Diagnosis of Schizophrenia Based on the Data of Various Modalities: Biomarkers and Machine Learning Techniques (Review).

Schizophrenia is a socially significant mental disorder resulting frequently in severe forms of disability. Diagnosis, choice of treatment tactics, and rehabilitation in clinical psychiatry are mainly based on the assessment of behavioral patterns, socio-demographic data, and other investigations such as clinical observations and neuropsychological testing including examination of patients by the psychiatrist, self-reports, and questionnaires. In many respects, these data are subjective and therefore a large number of works have appeared in recent years devoted to the search for objective characteristics (indices, biomarkers) of the processes going on in the human body and reflected in the behavioral and psychoneurological patterns of patients. Such biomarkers are based on the results of instrumental and laboratory studies (neuroimaging, electro-physiological, biochemical, immunological, genetic, and others) and are successfully being used in neurosciences for understanding the mechanisms of the emergence and development of nervous system pathologies. Presently, with the advent of new effective neuroimaging, laboratory, and other methods of investigation and also with the development of modern methods of data analysis, machine learning, and artificial intelligence, a great number of scientific and clinical studies is being conducted devoted to the search for the markers which have diagnostic and prognostic value and may be used in clinical practice to objectivize the processes of establishing and clarifying the diagnosis, choosing and optimizing treatment and rehabilitation tactics, predicting the course and outcome of the disease. This review presents the analysis of the works which describe the correlates between the diagnosis of schizophrenia, established by health professionals, various manifestations of the psychiatric disorder (its subtype, variant of the course, severity degree, observed symptoms, etc.), and objectively measured characteristics/quantitative indicators (anatomical, functional, immunological, genetic, and others) obtained during instrumental and laboratory examinations of patients. A considerable part of these works has been devoted to correlates/biomarkers of schizophrenia based on the data of structural and functional (at rest and under cognitive load) MRI, EEG, tractography, and immunological data. The found correlates/biomarkers reflect anatomic disorders in the specific brain regions, impairment of functional activity of brain regions and their interconnections, specific microstructure of the brain white matter and the levels of connectivity between the tracts of various structures, alterations of electrical activity in various parts of the brain in different EEG spectral ranges, as well as changes in the innate and adaptive links of immunity. Current methods of data analysis and machine learning to search for schizophrenia biomarkers using the data of diverse modalities and their application during building and interpretation of predictive diagnostic models of schizophrenia have been considered in the present review.

[Perception of Verbal Stimuli in the Norm and in Schizophrenia].

The present study investigates the early stages of selection of meaningful and meaningless verbal-in- formation in an implicit and two explicit tasks by means of the parameters of latency and amplitude of P100 EP component in healthy subjects (n = 99) and in schizophrenia patients with the first psy- chotic episode (n = 102). The obtained results indicate the disturbance of passive perception of meaningful verbal information in psychotic patients. When the instruction is presented patients re- spond similar to norm. The decreased amplitude of P100 component during the,passive perception of words in patients may be related to the severity of hallucinatory behavior. The analysis of changes in the characteristics of the P100 wave in task with instruction as compared to passive perception in the norm revealed a shortening of the time window'of the processing of information regardless to its category and relevance. In schizophrenia patients this feature was found only when reading of the pseudo-words. The results indicate the disturbance of automated attraction of attention to the semantically significant content of the verbal stimulus in the patients' group. The study demonstrat- ed the association between P100 wave characteristics and behavioural responses.

[The Association of Brain-Derived Neurotrophic Factor and Serotonin Transporter Genes with the Parameters of Early Event-Related Potentials During the Passive Perception of Words].

We explored the association of brain-derived neurotrophic factor (BDNF) and serotonin transporter genes with neurophysiological characteristics of the early stages of verbal information processing in the brain in the groups of patients with schizophrenia and schizophrenia spectrum disorders and healthy people. It has been shown that Val66Met and 5-HTTLPR polymorphisms are associated with P100 and N170 during the passive reading of single words written in Russian presented with different occurrence frequency. The healthy carriers of the ValVal genotype (BDN F Val66Met) allele or the SS (5-HTTLPR) genotype performed the task better compared to those with an Met or an L allele. The differences were significant in healthy people and observed as a trend in thepatients.

[The Influence of Threatening Stimuli on the Component P200 in Patients with Paranoid Schizophrenia].

We studied schizophrenic patients with the dominance of pseudohallucinations. As is well known, pseudohallucinations are the main syndrome of schizophrenia, the so-called first rank syndrome. Pseudohallucinations are defined as a disorder of sense (affective) perception. This disorder is mainly diagnosed from the clinical picture or by pathopsychologichal observations. We investigated the evoked potentials (EP) of brain after neutral and emotionally meaningful (threatening) visual stimuli in order to specify the neurophysiological disorders of affective perception in schizophrenic patients with severe paranoid-hallucinatory syndrome who did not receive neuroleptic therapy. The analysis of P200 component in healthy subjects showed an increase in the amplitude and shortening of the latency of this wave in response to thretaning stimuli, as compared to neutral stimuli. In the group of patients with schizophrenia, the analysis showed the same increase in the level of excitation in response to emotionally threatening stimuli. However, in schizophrenic patients there were also found certain areas where the amplitude and latency decreased or increased at the same time. The results show that patients with schizophrenia have the pathological effect of having parameters typical of the processes of both excitation and inhibition.

[Latencies of Sensory and Cognitive Components of Event Related Potentials during Perception of Verbal Stimuli in the Norm and Schizophrenic Patients].

The aim of this work is the study of early and later indices of brain informational processing during the passive reading of concrete words in healthy subjects and schizophrenic patients using the ERP method. Comparative analysis of components P100, N170, P200 and P300 in implicit situation showed that in schizophrenic patients the latency of early components P100 and N170 is shorter while the latency of later components P200 and P300--is longer than in healthy subjects. It could be supposed that the patients have deficit of the early automatic sensory processing of the stimuli revealing through the shortening of their recognition time and this results in the decrease of completeness and preciseness of sensory analysis. In the study there were also revealed negative correlations between the latencies of P100 and P200 components (P200 being a "recognition potential") in healthy subjects confirming the hy pothesis that longer sensory processing of verbal stimuli leads to the shortness of the time for its recognition. For schizophrenic patients the relation between the duration of sensory and cognitive ERP components is disturbed. They have positive correlations between the latencies of early and late components possibly on account of the nonspecific contribution both in early and late components while in normal subjects the early components are more specific than the late ones.

[Neurophysiological Features of Perception of Emotional Stimuli in Health and in Patients with Paranoid Schizophrenia].

Cognitive and emotional disorders, as far as is known, are the main syndromes of schizophrenia. Disorders of these functions are mainly determined by the clinical picture, as well as by psychophysiological correlates. The purpose of our study was to identify some psychophysiological factors which cause perceptual and emotional disturbances in patients with schizophrenia. These disorders of mental functions form the first rank (top) syndrome in patients with schizophrenia [1]. The studied patients had acute psychosis with a predominance of paranoid hallucinatory syndrome and did not receive antipsychotic therapy; i.e., the disturbances of sensory perception were most pronounced. The analysis of early component P100 and intermediate one N170 of event related potentials (ERPs) in the control group showed an increased level of excitation in response to emotionally threatening stimuli; the amplitude increased and the latency decreased in all leads. In contrast the analysis of components P100 and N170 in the group of patients with schizophrenia showed the increased latency and decreased amplitude. The obtained data provide evidence of pathological inhibition in the passive perception of emotionally significant stimuli.

[EEG synchronisation in autistic children. Analysis of coherency].

EEG study of 5-7 years boys with autism revealed lower values of coherence in background delta, theta and alpha bands and higher values of coherence in background beta 1, beta 2 and gamma bands. Healthy boys showed higher values of beta and gamma coherence during cognitive task. Autistic persons demonstrated higher values of theta coherence during cognitive task.

[Autism spectrum disorder. Contemporary experimental researches review].

Autism, like schizophrenia, are heterogeneous diseases, which are directed by both genetic factors and external influences in the early stages of development. Knowledge about the similarities and differences of these disorders can help early diagnosis and treatment. Patients with autism have specific cognitive difficulties in social relations. They are characterized by impairment of social interaction, communication and behavioral flexibility. The severity of the delay the development of autistic children, clinical and psychological indicators is correlated with an increase in the high frequency of spontaneous EEG activity. Cognitive task in autistic children, unlike normal persons, does not lead to a significant restructuring of high-frequency EEG activity, which may be a violation of the reaction mechanism to external stimuli and behavioral disorders. Abnormality in high-frequency components of EEG reactivity on cognitive task, the perception of human faces and visual illusions as well as the inadequate system of mirror neurons, can be considered common mechanisms underlying disorders of autism and schizophrenia. These general mechanisms may be considered as related to violation of the inhibition-exitation balance, controlled via GABA-transmission and NMDA-receptors. A multidimensional study of patterns of disontogenesis in autism, in addition to detailing the clinical picture of disease and rehabilitation activities, allows us to clear the fundamental understanding of the brain.

[Sensory analysis of the words with different occurrence frequency in the norm and in patients with schizophrenia and schizophrenic spectrum disorders].

The paper introduces the study of the early stages of verbal information processing in the brain during the passive reading of single words with different occurrence frequency in Russian and of pseudo-words in healthy subjects and in patients with schizophrenia and schizophrenic spectrum disorders using evoked potentials method. It is shown that the latency of P100 and N170 in healthy subjects increased during visual perception of rare words compared to frequent ones and pseudo-words that apparently reflected the necessity to involve large quantity of brain resources during sensory stages of the processing of the verbal stimulus with intricate semantic. In patients with schizophrenia and schizophrenic spectrum disorders more complicate pattern was observed during the perception of verbal stimuli of various categories. P100 latency was the largest during pseudo-words reading, and P100 amplitude--during frequent words reading in this group. N170 atency in the patients' group was maximal during frequent words reading. Abnormality of evoked potentials polarity in anterior cortical areas most evident during visual perception of meaningful verbal information was also found in these subjects. The obtained results may point to the dysfunction ofprefrontal cortex top-down influence in schizophrenia and schizophrenic spectrum disorders, which is manifested in the disturbed sensory processing ofvarious categories verbal stimuli.

[Event-related brain activity changes to consonant and dissonant chords in musicans and non-musicans].

The present study assessed brain activity changes related to perception of consonant and dissonant chords by musicians and non-musicians. Perception of dissonant chords in non-musicians was accompanied by increase of lower theta activity over right anterior regions, while consonant chords induced greater theta activity over left anterior regions; this pattern of asymmetrical activation was not observed in musicians. ERP analysis revealed that musicians had greater amplitude of early components (P100, N200) than non-musicians irrespective of chord type. The obtained results reflect more efficient musical harmony processing and, possibly, less emotional perception of chords in musicians.

[Comparative EEG-study of normal and autistic children].

The work represents the results of a comparative study of a spectral power as well as averaged coherence in theta and gamma-EEG band in a healthy and autistic boys (the mean age 6 years 1 month). Healthy boys showed a decreasing in theta spectral power as well as in averaged coherence, and increasing in gamma spectral power as well as in averaged coherence during cognitive task. Spectral power of gamma band shows more high scores in autistic boys than in normal ones. Cognitive task situation do not change spectral power of the fast oscillations in autistic children. Spectral power of theta--band shows more low scores in autistic boys than in normal ones. Cognitive task situation do not change spectral power and averaged coherence of theta oscillations in autistic children.

[EEG coherence analysis in depressive disorders and its possible use in clinical practice: a literature review].

Recent reviews and meta-analyses of clinical data have revealed that there is a clear need in objective biomarkers of mental disorders and, in particular, of depression. There is a lot of evidence that EEG coherence can be an important marker of depressive disorders, and can predict response to different antidepressants. The most consistent finding is a decrease of frontal interhemispheric EEG coherence which is observed for most disorders related to depression. Methodological issues are discussed with a particular emphasis on use of statistical classifiers and on coupling EEG coherence with other methods of EEG analysis.

[Early stage of processing of target, non-target known and unknown verbal stimuli].

Characteristics of P100/N100 and N170 components of ERPs in response to target and non-target known words and unknown words were studied. EEG was recorded while participants made a decision whether or not visually presented words were related to a given category. Intra- and interhemispheric features of P100/N100 and N170 components evoked by different types of verbal stimuli were revealed. It was found that N170 amplitude evoked by target known words was higher than that evoked by nontarget known words and unknown words. The results suggest that motivation can affect the early word processing.

[Evoked spectral EEG power during presentation of pseudowords and words from "animate" and "inanimate" categories].

Pseudowords and words of "animate" and "inanimate" categories were shown to healthy young adults (14 women and 9 men) in three series. In the first series, subjects were just reading presented verbal stimuli (words and pseudowords), in the second series, they had to click a mouse button in response to presentation of a word, and in the third series they clicked a button when pseudowords were presented. Presentation of words and pseudowords caused desynchronization of the alpha rhythm and synchronization of the theta rhythm. Early synchronization (50-250 ms) was stronger for pseudowords and words of "animate" category during passive perception of stimulus. The middle synchronization period (250-800 ms) was stronger in projections of Broca's and Wernicke's areas. The relevance of the stimuli led to an increase in desynchronization and reduction of early and late (800-1500 ms) synchronization periods after presentation of both words and pseudowords. For words of "animate" categories, the synchronization of the theta rhythm was more pronounced in the early periods, and for words of "inanimate" categories, the theta rhythm synchronization was more distinct in the middle periods.

[Adolescents under conditions of chronic family stress].

The influence of the type of the nervous system on psychophysiological stress reaction was studied in a group of adolescents at the age of 15-17 years with chronic stress. Adolescents with the weak type of the nervous system were to a greater extent subject to psychological disorders; adolescents with the intermediate type of the nervous system suffered more from disorders in physiological sphere, whereas persons with the strong type appeared to be most stable in the situation of chronic family stress.

[Perception of consonant and dissonant chords: changes in the power of the EEG evoked activity].

Human perception of dissonant and consonant chords was studied by analyzing brain evoked activity. It was found that the perception of dissonant chords was accompanied by activation of the right frontal lobe, which controls negative emotions. Consonant chords activated the left frontal region, which controls positive emotions.

[Analysis of event-related potentials to verbal stimuli in healthy subjects and schizophrenia patients].

In 30 healthy subjects and 32 patients after the first episode of schizophrenia 19 channel-EEG was recorded during visual presentation of a random sequence of words and pseudo-words. In the first series of the experiments, subjects had to read the presented verbal stimuli, in the second series they had to press a button when seeing a word, and in the third series they were instructed to press the button when seeing a pseudo-word. We studied components N170, P300 and N400. In the group of healthy subjects, the amplitude of N170 increased to words in the situation of their relevance, which corresponds to the "recognition potential", whereas in the group of patients, the amplitude of N170 increased to pseudo-words when they were relevant. So it was a paradoxical response. The amplitude of the ERP later waves (P300 and N400) in the group of schizophrenic patients was smaller and the relevance effect was impaired when the target stimuli were pseudo-words. However, the incongruity effect consisting in an increase in N400 amplitude to a non-target stimulus remained intact in patients.

[Temporal characteristics of the initial stage of the verbal information processing in healthy subjects and in schizophrenia].

The study aimed to investigate the early coding of visually presented words and pseudowords using event-related potentials (ERP). We conducted comparative analysis of the characteristics of P100 and N170 in healthy controls and in patients with the first episode of schizophrenia during passive perception of verbal stimuli as well as under conditions of relevant words and pseudowords. The latency of early ERP components P100 and N170 appeared to be shorter in comparison with healthy subjects in the temporal, parietal and occipital areas. The latency of P100 in patients was significantly shorter in the temporal, parietal and occipital areas, whereas the latency of N170 was shorter in the parietal and occipital areas than in controls. The latency of N170 in healthy subjects was significantly longer to words than to pseudowords and in patients - vice versa. The latencies of N170 in all TPO areas were equal in healthy subjects during word processing, and this equality was upset during non-word processing. In patients with schizophrenia the equality was upset, but, opposite to healthy patients, the upset of equality was more expressed during words processing. Thus, the early stage of verbal information processing in schizophrenic patients is insufficient in time. The time deficit of the automatic processes may lead to defective processing of overall information.

[Features of the spectral power of the EEG rhythms in autistic children and their relation with the progress of different symptoms in schizophrenia].

Right hemispheric dominance of the baseline alpha-band spectral power was revealed in 5-7 years boys with autism. This feature persisted during performance of a cognitive task (counting). Also, boys with autism showed lowered level of the alpha spectral power as compared with healthy children. In healthy children, the gamma spectral power increased during performance of the cognitive task as compared to baseline state. Autistic persons showed higher values of the gamma spectral power as compared with normal boys. Boys with autism showed less expressed changes in the gamma spectral power during the cognitive task than healthy children. The reduced spectral power of the alpha band in autistic boys may serve as a precursor of conversion from autism to schizophrenia. Higher level of the gamma spectral power in autistic boys is characteristic also of schizophrenic patients with positive symptoms. Lowered levels of fast rhythms reactivity revealed in autistic boys and the same effect earlier described in schizophrenic adults probably have the similar nature.

[Activation of brain structures by fMRI data when viewing the video clips and recall of shown actions].

In 10 healthy volunteers, brain tomograms were recorded using an fMRI scanner with a 3T-field magnet. Emotionally neutral and emotionally involving videos were used for stimulation. Registration consisted of seven series: two series of viewing a fixation point and two kinds of video clips, one series of viewing of a succession of two types of video clips, two series of watching videos with subsequent recall, and two series of viewing the fixation point followed by recall of content online. Viewing content online caused the greatest degree of metabolism increase localized in the visual cortex. This activation was more pronounced during the presentation of an emotionally involving video clip. In addition to the occipital lobe, it actively involved the temporal, parietal and, to a lesser extent, the frontal cortex. Activation of the motor cortex was detected only in some subjects. The "interference" effect in which the increase in metabolism was minimal was observed during a consequent demonstration of video-clips. Immediate recall of video-clips after viewing caused the greatest activation of the posterior frontal and motor cortex. Delayed recall activated mostly the anterior frontal cortex. There was a decrease of metabolism in the visual cortex during the recall. The greatest reduction in the visual cortex was observed during immediate recall. Immediate and delayed recall activated the structures associated with the maintenance of consciousness, memory and a system of mirror neurons.