CN112618962A

CN112618962A - Mid-infrared nerve stimulation technology

Info

Publication number: CN112618962A
Application number: CN202010930902.0A
Authority: CN
Inventors: 常超; 贾宏博
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-09-08
Filing date: 2020-09-08
Publication date: 2021-04-09

Abstract

The invention relates to the field of neuroscience foundation and clinical research, discloses a technology for activating cranial nerve cells by mid-infrared fixed-point irradiation, and simultaneously discloses demonstration of a specific implementation mode of the technology. The mid-infrared light output by the mid-infrared light source (1) is transmitted to a stimulation target site of brain tissue through the light modulator (2), the optical fiber adapter (3) and the mid-infrared optical fiber (4) and is irradiated for a period of time, so that the mid-infrared light energy is absorbed by the tissue of an irradiated area with high gradient distribution, and the activity of nerve cells contained in the tissue of the area is improved. The mid-infrared nerve stimulation technology disclosed by the invention is different from the existing nerve stimulation technology called optogenetic technology in that: the wavelength of the adopted light source is in the middle infrared band but not in the visible band or the near infrared band; and the stimulated brain tissue does not contain any gene or chemical substance intervened by the outside, so that the technology has wider application scenes compared with the optogenetic technology.

Description

Mid-infrared nerve stimulation technology

Technical Field

The invention relates to the fields of basic research of neuroscience and treatment of neurological diseases, and discloses an implementation method of a neurostimulation technology. Neurostimulation, also called neuromodulation, is a technique that alters the activity of nerve cells in brain tissue through the action of external intervention and is used in a great deal of basic research in neuroscience and in the treatment of neurological diseases. The mid-infrared nerve stimulation technology provided by the invention is a nerve stimulation technology for improving the activity level of nerve cells in an irradiated area through fixed-point irradiation of mid-infrared light.

Background

Currently available neurostimulation techniques can be distinguished according to the basic type and nature of the external intervention, mainly including two major types, drug stimulation and physical stimulation.

The drug stimulation means that nerve cell activity is changed by taking or injecting nerve drugs, and the nerve drugs are various and have different action mechanisms and effects, but generally have obvious toxic and side effects, and are easy to generate dependence and addiction after long-term use.

The physical stimulation means that the activity of nerve cells is changed through physical actions such as electricity, magnetism, sound, light, heat and the like, and the toxic and side effects are generally not obvious, and the addiction is not obvious.

Electrical and magnetic stimulation are relatively traditional neurostimulation techniques because the fundamental mode of activity of nerve cells is the bioelectric signal. Through the development of recent decades, the conversion of electrical stimulation and magnetic stimulation from laboratory to clinical application is mature, which has the advantages of non-invasion and large depth of action, but has the disadvantages that the stimulation positioning precision is limited and the action range is difficult to control.

Acoustic stimulation is a new type of neurostimulation technology that has gained attention in recent years, and refers to pulse stimulation using ultrasound outside the normal auditory perception range. The acoustic stimulation has the advantages of easy and accurate positioning and the disadvantages of weak action effect and obvious effect only by needing high-intensity focused ultrasonic waves, and the safety of the high-intensity ultrasonic waves is not clear yet.

Light stimulation refers to a technique for regulating nerve activity by applying light to brain tissue, not to the eye. However, except for the photoreceptor cells on the retina of the eye, all brain tissue cells are insensitive to light, and it is difficult to directly regulate brain nerve activity with light, so the mechanism of light stimulation of nerves mainly influences nerve activity by means of the thermal effect generated by near infrared light, which is basically the same as that of thermal stimulation. Thermal stimulation is very destructive and often exceeds the thermal tolerance limit of brain tissue without producing sufficient neurostimulation effect, so that the thermal stimulation is difficult to be applied practically.

In 2005, the group of research at the university of stanford Karl deisseoth in the united states reported for the first time a new nerve stimulation technique named "optogenetics", which was characterized by skillfully allowing nerve cells of any given genotype to express a specific photosensitive ion channel protein that could not be expressed originally by means of transgenosis, thereby making them become sensitive to light and producing a bioelectrical response to light stimulation. The optogenetic technology has gained great attention and wide application in the basic research field of neuroscience since its birth, can provide positioning accuracy accurate to single cell and even subcellular structures and time accuracy accurate to millisecond level, and can stimulate or inhibit nerve cell activity. By means of the optogenetic technology, a large number of advanced neuroscience researches make breakthrough progress, the understanding of brain neural circuits and functions is greatly improved, some serious nerve diseases are successfully treated in animal model experiments, and the prospect is bright.

However, the greatest advantage of optogenetic technology is the greatest disadvantage, and since transgenic technology must be used to express the desired photoperions in nerve cells, which is the most sensitive category and conserved baseline in medical ethics, optogenetic technology is almost impossible to use directly in the clinic for a long time in the future. Similarly, any neurostimulation technique that uses transgenic technology to make nerve cells more sensitive to externally applied physical action fields (e.g., more sensitive to magnetic fields) is nearly impossible to translate into clinically useful medical techniques in the near future.

We have briefly reviewed various neurostimulation techniques that are currently known. From this review, those skilled in the art will be aware of the merits of each technique and understand the essential differences between the mid-infrared neurostimulation technique disclosed in the present invention and the existing neurostimulation techniques described below. The key technical problems solved by the invention are as follows: how to design and implement a neurostimulation technology which simultaneously meets the following application requirement conditions: 1. the positioning of the stimulation target site is accurate to millimeter precision; 2. the inability to introduce any foreign genes or chemicals; 3. can stimulate repeatedly, the effect can be repeated, and does not produce obvious damage to the target biological tissue.

Disclosure of Invention

The mid-infrared nerve stimulation technology can be generally classified as the light stimulation technology. The light has good directivity, the requirement of the 1 st application is easy to realize, and the positioning precision of the stimulation target site is high. Mid-infrared refers to electromagnetic waves having a wavelength between 3 and 50 microns, according to the definition given in international standard ISO 20473. The definition of the mid-infrared light used by the mid-infrared nerve stimulation technology is the same, namely the electromagnetic wave with the wavelength between 3 microns and 50 microns. It will be clear to those skilled in the art that mid-infrared light having a wavelength in any one of the values of this band or in any one of the sub-ranges may be used in the practice of the present invention.

According to the same ISO 20473 standard, the visible light referred to in the present invention is defined as electromagnetic waves having a wavelength between 0.38 and 0.78 micrometers, and the near infrared light is defined as electromagnetic waves having a wavelength between 0.78 micrometers and 3 micrometers. At first glance, mid-infrared stimulation appears to be an extension of existing near-infrared light stimulation and optogenetic techniques. However, this is a big misunderstanding and is the originality of the key technical problem solved by the present invention, which is described in detail below.

According to the existing neuroscience knowledge, the uniform heating of nerve tissues can not effectively stimulate the activity of nerve cells, mainly because the ion channel mechanism for regulating the activity of nerve cells up by heat and the ion channel mechanism for regulating the activity of nerve cells down by heat exist, and the net effect is in a state close to balance on the whole, so that the obvious change of the nerve activity level can not be generated by the uniform increase or decrease of the temperature, and the mechanism is a reasonable mechanism formed by natural evolution of organisms and can effectively keep the work of a nervous system to be free from the influence of heat and temperature change in a certain range. However, if the distribution of the photo-thermal energy transmitted to the nerve tissue is not uniform and has a large gradient in the local space, the different ion channel mechanisms described above can produce an unbalanced net effect in the corresponding local space, thereby producing a net effect of up-regulation of the activity of the nerve cells. The application of this biophysical principle does not require any ion channel for the expression of foreign genes (corresponding to the case of optogenetic technology) and any chemical agent acting on the ion channel, thus well meeting the requirement of item 2, i.e., no introduction of any foreign gene or chemical agent.

Therefore, the key point of the effective effect of light stimulation on the nerve tissue is that the nerve tissue is not irradiated by the light with more power in total, but the spatial distribution of the light energy absorption is more uneven, and the formed spatial gradient is more favorable for activating the nerve cells. All the light energy irradiated to the designated area is finally converted into heat energy, and warm-blooded animals including human beings can take away the excessive heat energy through the blood flow of capillaries, so that the average temperature of the whole tissue is kept in a stable state. However, it is clear that the ability of the blood stream to maintain temperature is limited, and therefore the power of the optical energy radiation that biological nerve tissue can tolerate is limited, and a simple increase in optical power only leads to an irreversible thermal injury beyond the tolerance threshold. The key technical problem is therefore how to create as large a gradient of light energy absorption as possible given the optical power limit.

Fig. 1 shows the absorption of electromagnetic waves of different wavelengths by liquid water. Therefore, the absorptivity of water to mid-infrared light is very high, and greatly exceeds the absorptivity to visible light and near-infrared light. The higher the absorption rate, the higher the absorption distribution gradient in the same space. The invention skillfully utilizes the basic physical knowledge, leads the mid-infrared light to the stimulation target site (figure 2) through the optical fiber, selects the multimode optical fiber with smaller numerical aperture, and the light beam emitted from the tail end of the optical fiber can exactly establish a light energy absorption field similar to the bullet shape at the periphery of the target site, and has great spatial gradient.

From the water absorption values shown in fig. 1, for the same total average irradiation power, mid-infrared light can establish a spatial distribution gradient of light energy absorption in biological tissue that is 100 times to 10000 times higher than near-infrared light and visible light. Conversely, for the gradient of the spatial distribution of light energy absorption required to activate nerve cells, a sufficient gradient can be achieved with a lower total irradiation power, thereby greatly reducing the cumulative effects of thermal damage, allowing repeated stimulation many times without significant thermal damage, and meeting the requirements of item 3. For the light stimulation technology using near infrared or visible light but not introducing foreign genes to express photosensitive proteins, the application requirement is difficult to achieve, the nerve cells cannot be effectively activated when the irradiation power is low, irreversible heat damage can be generated when the irradiation power is high, and almost no feasible compromise parameter range exists in many specific application occasions. In fact, there have been many prior art inventions and studies reporting the use of spatially focused visible or near infrared light to produce a neurostimulation effect. However, this focusing approach produces extremely high power densities near the focal point (on the order of microns in the scale of the point spread function), and can irreversibly damage the cell in a very short time (on the order of milliseconds) if the focal point is not moved. From the above analysis, those skilled in the art will understand that it is difficult to actually activate nerve cells with light and to limit the ability to introduce foreign genes into nerve cells to express photosensitive proteins (i.e., optogenetic techniques). There is a contradiction that it is difficult to reconcile that the effect of thermal injury caused by light is generally greater than the effect of activating nerve cells, so that the technical problem cannot be solved by simply designing the illumination mode or controlling the light power.

In order to continuously generate a high gradient of light energy absorption field, the mid-infrared light used needs to be output in a pulsed mode rather than a continuous mode. This is because the continuous mode light can only establish a temperature distribution field that forms a steady state with thermal diffusion, while the pulsed mode light can form a temperature distribution field in an oscillating form, which is beneficial for forming high gradients. Under the same total sustained average irradiance power, the mid-infrared light output in a pulsed manner can create a larger gradient of energy absorption field, see the light modulator in fig. 2. The selection of total irradiation power, pulse frequency, duty cycle, and duration of each stimulation cycle requires appropriate experimentation for each application scenario to obtain optimum values, and such experimentation is readily accomplished by those skilled in the art.

The high absorption of mid-infrared light also brings another beneficial effect, namely the positioning accuracy of the stimulation target. Due to the flexibility and flexibility of the fiber, it can be directed to almost any desired location, making practical use of the invention easier to handle, see the fiber in fig. 2. It should be appreciated by practitioners of the present invention that although the use of optical fibers to direct light is a very commonly used technique, the selection of parameters for optical fibers suitable for mid-infrared nerve stimulation needs to be within suitable ranges. First, the optical fiber material must have high transmittance in the mid-infrared region, such as silicon, fluoride, antimonide, etc.; secondly, the optical fiber needs to be multimode and cannot be single mode, because the section of the tail end output window of the single mode optical fiber is too small, the local power density is too high, and tissues close to the optical fiber are easily damaged; finally, the numerical aperture of the optical fiber cannot be high, because an excessively high numerical aperture would generate an emergent light cone with a large divergence angle, and the light energy is too dispersed to form a local high-gradient absorption field.

In conclusion, the mid-infrared nerve stimulation technology disclosed by the invention well solves three important practical requirements of the nerve stimulation technology: 1. the positioning of the stimulation target site is accurate to millimeter precision; 2. the inability to introduce any foreign genes or chemicals; 3. the stimulation can be repeated for a plurality of times, the effect of activating nerve cells can be repeated, and obvious damage to target tissues is not generated. As a brand new physical stimulation technical means, the mid-infrared nerve stimulation technology has very wide application prospect. It will be clear to the person skilled in the art that laboratory instruments or medical devices manufactured according to the solution described in the present invention are likewise within the scope of the present invention.

[ description of the drawings ]

Fig. 1 shows the absorption of electromagnetic waves of different wavelengths by liquid water.

One embodiment of the infrared nerve stimulation technique of fig. 2.

Claims

1. A nerve stimulation technology is characterized in that mid-infrared light output by a mid-infrared light source is modulated and then irradiated to brain tissues at fixed points through a guide optical fiber, so that nerve cells in an irradiated area are activated.

2. The neurostimulation technique of claim 1, wherein the mid-infrared light source is used to output light having a wavelength comprised between 3 microns and 50 microns.

3. The neurostimulation technique of claim 1, wherein the brain tissue of the subject is absent of any light sensitive protein expressed by an external intervention.

4. The neurostimulation technique of claim 1 and the mid-infrared light source for use of claim 2, wherein the light is irradiated in a pulsed mode at a frequency of between 10Hz and 100 kHz.

5. The neurostimulation technique of claim 1 and the mid-infrared light source for use of claim 2, wherein the guiding fiber is a multimode fiber having a numerical aperture of no more than 0.3 and an inner diameter of no more than 1 mm.