Genetic determination of the neurophysiological mechanisms of the cortico-subcortical integration of bioelectrical activity of the brain

Contribution of genetical factors to neurophysiological mechanisms of cortico-subcortical integration was investigated in 12 pairs of the monozygotic and 5 pairs of dizygotic twins (aged from 18 to 25). In each pair of twins as well as in all 544 unrelated pairs of subjects from both groups, interpairs similarity of the character of the spatial interaction of bioelectrical activity of the neocortex for different combinations of statistical correlations of EEG (from 16 monopolar electrodes) was estimated. The data obtained allow to suggest a higher common population invariance and a relatively small hereditary and phenotypic variability of morphofunctional systems, which underlie neurophysiological mechanisms of the brain integration in general. Apparently, the formation of the brain stem and subcortical regulatory structures in the ontogenesis, the structures that play the main role in the realization of system combination of different parts of the brain into united formation, occurs to all individuals according to a single principle since its disturbance can probably affect the fundamental monomorphal features of the species. In turn, one can expect a great interindividual variability of establishing of the intraregional connections of neocortex, the role of genetic and environmental factors in the formation of short and relatively long interactions being complex.     

Role of genetic factors in the formation of trace reactions in man

Trace processes due to presentation of visual nonverbal information, and the dynamics of the bioelectrical parameter (mean level of asymmetry of EEG-waves) were studies in 32 pairs of monozygote and 38 pairs of dizygote twins with twins method. Statistical processing of the data revealed a significant effect of genetic factors on the formation of individual variability of the characteristics of trace processes in humans. The results obtained showed that with increased functional load the intrapair similarity of trace reactions increased in monozygote twins and did not change or decrease in dizygote twins and in unrelated pairs. This fact is interpreted at a dependence of appearance of geneticly determined neurophysiological characteristics on the level of functional activity of the nervous system.     

Functional maturation of the brain and formation of the neurophysiological mechanisms of selective voluntary attention in young schoolchildren

A particular role was demonstrated for functional maturation of the frontothalamic system (FTS) of the brain in forming the cerebral organization of selective voluntary attention in ontogeny. Analysis of the coherence of the rhythmic components of the EEG α range in adults and seven-to eight-and nine-to ten-year-old children showed that, if the functional state of the control structures corresponds to the age, the formation of the neurophysiological mechanisms selectively modulating cortical activity and supporting selective tuning of the cerebral structures to the cognitive task is completed by the age of seven or eight years. Unlike adults, children demonstrated no interhemispheric features of the intercenter integration of cortical zones in the prestimulus period of voluntary attention. Children with a functionally immature FTS lacked selective specific integration of cortical zones in the pretuning period. The deficit of selective modulation of cortical activity in children with a functionally immature FTS is considered as the neurophysiological factor that delays the formation of voluntary attention and voluntary control of activity and, finally, leads to learning difficulties.     

Continuity and prospects of development of researches in area system-integrativity of psychophysiology of functional state and cognitive activity

In the review one of actual problems of psychophysiology in studying a phenomenon of integration of mechanisms of regulation of state of a brain and features of the organization is discussed by a brain of cognitive activity. Basic value of results of long-term researches of academician N.P. Bechterevoj and of her school is opened in the field of neurophysiology of functional states as bases of the organization of mental activity in conditions of direct, long and sparing contact to a cortical and subcortical structures of a brain, with the help long-term intracerebral electrodes. Arguments about a commensurability and complementary value similar on amplitud-time parameters slow and superslow gradual changes of neurophysiological processes registered simultaneously in identified zones of subcortical structures of a brain and with removal from a surface of a head in cortical projections of basic integrativity of the centres are submitted. Representations about a brain as difficultly organized "swimming" many-contour, neurodinamic informational-controlling suprasystem with hierarchically, probability a principle of the organization different on speeds and intensity of processes of the ability to live participating in maintenance of a condition of rest, mental conditions and cognitive activity are formulated and argued. At the limited set universal neurodinamic "languages", the brain has the multiregister mechanism of regulation of conditions and selectivity of mechanisms of the integration providing the contribution differing on information maintenance gradual neurophysiological of processes of different levels of the structurally functional organization in formation of brain systems of maintenance of concrete kinds of cognitive activity.     

Relation of the individual specificity of emotional autoregulation controlled by EEG feedback to the influence of a genetic factor as revealed by a twin study

On the model of biofeedback connection by the given parameters of the EEG alpha-rhythm the dynamics of bioelectrical and vegetative characteristics and correlative connections between them were compared in the pairs of mono- and dizygotic twins. More likeness in the dynamics of the studied parameters was found in the pairs of genetically identical monozygotic twins. There was a maximum increase of the objective similarity characteristics in the moment of activity realization, judging by the change of alpha-rhythm parameters. The obtained results testify to genetic determination of individual specific styles in organization of complex integrative processes of the higher nervous activity.     

Continuity and prospects of research in systemic integrative psychophysiology of functional states and cognitive activity

An important problem of psychophysiology related to the study of the integration of the mechanisms controlling the state of the brain and characteristics of the cerebral organization of cognitive activity is discussed. The fundamental role of the results of long-term research in the neurophysiology of functional states as the basis of the organization of mental activity under conditions of direct, long-term, sparing contact with the cortex and subcortical structures by means of long-term intracerebral electrodes carried out by Academician Bechtereva and her scientific school is demonstrated. The commensurability and complementarity of slow and ultraslow gradual neurophysiological processes with similar amplitude-time parameters recorded in intravitally identified zones of deep cerebral structures and from scalp sites corresponding to the cortical projections of the main integrative centers are substantiated. The notion of the brain as a complexly organized, “floating,” multicircuit neurodynamic suprasystem with hierarchically, probabilistically organized vital processes varying in rate and intensity that are involved in maintaining the state of rest, mental states, and cognitive activity are formulated and substantiated. While the set of universal neurodynamic languages is limited, the brain employs a multiregister mechanism controlling the state and selective mechanisms of integration, ensuring the contribution of gradual neurophysiological processes at different levels of the structural and functional organization that vary in terms of information content in the formation of the cerebral systems underlying specific cognitive activities.     

fMRI Resting Slow Fluctuations Correlate with the Activity of Fast Cortico-Cortical Physiological Connections

Recording of slow spontaneous fluctuations at rest using functional magnetic resonance imaging (fMRI) allows distinct long-range cortical networks to be identified. The neuronal basis of connectivity as assessed by resting-state fMRI still needs to be fully clarified, considering that these signals are an indirect measure of neuronal activity, reflecting slow local variations in de-oxyhaemoglobin concentration. Here, we combined fMRI with multifocal transcranial magnetic stimulation (TMS), a technique that allows the investigation of the causal neurophysiological interactions occurring in specific cortico-cortical connections. We investigated whether the physiological properties of parieto-frontal circuits mapped with short-latency multifocal TMS at rest may have some relationship with the resting-state fMRI measures of specific resting-state functional networks (RSNs). Results showed that the activity of fast cortico-cortical physiological interactions occurring in the millisecond range correlated selectively with the coupling of fMRI slow oscillations within the same cortical areas that form part of the dorsal attention network, i.e., the attention system believed to be involved in reorientation of attention. We conclude that resting-state fMRI ongoing slow fluctuations likely reflect the interaction of underlying physiological cortico-cortical connections.     

Structural and functional organization of a developing brain and formation of cognitive functions in child ontogeny

Results of multidisciplinary studies, including neuromorphological, neurophysiological, neuropsychological, and psychphysiological studies, are reviewed. They allow the brain mechanisms of cognition formation and development during maturation to be identified. The role of regulatory (modulatory) brain systems in forming the cognitive function in the child is demonstrated. Data on considerable changes in the brain systems responsible for the development of cognitive functions in children between the ages of five to six and seven to eight years are presented. At this age, the morphological and functional maturations of the frontal cortical areas and their descending connections with other cerebral structures increase the efficiencies of arbitrary selective attention, learning the activity program, inhibition of spontaneous responses, and regulation and organization of activity, i.e., the functions that are important for successful schooling.     

Organization of Regional Interactions of the Brain Cortical Activity during the Common-root Word Derivation Task

This study analyzed specificities in the activity of the neurophysiological mechanisms underlying the organization of active word-derivation processes. The regularities in the reorganization of the spatial structure for the systemic interaction of bioelectrical activity between different cortical areas of the cerebral hemispheres were studied in adult subjects during the test for mental derivation of common root words (i.е., using the modern methods of the so-called “functional connectome” investigations). Сross-correlation and coherent analysis of EEG has shown that the ipsilateral statistical EEG interactions in the left hemisphere, including Broca’s and Wernicke’s areas, were significantly increased in adults during mental derivation of common root words and, simultaneously, the interhemispheric connectivity and the EEG interactions in the right hemisphere were reduced. Comparison of our results with the previous data of verbal activity associated with speech perception and production has revealed significant differences in the degree of involvement of the left and right hemisphere cortical activity in verbal processing. For example, unlike the data of current study, an equal involvement of both hemispheres cortical activity was recorded during the phoneme recognition in auditory perceived words, grammatical and semantic errors in sentences, as well as during mental formation of words from a set of phonemes and sentences from a set of words, which was particularly manifested in the increased of hemispheric interactions, predominantly, in the inferior frontal and temporal areas and the overlapped areas of the temporal, parietal, and occipital cortical zones (TPO) of both hemispheres. Thus, the data obtained in this study indicate the presence of expressed specificities in the lateralization of activity in the neurophysiological mechanisms underlying the processes of active word derivation and inflexion.     

Emergence of Metastable State Dynamics in Interconnected Cortical Networks with Propagation Delays

The importance of the large number of thin-diameter and unmyelinated axons that connect different cortical areas is unknown. The pronounced propagation delays in these axons may prevent synchronization of cortical networks and therefore hinder efficient information integration and processing. Yet, such global information integration across cortical areas is vital for higher cognitive function. We hypothesized that delays in communication between cortical areas can disrupt synchronization and therefore enhance the set of activity trajectories and computations interconnected networks can perform. To evaluate this hypothesis, we studied the effect of long-range cortical projections with propagation delays in interconnected large-scale cortical networks that exhibited spontaneous rhythmic activity. Long-range connections with delays caused the emergence of metastable, spatio-temporally distinct activity states between which the networks spontaneously transitioned. Interestingly, the observed activity patterns correspond to macroscopic network dynamics such as globally synchronized activity, propagating wave fronts, and spiral waves that have been previously observed in neurophysiological recordings from humans and animal models. Transient perturbations with simulated transcranial alternating current stimulation (tACS) confirmed the multistability of the interconnected networks by switching the networks between these metastable states. Our model thus proposes that slower long-range connections enrich the landscape of activity states and represent a parsimonious mechanism for the emergence of multistability in cortical networks. These results further provide a mechanistic link between the known deficits in connectivity and cortical state dynamics in neuropsychiatric illnesses such as schizophrenia and autism, as well as suggest non-invasive brain stimulation as an effective treatment for these illnesses.     

Development of examination stress in subjects with various levels of cortical activation

The work is aimed at the study of neurophysiological mechanisms of examination stress in subjects with different levels of cortical activation. Spectral power and typical cortical connections of EEG rhythms were studied in students under conditions of stress before and immediately after examination as well as during usual academic semester. Students with relatively higher and relatively lower baseline alpha rhythm, i.e., with different levels of cortical activation revealed both similar and different EEG reactions. Before examination, in both groups of subjects the spectral power of EEG activity in the delta and thetal bands increased, and the number of connections in the bands of the alpha and beta 1 rhythms decreased as compared to usual baseline conditions. However, the EEG reactions in the theta 2 band in the two groups were oppositely directed. Significant changes in the beta 2 power were observed only in the group of subjects with higher baseline level of cortical activation.     

Features of the Brain Functional Organization in Right- and Left-Handed 6- to 7-Year-Old Children during Visuospatial Performance of Different Complexity: II. Analysis of EEG Parameters during Complex Visuospatial Performance

The features of brain functional organization during complex visuospatial performance were studied in 6- to 7-year-old right- and left-handed children. Differences in the brain functional organization were revealed between children with different profiles of manual asymmetry. Presentation of complex experimental tasks to right-handed children resulted in the formation of selective functional connections between centers, which is indicative of the use of economical and efficient mechanisms of the organization of activity. Generalized functional integration was observed in left-handed children, which reflected an immature type of regulation of cortical activity.     

Effect of disulfiram on the interconnected activity of cortical neurons in trained cats

The action of disulfiram on interconnected activity of neurones in the visual and motor cortical areas was studied in cats with food-procuring conditioned responses to light. Multiunit activity was recorded from the areas and, by means of amplitude discrimination, separated into impulse flows. Crosscorrelation analysis of the impulse series was used to reveal the character and temporal parameters of interconnected activities of neurones firing in correlation within the limits both of the same cortical area and of the two different ones. A depressing action was shown of the disulfiram on the food-procuring reaction, accompanied by a decrease of the number of pairs of neurones from the visual and motor cortical areas mostly acting in interconnection, interactions with long time delays being mostly affected. The character of action of neighbouring neurones in the visual and motor cortical areas changed in the same direction, expressed in their firing by a "common source" type. The question is discussed of disulfiram influence on interneuronal connections of both types suggesting a decrease of alimentary motivation as well as disturbance of food-procuring conditioned motor coordination.     

Physiological and pathological oscillatory networks in the human motor system.

Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.     

Causes of blood methylomic variation for middle-aged women measured by the HumanMethylation450 array

To address the limitations in current classic twin/family research on the genetic and/or environmental causes of human methylomic variation, we measured blood DNA methylation for 479 women (mean age 56 years) including 66 monozygotic (MZ), 66 dizygotic (DZ) twin pairs and 215 sisters of twins, and 11 random technical duplicates using the HumanMethylation450 array. For each methylation site, we estimated the correlation for pairs of duplicates, MZ twins, DZ twins, and siblings, fitted variance component models by assuming the variation is explained by genetic factors, by shared and individual environmental factors, and by independent measurement error, and assessed the best fitting model. We found that the average (standard deviation) correlations for duplicate, MZ, DZ, and sibling pairs were 0.10 (0.35), 0.07 (0.21), -0.01 (0.14) and -0.04 (0.07). At the genome-wide significance level of 10^?7, 93.3% of sites had no familial correlation, and 5.6%, 0.1%, and 0.2% of sites were correlated for MZ, DZ, and sibling pairs. For 86.4%, 6.9%, and 7.1% of sites, the best fitting model included measurement error only, a genetic component, and at least one environmental component. For the 13.6% of sites influenced by genetic and/or environmental factors, the average proportion of variance explained by environmental factors was greater than that explained by genetic factors (0.41 vs. 0.37, P value <10^?15). Our results are consistent with, for middle-aged woman, blood methylomic variation measured by the HumanMethylation450 array being largely explained by measurement error, and more influenced by environmental factors than by genetic factors.     

Correspondence between spectral power and synchronization of the brain rhythms in the norm and cognitive pathology

The work is aimed at the study of correlations between the measures of spectral power and cortical interactions of EEG rhythms in healthy subjects and schizophrenic patients ("acute" and chronic cases). All brain rhythms in healthy subjects appeared to be symmetrical and synchronous both in phase and frequency. In "acute" schizophrenics, opposite to healthy subjects, the distribution of cortical activity is asymmetrical, and in the chronic cases, the spectral power of most cortical rhythms is decreased as compared to healthy subjects. In the "acute" patients, interhemispheric connections are absent in all rhythms but alpha. In the chronic patients, the number of cortical connections is slightly higher than in the acute patients; and they are located in the posterior areas in the gamma rhythm. These neurophysiological aberrations evidently underlie the multiple mental activity disorders in schizophrenic patients. Thus, the correspondence between the brain rhythms and their synchronization is a necessary condition for normal perception, emotions and cognition evidently influencing behavior and consciousness.     

Genetic and Environmental Regulation on Longitudinal Change of Metabolic Phenotypes in Danish and Chinese Adult Twins

Objective

The rate of change in metabolic phenotypes can be highly indicative of metabolic disorders and disorder-related modifications. We analyzed data from longitudinal twin studies on multiple metabolic phenotypes in Danish and Chinese twins representing two populations of distinct ethnic, cultural, social-economic backgrounds and geographical environments.

Materials and Methods

The study covered a relatively large sample of 502 pairs of Danish adult twins followed up for a long period of 12 years with a mean age at intake of 38 years (range: 18–65) and a total of 181 Chinese adult twin pairs traced for about 7 years with a mean baseline age of 39.5 years (range: 23–64). The classical twin models were fitted to the longitudinal change in each phenotype (Δphenotype) to estimate the genetic and environmental contributions to the variation in Δphenotype.

Results

Moderate to high contributions by the unique environment were estimated for all phenotypes in both Danish (from 0.51 for low density lipoprotein cholesterol up to 0.72 for triglycerides) and Chinese (from 0.41 for triglycerides up to 0.73 for diastolic blood pressure) twins; low to moderate genetic components were estimated for long-term change in most of the phenotypes in Danish twins except for triglycerides and hip circumference. Compared with Danish twins, the Chinese twins tended to have higher genetic control over the longitudinal changes in lipids (except high density lipoprotein cholesterol) and glucose, higher unique environmental contribution to blood pressure but no genetic contribution to longitudinal change in body mass traits.

Conclusion

Our results emphasize the major contribution of unique environment to the observed intra-individual variation in all metabolic phenotypes in both samples, and meanwhile reveal differential patterns of genetic and common environmental regulation on changes over time in metabolic phenotypes across the two samples.     

Convergence and divergence are mostly reciprocated properties of the connections in the network of cortical areas

Cognition is based on the integrated functioning of hierarchically organized cortical processing streams in a manner yet to be clarified. Because integration fundamentally depends on convergence and the complementary notion of divergence of the neuronal connections, we analysed integration by measuring the degree of convergence/divergence through the connections in the network of cortical areas. By introducing a new index, we explored the complementary convergent and divergent nature of connectional reciprocity and delineated the backward and forward cortical sub-networks for the first time. Integrative properties of the areas defined by the degree of convergence/divergence through their afferents and efferents exhibited distinctive characteristics at different levels of the cortical hierarchy. Areas previously identified as hubs exhibit information bottleneck properties. Cortical networks largely deviate from random graphs where convergence and divergence are balanced at low reciprocity level. In the cortex, which is dominated by reciprocal connections, balance appears only by further increasing the number of reciprocal connections. The results point to the decisive role of the optimal number and placement of reciprocal connections in large-scale cortical integration. Our findings also facilitate understanding of the functional interactions between the cortical areas and the information flow or its equivalents in highly recurrent natural and artificial networks.     

The Role of Transposons in Epigenetic Regulation of Ontogenesis

A new insight into the mechanisms underlying implementation of genomic information in the individual development of eukaryotes through interactions of transposons with epigenetic factors dynamically changing during each cell division is described. These mechanisms of stepwise implementation of individual genetic information with characteristic stage- and tissue-specific features in the activities of certain mobile genetic element families are evolutionarily fixed at the species level. In addition, the individual differences caused by their “unscheduled” transpositions can significantly change the regulatory network of the genome altering the phenotype. These changes in individual development can bring about new traits leading to either a disease or better fitness and represent an important component of the variation for natural selection in evolution. A large part of the eukaryotic transposons is altered by mutations and used for formation of the regulatory gene network, changes in the protein-coding genes, and emergence of new nonprotein-coding genes. When inserted into new loci, mobile genetic elements form the basis for microRNA and the domain structures of long noncoding RNA, responding to various types of stress; this is reflected in the specific features of individual development and contributes to variation. The epigenetic factors, including noncoding RNA, DNA methylation, and histone modifications, are tightly associated with mobile genetic elements. The specific features in transposon location in individuals that have emerged owing to spontaneous mutations or those caused by stress impacts can considerably change the interactions in gene networks. This influences the likelihood of survival under changing environmental conditions and reflects a distinct interrelation between the mechanisms of individual development and evolution. There is a parallelism between the mechanisms underlying the rearrangements of genomes caused by transposons in evolution and in individual development. In particular, the responsiveness of transposons to external and internal (microenvironment) factors forms the background for evolutionary construction of transposon-mediated tissue-specific activation patterns of certain transposons during each cell division, which leads to maturation of a reproductive organism. This mechanism is based on tight stage- and tissuespecific interrelation between transposons, epigenetic factors, and protein-coding genes.     

Genome-wide prediction of functional gene-gene interactions inferred from patterns of genetic differentiation in mice and men

The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits is to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting GxG interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidate interactions that can be empirically tested. In both the mouse and human data we observed two-locus genetic differentiation in excess of what can be expected from chance alone based on simulations. In an attempt to validate our hypothesis that pairs of genes showing excess genetic divergence represent potential functional interactions, we selected a small set of gene combinations postulated to be interacting based on our analyses and looked for a combined effect of the selected genes on variation in complex traits in both mice and man. In both cases the individual effect of the genes were not significant, instead we observed marginally significant interaction effects. These results show that genome wide searches for gene-gene interactions based on population genetic data are feasible and can generate interesting candidate gene pairs to be further tested for their contribution to phenotypic variation in complex traits.