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.

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype.

The aim of the study was to analyze the immune-inflammatory profile of patients with paranoid schizophrenia and relate it to the severity of negative symptoms and the MRI data in order to identify biomarkers of schizophrenia severity, search for new approaches to therapy, and control its effectiveness. Materials and Methods: The main group included 51 patients with paranoid schizophrenia, the control group - 30 healthy subjects. Patients underwent MRI scans and immunological studies, which included an assessment of natural and adaptive immunity, the systemic level of key pro-inflammatory and anti-inflammatory cytokines, and other markers of inflammation. Results: Disorders of immunity and immunoinflammatory profile in patients with paranoid schizophrenia with severe negative symptoms were revealed for the first time: in the presence of severe negative symptoms (>15 points according to the NSA-4 scale), the levels of humoral immunity factors, cytokines IL-10 and IL-12p40 and neurotrophin NGF were increased as well as the markers of systemic inflammation. Morphometric changes in the brain, typical for patients with schizophrenia, and also specific for patients with severe negative symptoms, were determined. The data analysis revealed correlations between the immune changes with structural changes in some of the brain areas, including the frontal cortex and hippocampus. Associations were found between the levels of anti-inflammatory IL-10, IL-12p40 cytokines and morphometric parameters of the brain, specific only for schizophrenic patients with severe negative symptoms. Conclusion: The interdisciplinary approach, combining brain morphometry with in-depth immunological and clinical studies, made it possible to determine neurobiological, immune, and neurocognitive markers of paranoid schizophrenia with severe negative symptoms. The results are important for further deciphering the pathogenesis of schizophrenia and its subtypes, as well as for the search for new approaches to the treatment of severe forms of the disease.

[The relationship between inflammation, cognitive disorders and neuroimaging data in schizophrenia]. / Svyaz' mezhdu vospaleniem, kognitivnymi narusheniyami i dannymi neirovizualizatsii pri shizofrenii.

OBJECTIVE: To search for the relationship between the results of functional imaging, immunological parameters and laboratory markers of inflammation in schizophrenia, taking into account cognitive impairment in patients, and to consider the possibility of using a multidisciplinary approach to diagnosis, treatment and prognosis of schizophrenia. MATERIAL AND METHODS: The study included 25 patients with schizophrenia and 13 healthy volunteers. Psychiatric scales were administered to evaluate the patient's condition. The main indicators of humoral immunity, the level of markers of inflammation, key pro-inflammatory and anti-inflammatory cytokines, and growth factor VEGF were determined by ELISA. Brain MRI was performed. All calculated tractographic data are included in the connection database to study the effect of immunological markers and the degree of severity of cognitive impairment. RESULTS AND CONCLUSION: Levels of markers of systemic inflammation and growth factor VEGF-A as well as the activation of humoral immunity are increased in patients with schizophrenia compared with controls. For the first time, the relationship of immunological parameters with the coefficient of quantitative anisotropy in the area of the corpus callosum in schizophrenia was revealed. The results indicate the possible value of indicators of the activation of the humoral immune response and systemic inflammation as markers of neurophysiological changes and cognitive dysfunction in schizophrenia.

Towards Semantic Brain Mapping Methodology Based on a Multidimensional Markup of Continuous Russian-Language Texts: an Attempt at Validation and Development.

In the present study, we combine linguistic annotation of oral texts in Russian with the registration of BOLD signal in functional MRI experiments to determine how and where semantic categories are represented in the human brain. Using the same stimuli material, we also analyze the differences in cortical activation in three thematic domains: description of nature, description of working principles of technical devices and more self-referential texts, addressing the question of human identity in conflict situations. We discuss methodological problems within the two approaches (microanalysis and macroanalysis) to study brain activation in natural conditions, i.e. under a continuous speech flow. Within the thematic domain studies, only minimally significant differences in brain activation were registered during the listening to texts from the three thematic groups. This outcome leads to the conclusion that the approach of thematic group contrasts (cognitive subtraction methodology) is not sufficient to study the mechanisms of text comprehension, and should be replaced by the modeling of multidimensional representations of semantic categories in time. Within the semantic category approach, we describe the neurolinguistic process of text understanding as the activation of 15 clusters responsible for semantic categories (e.g. "Conflict", "Mental", "Social"). Our data demonstrate that the clusters are widely distributed across the human brain. In contrast to the previous studies, we suggest that deep subcortical structures are involved in the processing of certain categories as well. The observed lateralization of category processing underlines the involvement of the right hemisphere in the processing of meaning.

[A role of the immune system in the pathogenesis of schizophrenia]. / Rol' immunnoi sistemy v patogeneze shizofrenii.

The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.

[Dynamics of Brain Activity during Voluntary Movement: fMRI Study].

The use of event-related fMRI makes it possible to investigate spatio-temporal dynamics of cortical and subcortical human brain structures activity during voluntary movement performance in response to presentation of relevant verbal stimuli. The results of the study showed that voluntary movement was associated with higher contralateral brain activation in a number of areas: primary motor and somatosensory cortex, premotor cortex, supplementary motor area and insula with adjacent regions. Ipsilateral activation of the cerebellum also was observed. It should be emphasized that contralateral strio-pallidal complex and ventral thalamus showed significant response to motor tasks. Similarly, the dynamics of cortex and deep brain structures activation involving in the phasic and tonic components of voluntary movement was uncovered. We showed, in particular, the noticeable difference in brain activation between the right and left hand movement performance. The obtained results enable to enhance understanding of the role of deep brain structures in voluntary movement organization in human and motor control system as a whole.

[Macroscopic Functional Networks of the Human Brain when Viewing and Recalling Short Videos].

Macroscopic functional network of the human brain were identified by use of the independent component analysis (ICA) of fMRI while viewing and imaging/recalling stories. The networks were relatively stable in structure, but had a specific dynamics in different experimental conditions. When comparing detected networks with previously detected resting state networks it was found that they coincide on localization. We. discovered also the specificity of activating the peripheral and central parts of retinotopic projections in the visual cortex. The peripheral areas were activated during subject viewing and imaging/recalling. On the contrary, the central departments strengthened their activation when viewing and reduced activity during the imaging/recalling.

[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.

[The influence of mutual arrangement of the electric dipole and the spatial nonuniformity of brain electrical conductivity on the solution of the direct task of electroencephalography using the method of finite elements].

The results of comparing the solutions of the direct task of electroencephalography on a spherical model and a spherical model with one nonuniformity are discussed. The nonuniformity was simulated by two parabolas situated on the same axis of symmetry and crossing the boundary of the gray and white matters. The region between the larger and the smaller parabolas had the physical characteristics of the gray matter, and the region inside the smaller parabola had the characteristics of the cerebrospinal fluid. The task was to find a combination of the parameters (the distance between the dipole and the nonuniformity, the angle of rotation of the dipole relative to the nonuniformity, the sizes of the dipole and the nonuniformity, etc.) that provides the maximum effect of the difference of potentials on the outer surface of the scalp in the spherical model with one nonuniformity and the spherical model. The influence of the points of ground location on the value of the effect was analyzed (ground only at the right ear and ground at both ears). The data obtained show that a maximum difference of potentials is reached at the positions of dipoles close to tangential relative to the scalp surface.

MRI morphometry of the cerebral ventricles in patients with attention deficit hyperactivity disorder.

A total of 27 right-handed patients aged 7-30 years with diagnoses of attention deficit hyperactivity disorder were studied using standard MRI scans. Of these, 14 were aged below 13 years. The volumes of the lateral ventricles were measured using T1-weighted MRI images of sagittal sections of the brain to a precision of 3 mm3. External head sizes were also measured to allow ventricle volumes to be normalized. All patients underwent complex neuropsychological investigations. Memory was assessed, along with visual, auditory, tactile, and spatial recognition functions and the motor and speech spheres. Test data were assessed in terms of the severity of impairments associated with one brain structure or another on a tenpoint scale. Assessment points were summed for each hemisphere, for the "first area" (cortical structures), and all structures for statistical analysis. Neuropsychological testing revealed functional impairments predominantly of the frontal areas of the hemispheres, the hippocampus, and the reticular formation. Neuropsychological deficits were least linked with alterations in the postcentral and parietal areas of the cortex. Statistical analysis demonstrated a significant positive correlation between the normalized left lateral ventricle volume and the degree of neuropsychological impairments (r = 0.5127 at p = 0.0063) for the whole study group. The correlation was more marked on comparison of the normalized left ventricular volume and the severity of neuropsychological impairments related to the left hemisphere (r = 0.6303 at p = 0.0004). A relationship was seen between the volume of the intraventricular space and cortical functional impairments (r = 0.5071 at p = 0.0069) in patients less than 13 years old. A relationship between ventricular volume and linear head size was confirmed (r = 0.5759 at p = 0.0017), which was more marked in subjects less than 13 years old (r = 0.6833 at p = 0.01).

[Decrease in N170 evoked potential component latency during repeated presentation of face images].

The 15 healthy volunteers EEG from 28 channels was recorded during the presentation of visual stimuli in the form of face and building images. The stimuli were presented in two series. The first series consisted of 60 face and 60 building images presented in random order. The second series consisted of 30 face and 30 building images. The second series began 1.5-2 min after the end of the first ore. No instruction was given to the participants. P1, N170 and VPP EP components were identified for both stimuli categories. These components were located in the medial parietal area (Brodmann area 40). P1 and N170 components were recorded in the superior temporal fissure (Brodmann area 21, STS region), the first component had the latency 120 ms, the second one--155 ms. VPP was recorded with the latency 190 ms (Brodmann area 19). Dynamic mapping of EP components with the latency from 97 to 242 ms revealed the removal of positive maximums from occipital to frontal areas through temporal ones and their subsequent returning to occipital areas through the central ones. During the comparison of EP components to face and building images the amplitude differences were revealed in the following areas: P1--in frontal, central and anterior temporal areas, N170--in frontal, central, temporal and parietal areas, VPP--in all areas. It was also revealed that N170 latency was 12 ms shorter for face than for building images. It was proposed that the above mentioned N170 latency decrease for face in comparison with building images is connected with the different space location of the fusiform area responsible for face and building images recognition. Priming--the effect that is revealed during the repetitive face images presentation is interpreted as the manifestation of functional heterogeneity of the fusiform area responsible for the face images recognition. The hypothesis is put forward that the parts of extrastriate cortex which are located closer to the central retinotopical projections can take part not only in the recognition process but also in memory traces fixation with the peripheral parts of these areas being responsible for the stimuli presented for the fist time.

[MRI morphometry of the brain ventricles in patients with attention-deficit hyperactivity disorder].

Twenty seven right-handed subjects aged 7-30 years with the attention deficit/hyperactivity disorder (ADHD) were exposed to standard MRI examination. From them, 14 were younger than 13 years old. The volumes of lateral ventricles were measured using T1-weighted MR-images of the sagittal brain sections to within 3 mm3. External head radii were measured additionally to normalize ventricle volumes. All patients passed complex neuropsychological testing. Memory and functions of visual, auditory, tactile and spatial recognition, motor and speech spheres were examined. Test results were evaluated by the degree of disorders with reference to corresponding brain structures on a 10-point scale. Absence of disorders corresponded to 0 points and maximum intensity of was scored as 10. Disorder scores were summed up for each of hemispheres, the first area (cortical structures), and all structures. Neuropsychological testing revealed disorders, predominantly, in the frontal area, hippocampus and reticular formation. Neuropsychological deficit was minimally related to the disturbances in post-central and parietal cortical areas. Statistical analysis revealed significant positive correlation between normalized volume of the left lateral ventricle and neuropsychological disorder score (r = 0.5127, p = 0.0063) for the whole group studied. The correlation between the normalized volume of the left lateral ventricle with the disorder score related to the left hemisphere was more significant (r = 0.6303, p = 0.0004). At the same time, a correlation of the ventricle volume and the dysfunction of the cortical structures was revealed (r = 0.5071, p = 0.0069) in subjects younger than 13 years old. The study corroborated interrelation between the volume of ventricles and linear head dimensions (r = = 0.5759, p = 0.0017) which was more pronounced in younger subjects (r = 0.6833, p = 0.01).

[Registration of changes in the nucleoide conformation based on the analysis of the time dependence of viscosity].

The sensitivity of the method of anomalous time dependence of viscosity to changes in the conformation of DNA-protein complexes (such as nucleoide) by the action of (1) nalidixic acid on cells and (2) one- and two-charged ions Na+, Cl-, Cu2+, Ca2+, Mg2+, Zn2+, SO4(2-) on Escherichia coli cells has been studied. The data obtained suggest that the method anomalous time dependence of viscosity is highly sensitive to the conformation of high-molecular DNA-protein complexes. It was shown that the method anomalous time dependence of viscosity can be used to register cell sensitivity to changes in the concentration of one- and two-charged ions in suspension.

[The use of the method of anomalous time dependence of viscosity for registration of changes in the nucleoide conformation. Part 1].

The sensitivity of the method of anomalous time dependence of viscosity to changes in the conformation of DNA-protein complexes (such as nucleoide) by the action of increased temperature (33, 70 and 85 degrees C) and the combined action of temperature and Na+, Cl- ions on lysates of Escherichia coli AB1157 cells has been studied. The optimal conditions of the cell lysis was determined on the basis of the curve parameters of the anomalous time dependence of viscosity.

[Modeling the effect of the layer thickness and tissue conductivities of the head and the brain on the EEG potentials using finite element method].

The influence of the thickness and specific resistance of the brain tissues and its surrounding coverings, brain sulci and anisotropy of white matter electric conductivity on the EEG potentials were modeled. The finite element method was used for simulation, which is realized in the Femlab module. During the comparison of two models with different thickness of the layers was shown the change of potentials by 40% for scull, which thickness varied by 9 mm, and for the gray matter and spinal fluid the change of potentials amounted to 15% by 3 mm variable thickness. The change of conductivity by 25% resulted in the difference of potentials amounted to 15% for the white matter and 1.5% for the cortex of the brain. During the assignment of the anisotropy in the model, by the whole volume of the white matter, sixfold difference of the potentials in comparison with application of isotropic parameters was discovered. The difference of the potentials for single heterogeneity, simulated the sulci of the brain, amounted to 10% in the heterogeneity projection point and increased during the drawing near to the "referent electrode". The model complex of the "sulci of cerebrum" gave significant contribution to the difference of the potentials and depended on the depth of dipole occurrence and nearness of the sulci complex. Significant influence of brain sulci on the EEG-potentials distribution, which can give rise to great artifacts, was discovered.

[Estimation of localization and dipole moment of alpha- and theta-rhythm sources by cluster analysis in healthy subjects and schizophrenics].

In 12 healthy subjects and 9 schizophrenic patients in the background conditions (with eyes closed) EEG was recorded from 16 standard derivations (10-20 system) during 3 min. The record underwent the spectral analysis detecting alpha- and theta-frequency bands. After the preliminary narrow band filtration for the main frequencies the sources of the spontaneous rhythms were localized. The data on localization for all healthy subjects and patients were summarized. The K-means clustering was used for identification of the sources clusters which were revealed in occipital and parietal lobes and limbic cortex for alpha-rhythm and also in frontal, temporal and parietal regions, limbic cortex and hippocampus for theta-rhythm. In schizophrenic patients in comparison with healthy subjects there was revealed significant increase of the numbers of dipole sources of alpha-rhythm in the clusters localized in limbic cortex and hippocampus. For theta-rhythm there was significant increase of the dipole moment of the sources in the clusters localized in the temporal and frontal cortices and hippocampus in patients in comparison with the norm.

[The peculiarities of the microwave in the frequency range of 51-52 GHz spectrum effects on E. coli cells].

The effects of microwaves on conformation of nucleoids in E. coli cells were studied by the method of anomalous viscosity time dependence (AVTD) at various frequencies in the range of 51-52 GHz and the power flux density of 100 microW/cm(2) . Linearly polarized microwaves resulted in significant effects within specific frequency windows of resonance type. The distances between frequency windows were in the range of 55-180 MHz. Only one of two possible circular polarizations, left-handed or right-handed, was shown to be effective at each frequency window. The sign of effective circular polarization alternated between frequency windows. We show that the effects of microwaves on E. coli cells as measured by the AVTD technique are not caused by adhesion of cells. The half-width of the 51.575 GHz resonance was measured to be 120+/-20 MHz. This value is very close to the half-width of the 51.755 GHz resonance as it has previously been determined at the same power flux density. The obtained data suggest similar targets for effects of microwaves at these two resonance frequencies and provide evidence for non-thermal nature of observed microwave effects.

[The effects of the microwaves on E. coli cells depend on oxygen concentration and static magnetic field].

The effects of non-thermal microwaves (MW), 10(-4) and 10(-10) W/cm(2), on conformation of nucleoids in E. coli cells were analyzed by the method of anomalous viscosity time dependence (AVTD). MW exposure was performed at different values of static magnetic field and concentration of oxygen, 8-90 microT, and 2.3-7.8 mg/l, respectively. It was shown, that slight changes in both static magnetic field and oxygen concentration result in significant changes of MW effects up to their disappearance. It was established, that changes in static magnetic field affected significantly the time kinetics of the MW effects. The obtained data provide further evidence for strong dependence of the effects of non-thermal microwaves on physical parameters of exposure and physiological factors. These dependences should be taken into account in replication studies. The obtained results encourage further investigation of possible modulation of non-thermal MW effects by additional electromagnetic fields.

[Method of the anomalous time dependence of viscosity for registration of changes in conformational state of Escherichia coli cell genome]. / Primenenie metoda anomal'noi vremennoi zavisimosti viazkosti dlia registratsii izmenenii v konformatsionnom sostoianii genoma kletok Escherichia coli.

The sensitivity of the anomalous time dependence of viscosity to the concentration of the DNA-protein complexes (DNA + histone-like proteins of bacteria or, in other words, the genome) such as chromatin and the conformations of these complexes in lysates of E. coli AB1157 cells were studied. A linear region of the anomalous viscosity time dependence on the concentration of E. coli cells was found in which the interactions between single DNA-protein complexes can be neglected. The response of the genome of E. coli to ethidium bromide at concentrations of 0.0003-3 mg/ml was studied. Significant differences in the effect of ethidium bromide on E. coli cells in the stationary and logarithmic growth phases were found. The effect of heating cell lysates, the molar concentration of NaCl in lysates, and the addition of proteins into lysates on the parameters of the anomalous viscosity time dependence was studied. It was shown that proteins do not contribute significantly to the effect of anomalous viscosity time dependence. The results obtained confirm that the method is sensitive to changes in the conformational state of the genome of E. coli cells.