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.     

Comprehensive bioelectrographic analysis of mechanisms of the alternative state of consciousness

Using complimentary capacities of modern computer technologies, such as digital electroencephalography and recording of current parameters of meridional biologically active points and evoked energy emission processes, the authors studied the bioelectrographic correlates of an alternative state of consciousness. The phenomenon of phasic activation of energy emission processes during the accomplishment of mental activity in an alternative state of consciousness was revealed for the first time. The data obtained are analyzed from the viewpoint of the specific features of neurophysiological and psychophysical mechanisms of the formation of alternative states of consciousness in conditions of systematic mental training.     

On the existence and the role of chaotic processes in the nervous system

Chaos theory is a rapidly growing field. As a technical term, “chaos” refers to deterministic but unpredictable processes being sensitively dependent upon initial conditions. Neurobiological models and experimental results are very complicated and some research groups have tried to pursue the “neuronal chaos”. Babloyantz's group has studied the fractal dimension (d) of electroencephalograms (EEG) in various physiological and pathological states. From deep sleep (d=4) to full awakening (d>8), a hierarchy of “strange” attractors paralles the hierarchy of states of consciousness. In epilepsy (petit mal), despite the turbulent aspect of a seizure, the attractor dimension was near to 2. In Creutzfeld-Jacob disease, the regular EEG activity corresponded to an attractor dimension less than the one measured in deep sleep. Is it healthy to be chaotic? An “active desynchronisation” could be favourable to a physiological system. Rapp's group reported variations of fractal dimension according to particular tasks. During a mental arithmetic task, this dimension increased. In another task, a P300 fractal index decreased when a target was identified. It is clear that the EEG is not representing noise. Its underlying dynamics depends on only a few degrees of freedom despite yet it is difficult to compute accurately the relevant parameters. What is the cognitive role of such a chaotic dynamics? Freeman has studied the olfactory bulb in rabbits and rats for 15 years. Multi-electrode recordings of a few mm² showed a chaotic hierarchy from deep anaesthesia to alert state. When an animal identified a previously learned odour, the fractal dimension of the dynamics dropped off (near limit cycles). The chaotic activity corresponding to an alert-and-waiting state seems to be a field of all possibilities and a focused activity corresponds to a reduction of the attractor in state space. For a couple of years, Freeman has developed a model of the olfactory bulb-cortex system. The behaviour of the simple model “without learning” was quite similar to the real behaviour and a model “with learning” is developed. Recently, more and more authors insisted on the importance of the dynamic aspect of nervous functioning in cognitive modelling. Most of the models in the neural-network field are designed to converge to a stable state (fixed point) because such behaviour is easy to understand and to control. However, some theoretical studies in physics try to understand how a chaotic behaviour can emerge from neural networks. Sompolinsky's group showed that a sharp transition from a stable state to a chaotic state occurred in totally interconnected networks depending on the value of one control parameter. Learning in such systems is an open field. In conclusion, chaos does exist in neurophysiological processes. It is neither a kind of noise nor a pathological sign. Its main role could be to provide diversity and flexibility to physiological processes. Could “strange” attractors in nervous system embody mental forms? This is a difficult but fascinating question.     

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.     

Neurophysiological Markers of Abnormal Development in Children with Mental Disorders

Longitudinal analysis of the spectral power of the main EEG bands was performed in the wakeful state with the eyes open and the eyes closed in children with mental disorders at various stages of correction by transcranial direct current stimulation (tDCS). A significant increase in the power of α-rhythm in the parietal-occipital areas and a significant decrease in the slow wave activity in the left frontotemporal areas were observed in the course of the correction process. The data obtained can be considered as the neurophysiological markers of the tDCS effects (formation of age-related EEG parameters in children with mental disorders). The data also prove the relations between the described phenomena and the cortical mechanisms of speech disorders and other psychic processes caused by perinatal CNS disorders.     

Pre-activated blood platelets and a pro-thrombotic phenotype in APP23 mice modeling Alzheimer's disease

Platelet activation and thrombus formation play a critical role in primary hemostasis but also represent a pathophysiological mechanism leading to acute thrombotic vascular occlusions. Besides, platelets modulate cellular processes including inflammation, angiogenesis and neurodegeneration. On the other hand, platelet activation and thrombus formation are altered in different diseases leading to either bleeding complications or pathological thrombus formation. For many years platelets have been considered to play a role in neuroinflammatory diseases such as Alzheimer's disease (AD). AD is characterized by deposits of amyloid-β (Aβ) and strongly related to vascular diseases with platelets playing a critical role in the progression of AD because exposure of platelets to Aβ induces platelet activation, platelet Aβ release, and enhanced platelet adhesion to collagen in vitro and at the injured carotid artery in vivo. However, the molecular mechanisms and the relation between vascular pathology and amyloid-β plaque formation in the pathogenesis of AD are not fully understood. Compelling evidence is suggestive for altered platelet activity in AD patients. Thus we analyzed platelet activation and thrombus formation in aged AD transgenic mice (APP23) known to develop amyloid-β deposits in the brain parenchyma and cerebral vessels. As a result, platelets are in a pre-activated state in blood of APP23 mice and showed strongly enhanced integrin activation, degranulation and spreading kinetics on fibrinogen surfaces upon stimulation. This enhanced platelet signaling translated into almost unlimited thrombus formation on collagen under flow conditions in vitro and accelerated vessel occlusion in vivo suggesting that these mice are at high risk of arterial thrombosis leading to cerebrovascular and unexpectedly to cardiovascular complications that might be also relevant in AD patients.     

Modeling cell-in-cell structure into its biological significance

Although cell-in-cell structure was noted 100 years ago, the molecular mechanisms of ‘entering'' and the destination of cell-in-cell remain largely unclear. It takes place among the same type of cells (homotypic cell-in-cell) or different types of cells (heterotypic cell-in-cell). Cell-in-cell formation affects both effector cells and their host cells in multiple aspects, while cell-in-cell death is under more intensive investigation. Given that cell-in-cell has an important role in maintaining homeostasis, aberrant cell-in-cell process contributes to the etiopathology in humans. Indeed, cell-in-cell is observed in many pathological processes of human diseases. In this review, we intend to discuss the biological models of cell-in-cell structures under physiological and pathological status.     

The Route to an Integrative Associative Memory Is Influenced by Emotion

Though the hippocampus typically has been implicated in processes related to associative binding, special types of associations – such as those created by integrative mental imagery – may be supported by processes implemented in other medial temporal-lobe or sensory processing regions. Here, we investigated what neural mechanisms underlie the formation and subsequent retrieval of integrated mental images, and whether those mechanisms differ based on the emotionality of the integration (i.e., whether it contains an emotional item or not). Participants viewed pairs of words while undergoing a functional MRI scan. They were instructed to imagine the two items separately from one another (“non-integrative” study) or as a single, integrated mental image (“integrative” study). They provided ratings of how successful they were at generating vivid images that fit the instructions. They were then given a surprise associative recognition test, also while undergoing an fMRI scan. The cuneus showed parametric correspondence to increasing imagery success selectively during encoding and retrieval of emotional integrations, while the parahippocampal gyri and prefrontal cortices showed parametric correspondence during the encoding and retrieval of non-emotional integrations. Connectivity analysis revealed that selectively during negative integration, left amygdala activity was negatively correlated with frontal and hippocampal activity. These data indicate that individuals utilize two different neural routes for forming and retrieving integrations depending on their emotional content, and they suggest a potentially disruptive role for the amygdala on frontal and medial-temporal regions during negative integration.     

The 90th Anniversary of B.V. Zeigarnik (1900-1988)

9 November 1990 marked the 90th anniversary of Bliuma Vol'fovna Zeigarnik, Doctor of Psychology, professor at Moscow University, outstanding Soviet psychologist who enjoyed wide recognition abroad, an author of basic works on clinical psychology, and a researcher who in 1927 discovered a phenomenon (the "Zeigarnik effect") on which, even today, comprehensive books are written and international symposia are held.     

The Effect of Chemical Chaperones on the Assembly and Stability of HIV-1 Capsid Protein

Chemical chaperones are small organic molecules which accumulate in a broad range of organisms in various tissues under different stress conditions and assist in the maintenance of a correct proteostasis under denaturating environments. The effect of chemical chaperones on protein folding and aggregation has been extensively studied and is generally considered to be mediated through non-specific interactions. However, the precise mechanism of action remains elusive. Protein self-assembly is a key event in both native and pathological states, ranging from microtubules and actin filaments formation to toxic amyloids appearance in degenerative disorders, such as Alzheimer''s and Parkinson''s diseases. Another pathological event, in which protein assembly cascade is a fundamental process, is the formation of virus particles. In the late stage of the virus life cycle, capsid proteins self-assemble into highly-ordered cores, which encapsulate the viral genome, consequently protect genome integrity and mediate infectivity. In this study, we examined the effect of different groups of chemical chaperones on viral capsid assembly in vitro, focusing on HIV-1 capsid protein as a system model. We found that while polyols and sugars markedly inhibited capsid assembly, methylamines dramatically enhanced the assembly rate. Moreover, chemical chaperones that inhibited capsid core formation, also stabilized capsid structure under thermal denaturation. Correspondingly, trimethylamine N-oxide, which facilitated formation of high-order assemblies, clearly destabilized capsid structure under similar conditions. In contrast to the prevailing hypothesis suggesting that chemical chaperones affect proteins through preferential exclusion, the observed dual effects imply that different chaperones modify capsid assembly and stability through different mechanisms. Furthermore, our results indicate a correlation between the folding state of capsid to its tendency to assemble into highly-ordered structures.     

EEG Effects of Therapeutic Electric Stimulation of the Human Brain in the Posttraumatic Unconscious State

The effects of therapeutic SCS and transcranial electric stimulation on the functional activity of the brain in seven patients in the posttraumatic unconscious state were compared. The therapeutic transcranial stimulation was shown to exert a positive effect on the EEG and the characteristics of its spatial–temporal organization in most cases, which corresponds with positive shifts in the mental and motor sphere. The phasic character of changes in the bioelectric activity reflecting the sequence of involvement of the cerebral structures (primary activation of the deep frontal lobe divisions, activation of the subcortical-diencephalic structures, activation of the cortex) in the developing adaptive reactions, which helps understand their neurophysiological mechanisms, was described. It was established that the formation of the foci of persistent pathological activity with dominant characteristics in the brain is one of the possible complications of both SCS and transcranial electric stimulation. The mechanisms of their neurogenesis and the electrographic equivalents require further study. The data may serve as the basis for further clinical study of the influence of transcranial electric stimulation on the recovery of patients in postcomatose unconscious states.     

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.     

Differential expression of heme oxygenase isoforms in rat brain by endotoxin (LPS)

Heme oxygenase‐1 (HO‐1) is a stress protein expressed in various pathological conditions associated with oxidative stress. Brain HO‐1 expression and activity in response to LPS treatment showed regional variability with the highest levels in the substantia nigra (SN) and hippocampus. HO‐1 induction by LPS was redox‐sensitive and associated with increased levels of NO synthase and arginase, two proteins involved in the regulation of cellular redox state. Brain HO‐2 and HO‐3 expression, studied by quantitative RT‐PCR, did not show significant changes. Our data suggest an interaction between NO and the HO system in the brain after LPS treatment. As SN and hippocampus are involved in Parkinson's and Alzheimer's diseases, understanding interaction of these proteins in the brain will help to elucidate the mechanisms involved in neurodegeneration.     

A Functional Genome-Wide In Vivo Screen Identifies New Regulators of Signalling Pathways during Early Xenopus Embryogenesis

Embryonic development requires exquisite regulation of several essential processes, such as patterning of tissues and organs, cell fate decisions, and morphogenesis. Intriguingly, these diverse processes are controlled by only a handful of signalling pathways, and mis-regulation in one or more of these pathways may result in a variety of congenital defects and diseases. Consequently, investigating how these signalling pathways are regulated at the molecular level is essential to understanding the mechanisms underlying vertebrate embryogenesis, as well as developing treatments for human diseases. Here, we designed and performed a large-scale gain-of-function screen in Xenopus embryos aimed at identifying new regulators of MAPK/Erk, PI3K/Akt, BMP, and TGF-β/Nodal signalling pathways. Our gain-of-function screen is based on the identification of gene products that alter the phosphorylation state of key signalling molecules, which report the activation state of the pathways. In total, we have identified 20 new molecules that regulate the activity of one or more signalling pathways during early Xenopus development. This is the first time that such a functional screen has been performed, and the findings pave the way toward a more comprehensive understanding of the molecular mechanisms regulating the activity of important signalling pathways under normal and pathological conditions.     

A speculative model of affective illness cyclicity based on patterns of drug tolerance observed in amygdala-kindled seizures

In this article, we discuss molecular mechanisms involved in the evolution of amygdala kindling and the episodic loss of response to pharmacological treatments during tolerance development. These phenomena allow us to consider how similar principles (in different neurochemical systems) could account for illness progression, cyclicity, and drug tolerance in affective disorders. We describe the phenomenon of amygdala-kindled seizures episodically breaking through effective daily pharmacotherapy with carbamazepine and valproate, suggesting that these observations could reflect the balance of pathological vs compensatory illness-induced changes in gene expression. Under certain circumstances, amygdala-kindled animals that were initially drug responsive can develop highly individualized patterns of seizure breakthroughs progressing toward a complete loss of drug efficacy. This initial drug efficacy may reflect the combination of drug-related exogenous neurochemical mechanisms and illness-induced endogenous compensatory mechanisms. However, we postulate that when seizures are inhibited, the endogenous illness-induced adaptations dissipate (the “time-off seizure” effect), leading to the re-emergence of seizures, a re-induction of a new, but diminished, set of endogenous compensatory mechanisms, and a temporary period of renewed drug efficacy. As this pattern repeats, an intermittent or cyclic response to the anticonvulsant treatment emerges, leading toward complete drug tolerance. We also postulate that the cyclic pattern accelerates over time because of both the failure of robust illness-induced endogenous adaptations to emerge and the progression in pathophysiological mechanisms (mediated by long-lasting changes in gene expression and their downstream consequences) as a result of repeated occurrences of seizures. In this seizure model, this pattern can be inhibited and drug responsivity can be temporarily reinstated by several manipulations, including lowering illness drive (decreasing the stimulation current.), increasing drug dosage, switching to a new drug that does not show crosstolerance to the original medication, or temporarily discontinuing treatment, allowing the illness to re-emerge in an unmedicated animal. Each of these variables is discussed in relation to the potential relevance to the emergence, progression, and suppression of individual patterns of episodic cyclicity in the recurrent affective disorders. A variety of clinical studies are outlined that specifically test the hypotheses derived from this formulation. Data from animal studies suggest that illness cyclicity can develop from the relative ratio between primary pathological processes and secondary endogenous adaptations (assisted by exogenous medications). If this proposition is verified, it further suggests that illness cyclicity is inherent to the neurobiological processes of episode emergence and amelioration, and one does not need to postulate a separate defect in the biological clock. The formulation predicts that early and aggressive long-term interventions may be optimal in order to prevent illness emergence and progression and its associated accumulating neurobiological, vulnerability factors.     

Purification,characterization and partial sequence of a pro‐inflammatory lectin from seeds of Canavalia oxyphylla Standl. & L. O. Williams

Recent studies have shown that lectins are promising tools for use in various biotechnological processes, as well as studies of various pathological mechanisms, isolation, and characterization of glycoconjugates and understanding the mechanisms underlying pathological mechanisms conditions, including the inflammatory response. This study aimed to purify, characterize physicochemically, and predict the biological activity of Canavalia oxyphylla lectin (CoxyL) in vitro and in vivo. CoxyL was purified by a single‐step affinity chromatography in Sephadex® G‐50 column. Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that the pure lectin consists of a major band of 30 kDa (α‐chain) and two minor components (β‐chain and γ‐chain) of 16 and 13 kDa, respectively. These data were further confirmed by electrospray ionization mass spectrometry, suggesting that CoxyL is a typical ConA‐like lectin. In comparison with the average molecular mass of α‐chain, the partial amino acid sequence obtained corresponds to approximately 45% of the total CoxyL sequence. CoxyL presented hemagglutinating activity that was specifically inhibited by monosaccharides (D‐glucose, D‐mannose, and α‐methyl‐D‐mannoside) and glycoproteins (ovalbumin and fetuin). Moreover, CoxyL was shown to be thermostable, exhibiting full hemagglutinating activity up to 60°C, and it was pH‐sensitive for 1 h, exhibiting maximal activity at pH 7.0. CoxyL caused toxicity to Artemia nauplii and induced paw edema in rats. This biological activity highlights the importance of lectins as important tools to better understand the mechanisms underlying inflammatory responses. Copyright © 2014 John Wiley & Sons, Ltd.     

Protein tyrosine kinases: autoregulation and small-molecule inhibition

Receptor and non-receptor protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. The kinase activity of PTKs is tightly controlled through steric, autoregulatory mechanisms, as well as by the action of protein tyrosine phosphatases. Recent structural studies have revealed several modes of autoregulation governing the catalytic state of these enzymes. Aberrant catalytic activity of many PTKs, via mutation or overexpression, plays an important role in numerous pathological conditions, including cancer. Structural studies of the Abl tyrosine kinase domain in complex with the small-molecule inhibitor STI571 provide a molecular basis for understanding the specificity determinants of this highly successful drug used in the treatment of chronic myeloid leukemia.     

Use of principles of prenosological diagnosis for assessing the functional state of the body under stress conditions as exemplified by bus drivers

The functional state of the body was assessed in healthy subjects performing their daily work under stress conditions. The study sample comprised bus drivers aged 25–65 years. A prenosological approach was used to assess the borderline between the physiologically normal state and pathological conditions. At the first stage of the study (prenosological screening), the subjects were divided into four groups with different adaptive capacities of the body. At the second stage of the study, a detailed prenosological examination was performed to determine the causes and mechanisms of evolution of prenosological conditions into premorbid conditions and further into adaptation failure, resulting in diseases. It was found that the bus drivers experienced chronic occupational stress leading to the overtension and exhaustion of regulatory mechanisms and to the rapid development of cardiovascular pathology. Long-term mental and psychoemotional tension in drivers associated with occupational stress leads to the activation of suprasegmental structures involved in the control of physiological functions; to a decrease in the functional reserves; and, consequently, to the worsening of the psychophysiological and cardiorespiratory function of the body. As a result of the study, a group of bus drivers with an increased risk of diseases, including cardiovascular, was determined and recommendations on workforce health protection were developed for the managers of the motor transport enterprise.     

Psychological Research on the Pathology of Activity and Its Significance for the Psychology of Personality

In his book Being and consciousness [Bytiye i soznaniye] S. L. Rubinshteyn explained that "an external influence has a particular mental effect only by being refracted through the subject's mental state, through a system of thoughts and feelings formed within him" (45, p. 226). To apply this to particular research on pathology it is necessary to pass from studying disorders of specific functions to studying changes in various forms of the patient's activity, in whose structure are included changes in personality sets and motives.     

Source monitoring and memory distortion.

Memory distortion reflects failures to identify the sources of mental experience (reality monitoring failures or source misattributions). For example, people sometimes confuse what they inferred or imagined and what actually happened, what they saw and what was suggested to them, one person''s actions and another''s what they heard and what they previously knew, and fiction and fact. Source confusions arise because activated information is incomplete or ambiguous and the evaluative processes responsible for attributing information to sources are imperfect. Both accurate and inaccurate source attributions result from heuristic processes and more reflectively complex processes that evaluate a mental experience for various qualities such as amount and type of perceptual, contextual, affective, semantic and cognitive detail, that retrieve additional supporting or disconfirming evidence, and that evaluate plausibility and consistency given general knowledge, schemes, biases and goals. Experimental and clinical evidence regarding cognitive mechanisms and underlying brain structures of source monitoring are discussed.