Vol 12, No 5 (2018)

Original articles

Structural and functional basis of chronic disorders of consciousness

Piradov M.A., Suponeva N.A., Sergeev D.V., Chervyakov A.V., Ryabinkina Y.V., Sinitsyn D.O., Poydasheva A.G., Kremneva E.I., Morozova S.N., Iazeva E.G., Legostaeva L.A.

Abstract

The problem of chronic disorders of consciousness (DOC) remains challenging due to increasing number of these patients and limited therapeutic options. Novel diagnostic approaches provided us with valuable insights into the mechanisms of DOC, such as structural and/or functional disconnection of elements of brain networks that are essential for information processing. Depending on the modality of the study, it may be represented as low-frequency EEG patterns, global or more localized decrease of cortical metabolism on PET scanning, abnormal connectivity structural or functional MRI, or low-differentiated/disintegrated TMSEEG responses. Deeper knowledge of nature of abnormalities underlying chronic DOC may improve accuracy of diagnosis and efficacy of treatment interventions, as well as bring us somewhat closer to the understanding the phenomenon of consciousness.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Neurotransplantation: the time has come?

Illarioshkin S.N.

Abstract

Problems in curing disorders of the brain are caused by several characteristic features of the nervous tissue, such as postmitotic nature of neurons, their limited reparative potential, significant energy dependence, etc. Because of special vulnerability and extremely high specialization, neurons are very sensitive to the action of any pathological factors, while existing possibilities of their trophic and metabolic support are scanty. Therefore, the creation of new reparative strategies, including substitutive cell technologies, is immediate task in neurology. Neurodegenerative disorders, Parkinson’s disease (PD), Huntington’s disease and others, are an “ideal” model for elaborating such strategies. As main motor symptoms of PD are related to degeneration of the dopaminergic nigrostriatal pathway, treatment of these patients, theoretically, may be based on transplantation of dopamine-producing neurons into the striatum. In the paper, analyzed are the results of many-year experimental (on models of parkinsonism) and preliminary clinical trials of neurotransplantation with the use of fetal tissues (dopaminergic cells of the ventral midbrain) and dopaminergic neurons differentiated from embryonal stem cells and induced pluripotent. Newest scientific achievements in this field, improvement of cell protocols and successful resolving of a number of technical and medical problems allow saying that neurotransplantation becomes clinical reality just before our eyes.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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New horizons of non-invasive brain stimulation in clinical medicine

Poydasheva A.G., Bakulin I.S., Suponeva N.A., Troshina E.A., Tanashyan M.M., Dedov I.I., Piradov M.A.

Abstract

Non-invasive brain stimulation belongs to most significant neurotechnologies which have arisen in the XXIth century and are characterized by universal medical importance. This group of methods comprises rhythmic transcranial magnetic stimulation (rTMS) and transcranial electric stimulation (transcranial direct current stimulation, tDCS). A spectrum of conditions for which these methods may be effective is steadily expanding and includes a variety of prevalent disorders of the modern society, such as obesity, depression, etc. The low effectiveness of lifestyle modification, as well as a wide range of pharmacological drugs’ side effects and high risks of surgical treatment determine the need to search for new safe methods of correction of eating behavior and obesity, a real pandemy of our society. A number of data suggest the patogenic role of changes of the frontal-striatal interactions in eating behanior disorders. Taking into account the existing models of the development of food dependence, the main approach to the use of rTMS and tDCS is stimulation of areas involved in cognitive control, such as the dorsolateral prefrontal cortex. Current data on studies of rTMS and tDCS in patients with impairment of eating behavior, as well as safety issues of using these techniques in routine clinical practice are reviewed.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Modern aspects of surgical neuromodulation

Gushcha A.O., Tyurnikov V.M., Kashcheev A.A.

Abstract

The review focuses on modern application of surgical neuromodulation method for different diseases and pathological conditions. The method, initially designed and applied for deep brain stimulation, is now widely used in many fields of clinical medicine, and the effect is exerted not only by electrical stimuli. The main criterion to classify method as a variant of neuromodulation is the presence of implantable device, which allows minimizing the action of electric, magnetic, ultrasound impulses or pharmacological compounds, with a decrease in the incidence of adverse effects and the precision of modulation parameters. International experience of neuromodulation in the treatment of extrapyramidal hyperkinesias, drug-resistant epilepsy and drug-resistant pain syndromes of different origin is analyzed, and that results are compared with the data obtained by the neurosurgical team from Research Center of Neurology. Several unique authors’ inventions allowed improving the precision of electrode positioning for deep brain stimulation (microelectrode registration) and for chronic epidural stimulation in spastic syndromes.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Autonomic support of cognitive functions and functional asymmetry in normal aging and chronic cerebrovascular disorders

Fokin V.F., Ponomareva N.V., Medvedev R.B., Shabalina A.A., Tanashyan M.M., Lagoda O.V.

Abstract

The increase in life expectancy is accompanied by an increase in the number of patients suffering from chronic cerebrovascular diseases with progressive cognitive decline, up to dementia. Therefore, the search for new approaches to studying the disease pathogenesis, prevention and treatment is relevant. We analysed the data on correlation of cognitive characteristics with reactions of the autonomic nervous system (ANS) and ANS-regulated systems in normal aging and in patients with vascular encephalopathy (VE). Reactivity of cerebral blood flow as a result of cortical-ANS interaction was studied, characteristics of cerebral blood flow influencing the interhemispheric energetic processes (studied with direct current potentials of the brain) were analyzed, and correlation of blood pressure and heart rate with cognitive characteristics were assessed. Since the signs of cognitive decline are observed during normal aging and VE, an attempt was made to analyze the dependence of cognitive and ANS functions not only on VE, but also on the age. We showed some specific features of cortical-ANS interaction in groups of patients divided in accordance with small criteria of functional asymmetry. The obtained results are of value for studying VE pathogenesis and for prognosing cognitive impairment in patients with VE.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Influence of genetic factors on neurophysiological mechanisms of neurodegenerative diseases

Ponomareva N.V., Fokin V.F., Rogaev E.I., Illarioshkin S.N.

Abstract

The review summarizes the main results of studies on the influence of genetic factors on neurophysiological changes in neurodegenerative age-related diseases – Alzheimer's (AD), Parkinson's (PD) and Huntington (HD) diseases. In some cases, neurophysiological methods make it possible to detect early changes already at the preclinical stage of neurodegenerative process. Such neurophysiological markers may be considered as endophenotypes and used for the early diagnosis of the diseases. The conducted studies are promising for clarifying which factors underlie the heterogeneity of diseases not only at the genetic level, but also at the neurophysiological level. At the same time, such an approach showed the presence of a number of neurophysiological alterations common to AD, PD, and HD. Disconnection of neural circuits, including interhemispheric disintegration, slowdown of information processes, disinhibition, hyperexcitability and epileptogenesis, as well as alterations in neurovascular coupling, are of great importance for the development of diseases. On the other hand, neurophysiological changes can directly affect the development of the disease, including the genetic level, as evidenced by experimental optogenetic studies, the results of deep brain stimulation and other neuromodulation methods. These data are valuable for a personalized approach to the prevention and treatment of age-dependent neurodegenerative diseases.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Methods of immunohistochemistry and computerized morphometry as promising tools in the study of pathogenic patterns of neurodegenerative processes

Khudoerkov R.M., Salkov V.N., Voronkov D.N.

Abstract

Modern methods of immunohistochemistry and computer morphometry provide powerful possibilities for the study of pathogenetic patterns of neurodegeneration process occurring in physiological aging of men and women, as well as in experimental animals on modeling of Parkinson’s and Huntington's diseases. Threedimensional reconstruction of the substantia nigra pars compacta of the human and rat brains revealed both common features in their organization (heterogeneity of structures) and differences in quantitative morphochemical parameters determining their species-specific characteristics. On modeling of the Huntington's disease with the neurotoxin 3-nitropropionic acid (3-NPA), it was shown not only the death of neurons in the striatum and a decrease in its dopaminergic innervation, but also dysfunction of astrocytes with reduced expression of glutamine synthase that can increase the extracellular content of glutamate. The latter,along with direct succinate dehydrogenase-blocking action of 3-NPA, is one of the factors leading to neurodegenerative changes in the striatum. On modeling of Parkinson's disease, the important role of neuroglia in the neurodegenerative process was shown: it was found that activated astroglia had not only destructive, but also neuroprotective functions, which may serve the basis for the development of respective methods of pharmacological correction directed at regulation of the of glial cell functions.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Current problems of synaptic plasticity

Skrebitsky V.G., Sharonova I.N.

Abstract

The present review focuses on the results of modern studies confirming the last century ideas about the effect of neuron discharge on the effectiveness of its synaptic inputs. This concept is being developed now at the receptor, channel and intracellular levels, which allows to reveal the special role of calcium ions in the activation of a number of cascades leading to transient or long-lasting changes in synaptic transmission. An important role of various physiologically active compounds that affect synaptic plasticity and, through it, the cognitive processes in humans is emphasized, which has not only fundamental, but also applied significance. Cellular and receptor targets of nootropic drugs aimed at the correction of various types of cognitive impairment are specifically considered

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Cellular models of the nervous system diseases

Khaspekov L.G.

Abstract

Cellular models are a very important research tool in modern neurobiology. The presented review of Russian and international literature summarizes the main data of experimental studies, conducted over the past 15 years, aimed at modeling in vitro acute and chronic forms of cerebral pathology in order to reveal the mechanisms of their pathogenesis and to develop approaches to their pharmacological correction. The results of modeling of ischemic neurodestructive processes, epilepsy, Parkinson's disease, Alzheimer's disease and Huntington's disease, obtained using modern cellular research methods, such as cell cultivation in a multielectrode system and technology of induced pluripotent stem cells, are presented. A number of key concepts related to this problem are illustrated with the data obtained by the author and his laboratory. In conclusion, the short-term goals and prospects of in vitro studies of pathogenic mechanisms of neurological diseases and of the search for new neuroprotectors are formulated.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Modeling of age-dependent disorders: relationship between the nervous and endocrine systems

Stavrovskaya A.V., Voronkov D.N., Shestakova E.A., Ol’shansky A.S., Yamshchikova N.G., Gushchina A.S., Illarioshkin S.N.

Abstract

Age-dependent disorders are a challenging problem of modern society. Among the most significant age-dependent disorders are Alzheimer's disease (AD), diabetes, metabolic syndrome, etc.; these conditions may be associated to each other and have, at least in part, an interconnecting character. An experimental model of AD induced by intracerebroventricular administration of streptozocin (STZ) mimics some key characteristics of sporadic AD, altering insulin metabolism. The aim of this work was to study glucose metabolism in rats at different periods after intracerebroventricular injection of STZ. To obtain an AD model, STZ in a 0.9% NaCl solution at a dose of 3 mg/kg in 10 μl was administered bilaterally in the brain lateral ventricles on stereotaxic operations. Two and seven weeks after the administration, the weight of the animals was determined, and the glucose levels in tail vein whole blood after intraperitoneal glucose administration at a dose of 1.5 g/kg was measured. A standard glucose tolerance test was performed, and hyperglycemic and postglycemic ratios were calculated. As a result, an impairment of glucose metabolism in rats 7 weeks after intracerebroventricular application of STZ was detected for the first time. Close connection of Alzheimertype neurodegenerative changes and glucose metabolism revealed on this model allows using it for deeper assessment of relationships between the nervous and endocrine systems, including translational studies of novel therapeutic strategies.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Neurovascular coupling and cerebral perfusion in aging, cerebral microangiopathy and Alzheimer’s diseases

Dobrynina L.A.

Abstract

Integrity of neurovascular unit (NVU) and interaction of its components is the basis for brain function. Exceptional role of NVU for providing metabolism of all cerebral processes substantiates obligate participation in pathophysiology of wide range of neurological disorders. Established similarity of structural changes in NVU at early stages of aging and hypertensive cerebral microangiopathy (CMA) suggests common pathogenic mechanisms of its damage and, in view of reversibility of early changes in neurovascular coupling (NVC), allows considering several forms of CMA as variants of early accelerated vascular wall aging. Understanding small vessel damage as a significant risk factor for Alzheimer’s disease and mixed dementias has encouraged revision of the current concept of the development of cognitive decline. A universal role of early NVC impairments in the development of various dementias has been shown. Further studies should improve our understanding of mechanisms of NVC impairment, role of classical and newly specified risk factors in their development and perspectives for preventive strategies. Apparently, success can be achieved through collaboration of neuroscience researchers, which allows translation of advantages of fundamental studies into clinical practice

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Gender features in neurological disorders

Bogolepova I.N.

Abstract

In recent years, fundamental studies of common factors and specific features of various nosological forms of neurological disorders led clinicians to a new understanding of frequent " female" and "male" diseases. The present paper provides an overview of current opinions about gender specificities of the prevalence and the course of particular neurological diseases in male and female populations, with an accent to many-year studies of this problem conducted by researchers of the Research Center of Neurology. It has been shown that major gender differences are related to cerebrovascular and demyelinating diseases, movement disorders, and some forms of neuro-hereditary disorders. Modern concepts of a new field of neuroscience, gender neuromorphology, are analyzed.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Monoclonal antibodies in neurology: current state and future development

Zakharova M.N.

Abstract

Monoclonal antibodies are one of the most fastly developing areas of specific therapy for cancer, infectious, autoimmune and demyelinating diseases. The main targets of monoclonal antibodies in autoimmune and demyelinating diseases are T and B-lymphocytes, cytokines, complement, and adhesion molecules. In the field of neurodegenerative diseases, the largest number of studies has been carried out in patients with Alzheimer's disease, in which monoclonal antibodies are targeted to brain aggregates of beta-amyloid. This review presents new therapeutic approaches to the use of antibody fragments, with a focus of their new class, nanobodies. A special attention is paid to new anti-CD20 and anti-CD19 monoclonal antibody drugs in multiple sclerosis (ocrelizumab, ofatumumab) and neuromyelitis optica (inebilizumab). Ocrelizumab is the first medication that proved to be effective in primary progressive multiple sclerosis. There have been significant advances in the treatment of neuromyelitis optica: the first multicenter study of Inebilizumab (MEDI-551) is currently underway.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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Epilepsy and sleep

Broutian A.G., Belyakova-Bodina A.I.

Abstract

This review focuses on the interrelation between clinical and electrophysiological manifestations of various epilepsy forms and level of wakefulness or sleep. In case of some epileptic syndromes seizures occur predominantly or solely in sleep. Epilepsy can modify normal sleep patterns; on the other hand, sleep influences interictal epileptiform discharges, increasing their number and changing their morphology and spreading depending on sleep stage. Although interictal discharges in focal epilepsy are more common in sleep than in wakefulness, discharge distribution in generalized epilepsy is more variable. For some epileptic syndromes there is a strong correlation between time of onset, frequency, severity of attacks and stage of sleep cycle or wakefulness. Further research in this area can shed light not only on mechanisms of epileptic networks functioning, but also on the sleep-wake cycle regulatory systems.

Annals of Clinical and Experimental Neurology. 2018;12(5):
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