KR20200046744A - Method and Device for stimulating the neual tissue and measuring the response signal - Google Patents

Abstract

According to a preferred embodiment of the present invention, a signal stimulation and measurement device comprises: an electrical stimulation generating unit generating an electrical stimulation signal; a neural signal measuring unit measuring a recording signal including an electrical response of a nerve tissue; an analog signal converting unit converting the recording signal into a digital output signal; a synchronization unit synchronizing the electrical stimulation signal and the recording signal converted into the digital output signal; a channel estimating unit estimating a neural tissue channel based on the electrical stimulation signal and the recording signal converted into the digital output signal, using a synchronization time point; and an artifact processing unit reproducing an artifact based on the electrical stimulation signal and the estimated neural tissue channel at the synchronization time point, and removing the reproduced artifact from the recording signal measured by the neural signal measurement unit. According to the present invention, the signal stimulation and measurement device can measure an electrical signal of the nerve tissue even in a shadow zone.

Description

Method and device for stimulating the neual tissue and measuring the response signal

The present invention relates to a device for stimulating nerve tissue and measuring a response signal.

Methods for stimulating nerve tissue using electrical stimulation have been widely used as a method of identifying connectivity in neuronal tissue and treating degenerative brain disease or symptom relief. Accurate and simultaneous measurement of the electrical response of nerve cells at the site to which electrical stimulation is applied is very important in analyzing the effect of stimulation. However, the stimulus signal acts as an artifact on the recording signal, which causes great difficulty in analyzing the recording signal.

In order to remove artifacts of the stimulus signal, a high-resolution digital converter was conventionally used. A high-resolution digital converter can convert a signal that has passed through a high-gain amplifier without distortion in the analog domain to digital without distortion, but it is difficult to implement it in an implant form because it is a obstacle to device miniaturization. In addition, the prior art has focused on minimizing the time period from immediately after the stimulation to the time at which recording is possible without completely eliminating the shadow section where the neural signal cannot be recorded after the stimulus signal has been introduced.

* Zhao, Zongya, et al. "Design, fabrication, simulation and characterization of a novel dual-sided microelectrode array for deep brain recording and stimulation." Sensors 16.6 (2016): 880. * Carron, Romain, et al. "Closing the loop of deep brain stimulation." Frontiers in systems neuroscience 7 (2013): 112.

The present invention proposes a technique for removing stimulus signal artifacts in the analog and digital domains suitable for device miniaturization.

As a preferred embodiment of the present invention, the signal stimulation and measurement device includes an electrical stimulation generating unit for generating an electrical stimulation signal; A neural signal measuring unit measuring a recording signal including an electrical response of a nerve tissue in response to the generated electrical stimulation signal; An analog signal converter converting the recording signal into a digital output signal; A synchronization unit synchronizing the electrical stimulation signal and the recording signal converted to the digital output signal; A channel estimator for estimating the neural tissue channel based on the electrical stimulation signal and the recording signal converted to the digital output signal using the synchronization time synchronized by the synchronization unit; and the electrical stimulation signal and estimation at the synchronization point And an artifact processing unit for reproducing artifacts based on the neural tissue channel and removing the reproduced artifacts from a recording signal measured by the neural signal measuring unit.

As a preferred embodiment of the present invention, the analog signal conversion unit VCO (Voltage Controlled Oscillator) to generate a frequency proportional to the input voltage; And a counter, and when the recording signal is input to the VCO, the counter counts the frequency in units of a specific time interval from the output of the VCO and converts the recording signal into the digital output signal. do.

수식에서 h로부터 상기 신경조직채널을 추정하고, 상기 수식에서 y는 레코딩신호, h는 신경조직채널 응답 벡터, A는 전기자극신호를 기준신호로 사용하여 생성된 Toeplitz 행렬, 그리고 w는 노이즈벡터를 각각 나타내는 것을 특징으로 한다.As a preferred embodiment of the present invention, the channel estimation

In the equation, the neural tissue channel is estimated from h, in the equation, y is a recording signal, h is a neural tissue channel response vector, A is a Toeplitz matrix generated using an electrical stimulation signal as a reference signal, and w is a noise vector. It is characterized by showing each.

As a preferred embodiment of the present invention, the channel estimator is characterized by calculating the neural tissue channel response vector h using a maximum likelihood estimation method that minimizes noise magnitude.

As a preferred embodiment of the present invention, the artifact processing unit is a convolution between the nerve tissue channel (h) estimated by the channel estimation and the electrical stimulation signal generated by the electrical stimulation generating unit at the synchronization time performed by the synchronization unit. It is characterized in that an artifact is generated by performing a convolution operation, and the artifact generated from the recording signal measured by the neural signal measuring unit is removed.

As a preferred embodiment of the present invention, a point at which the electrical stimulation signal is applied and a point at which the recording signal is measured are the same or different.

In yet another preferred embodiment of the present invention, a method of removing artifacts from a signal stimulus and a recording signal of a measuring device includes generating an electrical stimulation signal; Measuring a recording signal including an electrical response of the nerve tissue to which the electrical stimulation signal is applied; Input the recording signal to a VCO (Voltage Controlled Oscillator) that generates a frequency proportional to the input voltage, and count the frequency in units of a specific time period from the output of the VCO using a counter to convert the recording signal to a digital output signal To do; Synchronizing the electrical stimulation signal and the recording signal converted to the digital output signal; Estimating the neural tissue channel based on the electrical stimulation signal and the recording signal converted to the digital output signal; and based on the neural tissue channel and the electrical stimulation signal estimated at the synchronization time at which synchronization was performed in the synchronizing step. And reproducing artifacts and removing the reproduced artifacts from the measured recording signal.

The present invention proposes a technique for removing stimulus signal artifacts in the analog and digital domains suitable for device miniaturization. In the prior art, there has been a shadow section in which it is impossible to record a nerve signal after the stimulus signal is introduced, but the present invention can measure the electrical signal of the nerve tissue even in the shadow section, and also has the effect of measuring the nerve signal simultaneously with the stimulus. This can improve the performance of a closed-loop system for the treatment of brain diseases because the electrical response of the nerve can be recorded more accurately.

The present invention has an effect capable of producing an implantable size in the brain of a patient by converting an analog signal into a digital signal by utilizing a VCO and a counter element instead of deleting the low-gain amplifier and high-resolution digital converter configuration. It can be used to study brain diseases such as Parkinson's disease, Alzheimer's disease, and depression.

1 to 2 is a preferred embodiment of the present invention, showing the internal configuration of the signal stimulation and measurement device.
Figure 3 shows an example of applying a micro electrical stimulation to the nerve tissue, measuring the electrical response of the nerve cells.
4 is a preferred embodiment of the present invention, and shows an example of a matrix used in channel estimation.
5 is a preferred embodiment of the present invention, showing an example of measuring the recording signal together in the electrode applied to the micro-electro stimulation.
6 is a preferred embodiment of the present invention, showing an example of measuring the recording signal at the electrode for applying the micro electrical stimulation and another recording electrode located at a short distance.
7 is a preferred embodiment of the present invention, after stimulating the signal to the nerve tissue and showing a flow chart of a method for measuring the response signal by removing artifacts.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that those skilled in the art to which the present invention pertains can easily practice. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. In addition, in order to clearly describe the present invention in the drawings, parts irrelevant to the description are omitted, and like reference numerals are assigned to similar parts throughout the specification. Also, when a part “includes” a certain component, this means that other components may be further included rather than excluding other components, unless otherwise specified.

The present invention proposes a technique for removing stimulus signal artifacts in the analog and digital domains suitable for device miniaturization.

1 to 2 is a preferred embodiment of the present invention, showing the internal configuration of the signal stimulation and measurement device.

More specifically, Figure 1 is a preferred embodiment of the present invention, the electrical stimulation generating unit for generating an electrical stimulation signal and the recording signal representing the electrical response of the nerve tissue in response to the electrical stimulation signal to measure the signal at the same location at the same time An example is shown. Referring to FIG. 5, an example of a point 510 for applying an electrical stimulation signal to a brain tissue and a point 510 for measuring a recording signal in response to the electrical stimulation signal are the same.

As a preferred embodiment of the present invention, the electrical stimulation signal includes electrical signals of various shapes and sizes in addition to the micro electrical stimulation signal. In addition, the recording signal refers to a signal that contains both the electrical response or noise of the nerve tissue to the electrical stimulation signal.

2 is a preferred embodiment of the present invention, and shows an example of a case in which the point of applying the electrical stimulation signal and the point of measuring the recording signal are different. Referring to FIG. 6, an example in which a point 610 for applying an electrical stimulation signal to a brain tissue and a point 620a, 620b for measuring a recording signal are different.

1 and 2 are both preferred embodiments of the present invention, and the functions of the components substantially corresponding to the reference numerals other than the above differences will be described based on the internal configuration diagram illustrated in FIG. 2 below.

The signal stimulation and measurement device 200 includes an electrical stimulation generation unit 210a, a neural signal measurement unit 210b, an analog signal conversion unit 220, a synchronization unit 230, a channel estimation unit 240, and an artifact processing unit 250 ). As a preferred embodiment of the present invention, the analog signal conversion unit 220 may be implemented in the form of physical hardware including the VCO 222 and the counter 224. In addition, as a preferred embodiment of the present invention, the electrical stimulation generation unit 210a, the synchronization unit 230, the channel estimation unit 240 and the artifact processing unit 250 are software in the form of a digital signal processing unit 260 in the processor. It can be implemented in the form of. However, it is noted that this corresponds to one embodiment of the present invention, and various modifications are possible.

The electrical stimulation generating unit 210a generates an electrical stimulation signal. Micro-stimulation through micro-electrodes induces the activity of nerve cells in localized areas of nerve tissue. Referring to one embodiment of FIG. 3, the electrical stimulation generating unit 210a may apply the electrical stimulation signal to the nerve tissue in the same form as the stimulation waveform S310 shown in FIG. 3 (310).

The neural signal measuring unit 210b measures a recording signal including an electrical reaction in a region of a nerve tissue to which micro electrical stimulation is applied. It is very important to accurately analyze the electrical response of nerve cells at the site to which microstimulation is applied simultaneously with stimulation. However, the stimulus signal acts as an artifact on the recording signal, which causes great difficulty in analyzing the recording signal. Referring to an embodiment of FIG. 3, the neural signal measuring unit 210b may measure a recording signal having the same shape as the distortion waveform S320 illustrated in FIG. 3 due to artifacts. In order to solve this problem, when a pulse train type signal such as the stimulus waveform S310 shown in FIG. 3 is applied, there is a problem in that a shadow section in which a recording signal cannot be recorded becomes large. In addition, in order to remove signal artifacts from the distortion waveform S320 shown in FIG. 3, the signal that has passed through the high gain amplifier was converted to digital without distortion using a high resolution digital converter. However, in this case, the physical size of the high-resolution digital converter becomes an obstacle to miniaturization, and there is a problem that it is difficult to use it as an implant for brain stimulation.

In one preferred embodiment of the present invention, in order to solve this problem, the analog signal is converted into a digital signal by using the analog signal converter 220 without using a high-resolution digital converter. The size can be downsized. In addition, in a preferred embodiment of the present invention, by removing the artifacts generated from the micro electrical stimulation applied to the nerve tissue by the digital signal processing unit 260, only the recording signal indicating the electrical response of the nerve tissue can be measured. Examples of artifacts include local field potential (LFP) and neural spikes. Hereinafter, functions of the analog signal conversion unit 220 and the digital signal processing unit 260 will be described in detail.

The analog signal conversion unit 220 includes a VCO (Voltage Controlled Oscillator) 222 and a counter 224. VCO (Voltage Controlled Oscillator) 222 generates a frequency proportional to the input voltage, and the counter 224 counts the number of frequencies in units of a specific time interval based on the output of the VCO 222 to measure the neural signal measurement unit ( 210b) converts the recording signal transmitted in digital output signal.

The digital signal processing unit 260 includes an electrical stimulation generation unit 210a, a synchronization unit 230, a channel estimation unit 240, and an artifact processing unit 250.

The synchronization unit 230 synchronizes the electrical stimulation signal generated by the electrical stimulation generation unit 210a and the recording signal converted into a digital output signal by the analog signal conversion unit 220. The synchronization unit 230 calculates on the basis of cross-correlation how similar the recording signal converted to the digital output signal is to a certain section of the electrical stimulation signal, and that the two signals represent the most similar value, that is, the correlation. The point at which the maximum value of the calculated value calculated by the method is determined is the synchronization time point, and time synchronization is performed. The synchronization unit 230 may separate the electrical stimulation signal into a tn section, and perform synchronization by determining a point where the two signals are most similar to a sync point in each of the t1 section, the t2 section, the t3 section, and the ... tn section. .

The synchronization unit 230 may also additionally use an electrical signal for other purposes than the electrical stimulation signal generated by the electrical stimulation generation unit 210a. In this case, the electrical signals for other purposes include separate electrical signals used for channel estimation. In one embodiment, the electrical stimulation generating unit 210a generates an electrical stimulation signal having a specific period. The synchronization unit 230 may generate and use a separate electrical signal for channel estimation that has a magnitude that does not stimulate the nerve tissue at a time interval of the electrical stimulation signal having a specific period.

로 나타낸다. The channel estimator 240 estimates the neural tissue channel by using the electrical stimulation signal and the recording signal converted into a digital output signal in consideration of the synchronization point of the synchronization unit 230. The estimated neural tissue channel

It is represented by.

In Equation 1, y is a recording signal converted to a digital output signal from the analog signal conversion unit 220, h is a neural tissue channel response vector, and A is generated using the electrical stimulation signal generated by the electrical stimulation generation unit 210a. The Toeplitz matrix and w represent noise vectors, respectively. 4 is a preferred embodiment of the present invention, and shows an example of generating a Toeplitz matrix A when a pulse train type electrical stimulation signal is applied. Since the neural signal measuring unit 210b already knows the X _{st_ (t)} 420 signal applied to the electrical stimulation signal S400, k samples 410 before and after the X _{st_ (t)} 420 signal. , 430) to form a Toeplitz matrix A by linear combination. It should be noted that FIG. 4 is only one embodiment of the present invention, and may use all types of electrical stimulation signals.

As a preferred embodiment of the present invention, the channel estimator 240 may calculate the neural tissue channel response vector h using the maximum likelihood estimation method that minimizes the noise level in Equation (1). The maximum likelihood estimation method is as shown in Equations 2 to 3. However, it should be noted that the maximum likelihood estimation method is only an example for calculating the neural tissue channel response vector h, and various modifications are possible.

In Equation 3, A ⁺ represents a Pseudo inverse matrix of Toeplitz matrix A.

The artifact processing unit 250 includes an artifact reproduction unit (not shown) and an artifact removal unit (not shown). The artifact reproducing unit calculates the convolution operation of the nerve tissue channel (h) estimated by the channel estimator 240 and the electrical stimulation signal generated by the electrical stimulation generating unit 210a at the synchronization time of the synchronization unit 230. Perform accordingly to create artifacts. The artifact removing unit removes artifacts generated by the artifact reproducing unit from the recording signal including the artifacts measured by the neural signal measuring unit 210b according to the synchronization point.

7 is a preferred embodiment of the present invention, after stimulating the signal to the nerve tissue and showing a flow chart of a method for measuring the response signal by removing artifacts.

The electrical stimulation generating unit generates an electrical stimulation signal (S710). In this case, the generated electrical stimulation signal includes a pulse train, a sine wave, and various other types of signals. The nerve signal measuring unit measures a recording signal including an electrical response of the nerve tissue to which the electrical stimulation signal is applied (S720). The electrical stimulation signal may be applied to the nerve tissue through a digital-analog converter (DAC) and a power amplifier (PA).

The analog signal conversion unit 120 inputs a recording signal measured by a nerve tissue into a voltage controlled oscillator (VCO) generating a frequency proportional to the input voltage. Then, a frequency is counted in units of a specific time interval from the output of the VCO using a counter to convert the recording signal into a digital output signal (S730).

The synchronization unit determines the point at which the calculated value is the maximum as a synchronization point by using a correlation method that calculates the similarity between a portion of the electrical stimulation signal and the recording signal converted to a digital output signal, and the electrical stimulation signal and digital for each synchronization point. The recording signal converted to the output signal is synchronized (S740). The channel estimator 140 estimates the nerve tissue channel based on the electrical stimulation signal and the recording signal converted into a digital output signal (S750). For a calculation method of estimating a nerve tissue channel, refer to one embodiment of Equations 1 to 3.

The artifact processing unit reproduces artifacts based on the nerve tissue channels and electrical stimulation signals estimated at the synchronization-synchronized time, and removes the artifacts reproduced from the recording signals measured by the nerve signal measuring unit (S760). As a result, the electrical stimulation generating unit can measure only the electrical response signal of the nerve tissue in which the effects of artifacts generated when the electrical stimulation signal is applied to the nerve tissue are removed.

One embodiment of the invention may also be implemented in the form of a recording medium comprising instructions executable by a computer, such as program modules, being executed by a computer. Computer readable media can be any available media that can be accessed by a computer and includes both volatile and nonvolatile media, removable and non-removable media. In addition, computer readable media may include computer storage media. Computer storage media includes both volatile and nonvolatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules or other data.

Although the methods and systems of the present invention have been described in connection with specific embodiments, some or all of their components or operations may be implemented using a computer system having a general purpose hardware architecture.

The above description of the present invention is for illustration only, and a person having ordinary knowledge in the technical field to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims rather than the above detailed description, and it should be interpreted that all changes or modified forms derived from the meaning and scope of the claims and equivalent concepts thereof are included in the scope of the present invention. do.

Claims (13)

An electrical stimulation generating unit generating an electrical stimulation signal;
A neural signal measuring unit measuring a recording signal including an electrical response of a nerve tissue in response to the generated electrical stimulation signal;
An analog signal converter converting the recording signal into a digital output signal;
A synchronization unit synchronizing the electrical stimulation signal and the recording signal converted to the digital output signal;
A channel estimator for estimating the neural tissue channel based on the electrical stimulation signal and the recording signal converted to the digital output signal; and
An artifact processing unit for reproducing artifacts based on the electrical stimulation signal and the estimated neural tissue channel at a synchronization time at which the synchronization unit is synchronized, and removing the reproduced artifacts from the recording signal measured by the nerve signal measurement unit; Signal stimulation and measurement device comprising a. The method of claim 1, wherein the analog signal conversion unit
A voltage-controlled oscillator (VCO) generating a frequency proportional to the input voltage; And
Including a counter,
When the recording signal is input to the VCO, the counter is a signal stimulation and measurement device, characterized in that by counting the frequency in units of a specific time interval from the output of the VCO to convert the recording signal to the digital output signal. The method of claim 1, wherein the channel estimation

In the formula, the nerve tissue channel from h

To estimate,
In the above formula, y is a recording signal, h is a neural tissue channel response vector, A is a Toeplitz matrix generated by using an electrical stimulation signal as a reference signal, and w is a signal stimulation and measurement device, respectively. The method of claim 1, wherein the channel estimation
Signal stimulation and measurement device, characterized in that for estimating the neural tissue channel using the synchronization point of time at which the synchronization unit performs synchronization. The method of claim 1, wherein the channel estimation
Signal stimulation and measurement device, characterized in that for calculating the response vector h of the neural tissue channel using the maximum likelihood estimation method to minimize the noise size. According to claim 3, The artifact processing unit
The neural tissue channel estimated by the channel estimation at the time of synchronization performed by the synchronization unit (

) And generating an artifact by performing a convolution operation between the electrical stimulation signal generated by the electrical stimulation generating unit, and removing the artifact generated from the recording signal measured by the neural signal measurement unit. Signal stimulation and measurement devices. According to claim 1,
Signal stimulation and measurement device, characterized in that the point where the electrical stimulation signal is applied and the point where the recording signal is measured are different. According to claim 1,
Signal stimulation and measurement device, characterized in that the point where the electrical stimulation signal is applied and the point where the recording signal is measured are the same. The method of claim 1, wherein the synchronization unit further uses an electrical signal for other purposes than the electrical stimulation signal generated by the electrical stimulation generator, and the electrical signal for the other uses includes an electrical signal used for channel estimation. Signal stimulation and measuring device characterized in that. As a method for removing artifacts from signal stimulation and recording signals of measuring devices,
Generating an electrical stimulation signal;
Measuring a recording signal including an electrical response of the nerve tissue to which the electrical stimulation signal is applied;
Input the recording signal to a VCO (Voltage Controlled Oscillator) that generates a frequency proportional to the input voltage, and count the frequency in units of a specific time period from the output of the VCO using a counter to convert the recording signal to a digital output signal To do;
Synchronizing the electrical stimulation signal and the recording signal converted to the digital output signal;
Estimating the neural tissue channel based on the electrical stimulation signal and the recording signal converted to the digital output signal; and
And an artifact processing step of reproducing artifacts based on the neural tissue channel and the electrical stimulation signal estimated at the synchronization point at which synchronization was performed in the synchronizing step, and removing the reproduced artifacts from the measured recording signal. Method characterized in that. The method of claim 10, wherein estimating the nerve tissue channel is

Estimate the nerve tissue channel from h in the formula,
In the above formula, y is a recording signal converted to the digital output signal, h is a neural tissue channel response vector, A is a Toeplitz matrix generated by using an electrical stimulation signal as a reference signal, and w is a noise vector. How to. The method of claim 10,
A method characterized in that the point where the electrical stimulation signal is applied and the point where the recording signal is measured are the same. The method of claim 10,
The method characterized in that the point where the electrical stimulation signal is applied and the point where the recording signal is measured are different.

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