KR102549663B1 - Low-intensity, non-invasive focused ultrasound system for deep brain stimulation - Google Patents

Abstract

The present invention relates to an ultrasound system, and more particularly, to a low-intensity, non-invasive, focused ultrasound system for deep brain stimulation. To this end, a pulse bundle 150 composed of pulses 160 of a first frequency is generated with low intensity of ISPPA (Intensity Spatial Peak Pulse Average) 50 W/cm ² or less, and the ultrasonic wave 120 is generated, and the pulse bundle 150 ) An ultrasonic generator 200 for forming and outputting a second frequency; A transducer 110 connected to the ultrasonic generator and irradiating ultrasonic waves in contact with the head 130; and an image display means for overlaying and displaying the simulation result based on the output signal of the transducer 110 on the MRI image 100 of the head 130. Low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that

Description

Low-intensity, non-invasive focused ultrasound system for deep brain stimulation

The present invention relates to an ultrasound system, and more particularly, to a low-intensity, non-invasive, focused ultrasound system for deep brain stimulation.

Ultrasound is a sound wave with a frequency greater than the audible frequency (16 Hz to 20 kHz), and is widely used in clinical practice as it is applied to ultrasound medical imaging devices, high-intensity focused ultrasound surgical devices, and ultrasound tumor treatment devices.

Through recent brain science research on major depressive disorder, specific brain regions (deep) including the dorsolateral prefrontal Cortex (DLPFC), cingulate Cortex (CC), and nucleus accumbens (NAcc) were found to be involved. In addition, selective modulation of these neurological circuits has been shown to be effective in improving major depressive disorder.

On the other hand, conventional pharmacological methods aim at controlling the uptake of measured neurotransmitters, but have the disadvantage of not targeting specific brain regions, and in some patients, some symptoms do not respond to drugs. Non-invasive brain stimulation technology is being applied as a non-pharmacological intervention, and a representative method is to stimulate the prefrontal cortex (PFC) non-invasively through transcranial magnetic stimulation (TMS). . However, transcranial magnetic stimulation (TMS) has disadvantages such as low positional accuracy (30 to 50 mm) and stimulation of only the surface of the brain, which cannot stimulate deep areas.

In addition, if patients with a history of epilepsy or epileptic seizures receive transcranial magnetic stimulation (TMS) treatment, the seizure threshold is lowered and is a relative contraindication. It can be included as an internal combustion of treatment. In addition, even if you are treated with transcranial magnetic stimulation (TMS), the success rate is known to be only 30% according to the results of studies so far.

1. Republic of Korea Patent Registration No. 10-1428547 (headset for depression treatment, stress relief and concentration improvement), 2. Republic of Korea Patent Registration No. 10-0784117 (cranial embedded ultrasound 24-hour brain monitoring device), 3. Korean Patent Publication No. 10-2019-0047251 (platform for brain treatment under ultrasound guidance).

Therefore, the present invention has been made to solve the above problems, and the problem to be solved by the present invention is a low-intensity non-invasive focused type for deep brain stimulation capable of stimulating the deep brain of a depressed patient to alleviate symptoms. To provide an ultrasound system.

However, the technical problems to be achieved in the present invention are not limited to the above-mentioned technical problems, and other technical problems not mentioned will be clear to those skilled in the art from the description below. You will be able to understand.

In order to achieve the above technical problem, ISPPA (Intensity Spatial Peak Pulse Average) is low intensity of 50 W/cm ² or less, and generates a pulse bundle 150 composed of pulses 160 of a first frequency by ultrasonic waves 120. and an ultrasonic generator 200 that forms and outputs a second frequency with the pulse bundle 150; A transducer 110 connected to the ultrasonic generator and irradiating ultrasonic waves in contact with the head 130; and an image display means for overlaying and displaying the simulation result based on the output signal of the transducer 110 on the MRI image 100 of the head 130. There is provided a low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that.

Also, the low intensity is ISPPA 14 W/cm ² or less.

In addition, the first frequency is 10 to 10,000 Hz, and the second frequency is 1.4 to 10 Hz.

In addition, the ultrasonic wave has a low frequency band of 240 to 260 kHz.

Also, the output signals of the transducer 110 are current and voltage signals of the transducer 110 .

Also, in the transducer 110, 90% of the focusing energy forms a focus less than 10 mm (preferably 3 to 7 mm) at a distance of 20 to 40 mm from the surface of the transducer 110.

In addition, the ultrasonic generator 200 operates in a range of 60 seconds to 3,600 seconds.

Another object of the present invention as described above is a method for stimulating the deep brain using the above-described ultrasonic device, wherein the ultrasonic generator 200 has a low intensity of ISPPA (Intensity Spatial Peak Pulse Average) 50 W/cm ² or less. And generating a pulse bundle 150 composed of pulses 160 of a first frequency using the ultrasonic wave 120, which is a low frequency band of 240 to 260 KHz, and forming and outputting a second frequency with the pulse bundle 150. ; The transducer 110 irradiates ultrasonic waves to the head 130 so that 90% of the focusing energy forms a focus of 10 mm or less at a distance of 20 to 40 mm from the surface of the transducer 110; displaying the simulation result based on the voltage and current signals of the transducer 110 superimposed on the MRI image 100 of the head 130 by the image display unit; thereby operating the transducer 110 while viewing the simulation result. It can also be achieved by a method of stimulating the deep brain using a low-intensity, non-invasive, focused ultrasound device.

According to one embodiment of the present invention, it is possible to stimulate the deep brain of depressed patients who have not seen the effect of transcranial magnetic stimulation (TMS) with ultrasound.

In addition, the focused ultrasound according to the present invention can safely stimulate the dorsolateral prefrontal cortex (DLPFC) area on the left side of the cerebrum.

However, the effects obtainable in the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below. You will be able to.

The following drawings attached to this specification illustrate preferred embodiments of the present invention, and together with the detailed description of the present invention serve to further understand the technical idea of the present invention, the present invention is the details described in such drawings should not be construed as limited to
1 is an example of simulation results for a low-intensity non-invasive focused ultrasound system and MRI images for deep brain stimulation according to the present invention;
2 is a waveform diagram of an ultrasound system according to the present invention.

Hereinafter, with reference to the accompanying drawings, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. However, since the description of the present invention is only an embodiment for structural or functional description, the scope of the present invention should not be construed as being limited by the embodiments described in the text. That is, since the embodiment can be changed in various ways and can have various forms, it should be understood that the scope of the present invention includes equivalents capable of realizing the technical idea. In addition, since the object or effect presented in the present invention does not mean that a specific embodiment should include all of them or only such effects, the scope of the present invention should not be construed as being limited thereto.

The meaning of terms described in the present invention should be understood as follows.

Terms such as "first" and "second" are used to distinguish one component from another, and the scope of rights should not be limited by these terms. For example, a first element may be termed a second element, and similarly, a second element may be termed a first element. It should be understood that when an element is referred to as “connected” to another element, it may be directly connected to the other element, but other elements may exist in the middle. On the other hand, when an element is referred to as being “directly connected” to another element, it should be understood that no intervening elements exist. Meanwhile, other expressions describing the relationship between components, such as “between” and “immediately between” or “adjacent to” and “directly adjacent to” should be interpreted similarly.

Singular expressions should be understood to include plural expressions unless the context clearly dictates otherwise, and terms such as “comprise” or “having” refer to a described feature, number, step, operation, component, part, or It should be understood that it is intended to indicate that a combination exists, and does not preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

All terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs, unless defined otherwise. Terms defined in commonly used dictionaries should be interpreted as consistent with meanings in the context of related art, and cannot be interpreted as having ideal or excessively formal meanings unless explicitly defined in the present invention.

1 is an example of simulation results for a low-intensity non-invasive focused ultrasound system and MRI images for deep brain stimulation according to the present invention. As shown in FIG. 1, the ultrasonic generator 200 is connected to the transducer 110, and the transducer 110 irradiates the head 130 with ultrasonic waves 120. The image may be an MRI (Magnetic Resonance Imaging) image 100 and a CT (Computed Tomography) image.

A dedicated program (simulation program) of a computer simulates and displays the intensity of the ultrasound 120 based on the voltage and current signals of the transducer 110 . Ultrasound 120 irradiated into the brain is displayed as an ultrasonic range of the transducer 110 . In the simulation, the ultrasonic wave 40 is displayed in a conical shape or a rectangle, and the inside of the rectangle changes with a red to blue gradation depending on the intensity. For example, the length and direction of the conical ultrasonic wave 120 indicate the limit and direction of the ultrasonic wave 120, the inner red color may be the strongest ultrasonic intensity, and the blue color may be the lowest ultrasonic intensity. Therefore, the therapist (operator) can operate the transducer 110 while viewing the simulation result (feedback effect).

The ultrasonic generator 200 generates focused ultrasonic waves. The ultrasonic generator 200 can change an electrical waveform into a mechanical waveform by using a piezoelectric material, and when the piezoelectric material is operated in a degassed medium (eg, degassed water), an ultrasonic pressure shock wave of 20 kHz or more is generated. can be converted to As this shock wave is generated from piezoelectric materials arranged in a hemispherical shape, it is concentrated at a position corresponding to the radius of curvature (ROC) of the hemispherical circumference. The intensity of the ultrasound 120 uses a low intensity of 50 W/cm ² or less, and according to the standards of the Food and Drug Administration (hereinafter referred to as the Food and Drug Administration), the ultrasonic wave applies an effective intensity of less than 3 W/cm ² , and heat or cavity ( It can be used within the range where cavitation phenomenon does not occur.

The ultrasound stimulation to be used is a pressure sonic wave, and is provided at a frequency of a low frequency band of 240 to 260 kHz (preferably 250 kHz), rather than high-frequency ultrasound used in conventional diagnostic ultrasound devices, so that it can penetrate the skull and deep in the brain. The focus can be placed up to .

The size (focus area) affected by the ultrasound 120 is deep, at a distance of 20 to 40 mm (preferably 30 mm) from the surface of the transducer 110, and 90% of the focusing energy is less than a focus of 10 mm (preferably 30 mm). preferably 3 to 7 mm, more preferably 5 to 6 mm). Since this focal area is a sphere or an elliptical conical sphere (shaped like a grain of rice), detailed function control of a specific area is possible. In addition, it can be used within the range of not exceeding 1.9 in mechanical safety index. In addition, the depth can be selected from the range of 40 to 70 mm depending on the disease.

2 is a waveform diagram of an ultrasound system according to the present invention. As shown in FIG. 2 , a pulse 160 is formed using an ultrasonic wave of 250 kHz. The frequency of the pulse 160 is 10 to 10,000 Hz. To this end, the TBD of the pulse 160 is 0.1 to 100 ms, and the duty cycle can be adjusted in the range of 1 to 100%.

The pulse bundle 150 is composed of regular pulses 160, and the frequency of the pulse bundle 150 is 1.4 to 10 Hz. To this end, the width (SD) of the pulse bundle (sound wave processing, 150) is set to 10 to 3,000 ms. And, the period (SI) of the pulse bundle (sound wave treatment, 150) is set to 10 to 7,000 ms.

And, the total ultrasonic time (T/T) can be appropriately selected within the range of 60 seconds to 3,600 seconds. This is because the effect of stimulation is insignificant when the duration is less than 60 seconds, and excessive stimulation may cause excitement or side effects when the duration exceeds 3,600 seconds.

Experimental example

First, an MRI image 100 and a CT image are taken of the human head 130 to generate image data. Next, patients with major depressive disorder (Major Depressive Disorder) who show mild or more major depressive episodes without psychotic features are selected.

The patient must fall under one of the following (1) to (6).

(1) Adult men and women between the ages of 19 and 60

(2) Corresponds to major depressive disorder without psychotic features (ICD-10 code: F32.0, F32.1, F32.2, F33.0, F33.1, F33.2) according to DSM-5 diagnostic criteria patient to

Here, the DSM-5 major depressive disorder diagnosis criteria must correspond to 5 or more of the 9 items below, and one of 1. and 2. must be included.

1. Persistent depressed mood

2. Marked decline in interest or pleasure in all daily activities

3. Significant weight loss or weight gain without weight control

4. Insomnia or hypersomnia

5. Psychomotor agitation or retardation

6. Fatigue or loss of energy

7. Feelings of worthlessness or excessive or inappropriate guilt

8. Decreased ability to concentrate (or subjective complaints of indecisiveness or observed by others)

9. Recurrent thoughts of death (recurrent suicidal thoughts without specific plans or suicide attempts or specific plans to commit suicide, as well as fear of death).

And, according to the ICD-10 code, F32.0 mild depressive episode, F32.1 moderate depressive episode, F32.2 severe depressive episode without psychotic symptoms, F33.0 recurrent depressive disorder, present mild, F33.1 recurrent Depressive disorder, present moderate, F33.2 Recurrent depressive disorder, severe diagnosis without present psychotic symptoms

(3) Montgomery-Asberg Depression Rating Scale (MADRS) score of 12 points or more for patients showing mild or more depressive symptoms It consists of a 7-item Likert scale up to a point. The higher the score, the more severe the depressive symptoms are, and more than 12 points are mild or more depressive disorder).

(4) Patients with no history of suicide attempts and who scored 9 or less in the Mini International Neuropsychiatric Interview (MINI) module C suicide tendency assessment

(5) Patients who did not take antidepressants for 4 weeks before participating in the clinical trial

(6) Patients who had taken antidepressants before participating in the clinical trial and maintained mild depressive symptoms of MADRS score of 12 points or higher despite antidepressant treatment for more than 4 weeks, and who would not change the drug dose during the study period

For example, [Table 1] is a table showing the change (mlTT) after 4 weeks compared to the baseline of the Suicidal Thought Scale score change (SSI).

Test group (n=12) Control group (n=13) p-value ^& p-value ^‡ SSI_baseline
SSI_2nd
SSI_3rd 14.8±9.2
6.2±6.0
6.0±6.4 18.0±8.7
16.0±9.4
15.9±8.4 .347
.005*
.002* MT: .003*
MG: .017*
Int: .077 ^2nd -baseline -8.6±8.5 -2.0±5.1 .035* ^3rd -baseline -8.8±8.3 -2.1±5.0 .040*

& : Wilcoxon's rank-sum test

‡ : RM ANOVA

As shown in [Table 1], the main effect of time (MT, p=.003, .001) and group (MG, p=.017, .035) were able to confirm statistical significance, and it was found that there was an interaction (Int, p=0.015) between the two groups in PPS. Accordingly, in addition to the results of the between-subject effect and time effect test, it is necessary to compare each time point. In mITT, the test group decreased by 8.8 points from 14.8 points to 6.0 at 4 weeks from the baseline, and the control group decreased by 8.8 points at 4 weeks from the baseline. At the time point, the average score decreased by 2.1 points from 18.0 points to 15.9 points, confirming that the test group decreased by 6.7 points more than the control group. It was confirmed that both the results of the comparison between groups for the amount of change and the comparison at each time point of 2 weeks and 4 weeks were statistically significant for the large amount of change in the test group.

Therefore, through the experiment, it was confirmed that low-intensity focused ultrasound could be used as a new treatment for major depressive disorder in patients with major depressive disorder, and the effect of improving depressive symptoms including suicidal ideation was confirmed.

Detailed descriptions of the preferred embodiments of the present invention disclosed as described above are provided to enable those skilled in the art to implement and practice the present invention. Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art will understand that the present invention can be variously modified and changed without departing from the scope of the present invention. For example, those skilled in the art can use each configuration described in the above-described embodiments in a manner of combining with each other. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

The present invention may be embodied in other specific forms without departing from the spirit and essential characteristics of the present invention. Accordingly, the above detailed description should not be construed as limiting in all respects and should be considered as illustrative. The scope of the present invention should be determined by reasonable interpretation of the appended claims, and all changes within the equivalent scope of the present invention are included in the scope of the present invention. The invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. In addition, claims that do not have an explicit citation relationship in the claims may be combined to form an embodiment or may be included as new claims by amendment after filing.

100: MRI image,
110: transducer,
120: ultrasound,
150: pulse bundle,
160: pulse,
200: ultrasonic generator,
T/T: total ultrasonic treatment time (Treatment Time),
SI: Period of Pulse Bundle (Sonic Treatment) (Sonication Interval),
SD: width of pulse bundle (sonic processing) (Sonication Duration),
TBD: Tone Burst Duration,
PRP: Pulse Repetition Period,
PRF: Pulse Repetition Frequency.

Claims (9)

A pulse bundle 150 composed of pulses 160 of a first frequency is generated with a low intensity of ISPPA (Intensity Spatial Peak Pulse Average) 50 W/cm ² or less, and the ultrasonic waves 120 are generated, and the pulse bundle 150 An ultrasonic generator 200 that forms and outputs a second frequency;
A transducer 110 connected to the ultrasonic generator and irradiating the ultrasonic waves in contact with the head 130; and
Image display means for superimposing and displaying the simulation result based on the output signal of the transducer 110 on the MRI image 100 of the head 130;
The transducer 110 can be operated while looking at the simulation result,
The low intensity ratio for deep brain stimulation, characterized in that the transducer 110 is configured such that 90% of the focusing energy forms a focus of 10 mm or less at a distance of 20 to 40 mm from the surface of the transducer 110. Invasive focused ultrasound device. According to claim 1,
The low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that the low intensity is ISPPA 3 W / cm ² or less. According to claim 1,
The low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that the first frequency is 10 to 10,000 Hz. According to claim 1,
The low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that the second frequency is 1.4 or more and less than 10 Hz. According to claim 1,
The ultrasound is a low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that the low-frequency band of 240 ~ 260 kHz. According to claim 1,
The low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that the output signal of the transducer (110) is the current and voltage of the transducer (110). delete According to claim 1,
The ultrasonic generator 200 is a low-intensity non-invasive focused ultrasound device for deep brain stimulation, characterized in that it operates in the range of 60 seconds to 3,600 seconds. delete

Images