KR101070122B1 - A device and method for diagnosing schizophrenia using heart rate variability measures - Google Patents

Abstract

The present invention relates to an apparatus and method for diagnosing schizophrenia by measuring heart rate variability (HRV) of schizophrenic patients. More specifically, the present invention suggests that several measures of HRV show characteristic changes in schizophrenic patients. Among the indicators of HRV, SampEn (sample entropy) is an indicator of the complexity of HRV, and LF / HF (ration of low frequency to high frequency) indicates the degree of balance between the sympathetic nervous system and the parasympathetic nervous system in HRV. SampEn and LF / HF measurements can be used to specifically diagnose schizophrenic patients and to screen and evaluate efficacy of schizophrenic agents.

Schizophrenia, Heart Rate Variability, SampEn, LF / HF

Description

A device and method for diagnosing schizophrenia using heart rate variability measures

The present invention relates to an apparatus for diagnosing schizophrenia using the results of a study on the relationship between HRV measurement indicators and schizophrenia, to easily display information for diagnosing schizophrenia. The present invention also relates to a method for diagnosing schizophrenia and a screening method for treating schizophrenia using the above indicators.

Schizophrenia is one of the most common psychiatric disorders, with a prevalence of 0.4-0.7%, and if not treated properly, not only can cause the patient's own function but also increase family burden and overall socioeconomic costs. Let's do it. Thus, means for efficiently diagnosing these schizophrenia and evaluating the effectiveness of treatment can play an important role for proper treatment.

It is known that mortality from cardiovascular disease is high in schizophrenic patients. In addition, it has been reported that the psychopathology of schizophrenic patients and the autonomic nervous system abnormalities related to the heart are related. Recent studies on pupillary reflexes and baroreflex in schizophrenic patients have also reported a decrease in vagal tone. These changes observed in schizophrenic patients are associated with abnormalities of the central autonomic system (CAN), and there have been reports that this may be due to a decrease in HRV. It has been argued that the deactivation of the amygdala-prefrontal circuit in schizophrenic patients leads to an autonomic imbalance. However, no specific indicator of ECG has been used to diagnose schizophrenia.

In this regard, the present inventors conducted a study on the relationship between various measures of HRV and schizophrenia, and found specific indicators in schizophrenic patients. Using multivariate analysis of variance (MANOVA) with nine of the HRV measures, SampEn values tend to be significantly lower and LF / HF values tend to be higher in schizophrenic patients. Hierarchical clustering (HC) has reported that SampEn clusters with LF / HF values (JS Chang, et al., 2009. "Differential Pattern of heart rate variability in patients with schizophrenia", Progress in Neuro -Psychopharmacology & Biological Psychiatry 33, p. 991-995. Reference)

Meanwhile, as research on the relationship between measurement indicators using the results of heart rate variability (HRV) and schizophrenia has been conducted, schizophrenia using the results of the medical research and the results of the research are being conducted. The development of a schizophrenic diagnostic device that assists in effectively diagnosing the disease has become possible. Conventionally, a diagnosis is performed by using a sensor from a human body to measure data such as physiological changes of the human body, such as body temperature, brain waves, and heart rate variability (HRV), and perform evaluation and diagnosis on a measurement target using the measured data. The device is widely used. With the recent development of electronic and information processing technologies, such diagnostic medical devices are expected to be further developed and applied to various medical fields.

It is an object of the present invention to provide an apparatus and method for easily and accurately diagnosing schizophrenia by measuring HRV. In addition, an object of the present invention is to provide a method for confirming the efficacy of a schizophrenic agent or screening for a novel agent by a simple method as described above.

In order to achieve the above object, the present invention provides a schizophrenia diagnostic apparatus using a heart rate variability indicator as a first aspect. Specifically, the diagnostic device, heart rate variability measuring unit for measuring the heart rate variability from the subject; SampEn (sample entorpy) and LF / HF (low frequency) are distinguished from normal among heart rate variability in clinical trials conducted under pre-determined conditions in a group of schizophrenic patients with statistical significance. a database unit storing reference diagnostic indicators for high frequency); Calculate SampEn (sample entorpy) and LF / HF (low frequency / high frequency) values using the data measured by the heart rate variability measurement unit from the subject, and store the calculated values in the database diagnostic reference index. And a processing unit for extracting a difference value from the comparison.

Preferably, the schizophrenia diagnostic apparatus further includes a display unit for displaying the difference value extracted by the processing unit to the outside.

Preferably, the baseline diagnostic indicators of the database unit are calculated using the result of measuring heart rate variability obtained by performing an electrocardiogram test from a schizophrenic patient who is not dosed with antipsychotics.

Preferably, the reference diagnostic indexes of the database unit are standardized through log transform and calculated through Bonferroni correction.

In a second aspect, the invention provides a method for diagnosing schizophrenia using heart rate variability indicators. The method comprises the steps of measuring the heart rate variability in the normal population and the schizophrenic patient population to establish the reference diagnostic indicators for SampEn and LF / HF; Measuring heart rate variability from the subject; And comparing the measured SampEn and LF / HF values of the heart rate variability with the values of the reference diagnostic index, and diagnosing the subject as a schizophrenic patient when belonging to the values of the schizophrenic patient group.

In a third aspect, the present invention provides a method for screening a schizophrenia therapeutic agent using a heart rate variability index. The method comprises the steps of measuring the heart rate variability in the normal population and the schizophrenic patient population to establish the reference diagnostic indicators for SampEn and LF / HF; Measuring the heart rate variability of the subject being schizophrenic; Administering a target substance to the schizophrenic patient; Calculating a SampEn and LF / HF value by periodically measuring a heart rate variability of the schizophrenic patient to which the target substance is administered; And comparing the calculated SampEn and LF / HF values with the reference diagnostic index, and recognizing the target substance as a schizophrenic therapeutic agent when the schizophrenic patient changes from an indicator range to a normal person. do.

When using the schizophrenia diagnosis apparatus and diagnostic method of the present invention, it is possible to objectively diagnose schizophrenia, which is difficult to accurately diagnose, by a simple method of measuring heart variability. In addition, the effectiveness of schizophrenic agents can be verified in a simple and objective way.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples.

Example  One. Heart rate variability ( HRV Relationship between Metrics and Schizophrenia

(1) Test subject

Thirty non-drug patients with DSM-IV schizophrenia and thirty normal subjects of age and sex matched with them as controls. The patients were recruited from the patient ward of Yongin Mental Hospital in Gyeonggi-do, South Korea, and the control group was recruited from hospital staff and students. Diagnosis of schizophrenia was confirmed according to the DSM-IV diagnostic criteria from at least two psychiatrists. In addition, medical records were reviewed in advance to rule out any medical factors that may affect the regulation of the autonomic nervous system, such as hypertension, obesity, diabetes and thyroid disease. Routine electrocardiograms (ECGs) of all participants were examined to determine clinical abnormalities. The extent of clinical symptoms was measured using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). No drug administration refers to a condition in which antipsychotic medications are suspended for at least 28 days or depot antipsychotics are suspended for at least 24 weeks.

The experimental protocol of the present invention was approved by the Ethics Committee of Yongin Mental Hospital, received written consent from the participants prior to registration, and the patients and their legal guardians made it clear that there was no conflict of opinion in the decision of participation. All methods used in the present invention are based on the guidelines of Good Clinical Practices and comply with the Declaration of Helsinki.

(2) measuring and analyzing HRV indicators;

1) Measurement of ECG

In order to rule out the effects of diurnal variation, the test was performed during regular breathing between 9 am and 11 am, and morning smoking and caffeine intake were prohibited on the day of the test. We had a 15-minute test session to confirm reliable breathing and ECG recording patterns. Resting heart rate was obtained from the subject lying down in complete rest. After 15 minutes of rest, we had an ECG recording time of 5 minutes. ECG signals were digitized at a sampling rate of 250 Hz. After removal of artefacts and ectopic complexes, HRV values were calculated based on normal intervals.

2) HRV Metrics

The following nine HRV indicators were calculated from the electrocardiogram information of each subject.

① Mean RR: Average value of all RR intervals

SDNN: standard deviation of all RR intervals

③ RMSSD: Square root of the mean value of the squared difference of successive RR interval values

④ pNN20: The ratio of the difference of consecutive RR intervals over 20 ms in total

LF (low-frequency band): 0.04-0.15 Hz component obtained through spectral analysis reflects both sympathetic and parasympathetic components

⑥ HF (high-frequency band): 0.15-4 Hz component obtained through spectral analysis reflects parasympathetic modulation

⑦ LF / HF (ratio of LF to HF): reflects the function of autonomic regulation system

⑧ SampEn (sample entropy): The complexity of a limited length biosignal is calculated. The smaller the value, the lower the complexity.

(9) CSE20 (corrected Shannon entropy): Calculated using a pattern generated from a permutation of this binary method by treating it as 0 if the difference between consecutive RR intervals is less than 20 ms and 1 or more. Smaller values mean greater regularity

3) Statistical analysis of HRV measurement index

① We analyzed statistically the difference between the above nine HRV indicators in patients and normal people. Measured parameters with frequency characteristics were standardized by log transform, and then analyzed for the difference between nine measures in patients and normal groups using multivariate analysis of variance (MANOVA). After Bonferroni correction to reduce type I error, SampEn values were observed to show significant group effects, and LF / HF values showed a trend. . No differences were observed between patients and normal subjects in other HRV metrics (Table 1).

Normal patient Significance n = 30 n = 30 Mean RR 877.73 ± 150.29 803.70 ± 130.24 t ₅₈ = 2.04; P = 0.046 SDNN 51.19 ± 18.79 64.77 ± 40.84 t ₅₈ =-1.65; P = 0.103 RMSSD 53.00 ± 30.87 79.88 ± 60.55 t ₅₈ = -2.17; P = 0.034 lnpNN20 3.80 ± 0.62 3.32 ± 1.08 t ₅₈ = 2.10; P = 0.040 lnLF 5.73 ± 0.69 5.64 ± 0.93 t ₅₈ = 0.43; P = 0.673 lnHF 6.24 ± 0.94 5.62 ± 1.24 tt ₅₈ = 2.19; P = 0.033 lnLF / HF -0.51 ± 0.70 0.02 ± 0.79 t ₅₈ = -2.74; P = 0.008 SampEn 1.80 ± 0.36 1.46 ± 0.42 t ₅₈ = 3.40; P = 0.001 lnCSE20 0.89 ± 0.23 0.68 ± 0.55 t ₅₈ = 1.99; P = 0.051

② The relationship between nine HRV indicators in each patient and normal group was analyzed using hierarchical clustering (HC). The Ward's method was used to classify HRV metrics into potential clusters with minimal variance. Word's method refers to a method in which the sums of the squares of Euclidean distance between HRV measurement indicators are grouped together with the minimum increase. In normal subjects, except for LF / HF, all were classified into one cluster. In the patient group, LF / HF and SampEn were separated from the main cluster to form clusters separately. In addition, in the patient group, the distance between the HRV measurement indicators was also observed to be lower, indicating that there is a higher level of correlation between the indicators (Fig. 2).

Example  2. Heart rate variability ( HRV Schizophrenia Diagnosis Device Using Indicators

Referring to Figure 1 will be described in detail for the schizophrenia diagnostic apparatus according to an embodiment of the present invention. 1 is a block diagram of an apparatus for diagnosing schizophrenia according to an embodiment of the present invention. As shown in FIG. 1, the apparatus for diagnosing schizophrenia according to the present exemplary embodiment includes a heart rate variability measuring unit 110, a database unit 120, a processing unit 130, and a display unit 140.

As shown in FIG. 1, the heart rate variability measuring unit 110 measures a heart rate variability from a human body determined as a measurement object and transmits the heart rate variability to the processing unit 130.

As shown in FIG. 1, the database unit 120 includes a normal person among measurement indicators of heart rate variability collected through clinical trials performed under a predetermined condition on a group of schizophrenic patients having statistical significance. Load standard diagnostic indicators. Preferably, the database unit 120 stores SampEn (sample entorpy) and LF / HF (low frequency / high frequency) indices among the measurement indices of heart rate variability, as reference diagnostic indices, and is searched by the processing unit 130. The reference diagnostic index value is transmitted to the processing unit 130.

The reference diagnostic index loaded on the database unit 120 is derived as a result of a study on the relationship between various measurement indexes of HRV and schizophrenia, and details thereof are as described in Example 1 above.

As illustrated in FIG. 1, the processor 130 may use SampEn (sample entorpy) and LF / HF (low frequency / high frequency) using data measured by the heart rate variability measuring unit 110 from a human body determined as a measurement target. ) Values are calculated, and the difference values are extracted by comparing the calculated values with reference diagnostic indicators stored in the database unit 120. In addition, the processing unit 130 transmits the difference value to the display unit 140. The display 140 displays a character or a diagram corresponding to the transmitted difference value to the outside. Characters or diagrams displayed on the display unit 140 are displayed to enable diagnosis of schizophrenia by neuropsychologists and medical professionals.

Example  3. Heart rate variability ( HRV Screening of Schizophrenia Therapeutics Using Indicators

(1) Test subject

Twenty-five patients who did not take the drug and agreed to take antipsychotics and electrocardiograms were included. Eight patients took risperidone, five olanzapine, four amisulfrides and two aripiprazole.

(2) measuring and analyzing HRV indicators;

1) Measurement of ECG

The electrocardiogram of the patient group and the normal group was measured. The test was conducted between 9 am and 11 am to exclude the effects of diurnal variation. Smoking and caffeine in the morning were prohibited on the day of the test. ECG was measured for 5 minutes after resting for 15 minutes before the test. The information stored in the ECG machine was digitized again at 250 Hz. Electrocardiograms were repeatedly measured before and after 1 week of antipsychotic medication and 6 weeks after dosing.

2) Evaluation of psychopathology and side effects

The following evaluation tools were used to measure repeatedly before and after 1 week of administration of antipsychotics and 6 weeks after dosing.

① PANSS (Positive and Negative Syndrome Scale): A 30-question psychopathology scale that evaluates positive symptoms, negative symptoms, and general psychopathology.

② DIEPSS (Drug Induced Extrapyramidal Symptoms Scale): 10 questions to evaluate the extrapyramidal side effects associated with taking antipsychotics

3) Calculation of HRV Metrics

Nine HRV measurement indices of Mean RR, SDNN, RMSSD, pNN20, LF, HF, LF / HF, SampEn, and CSE20, which were mentioned in Example 1, were calculated.

4) Statistical analysis of HRV measurement index and PANSS, DIEPSS

① We analyzed statistically the difference between the above 9 HRV index, PANSS and DIEPSS score according to the progress of antipsychotic treatment. Indicators with frequency characteristics were standardized by log transform and then checked for change using multivariate analysis of variance (MANOVA). Among the 9 indicators, only LF / HF values were measured after treatment. Significant changes were observed (Table 2).

Baseline Week 1 Week 6 F _2,48 P value Mean SD Mean SD Mean SD PANSS 94.04 22.71 76.48 14.40 63.76 11.88 50.50 <0.001 DIEPSS 0.88 1.64 3.52 3.69 4.12 3.94 12.07 <0.001 Mean RR 803.14 145.11 815.99 173.18 850.33 143.63 1.44 0.25 SDNN 34.78 15.30 33.72 16.15 30.54 13.80 0.90 0.41 RMSSD 29.82 22.61 26.27 18.57 26.34 17.43 0.35 0.71 lnpNN20 3.04 1.29 2.59 1.86 3.27 1.00 2.20 0.12 lnLF 5.34 0.73 5.19 1.06 4.82 0.82 3.96 0.03 lnHF 5.39 1.26 5.04 1.65 5.33 1.02 0.89 0.42 lnLF / HF -0.04 0.84 0.15 1.08 -0.51 0.64 6.33 0.004 SampEn 2.00 0.47 1.84 0.44 2.06 0.50 1.44 0.25 lnCSE20 0.71 0.42 0.19 1.25 0.77 0.58 4.69 0.01

② At each time point, the relationship between 9 HRV measurement indexes and PANSS and DIEPSS scores was analyzed using hierarchical clustering (HC), and the Word's method was used. LF / HF and SampEn were clustered independent of PANSS score and DIEPSS score both before and after 1 week and 6 weeks after dosing. This suggests that psychopathology and extrapyramidal changes in schizophrenic patients are associated with the balance and complexity of the sympathetic-vaginal nervous system (FIG. 3).

1 is a block diagram of an apparatus for diagnosing schizophrenia using a heart rate variability index according to an embodiment of the present invention.

2 is a schematic diagram showing the correlation between the indicators of HRV.

Figure 3 is a schematic diagram showing the correlation between the HRV index and the PANSS and DIEPSS score measured before and after schizophrenia treatment.

Claims (6)

Heart rate variability measuring unit for measuring the heart rate variability from the subject; SampEn (sample entorpy) and LF / HF (low frequency) are distinguished from normal among heart rate variability in clinical trials conducted under pre-determined conditions in a group of schizophrenic patients with statistical significance. a database unit storing reference diagnostic indicators for high frequency); Calculate SampEn (sample entorpy) and LF / HF (low frequency / high frequency) values using the data measured by the heart rate variability measurement unit from the subject, and store the calculated values in the database diagnostic reference index. Processing unit for extracting a difference value by comparing with the; Schizophrenia diagnostic device characterized in that it is provided. The schizophrenia diagnostic apparatus according to claim 1, wherein the reference diagnostic indicators of the database unit are calculated using a cardiac variability measurement result obtained by performing an electrocardiogram test from a schizophrenic patient who has not been administered antipsychotic drugs. The apparatus of claim 1 or 2, wherein the reference diagnostic indicators of the database unit are standardized through a log transform and calculated through Bonferroni correction. The method of claim 1, The schizophrenia diagnostic apparatus further comprises a display unit for displaying the difference value extracted by the processing unit to the outside. delete delete

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