, midbrain, cerebellum. And it can arrange | position so that a part (part which is not covered with an insulator) of the fluctuation potential conversion means (13) may contact these target locations or its vicinity so that it may become a medulla.
In addition to this, a variable potential conversion means (13) arranged at a position in contact with a tissue group by cell division, organ regeneration, or a cell population for constructing blood vessels, or embedded at a position away from a target location. The potential fluctuation generated in (1) may be guided to the target location or the vicinity thereof via a lead wire embedded under the skin. When implanted subcutaneously, it is suitable for long-term potential fluctuations.
When the variable potential converting means (13) is arranged outside the body, for example, the variable potential converting means is arranged so as to be in contact with an organ that is expected to undergo tissue regeneration or organ regeneration or skin near the blood vessel. The variable potential generated in (13) may be guided to the target location via a lead wire embedded under the skin. When arranged outside the body, it is suitable for short-term fluctuation potential generation.

Specifically, as shown in FIG. 3, the skull (b) is perforated to provide a hole, and the variable potential converting means (13) is disposed in this hole so as to be in contact with the dura mater (c). A method can be illustrated. Incidentally, an insulator is provided in a portion other than the portion in contact with the dura mater (c) of the fluctuating potential converting means (13) shown in FIG. 3, and the fluctuating potential generated by receiving the varying magnetic field is the dura mater. Can be reached directly. The fluctuation potential transmitted to the dura mater is transmitted to the brain via the arachnoid membrane, the buffy coat and surrounding structures.
As shown in FIG. 4, the variable potential converting means (13) is disposed on the surface of the scalp (a), and the skull is perforated to provide a hole, from which the lead wire (13c) is connected to the dura mater ( The method of connecting to c) can be illustrated. 4 is covered with an insulator, and the potential fluctuation generated by receiving the fluctuation magnetic field can reach the dura mater through the lead wire (13c). .

Next, the operation of the control device (1) according to the present invention will be described.
When the current is supplied from the power supply unit (11) to the variable magnetic field generating means (12), the variable magnetic field generating means (12) generates a variable magnetic field.
In the living body, a plurality of variable potential conversion means (13) that can generate a potential variation by being placed in a varying magnetic field are arranged at a required position. In the example of FIG. 1, a case where potential fluctuation is applied to the brain (B) is shown, and a total of four fluctuation potential conversion means (13) are arranged so as to be in contact with the dura mater of the unilateral brain (B). (The number of variable potential means to be arranged is not particularly limited).
By placing the fluctuation potential conversion means (13) within the fluctuation magnetic field generated by the fluctuation magnetic field generation means (12), a fluctuation potential is generated in the fluctuation potential conversion means (13). This fluctuation potential becomes a depolarizing stimulus for the cerebral nerve cell, and when the stimulus reaches a certain threshold value, spreading suppression occurs in the brain (B).
The continuous spreading suppression over a long period of time can increase the endogenous neural stem (progenitor) cell division activity and the production of brain-derived neurotrophic factor. Thereby, in the brain (B), the development of neurites related to functional recovery, production of new neurons, and the like are promoted. Therefore, the control device (1) according to the present invention can be used as a nerve function recovery device.

  The in vivo local membrane potential control method and apparatus, and the nerve function recovery method and apparatus according to the present invention can be applied to the brain and nerve stem (progenitor) cells of any animal, and particularly humans, monkeys, cows, sheep, horses. It can apply suitably to mammals, such as.

EXAMPLES Hereinafter, although this invention is demonstrated based on an Example, this invention is not limited to these Examples at all.
(Test example)
In the cranium of 8-9 week old Sprague-Dawley male rats, as a variable potential conversion means, 4 spherical metal conductors (made of stainless steel) with a diameter of 2 mm were placed in a small hole drilled in the skull so as to contact the dura mater. It was placed surgically and fixed in the bone using an adhesive from the outer surface. By arranging the partial surface of the variable potential converting means so as to contact the dura mater covering the brain surface, the potential fluctuation generated by the variable potential converting means can reach the brain through the dura mater.
After fixing the variable potential conversion means, the head skin was sutured and closed. After this treatment, a fluctuation magnetic field having a stimulation frequency of 25 pulses / second, a pulse width of 0.2 msec, and a magnetic flux change rate of 30 to 120 kT per second is continuously applied to the fluctuating potential converting means once for 2 seconds. By giving a total of 18 times per minute, the brain local potential was varied to try to induce spreading suppression. Three days after the potential fluctuation due to the changing magnetic field, the brain was taken out, and glial fibrillary acidic protein (GFAP) or brain-derived neurotrophic factor (BDNF) is used as a histological indicator that spread suppression in the brain has appeared. The expression of was observed.
FIG. 5 shows a micrograph of a rat brain used for observation of glial fibrillary acidic protein (GFAP), and FIG. 6 shows a micrograph of a rat brain used for observation of brain-derived neurotrophic factor (BDNF). . (1) in FIGS. 5 and 6 are micrographs showing the brains of comparative rats, and (2) in FIGS. 5 and 6 are micrographs showing the brains of rats subjected to varying potential stimulation with a spherical metal conductor. It is.
As a result of histological observation of the isolated brain, it was confirmed that GFAP and brain-derived neurotrophic factor increased extensively in the stimulating brain. That is, it has been clarified that the cell depolarization generation method using the variable magnetic field caused the spread suppression in the brain.

  On the other hand, the experimental system using rats was also used for 48 hours of continuous spreading suppression induced by local potassium chloride injection (spreading suppression occurred not only by potential stimulation but also by cell membrane depolarization by chemical stimulation. Abruptly increases the number of juvenile neurons in the rat frontal lobe subventricular wall after normal growth and development, and other parts of the brain that are not normally present, i.e. It has been found that a large number of new neurons appear in the basal ganglia and brain cortex.

The in vivo local membrane potential control method and nerve function recovery method according to the present invention can safely and yet cause an intended change in membrane potential locally, accompanied by a change in DC potential in vivo. It can be applied as a control means or stimulation means for phenomena such as central nervous activity, nerve transmission, contraction or relaxation of skeletal muscle, contraction or relaxation of myocardium, peristaltic movement in the digestive tract, contraction or relaxation of various sphincters .
The in vivo local membrane potential control device and nerve function recovery device according to the present invention can cause continuous spread suppression using transient reversible cell depolarization stimulation, and as a result, derived from the brain. It is possible to increase the production of neurotrophic factors and to regenerate nerve cells.
The nerve function recovery device according to the present invention is a therapeutic device for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar degeneration, amyotrophic lateral sclerosis, or other causes of brain function decline. Can be used. Moreover, in order to increase the resistance of the brain to various stresses, it can be used as a device for reducing various cranial nerve damages / disorders. Furthermore, the production of transient reversible cell depolarization or spreading suppression newly produces cranial nerve cells or other cells, so that the function recovery device for brain or other organs that have been contusioned by cerebral infarction or trauma, etc. It can be used as an organ regeneration device.

It is a block diagram which shows the outline of the in-vivo local membrane potential control apparatus which concerns on this invention. (A) And (b) is a fragmentary sectional view of a fluctuation potential conversion means. It is the figure which showed the state which arrange | positions a fluctuation potential conversion means to a biological body. The variable potential converting means is disposed in contact with the dura mater in a hole provided by being drilled in the skull. It is the figure which showed the state which arrange | positions a fluctuation potential conversion means to a biological body. The variable potential converting means is arranged on the scalp surface, and the variable potential converting means is provided with a lead wire, and the lead wire is arranged so as to be in contact with the dura mater. It is a micrograph of a rat brain used for observation of glial fibrillary acidic protein (GFAP), (1) is a micrograph showing the brain of a comparative rat, and (2) is a spherical metal conductor with a variable potential. It is a microscope picture which shows the brain of the rat which gave irritation | stimulation repeatedly. It is the microscope picture of the brain of the rat used for observation of a brain origin neurotrophic factor (BDNF), (1) is a microscope picture which shows the brain of the rat of a comparison control, (2) is a spherical metal conductor, and is a fluctuation potential. It is a microscope picture which shows the brain of the rat which gave irritation | stimulation repeatedly.

Explanation of symbols

DESCRIPTION OF SYMBOLS 10 In-vivo local membrane potential control apparatus 11 Electric signal generation means 11a Power supply part 11b Control part 11c Output part 12 Fluctuation magnetic field generation means 13 Fluctuation potential conversion means 13a Conductor 13b Insulator 13c Lead wire B Brain a Scalp b Skull c Dura d Arachnoid e Subarachnoid space f Luffy coat g Cerebral cortex

Claims (12)

  A method for controlling a local membrane potential in a living body, wherein a potential fluctuation is caused in a conductor placed in the living body, thereby controlling a membrane potential in a local area in the living body.   A method for recovering a nerve function, characterized by causing a potential fluctuation to occur in a conductor placed in a living body, thereby controlling a membrane potential in a local area in the living body. Fluctuating magnetic field generating means for generating a fluctuating magnetic field by supplying current, a current supply unit for supplying current to the fluctuating magnetic field generating means, and converting the fluctuating magnetic field generated by the fluctuating magnetic field generating means to a fluctuating potential to a living body A variable potential conversion means for applying a variable potential stimulus,
The fluctuation potential converting means converts the fluctuation magnetic field generated by the fluctuation magnetic field generation means by current supply from the current supply section into a fluctuation potential locally in the living body, gives the fluctuation potential to the living body, and reversible cells. An in-vivo local membrane potential controller characterized by causing depolarization or propagation suppression.   The in-vivo local membrane potential control apparatus according to claim 3, wherein the fluctuating magnetic field generated by the fluctuating magnetic field generating means is a pulsed magnetic field.   The in vivo body according to claim 3 or 4, wherein the fluctuating magnetic field generated by the fluctuating magnetic field generating means has a frequency of 1 to 3000 Hz, a pulse width of 0.0001 to 10000 ms, and an average magnetic field strength of 0.1 to 100T. Local membrane potential control device.   The in-vivo local membrane potential control apparatus according to any one of claims 3 to 5, wherein the variable potential conversion means includes a conductor.   The in-vivo local membrane potential control apparatus according to claim 6, wherein a part or the entire surface of the conductor is covered with an insulator. Fluctuating magnetic field generating means for generating a fluctuating magnetic field by supplying current, a current supply unit for supplying current to the fluctuating magnetic field generating means, and converting the fluctuating magnetic field generated by the fluctuating magnetic field generating means to a fluctuating potential to a living body A variable potential conversion means for applying a variable potential stimulus,
The fluctuation potential converting means converts the fluctuation magnetic field generated by the fluctuation magnetic field generation means by current supply from the current supply section into a fluctuation potential locally in the living body, gives the fluctuation potential to the living body, and reversible cells. A nerve function recovery device characterized by causing depolarization or propagating suppression.   9. The nerve function recovery apparatus according to claim 8, wherein the fluctuation magnetic field generated by the fluctuation magnetic field generation means is a pulse magnetic field.   The neural function according to claim 8 or 9, wherein the fluctuation magnetic field generated by the fluctuation magnetic field generation means has a frequency of 1 to 3000 Hz, a pulse width of 0.0001 to 10000 ms, and an average magnetic field strength of 0.1 to 100T. Recovery device.   The nerve function recovery apparatus according to claim 8, wherein the variable potential conversion means includes a conductor. The nerve function recovery apparatus according to claim 11, wherein a part or the entire surface of the conductor is covered with an insulator.

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