The accuracy of electromyographic differential diagnostics of essential tremor and Parkinson's disease in various patient postures was studied. To assess the accuracy of differential diagnostics, a mathematical method was developed on the basis of the analysis of wave trains of the electrical activity of antagonist muscles. To compare the accuracy of differential diagnostic methods, we used a computational experiment. Patients with the first stage of Parkinson's disease with a tremor in the left arm (14 subjects) and right arm (14 subjects), as well as patients with essential tremor (14 subjects), were studied. A relaxed posture and posture with arms extended forward were compared. The results of comparing the relaxed posture and the posture with outstretched arms demonstrated that differential diagnostics should be performed in the relaxed posture of the patient regardless of which side of the patient's body tremor is observed. If diagnostics in the relaxed posture is impossible due to the fact that the patient does not have resting tremor, it is advisable to use the posture with outstretched arms.

Background: Absence epilepsy is a non-convulsive form of genetic generalized epilepsy characterized by spontaneous bilateral spike-and-wave discharges (SWDs) in EEG. In contrast to grand-mal epilepsy, absence epilepsy without greatly expressed motor and interictal EEG abnormalities is difficult to detect, especially at the early stages. The WAG/Rij rat strain is a well-validated animal model of childhood absence epilepsy. At the early, preclinical stage, precursors or immature SWDs appear. Then, with age, immature discharges gradually turn into mature ones and mature SWDs prevail at the clinical stage. Mature SWDs, with an amplitude several times higher than the background EEG, can be easily distinguished visually. However, the amplitude of immature discharges is significantly lower than that of mature SWDs and is comparable to the amplitude of sleep spindles. Therefore, it is quite a difficult problem to distinguish immature discharges from sleep spindles. The task is further complicated by the fact that absence seizures mainly appear in a state of drowsiness and slow-wave (non-REM) sleep, when a lot of sleep spindles occur. The purpose of the present study was to develop a diagnostic method that allows us to precisely distinguish immature forms of epileptic seizures from background EEG and sleep spindles. Methods: The idea of analyzing wave-train electrical activity is to investigate the wavelet spectrum, find local peculiarities in this spectrum, and estimate generalized time-frequency peculiarities of the signal in terms of the found local peculiarities. Results: The criteria for diagnosis of the immature form of epileptic discharges and sleep spindles have been developed based on the analysis of wave-train activity with the construction of AUC diagrams (area under the curve diagrams). Conclusions: The method of wave-train analysis with the construction of AUC diagrams can be used for extracting the diagnostic features necessary for the diagnosis of absence epilepsy at the early stages of the disease in people with a genetic predisposition.

Исследованы и разработаны методы автоматического поиска признаков нейродегенеративных заболеваний "болезнь Паркинсона" и "эссенциальный тремор" на основе AUC-диаграмм и алгоритмов оптимизации. AUC-диаграммы являются новым методом статистического анализа биомедицинских сигналов, основанным на визуализации параметров всплескообразной электрической активности мозга и мышц. Эффективность этого метода была продемонстрирована при решении задач ранней и дифференциальной диагностики болезни Паркинсона и эссенциального тремора. Недостатком данного метода является необходимость построения и анализа большого количества графических диаграмм. В связи с этим, автоматизация анализа AUC-диаграмм является актуальной задачей. Математическая задача поиска признаков на основе анализа AUC-диаграмм сводится к задаче оптимизации в многомерном пространстве признаков. Отличительной особенностью пространства признаков, построенного с использованием AUC-диаграмм, является наличие сравнительно больших компактных областей, содержащих локальные максимумы и минимумы. Это свойство пространства признаков облегчает поиск решений задачи оптимизации, но при этом требует выбор алгоритмов оптимизации и целевых функций, повышающих вероятность обнаружения глобальных экстремумов. В данной работе исследованы и разработаны методы автоматического поиска глобальных экстремумов в многомерном пространстве признаков всплескообразной электрической активности.

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep–wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep–wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep–wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: (1) what effects do imipramine and fluoxetine have on the sleep–wake cycle and the characteristics of sleep spindles in WAG/Rij rats and (2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep–wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of “slow” and “medium” spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep–wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data.

WAG/Rij rats are a valid model of absence epilepsy and comorbid depression. We have previously shown that WAG/Rij rats have disturbances in the sleep-wake cycle and changes in the characteristics of sleep spindles. A negative correlation was also found between the number of spike-wave discharges (SWD) and the duration of rapid eye movement (REM) sleep. Clinical evidence suggests that the traditional antidepressants imipramine and fluoxetine are effective in suppressing symptoms of depression, but may have a negative impact on the sleep-wake cycle and comorbid epilepsy in patients. Our previous studies in WAG/Rij rats showed that imipramine, when administered chronically, increases the number of SWDs, while fluoxetine at the same dose reduces their number, although both antidepressants have a pronounced antidepressant effect. Comparison of the effects of the antidepressants imipramine and fluoxetine on the sleep-wake cycle and sleep spindles in WAG/Rij rats remains unstudied. The purpose of this work is to find out: 1) what effects do imipramine and fluoxetine have on the sleep-wake cycle and the characteristics of sleep spindles in WAG/Rij rats and 2) whether there are differences in their effects. To achieve this goal, the characteristics of the sleep-wake cycle and sleep spindles were compared in WAG/Rij rats after chronic administration of antidepressants and saline and in non-epileptic Wistar rats. Administration of imipramine led to a significant decrease in the duration of REM sleep. The administration of imipramine, compared with fluoxetine, also increased the latency of the transition to sleep and the transition to REM sleep. Sleep spindle amplitude was significantly increased by both antidepressants. However, the spectral power density of “slow” and “medium” spindles, which predominate in WAG/Rij rats compared to Wistar rats, was significantly higher after administration of imipramine than fluoxetine. The results suggest that imipramine causes greater negative changes in the sleep-wake cycle and sleep spindles than fluoxetine. Studies in the WAG/Rij rat model indicate that fluoxetine is more preferable antidepressant for the treatment of depressive disorders comorbid with absence epilepsy, since it does not cause a significant deterioration in sleep quality. These results are consistent with clinical data.

The problems associated with the development of a method for early and differential diagnosis of Parkinson's disease (PD) and essential tremor (ET) using the analysis of wave train muscle activity are investigated. In the study of patients with PD, it is very difficult to find un treated patients who have not previously taken antiparkinsonian drugs. To solve the problem of small samples, it was proposed to increase artificially t he sample of subjects using the bootstrap method. Three artificially enlarged samples of subjects were created: a sample of patients with PD, a sample of patients with ET, and a sample of control subjects. When constructing models, two problems arise: the problem of inadequacy and the problem of insufficient generalizing ability of the model. Both of these issues must be considered when building models. The paper proposes models that, according to the authors, are promising for the early and differential diagnosis of PD and ET. Using these models, a good accuracy of PD recognition at the early stage was obtained (about 100%); the accuracy of differential diagnostics (distinguishing between PD and ET) was more than 90%.

As we have shown previously, a perinatal maternal methyl-enriched diet (MED) reduces the number of spike-and-wave discharges (SWDs) and behavioral symptoms of depression in an adult offspring of WAG/Rij rats. Epilepsy and depression are usually accompanied by sleep–wake disorders. SWDs and sleep spindles represent different manifestations of thalamocortical activity. It is assumed that pathological alterations in the thalamocortical system that lead to SWD alter sleep spindles as well. Probably, maternal MED has a positive effect not only on SWDs, but also on sleep spindles. The aim of this work was to find out whether maternal MED affects the sleep–wake cycle and whether it alters the characteristics of sleep spindles in adult offspring of WAG/Rij rats. It has been shown that in the offspring of WAG/Rij rats born to mothers fed on a MED during the perinatal period, the relative duration of REM sleep significantly increases compared to the offspring whose mothers consumed a control diet (CD). In the offspring of WAG/Rij rats whose mothers fed on a MED, the relative duration of REM sleep and the number of its episodes become indistinguishable from those in nonepileptic Wistar rats. Maternal MED also increases the number of transitions from slow-wave (non-REM) to REM sleep. There is a significant negative correlation between the number of SWDs and the duration of REM sleep. Maternal MED, as compared to CD, reduces the amplitude and spectral power density of sleep spindles; the latter become much closer to the amplitude and spectral power density of sleep spindles in Wistar rats. Thus, maternal MED normalizes characteristics of the sleep–wake cycle and sleep spindles in the adult offspring of WAG/Rij rats. We hypothesize that this positive effect is associated with a reduction in the symptoms of absence epilepsy and comorbid depression, as well as with the correction of thalamocortical activity.

This study was motivated by the well-known problem of the differential diagnosis of Parkinson’s disease and essential tremor using the phase shift between the tremor signals in the antagonist muscles of patients. Different phase shifts are typical for different diseases; however, it remains unclear how this parameter can be used for clinical diagnosis. Neurophysiological papers have reported different estimations of the accuracy of this parameter, which varies from insufficient to 100%. To address this issue, we developed special types of area under the ROC curve (AUC) diagrams and used them to analyze the phase shift. Different phase estimations, including the Hilbert instantaneous phase and the cross-wavelet spectrum mean phase, were applied. The results of the investigation of the clinical data revealed several regularities with opposite directions in the phase shift of the electromyographic signals in patients with Parkinson’s disease and essential tremor. The detected regularities provide insights into the contradictory results reported in the literature. Moreover, the developed AUC diagrams show the potential for the investigation of neurodegenerative diseases related to the hyperkinetic movements of the extremities and the creation of high-accuracy methods of clinical diagnosis.

Depression is a severe and widespread psychiatric disease that often accompanies epilepsy. Antidepressant treatment of depression comorbid with epilepsy is a major concern due to the risk of seizure aggravation. SAMe, a universal methyl donor for DNA methylation and the synthesis of brain monoamines, is known to have high antidepressant activity. This study aimed to find out whether L-methionine (L-MET), a precursor of SAMe, can have antidepressant and/or anxiolytic effects in the WAG/Rij rat model of depression comorbid with absence epilepsy. The results indicate that L-MET reduces the level of anxiety and depression in WAG/Rij rats and suppresses associated epileptic seizures, in contrast to conventional antidepressant imipramine, which aggravates absence seizures. The antidepressant effect of L-MET was comparable with that of the conventional antidepressants imipramine and fluoxetine. However, the antidepressant profile of L-MET was more similar to imipramine than to fluoxetine. Taken together, our findings suggest that L-MET could serve as a promising new antidepressant drug with anxiolytic properties for the treatment of depression comorbid with absence epilepsy. Increases in the level of monoamines and their metabolites-DA, DOPAC, HVA, NA, and MHPG-in several brain structures, is suggested to be a neurochemical mechanism of the beneficial phenotypic effect of L-MET.

Classical methods for signal analysis are limited to describe either the global features or the local features. This paper proposes a new mathematically founded concept called wave train electrical activity analysis to investigate both local and global features in biomedical signals simultaneously. First, mathematical means for the investigation of the properties of the wave trains observed in the biomedical signals, histograms of wave train parameters and AUC diagrams, are discussed. Second, several examples of the practical application of the method of the wave train electrical activity analysis are considered. Specifically, its application is demonstrated in the investigation of epileptic seizures as well as the differential diagnosis of neurodegenerative diseases, Parkinson’s disease and essential tremor.

An approach to diagnosing Parkinson’s disease and essential tremor based on the analysis of histograms of phase differences of the electromyogram envelopes of antagonist muscles was investigated. A comparison of two methods for calculating the instantaneous phase is carried out. The first method is based on the complex ridges of the Morlet complex wavelet spectrograms. The second method is based on the Hilbert transform. Statistically significant differences of medians of the instantaneous phase shift of electromyogram envelopes in antagonist muscles were found.

New approaches to the analysis of Morlet wavelet spectra of electroencephalograms, electromyograms, and accelerometer signals are proposed. The proposed approaches are based on the analysis of time−frequency distributions of local extrema and ridges of wavelet spectrograms. The paper describes the results of application of the proposed techniques for the diagnosis of the early stage of Parkinson’s disease and essential tremor, monitoring of postoperative patients with epilepsy, and assessment of inter-channel phase coupling of EEG during cognitive tests of patients after traumatic brain injury.

A statistical method for exploratory data analysis based on 2D and 3D area under curve (AUC) diagrams was developed. The method was designed to analyze electroencephalogram (EEG), electromyogram (EMG), and tremorogram data collected from patients with Parkinson’s disease. The idea of the method of wave train electrical activity analysis is that we consider the biomedical signal as a combination of the wave trains. The wave train is the increase in the power spectral density of the signal localized in time, frequency, and space. We detect the wave trains as the local maxima in the wavelet spectrograms. We do not consider wave trains as a special kind of signal. The wave train analysis method is different from standard signal analysis methods such as Fourier analysis and wavelet analysis in the following way. Existing methods for analyzing EEG, EMG, and tremor signals, such as wavelet analysis, focus on local time–frequency changes in the signal and therefore do not reveal the generalized properties of the signal. Other methods such as standard Fourier analysis ignore the local time–frequency changes in the characteristics of the signal and, consequently, lose a large amount of information that existed in the signal. The method of wave train electrical activity analysis resolves the contradiction between these two approaches because it addresses the generalized characteristics of the biomedical signal based on local time–frequency changes in the signal. We investigate the following wave train parameters: wave train central frequency, wave train maximal power spectral density, wave train duration in periods, and wave train bandwidth. We have developed special graphical diagrams, named AUC diagrams, to determine what wave trains are characteristic of neurodegenerative diseases. In this paper, we consider the following types of AUC diagrams: 2D and 3D diagrams. The technique of working with AUC diagrams is illustrated by examples of analysis of EMG in patients with Parkinson’s disease and healthy volunteers. It is demonstrated that new regularities useful for the high-accuracy diagnosis of Parkinson’s disease can be revealed using the method of analyzing the wave train electrical activity and AUC diagrams.

WAG-Rij rats are a model of genetic absence epilepsy, characterized by the presence of peak-wave discharges (PWD) on the EEG. The first PWD in WAG-Rij rats are known to occur at age 2–3 months, the number and duration then increasing. However, the evolution of PWD during the progressive development of absence epilepsy in WAG-Rij rats remains uninvestigated. The aim of the present work was to identify developmental changes in the time-frequency dynamics, frequency spectrum, and morphological features of PWD in WAG-Rij rats. The evolution of PWD was studied in individual rats from age two months to age 12 months. PWD were found to form at age 2–4 months, after which morphological changes in PWD were seen. During the progressive development of absence epilepsy, PWD displayed three stages of “maturation.” It is suggested that the age-related evolution of PWD in rats may reflect progressive electrophysiological changes in the somatosensory cortex – a brain area linked with the generation and generalization of PWD.

In the present study it has been shown for the first time that maternal methyl-enriched diet (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) during perinatal period reduces the expression of genetic absence epilepsy and comorbid depression in adult offspring of WAG/Rij rats. This beneficial effect was more pronounced in males compared with females. It is assumed that epigenetic modifications induced by maternal methyl-enriched diet in the offspring at the early stages of ontogenesis might be a possible mechanism underlying the correction of genetically-based pathologic phenotype in WAG/Rij rats. Results suggest that methyl-enriched diet during perinatal period can be potentially used for mitigation or prevention epileptogenesis and depression-like comorbid disorders in people genetically predisposed to absence epilepsy.