\r\n\tIn conclusion, this book is intended for Engineers for research in the domains of speech signals and ECG denoising and also in the domain of image denoising. Many mathematical tools can be used for speech enhancement, ECG Denoising, and Image Denoising. Among those tools, we can mention wavelets, Empirical Mode Decomposition, Total Variation Denoising, Non-Local Means (NLMS), Kalman Filtering, Wiener Filtering, Deep Learning, etc.
",isbn:"978-1-83768-030-6",printIsbn:"978-1-83768-029-0",pdfIsbn:"978-1-83768-031-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"9885534183ae520bcc63a91d4d083390",bookSignature:"Dr. Mourad Talbi",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11943.jpg",keywords:"Speech Enhancement, Thresholding, Signal to Noise Ratio, Wavelets, ECG Denoising, Empirical Mode Decomposition, Total Variation Denoising, Image Denoising, SNR, Non-local Means (NLMS), Kalman Filtering, Wiener Filtering",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 11th 2022",dateEndSecondStepPublish:"June 8th 2022",dateEndThirdStepPublish:"August 7th 2022",dateEndFourthStepPublish:"October 26th 2022",dateEndFifthStepPublish:"December 25th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"14 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Assistant Professor Mourad Talbi obtained his Ph.D. in Electronics at the Faculty of Sciences of Tunis, Tunisia. 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\n
1. Introduction
\n
Physiological processes in living systems undergo rhythmic fluctuations, called biological rhythms. Among the great variety of biological rhythms in maintaining the health and functioning of the organism, circadian rhythms (CR) with a period of oscillations of about 24 hours are particular important. Evolutionally formed synchronization of the CR as an indicator of internal and external synergism, indicates a health status [1]. In the case of discrepancy of the CR, there is desynchronosis – a form of circadian pathology, a nonspecific manifestation of pathological conditions characterized by changes in the structure of the rhythm: an increase (decrease) in amplitude; inversion of acrophases; change the duration of the period [2]. The manifestation of many diseases, such as myocardial infarction, stroke, sudden death, etc., is closely associated with certain periods of the day [3, 4, 5]. The diurnal rhythms of biochemical processes and physiological functions are synchronized in time, or synchronous. Thus, the number of heart rate (HR) and respiration rate are correlated as 4:1 (72:18, 80:20), that ensures optimal oxygen supply to tissues and is consistent with the rhythms of metabolism. There are several theories about the nature of endogenous factors. In 1976, the chronohypothesis was developed. According to it there is a site in the DNA structure – “chronon,” controlling biorhythms. According to the multi-oscillator model of biorhythms, there are many drivers of rhythm-pacemakers in the body [6].
\n
External factors of general synchronization include geophysical factors: photoperiods (day-night), fluctuations in the geomagnetic field of the Earth, changes in the temperature of the environment, etc. For a modern person, the change in the phylogenetically formed stereotype under the influence of social factors is very important [7].
\n
In the process of evolution, complex mechanisms of nervous and humoral regulation of biorhythms, their optimal synchronization were developed. The launching of circadian oscillations and their interconnection is carried out by the activity of the central nervous mechanism performing the pacemaker function, which is realized through the humoral regulating link [2]. Light is the main factor that determines the activity of suprachiasmatic nuclei (SCN) as a biological clock. The information on the light mode is fed into the SCN from the retina of the eye. They also receive signals from other parts of the brain (afferent inputs) and send impulses to various brain structures (efferent inputs) [8].
\n
Through the efferent pathways, the SCN are involved in the regulation of the rhythmic activity of the endocrine system, blood circulation, eating behavior and other functions. Another structure important for the rhythmic organization of functions is the epiphysis – neuroendocrine transducer, an organ that transmits information about the illumination of the environment from the nervous system to the endocrine. Biologically active substance-melatonin is synthesized in epiphysis cells [9].
\n
There are different methods for detecting biorhythmological personality: measuring body temperature, blood pressure, heart rate, breathing, sleep-wake cycle, metabolic rate during the day, determining the level of melatonin in the blood or its metabolites in saliva or urine [10]. The prevalence of sleep and wakefulness disturbances in patients with cardiovascular diseases (CVD) is very high. After a stroke, patients often experience sleep disorders such as insomnia, daytime sleepiness, fatigue, behavioral disturbances in the sleep phase with rapid eye movements and the restless legs syndrome, obstructive sleep apnea syndrome [11, 12, 13, 14, 15, 16].
\n
To detect sleep disorders, semi-quantitative scales and questionnaires, polysomnography are used [10]. Examination of Daily blood pressure and Holter monitoring of ECG allow to establish violations of daily dynamics of blood pressure and heart rate. Holter monitoring of ECG enables to evaluate the circadian index (CI), which is an informative method for assessing circadian diurnal fluctuations in the heart rhythm [17].
\n
The study of CR in patients with CVD has a great practical interest, since CRs are highly sensitive to various types of external influences and their disturbances can be the first symptoms of beginning abnormalities in the vital activity of the organism. There is a lot of data on the existence of chronobiological patterns in the development of stroke and myocardial infarction [11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26].
\n
The great scientific and practical interest is the study of the chronotropic activity of melatonin, the leading biochemical marker of CR. There is clear CR of melatonin production in the epiphysis and suppression of its secretion in the light [8].
\n
The role of melatonin in the regulation of diurnal fluctuations of blood pressure is proved [27]. It has anti-inflammatory and antioxidant, as well as possible epigenetic activity [28, 29]. A number of studies have shown the effectiveness of melatonin for normalizing sleep and circadian rhythms in patients with insomnia, acute stroke, depressive disorders, arterial hypertension, etc. [29, 30, 31, 32, 33, 34, 35]. Chronotropic or rhythm-organizing activity of melatonin determines the origin of two leading, official indications for its use: treatment of sleep disorders and desynchronosis [29, 31, 36].
\n
The analysis of published data shows the high scientific and practical relevance of further study of chronobiological disorders in patients with diseases of the cardiovascular system. It allows to reveal the pathogenetic relationship of comorbidity of disorders and to substantiate complex approaches to therapy [37, 38, 39].
\n
\n
\n
2. Morphofunctional, molecular, genetic and biochemical basis of circadian rhythm regulation
\n
\n
2.1. Morphofunctional features of suprachiasmatic nuclei and their connections with epiphysis
\n
Circadian rhythms (CR) are physiological and behavioral cycles, which are provided by the internal oscillator and remain in the absence of an external “regulator”. The ability to maintain a 24-hour rhythm is a fundamental characteristic of a circadian system that allows the body to adapt to environmental conditions [1].
\n
Circadian system operates due to four key components:
Photosensitive retinal neurons and retinohypothalamic tract through which light signals come from the environment;
Internal circadian oscillator, generating rhythms and synchronizing them with the environment;
Signal paths transmitting information from the central regulator to peripheral rhythm generators;
Peripheral rhythm generators – clock-genes and proteins in peripheral cells [10].
\n
The central circadian oscillator is the suprachiasmatic nuclei of the hypothalamus (SCN), which are heterogeneous in structure and neurochemical organization and are subdivided into the rostral and caudal divisions [8, 9].
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Most of the SCN neurons are GABA and secrete different peptide neurotransmitters. GABA provides a link between the neuronal populations of the ventral and dorsal sections of the SCN. It participates in stabilizing the activity of the SCN and maintaining high-frequency oscillations of neurons in the CR. Many of the individual SCN neurons exhibit electrical and molecular rhythms in isolation, but the rhythms are weaker and less stable [8, 9, 10].
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It is found, that light stimuli trigger the intra- and intercellular cascade of gene expression first in the center of the SCN, whence elements of peripheral parts are involved in the process through the GABA-ergic signaling pathways. Specific neuropeptides, gap junctions, astrocytes and GABA-ergic signaling realize interrelation between the SCN neurons. Vasoactive intestinal peptide (VIP) and arginine-vasopressin (AV), involved in the regulation of rhythms, are most studied. Studies show that VIP maintains and synchronizes rhythms of the SCN, while AV participates in maintaining high amplitude of the output signal from the SCN and in re-input pulse modulation [8, 9, 10].
\n
Rhythmicity and synchronism of the nuclei operation in the diurnal regime is maintained in this way. The physiological role of the SCN, which reduces to the generation of circadian signals and the subordination of the activity of neighboring brain structures and peripheral organs, is entirely determined by the nature of their afferent and efferent connections [8].
\n
Among the afferent projections of the SCN, the retinohypothalamic tract, which provides the nucleus with information about the state of photoperiodic processes, is of particular importance. It transmits to the SCN the main stream of optical impulses and is represented by collaterals of retinal ganglion cells. Its damage affects the dynamics of the CR in the form of a phase shift [8].
\n
Another significant afferent input for SCN is the ascending axons of the neurons of the seam nuclei projecting here. The existence of direct raphohypothalamic tracts explains the high content of serotonin in the SCN. The electrical stimulation of the seam nuclei clearly inhibits the rhythmic of the hypothalamic neurons. In experiments on isolated SCN neurons, agonists and antagonists of serotonin receptors when applied locally, simulating the effect of light, were shown to be able to shift the phase of CR cells [8, 9].
\n
The SCN forms neural connections with the nuclei of the stem, responsible for the regulation of sleep and wakefulness processes [10]. The SCN have direct connections with supraventricular and preoptic regions, dorsomedial divisions of the hypothalamus, arcuate and paraventricular nuclei. The direct and inverse relations of the SCN with the various elements of the limbic system and the motor centers have great functional significance. In particular, some nuclei of the amygdala and septa are projected onto the SCN [40].
\n
A special place in the temporal organization of adequate adaptive behavior and the genesis of affective disorders is attributed to the interaction of the SCN with the epiphysis and emotiogenic limbic structures. Epiphysis is an important relay station and the leading link in the realization of circadian signals in relation to different functional indicators [8, 9].
\n
The SCN almost entirely determines dependence of brain activity on the state of external illumination. During the day, light entering the retina activates its photosensitive ganglion cells, the information from which is transmitted through the retinohypothalamic tract and further into the SCN. Signals from the SCN are transmitted to the paraventricular nucleus of the hypothalamus, and further, trough the intermediolateral column of the spinal cord, reach the upper cervical ganglion. Sympathetic postganglionic noradrenergic fibers innervate melatonin-secreting cells in the epiphysis. Norepinephrine acts on postsynaptic beta-1 and alpha-1-adrenergic receptors in the cells of the epiphysis, which trigger the synthesis of melatonin. There is a clear daily periodicity: the production of melatonin begins with the onset of darkness, reaches a maximum at midnight and stops in the light. In the light phase of the day, this process is replaced by an increased synthesis of serotonin [7, 8, 41].
\n
There are reciprocal relationships between the SCN and the epiphysis, and melatonin is able to make certain corrections to circadian dysrhythmia, including inhibiting the discharges of SCN neurons. Under the influence of melatonin, the CR phase shift is also described in humans, which allowed recommending it for the correction of latitudinal desynchronosis [29, 41].
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By obeying the signals of the SCN, the epiphysis through melatonin can directly interfere with the functional activity of the limbic structures of the brain. Hyperactivity of the latter causes the development of dysrhythmia, accompanied by an increased level of anxiety. With steady stressing, the anxiety transforms into a depressive state. The SCN due to its direct efferent projections into the subcortical limbic nuclei, and indirectly (via melatonin) limits hippocampal excitability. Probably, this is one of the ways to realize anti-anxiety properties of the epiphyseal hormone. Thus, the disturbance of the interaction of SCN with the epiphysis is one of the pathogenetic factors of anxiety and depression [42, 43].
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In addition to managing the CR of the psychoemotional state, along with other circadian fluctuations, the SCN provide regulation of the basal cycle of calm-activity. It is known, the patients with depression are characterized by night sleep disturbance and phase structure of sleep disorder. One of the probable causes is legitimately sought in violation of the normal activity of the central pacemaker. It has been established that the SCN lesion in animals along with other CR disturbance significantly disturbs the sleep [42, 43]. Insomnia in humans is often combined with neurodegenerative pathology (Alzheimer’s disease (AD), etc.), which is usually accompanied by the SCN lesion. On the other hand, a rhythmic change in the states of sleep and wakefulness is quite an autonomous process and persists in people deprived of external time sensors, which emphasizes the dependence of sleep on the activity of the leading pacemaker [44, 45, 46, 47, 48].
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According to modern concepts, the periodic nature of the sleep-wake cycle is determined by the co-operation of the brainstem formations in the ascending awakening system of the brain and the hypnogenic pathways, the impulse from which, following to the forebrain, along with other structures, involves ventrolateral preoptic nuclei. The latter provide alternating excitation of activating and inactivating (hypnogenic) mechanisms with rhythmic change of sleep and wakefulness states during 24 hours, demonstrating a switching function. The weakness of the rhythm-organizing properties of the SCN can be determined by the pathological reorganization of intranuclear processes at the molecular level. An important reason for this is often the changes in the circadian oscillations of the clock genes [49, 50].
\n
\n
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2.2. Molecular mechanisms of circadian oscillations
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The molecular basis for the CR regulation is provided by the hour genes, whose work is carried out on the principle of loops of positive and negative feedback. The BMAL1 and CLOCK proteins accumulated during the day form the BMAL1/CLOCK complex. The BMAL1/CLOCK dimer activates the transcription of the PER genes (PER1, PER2, PER3) and CRY (CRY1, CRY2). Synthesized PER and CRY proteins also form a PER/CRY dimer acting on the principle of negative feedback. PER/CRY moves to the cell nucleus and inhibits the activity of the BMAL1/CLOCK complex, which leads to a decrease in the expression of PER and CRY proteins. During the night, the PER/CRY complex is destroyed, and the 24-hour cycle begins anew [49, 50].
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Another clock gene involved in the regulation of this cycle is REV-ERB-alpha. The BMAL1/CLOCK complex activates the transcription of the gene, which leads to the accumulation in the cell of the protein REVERB-alpha. The REVERB-alpha protein in turn inhibits the transcription of the BMAL1 gene and presumably the CLOCK and CRY1 genes [51].
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\n
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2.3. Melatonin involvement in the circadian rhythms regulation
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The leading regulator of biological rhythms is the epiphyseal hormone melatonin (N-acetyl-5-methoxytryptamine) acting on circadian systems via MT1- and MT2-melatonin receptors in the hypothalamus SCN [1, 28, 29].
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The melatonin donor is the amino acid tryptophan, which participates in the synthesis of the neurotransmitter serotonin, which under the influence of the enzyme N-acetyltransferase turns into melatonin (Figure 1) [29].
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Figure 1.
Мelatonin synthesis scheme.
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Melatonin is an indole derivative of serotonin and is produced at night with the participation of N-acetyltransferase and hydroxyindole-O-methyltransferase enzymes [29].
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Extrapineal sources of melatonin synthesis are enterochromaffin cells of the gastrointestinal tract (EC-cells), the main depot cells of serotonin (contain up to 95% of all endogenous serotonin). The synthesis of this hormone has been found in many neuroendocrine cells of the airways, lungs, in the cortical layer of the kidneys and along the boundary between the cortical and medullary layer of the adrenal glands, under the hepatic capsule, in the paraganglia, ovaries, endometrium, prostate gland, placenta, gallbladder and inner ear. In recent year’s studies, melatonin synthesis is found: in blood cells – mast cells, lymphocytes – natural killers, thrombocytes, eosinophilic leukocytes, in the thymus, pancreas, cerebellum, retina. Functionally, many melatonin-producing cells belong to the so-called diffuse neuroendocrine system – a universal system for adapting and maintaining the body’s homeostasis. Thus, two links of melatonin-producing cells are distinguished: central (includes the pineal gland and cells of the visual system), in which the rhythm of melatonin secretion coincides with the rhythm of light-darkness, and peripheral – all other cells where the secretion of the hormone does not depend on illumination [1, 2, 29].
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Melatonin is transported by serum albumin, after liberation from albumin it binds to specific receptors on the membrane of target cells, penetrates into the nucleus and performs its action there. The biological half-life of melatonin is 45 minutes. This makes it difficult to collect material for research purposes. Melatonin is rapidly hydrolyzed in the liver and excreted in the urine (80–90%), the main metabolites are 6-hydroxymelatonin-sulfate (6-SOMT) and 6-hydroxyglycuronide. The concentration of melatonin metabolites in saliva and/or urine correlates well with the total level of melatonin in the blood during the sampling period [1, 10, 30].
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It has been found that the effect of melatonin is realized through MTNR1A (MT1) receptors, which are expressed mainly on the cells of the anterior lobe of the pituitary gland, the hypothalamus SCN and in many peripheral organs; as well as MTNR1B (MT2) receptors, expressed in some parts of the brain, in the retina and in the lungs. The nuclear receptors of melatonin of the subfamily RZR/ROR of retinoid receptors have recently been discovered. Many immunostimulatory and antitumor effects of melatonin are mediated through them [52].
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During the first years of life, peak concentrations of melatonin increase and reach a maximum by 2–4 years, after which they begin to decrease and reach the plateau by the time of puberty. The secretion of melatonin continues to decrease yearly after the end of puberty [10]. Both basal and peak concentrations of melatonin decrease with age, the daily curve of melatonin secretion is smoothed and the peak of night secretion decreases [10, 52, 53, 54].
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The daily fluctuations in the melatonin level in the blood (melatonin curve) looks like the following. Its concentration is minimal by day (1–3 pg./ml), it starts to increase 2 h before the usual time for going to sleep (if there is no bright light). After turning the light off in the bedroom, the concentration of melatonin increases rapidly (up to 100–300 pg./ml). In the pre-hour hours, a recession usually begins, which ends after awakening. For each person, the melatonin curve is stable from night to night, while in different people of the same gender and age the curves differ significantly, so one can speak of an individual curve [10, 52].
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In a number of experiments on animals, the antioxidant properties of melatonin have been demonstrated. The mechanism of antioxidant action is manifested in the fact that melatonin has a pronounced ability to bind free radicals, including those formed during peroxidation of hydroxyl radical lipids, and exogenous carcinogens, and it also activates glutathione peroxidase, a factor protecting the body from free radical damage. The main functions of the melatonin antioxidant action are aimed at protecting DNA [10, 29, 52, 55]. To a lesser extent on the protection of proteins and lipids. Its addition to the ration of rats resulted in an increase in life expectancy and testosterone levels in males [52, 56]. In the study of V.A. Lesnikov and W. Pierpaoli transplantation of the pineal gland from young to older individuals increased their lifespan by 42% and, conversely, transplantation of the epiphysis of older individuals reduced it by 29% [57]. Against the background of the use of melatonin in aging mice, not only the duration of life but also the volume of thymus, adrenals and testes increased, which was accompanied by an increase in the level of testosterone and thyroid hormones in the blood. Thus, a decrease in melatonin synthesis probably plays an important role in aging processes [53].
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Reducing melatonin concentrations in the elderly is probably one of the main factors in the development of age-related neurodegenerative diseases. A retrospective analysis of 6-year-old data in patients with depression revealed a disruption in the regulation of the synthesis and metabolism of catecholamines, neurotransmitters, melatonin and immunological proteins [42]. It has also been shown that melatonin supports the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and its dynamics are also regulated by melatonin. Mitochondrial dynamics demonstrates an oscillatory pattern that corresponds to the CR of the secretion of melatonin in the pinealocytes and, possibly, in other cells [28, 52, 55]. A number of recent scientific studies have identified the neuroprotective effect of melatonin, which is manifested by affecting the proliferation and differentiation of neural stem cells, increasing the content of myelin and oligodendrocytes [58, 59].
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In other studies, melatonin demonstrated a neuroprotective effect in neurodegenerative diseases. Melatonin reduces the toxicity of beta-amyloid and prevents the death of cells in experimental AD models, and also reduces oxidative stress in PD models [44, 45, 46, 48].
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In addition, the experiment demonstrated the effect of melatonin on the proliferation and differentiation of stem nerve cells. Depending on the dose of melatonin introduced into the mice cortex, the proliferation rate of oligodendrocytes, the percentage of the main myelin protein, as compared with the control group, increased. Thus, melatonin may have a potential therapeutic effect for some neurological diseases associated with oligodendrocyte pathology and myelinopathy [59].
\n
In recently published papers it is reported that melatonin synchronizes not only central but also peripheral biorhythms, which allows to synchronize biological functions by means of CR with respect to periodic changes in the environment and, therefore, facilitates adaptation of the individual to the external environment [28, 52].
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The large number and diversity of the main effects of melatonin opens up important prospects for measuring the level of melatonin as a biomarker for the purpose of clinical, preventive and therapeutic use [10, 32].
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3. Violation of CR and cerebrovascular diseases (CVD)
In a comparative analysis of autonomic control of the rhythms of the cardiovascular system (CVS) in young and elderly healthy people in Ukraine, it was shown that circadian regulation of blood pressure and heart rate is impaired in elderly people. [25].
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There are reports that chronobiological disorders are detected in patients with arterial hypertension [70, 71, 72], diabetes mellitus [73, 74, 75], cardiac ischemia [11, 12, 14, 61, 66], dementia [67, 68, 69, 70], etc. Nowadays there is a lot of data on the existence of chronobiological patterns in the development of stroke and myocardial infarction (MI) [11, 12, 14].
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It is known that Ischemic stroke (IS) develops more often in the early morning hours [10]. This may be due to an increase in the activity of the coagulating system of blood at this time [71], as well as with a violation of the daily regulation of blood pressure and heart rhythm in these patients [72, 73]. In epidemiological studies, increased frequency of sudden cardiac death, MI and transient myocardial ischemia, pulmonary embolism and critical ischemia of the lower extremities, as well as rupture of the aortic aneurysm at dawn.
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The second small peak of incidence is noted in the early evening [74]. European researchers point to an increased incidence of stroke and MI in winter [75].
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In the epidemiological study conducted in Hawaii, it was found that the MI in local population of the Caucasoid race occurs most often between 04:00 and 12:00, and in Japanese visitors – from 12:00 to 16:00, which corresponds to the morning hours in Japan [76]. Similar daily dynamics of MI and stroke development early in the morning and between 12:00 and 18:00 was noted in a prospective study conducted in India involving 158 elderly patients [77]. Such a pattern of development of MI and stroke in the morning can be associated with an increase in platelet aggregation capacity in the morning hours with a peak at 09:00 [71, 72, 73]. Also in the early morning, endothelial cells reduce the synthesis of tissue activator plasminogen, nitric oxide and prostacyclin, the tone of the myocytes of the vascular wall is reduced, which promotes thrombosis [71].
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In addition, there is a seasonal and cyclical decompensation of the CNS. As a rule, exacerbations occur in the spring and autumn. There is evidence that hemorrhagic stroke (HS) often manifests in winter and spring, and IS in summer and autumn [78]. Daylight saving time transgresses the CR and shifts the picture of the diurnal variation at the beginning of the stroke, but the effect on the IS frequency is unknown.
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Effects of 2004–2013 daylight saving time (DST) transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during 2 weeks prior to and 2 weeks after the index week. DST transitions appear to be associated with an increase in IS hospitalizations during the first 2 days after transitions. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant comorbidities [79].
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Disorders of CR are associated with an increased risk of IS. A monitoring of blood pressure for 5 days after a previous IS or HS, conducted in 50 patients (India), indicates a decrease in natural circadian fluctuations with an increase in blood pressure during the night [77].
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According to the Stockholm population cohort study, 48-hour heart rate monitoring in 678 practically healthy people aged 55–75 years allowed to reveal a statistically significant risk of MI development in patients with reduced nighttime heart rate variability. Some authors point to a direct relationship between the frequency and severity of MI and the severity of violations of daily BP regulation. They divide patients into groups of “dippers” and “non-dippers”. It was established that the activity of the central link of the sympathetic nervous system was increased in patients with “non-dipper”, i.e., those who do not have a decrease in blood pressure during night sleep or less than 10% of the daytime sleep. These people are less active in endothelium-dependent vasodilation, and a possible cause of high pressure is the damage to the baroreceptor reaction. As a result, “non-dippers” are characterized by increased sympathetic activity during sleep and, as a consequence, have a high risk of general and cardiovascular mortality [80].
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The dependence between the amount of brain damage and the degree of decrease in nighttime blood pressure (BP) is established: the greater the amount of brain damage, the less it decreases at night. Thus, in patients with lacunar stroke, in contrast to patients with non-lacunar stroke, a greater BP reduction is detected during monitoring at night. This may indicate the safety of the mechanisms of regulation of circadian rhythms of pressure in the case of lacunar stroke [81].
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The results of the large clinical trial in Japan with a 24-hour outpatient BP measurement in 515 patients and parallel magnetic resonance imaging (MRI) of the brain showed that increasing the pulse pressure during sleep and mean BP on waking, especially in the elders, are independent predictors of MI in elderly hypertensives. In this case, the effect of pulse pressure and the mean value of BP on stroke risk differs in separate phases of the sleep-wake cycle. Thus, an increase in the pulse pressure for every 10 mmHg. in a sleep independently increases the risk of stroke by 43% (p = 0.001), while the average BP index during sleep is not so significant. At the same time, the mean BP increase for every 10 mmHg. on waking, independently increases the risk of stroke by 48% (p < 0.001), and the level of pulse pressure upon awakening is not a significant factor [82]. The study of night-time heart rate variability may have prognostic value for the stroke prevention.
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Our study with the inclusion of 226 patients with cardiovascular diseases (CVD) has shown a high incidence of sleep disorders and desynchronosis in these patients. A comparative analysis of the nature of sleep disorders in patients with cardiological disease (myocardial ischemia, essential hypertension) and CVD showed that sleep disorders due to anxiety-depressive disorders prevail in patients with CVD in the structure of detected sleep disorders, and after a stroke – sleep disturbances due to desynchronosis. This may indicate deeper violations of the adaptive mechanisms regulated by nonspecific brain systems, which leads to disturbances in the sympathetic and parasympathetic links in the vegetative status.
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Patients with MI also showed sleep disorders, which may indicate the role of cardio-cerebral interactions in the regulation of sleep mechanisms.
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Patients with CVD showed a decrease in the level of 6-SOMT, among which predominate the patients with MI [83, 84]. The presence of cognitive disorders, sleep disorders and chronobiological disorders (daily regulation of heart rhythm and BP) was related with a low level of 6-SOMT in daily urine examined [85, 86].
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The study of sleep characteristics in patients with CVD revealed high frequency of occurrence of sleep disorders and desynchronosis in these patients and their positive correlation with the development of behavioral and affective disorders (r = 0.57, p = 0.002), as well as their effect on the daily profile of the cardiac rhythm and BP (r = 0.46, p = 0.008). Therefore, timely diagnostic and complex psycho-pharmacological correction of sleep disorders and desynchronosis in patients with СVD will improve the psychological and emotional status of patients, normalize daily profile of heart rhythm and BP. A positive correlation between desynchronosis and stroke was proved (r = 0.39, p = 0.013). This suggests that desynchronosis is a risk factor for stroke in patients with CVD [25].
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3.2. Stroke and sleep disorders
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According to the polysomnographic study sleep disorders in stroke reach 100% of the cases and are manifested as insomnia, disturbance of the “sleep-wake” cycle and respiratory distress in sleep as the type of “sleep apnea” syndrome [87]. It was found that sleep disorder is one of the etiological factors of stroke, also increases the risk of recurrent stroke and prevents recovery after it [18, 19, 20, 21, 22, 23, 24, 25, 62, 87, 88, 89, 90, 91, 92, 93, 94, 95].
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Large population studies (more than 3000 patients) indicate that a reduction in sleep duration (less than 6 hours) is associated with an increased risk of hypertension, especially among women compared to men, and is stronger in premenopausal women than in postmenopausal women. The revealed relationship does not depend on the socioeconomic status, traditional cardiovascular risk factors and psychiatric comorbidity, and is stronger in premenopausal women. Consequently, a decrease in the duration of sleep increases the risk of developing hypertension, which can lead to the cardiovascular pathology (СVP) development in women [62].
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In the Danish cohort population study over 12 years, which included 20,432 men and women aged 20–65 years, a high incidence of CVP was found in people with insufficient duration and quality of sleep [15]. In the Australian study, among 218,155 people 45 years of age or older, it was found that sleep duration of less than 6 hours and more than 9 hours is associated with a high risk of diabetes, stroke, hypertension and coronary heart disease (CHD). A prospective study of 1986 patients aged 55–69 years (Great Britain) showed that IS is more likely to develop in patients with disturbed sleep at night, and MI is associated with increased daytime sleepiness [25].
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In 2016, scientists from the University Clinic of Essen published a meta-analysis of 29 scientific papers evaluating sleep disorders that may be associated with stroke. A total of 2.343 patients with IS, HS or transient ischemic attack (TIA) participated in the studies. Sleep disorders in these patients were divided into 2 groups: (1) disturbance of breathing during sleep (obstructive sleep apnea); (2) sleep and wakefulness disorders, which reduces the duration of sleep. It was revealed that sleep disturbance was observed in 72% of patients with IS, in 63% of patients with HS and in 38% of patients with TIA. A lot of patients had a sleep disorder before stroke. This allows to believe that sleep disorders increase the risk of stroke [22].
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The authors also proved that not only insomnia, but hypersomnia and restless leg syndrome increase the risk of stroke. To date, specific mechanisms for increasing cardiovascular risk in restless legs syndrome have been described: (1) periodic movements of limbs in a dream, accompanied by a significant increase in the heart rate and BP; (2) fragmentation of sleep and lack of sleep, invoking changes in the regulation of nervous and vascular systems, metabolism, oxidative, inflammatory processes; (3) iron deficiency, which creates new risks for CVP [90, 91, 92].
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In general, the exact mechanisms by which sleep disorders can lead to stroke are not disclosed. Nevertheless, it is shown that sleep has an important restorative function of the brain and affects the processes of neuroplasticity. Sleep disorders can persist after a stroke, and without appropriate correction may obstruct the after stroke rehabilitation.
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3.2.1. Characteristics of sleep disorders in patients with stroke
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Insomnia in stroke patients is characterized by a change in the duration of sleep, frequent nocturnal awakenings, lack of satisfaction at night sleep, and the appearance of “heaviness” in the head [22, 87]. According to the polysomnographic study, there is an increase in stages 1 and 2, a decrease in phases 3 and 4 of the slow-sleep phase (SSP), and often a reduction in the phase of fast sleep (FSP) [10, 13].
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Sleep-wakefulness disorders in patients with stroke are caused by damage of the hypothalamic structures associated with the “internal clock”, or their connections. Clinically manifested by disturbance of night sleep, pathological daytime drowsiness or a combination of both. This is more common in multiple lacunar stroke. In patients with severe cognitive impairment after stroke, the inversion of the sleep-wake cycle with sleeplessness at night and daytime drowsiness is often observed. As a rule, these conditions are accompanied by behavioral disorders. At the same time the patient is nervous, cannot understand where he is, tries to get out of bed, go, resists the actions of medical staff. These conditions cause the difficulties in rehabilitation of these patients in the hospital [22, 87].
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Studies of recent years have shown that obstructive sleep apnea (OSAS) is an independent modifiable risk factor for stroke. To date, it has been established that respiratory events associated with OSAS are involved in cyclical episodes of hypoxemia and hypertension, increased platelet aggregation, reduced fibrinolysis, endothelial dysfunction, increased intracranial pressure, decreased cerebral blood flow and local cerebral ischemia. In the acute period of IS the incidence of OSAS is 36% [93]. Respiratory disturbances in sleep in patients with stroke, cause the worst efficiency of the rehabilitation process. It is shown that the presence of OSAS is accompanied by greater functional insufficiency and a longer period of hospitalization of patients [94, 95, 96, 97, 98, 99, 100].
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In general, for all stages and forms of stroke, changes in both the mechanisms of sleep generation and the mechanisms of its maintenance are typical. The cause of these violations are not only the damage and death of brain tissue of a local nature, but also disorders of general and local hemodynamics, the appearance of edema and displacement of the brain substance, the ingress of blood into the cerebrospinal fluidways, and as a result – the irritation of various structures located in the brainstem [18].
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It is believed that the greatest impact on sleep is the nature, size, localization of the process and the stage of the disease.
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3.2.2. Features of sleep disorders depending on the type, localization of the focus, stage of stroke and development time of the stroke
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HS in comparison with IS leads to the most severe disorders of night sleep. Characterized by a deep reduction in the duration of sleep, frequent and prolonged awakening, an increase in the representation of the first stage. However, with a favorable outcome of the disease, the degree of recovery of the structure of sleep is faster than in IS. In IS there is a focus of necrotic decay of brain tissue, while with hemorrhage, damage occurs as a result of the stratification of brain structures with blood. Therefore, the restoration of both the clinical picture and night sleep is better and for a shorter period in HS [22, 101].
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The size of the focus of stroke plays a significant role in the formation of sleep disorders. A large focus leads to a common swelling of the hemisphere, sometimes even the opposite, the emergence of processes of compression of the brain stem. Hence the most severe disorders of sleep are observed in large foci of stroke. In the available studies it was shown that the maximum proximity of the focus to the median structures and the liquor-bearing pathways (medial arrangement) leads to more severe sleep disorders. Not only quantitative but also qualitative changes in the structure of sleep are noted. Thus, the medial focus with the capture of thalamic structures is characterized by the disappearance on the side of the lesion of “sleepy spindles” (electroencephalographic signs of stage II of sleep). The lateral processes are accompanied by less severe sleep disorders [19].
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The localization of the lesion in the hemispheres or in the brain stem causes specific changes in the structure of sleep. Greater disorders observed in the right hemispheric processes: decreases the duration of d-sleep and FSP, lengthen the waking period and stage I, the duration of falling asleep; the number of awakenings increases. The reason for such sleep disorders in right hemisphere patients is the damage of the deep mechanisms of the relationship between the right hemisphere and the hypnogenic structures of the brain. In addition to sleep disorders, these patients notice marked changes in vegetative regulation, which is manifested by tachycardia, various types of cardiac arrhythmia, high BP numbers. The left hemisphere is most closely associated with the activating systems of the brain. There is an opinion that this is the cause of frequent impairment of consciousness in left hemispheric strokes [19].
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When a process occurs in the area of the pons, the duration of the FSP dramatically decreases, and its latent period increases. Bulbar symptoms are accompanied by a decrease in the duration of d-sleep.
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The acute stage of stroke (week 1) is characterized by a number of clinical and polysomnographic features. In this period, there are difficult to control hemodynamic, general cerebral and local neurological processes. Depending on the direction of the disease, a different picture is observed in polysomnography. Severe disturbances of consciousness (sopor, coma), as a rule, are accompanied by a diffuse slow wave activity, which excludes the possibility of isolating individual stages of sleep. The emergence of separate stages and sleep phenomena against a background of diffuse cerebral electrical activity is a prognostically favorable sign. With conserved consciousness in the most acute period, polyphase and inversion of the “sleep-wakefulness” cycle due to circadian disorders are often enough. In the first case, patients fall asleep several times during the day; in the second – the cycle “sleep-wakefulness” shifts, there are daytime sleep and night wakefulness. In the presence of general cerebral symptoms, frequent awakenings, a decrease in d-sleep and the absence of FSP are observed [19].
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The structure of sleep in patients with stroke also differs depending on the time of its onset. A characteristic feature for a stroke that occurred during sleep is a high FSP presence, which, along with the “vegetative storm” in this phase, can be one of the causes of stroke at night. According to statistics, in patients with a “morning stroke” in comparison with “daytime” and “night”, the shortest FSP time is noted [19].
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Investigation of the night sleep structure in patients with stroke showed the premorbid sleep problems (frequent awakening, long sleep, dissatisfaction with sleep, early awakening), which are associated with worse parameters of sleep quality after stroke [18, 101]. Thus, the initial feature of the regulation of the “sleep-wake” cycle influences the formation of structural changes in sleep after stroke.
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3.2.3. Sleep disorders and recovery from stroke
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The quality of sleep can serve as a prognostic criterion for the possibility of recovering patients with stroke. So, changes in the structure of sleep in the acute period of stroke have an important prognostic value. If a normal pattern of sleep does not return within 7–10 days after a stroke, the prognosis is considered unfavorable [10]. A multicenter-observational and correlation study involving 280 patients with mild and moderate severity of stroke showed initially high rates of affective and cognitive impairment (26.9%) and sleep disorders (567%) in patients in the early recovery period of stroke. In patients with sleep disorders, regardless of the severity of the stroke, recovery of the neurological deficit, cognitive functions proceeded more slowly compared to patients without sleep disorders, primarily with regard to improving the Berg balance scale. It was found that sleep disturbance after stroke has a negative effect on functional recovery, especially on improving the balance in the group of moderate stroke [102].
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Restoring and maintain a natural biorhythm sleep-wakefulness with the use of physical and medicinal methods for the stroke prevention and treatment are recommended.
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Currently, in the correction of sleep in patients with stroke, the leading place is the drug therapy. The strategy of pharmacotherapy of sleep disorders in patients with stroke is reduced not to achieving a one-time hypnogenic effect, but to normalizing the adaptive-compensatory potential of the central nervous system. Based on such positions the advantages of melatonin as a hypnotic are estimated. As a natural chronobiotic, melatonin synchronizes CR, provides normalization of desynchronized CNS activity. Therefore, the correction of sleep disturbances with melatonin (as opposed to “classical” hypnotic drugs) becomes not only as the result of a hypnogenic effect, but due to normalizing the activity of various brain structures that support the processes of complex central regulation. Exogenous melatonin, taken in the evening, stabilizes the work of the SCN and marks the starting point for determining the subjective dark time of the day [29, 31, 32].
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A number of clinical studies have shown the positive effect of melatonin on daytime sleepiness, a reduction in the period of falling asleep and the number of nocturnal awakenings, the restoration of disturbed sleep initiation in patients with stroke [33, 34, 35, 36, 37].
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In one of the major studies to correct the disturbances of the sleep-wake cycle, patients with stroke were prescribed a melatonin (Melaxen, Unipharm, Inc., USA) in a dose of 3 mg at bedtime for 10 nights. Against the background of taking Melaxen, there was an increase in the time of night sleep and a decrease in the number of sleep episodes during the day. That is, there was a normalization of the distribution of the sleep time in the 24-hour sleep-wake cycle [35].
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When studying the condition of the CNS in 60 patients in the acute period of stroke, it was found that the inclusion in the scheme of complex therapy of Melaxen at a dose of 6 mg per day contributed to a faster and more complete recovery of motor disorders, improvement of the cranial nerves function. In addition, while Melaxen’s administration, a rapid normalization of a number of electrophysiological parameters during the recording of an electroencephalogram was observed: changes in activity in the EEG delta and theta bands, which were accompanied by a change in the BIS and ITA indices [104].
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We evaluated the effectiveness of chronotherapy (Melaxen) on the dynamics of sleep disorders, cognitive and emotional disorders, neurotrophic brain factor (BDNF), the level of melatonin secretion (6-SOMT) in patients in the early recovery period of cerebral stroke. 112 patients were examined in the early recovery period of the stroke (mean age 58.0 ± 9.74 years). The main groups of patients, along with the standard treatment regimen, received phototherapy and Melaxen 3 mg per day for 3 months. The effectiveness of the therapy was assessed by the dynamics of sleep disorders, psychoemotional status, the concentration of the neurotrophic brain factor BDNF, the level of 6-SOMT in the urine. The study demonstrated a high effectiveness of chronotherapy (Melaxen, phototherapy) in the rehabilitation of patients in the early recovery period of stroke. The presence of cognitive disorders, sleep disorders and emotional disorders correlated with a low level of 6-SOMT in urine in the patients.
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Complex therapy with Melaxen, revealed a significant increase in the level of excretion of 6-SOMT in patients by the end of the 3-month follow-up period. An increase in the concentration of BDNF after 3 months of therapy and throughout the observation period may indicate activation of the synthesis of growth regulators and differentiation of the nervous tissue (neurotrophic effect). Increased concentrations of BDNF, 6-SOMT in the urine correlated with improved sleep, cognitive and emotional status, motor disorders and quality of life of patients.
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In another our study, with 132 outpatients (59 men and 73 women) aged 61.4 ± 4.7 years in the early recovery period of ischemic stroke (IS), OSAS was detected in 52 (39.4%) cases. Light and medium OSAS was diagnosed in 49 cases, in 3 patients – severe OSAS, which required selection of CPAP therapy. Patients with OSAS of mild and moderate severity (49 persons) were divided into 2 groups, comparable by sex, age and neurological manifestations. All patients received drug therapy according to the standards of specialized medical care; positional therapy, exercise therapy, mechanotherapy, psychotherapy. Patients of the main group (25 people, mean age 59.5 ± 4.8 years), along with the treatment described above, received melatonin 3 mg per day for 30–40 minutes before sleep for 3 months and used intraoral repositioning applicators. Patients in the control group (24 patients, mean age 62.3 ± 4.2 years) were prescribed only standard therapy. Already a month after the start of therapy, the patients of the main group had a positive dynamic: decrease in daytime sleepiness, snoring, and an expression of morning fatigue. After 3 months, the sleep characteristics of the patients in the main group were statistically significant (p < 0.05), differed from the control group by a shorter sleep time (8.8 ± 3.2 vs. 20.9 ± 16.7 minutes), an extended total sleep duration (431, 0 ± 34.7 vs. 386.9 ± 90.4 minutes), greater representation of the 4th stage of slow sleep (12.6 ± 3.5% vs. 8.1 ± 6.7%) and a lower total waking time (8, 0 ± 4.2 vs. 37.5 ± 12.8 minutes). After 6 months of therapy, positive changes in the polysomnography index remained, a reduction in the frequency of obstructive events in the patients of the main group as compared with the control.
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Simultaneously with the normalization of sleep, the positive dynamic of clinical and neurological indicators was demonstrated. By the 3rd month. Therapy, the cumulative cognitive parameters of the MoCA test, the psychoemotional functions and the quality of life of the patients in the main group were statistically significantly improved, in contrast to the controls.
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Detailed study of night sleep in patients with stroke is not only of scientific interest, but also has serious practical significance in matters of prognosis, secondary prevention, as well as medical and rehabilitation measures.
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The use of a standardized criterion for assessing the dynamics of the CR of the heart rate extends the diagnostic capabilities, reveals new pathogenetic links of the CVD, optimizes the treatment regimen for patients with CVP. Identification of CR abnormalities in the management of BP and heart rhythm in combination with sleep disturbances allows to include melatonin drugs in therapy.
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Thus, the detection of sleep disorders and desynchronosis in patients with CVD requires that medical, psychological and social aspects is included in complex therapy.
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It is advisable to use the following chronotherapeutic approaches:
Change of daily regime according to a chronotype of the patient and reduction of a mode of work and rest in conformity with natural photoperiods;
Use of physiologically appropriate diet;
Optimization of the motor activity regime with the recommendation of walking outdoors and moderate insolation;
Inclusion of photo- and color therapy in the complex of rehabilitation;
The Chronopharmacological approach in Drug Administration.
Melatonin administration at a dose of 3 mg per day. For 30–40 minutes before bedtime.
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4. CR disorders in patients with DVB and development of cognitive disorders
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At present, there is enough evidence on the association of early and progressive CR disorders, changes in quality and sleep architecture with an increased risk of developing cognitive impairment (CI) [67, 68, 69, 70, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112].
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When analyzing 12,926 documents from the PubMed, EMBase, ISI WebofScience and PsycINFO databases published before October 28, 2016, among 246,786 patients in 25,847, an average of 9.49 years was observed in dementia. The prognostic role of sleep disturbances, their subtypes (insomnia, OSAS, excessive sleepiness during the day, sleep disorders, and nonspecific sleeping problems) in the development of dementia were evaluated. Compared to those without sleep disorders, patients with sleep disorders had a higher risk of developing dementia. Subgroup analysis showed that insomnia increases the risk of developing AD, but not vascular dementia (VD). In contrast, OSAS was associated with a higher risk of early onset of SI, incl. AD and VD [105].
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The relationship between the sleep architecture and the potential risk of developing CI in the community is considered on the basis of Framingham Heart Study (FHS). For 19 years’ study (the average follow-up period was 12 ± 5 years), there were 321 patients participating in Sleep Heart Health Study between 1995 and 1998, over the age of 60 at the time of sleep assessment. 32 cases of dementia were traced; 24 cases were due to AD. After adjusting for age and sex, a low percentage of FSP and greater latency of REM sleep were associated with a higher risk of dementia. Each percentage reduction in FSP was associated with an increasing the risk of dementia by approximately 9% (p < 0.05). The relationship between the percentage of FSP and dementia was similar for the following adjustments for multiple covariates, including vascular risk factors, depressive symptoms, and drug use. The stages of slow wave sleep were not associated with the risk of dementia [106].
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Among 96 patients in the acute period of IS, 79% of patients had heterogeneous post-stroke CI. In 21% of patients they had a dysmnestic character. The concentration of 6-SOMT was lower in patients with IS compared with the control. In the study of chronotypes, it was found that the majority of patients had an early variant, while the social jetlag value was 40 minutes. This indicator decreased with increasing age of patients. In most patients, IS developed in the morning, these patients had the lowest content of 6-SOMT in daily urine and the lowest values for MMSE. Potentially this is associated with a decrease in the protective activity of the melatonin. There was a correlation between chronobiological parameters and cognitive status. Thus, the expression of the “social jetlag” was associated with the semantic coding of memory, reflecting the function of the hippocampus. Patients with a late version of the chronotype were characterized by higher rates of delayed reproduction and semantic verbal fluency. With an increase in the social jostlag, the concentration of 6-SOMT in urine, probably compensatory, increased. The use of melaxen accelerated the recovery of CR, which had a positive effect on the rehabilitation of patients. It has been suggested that in elderly and senile patients, a high concentration of 6-SOMT in the acute period of IS was a marker of dysregulatory cognitive impairment, whereas its low content in the presence of a cognitive deficit may indicate a mixed, hippocampal type of CI [86].
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Possible prospects for the use of melatonin in elderly patients with CI are due to its antioxidant, neuroprotective and nootropic effects. The positive effect of exogenous forms of melatonin on sleep in elderly patients is confirmed by the results of two placebo-controlled studies in which more than 500 patients over the age of 55, with primary insomnia [1107].
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Using 6 mg of melatonin once a day before bedtime for 10 days in patients with moderate CI (MCI) led to significant improvement in memory and regression of depressive symptoms simultaneously with normalization of the sleep-wake cycle [103]. H. Jean-Louis et al. [108], Peck et al. [109], observed 26 patients with MCI syndrome received similar results. While 1 mg melatonin administration just before sleep for 4 weeks, there was a significant decrease in forgetfulness in the auditory memory modality and improvement in night sleep compared with placebo. By Cardinali et al. there was made the retrospective analysis of the effect of melatonin therapy on cognitive functions, night sleep and wakefulness in 96 patients with MCI (61 patients received melatonin in doses of 3–9 mg once daily for 9–18 months). It has been proven that melatonin therapy contributes to significant cognitive improvement and regression of depressive symptoms [110].
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The high efficiency of the combination of memantine and melatonin in the correction of MCI was shown in the experiment [111].
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There is a discussion about the importance of light therapy in correcting of CI. Most of the studies demonstrate the stabilization of CR sleep-wakefulness and a reduction in the time of sleep in dementia with melatonin and light therapy [112].
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The prevalence and correction of sleep disorders in patients with CVD need further study in randomized clinical trials in large groups of patients for understanding their impact and establishing cause-effect relationships in the development of CI. These investigations results will help to develop a treatment strategy.
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5. Conclusion
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Thus, literature data show that stroke has a peculiar organization in time. Тhe vegetative dysrhythmia and failure in the work of the Central control of biorhythms regulation play a key role in these processes.
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The night sleep structure investigation is essential part in patients with stroke and patients with cardiovascular disease risk factors. The CR violation leads to the syndrome of desynchronosis—mismatched dynamics of different indicators of the internal environment. This is a potential basis for the cerebrovascular and cardiovascular pathology.
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Therefore, including the restoration of the CR with the chronotherapeutics methods is need for the vascular diseases prevention and treatment. Distribution of daily cases of stroke depends on individual properties of CR hemostasis and cerebral hemodynamics, and the specific of the night sleep structure of the of patients. In this regard, there must be a differentiated approach in the treatment of “day” and “night” strokes. The main aspect of reducing the probability of primary and secondary cardiovascular “accidents” development should be the timely detection of sleep disorders and desynchronosis, as one of the leading risk factors. The use of the personalized chronotherapeutics approaches allows to neutralize the negative impact of desynchronosis.
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Acknowledgments
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We thank Dmitry Petrov for his assistance in translation of the text. We wish to acknowledge the patients who participated in our studies. The content of the chapter is solely the responsibility of the authors.
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Conflicts of interest
The authors declare no conflicts of interest regarding the content of the manuscript.
\n',keywords:"circadian rhythms, desynchronosis, chronobiology, SCN, melatonin, cerebrovascular disease, stroke, sleep disorders, cognitive disorders, phototherapy, chronodiagnostic, chronotherapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/61140.pdf",chapterXML:"https://mts.intechopen.com/source/xml/61140.xml",downloadPdfUrl:"/chapter/pdf-download/61140",previewPdfUrl:"/chapter/pdf-preview/61140",totalDownloads:924,totalViews:119,totalCrossrefCites:3,totalDimensionsCites:3,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:47,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"November 12th 2017",dateReviewed:"February 26th 2018",datePrePublished:"November 5th 2018",datePublished:"July 4th 2018",dateFinished:"April 30th 2018",readingETA:"0",abstract:"The chapter describes in detail the pathogenetic role of desynchronosis in the development of cerebrovascular diseases (CVD). The data of domestic and foreign literature on the study of desynchronosis are presented. The role of melatonin in the regulation of circadian rhythms (CR) is shown. Pathological changes in CR affect sleep disturbance, emotional and cognitive disorders. It is demonstrated the need of the further study of the prevalence and structure of desynchronosis in patients with CVD. The search of the most significant factors of desynchronosis development in patients with vascular diseases is of great scientific and practical significance. The importance of creating and introducing diagnostic and therapeutic algorithms for chronodiagnostics and chronotherapy of CVD into everyday practical activities. The effectiveness of melatonin for the normalization of sleep and CR in patients with insomnia, acute stroke, depressive disorders is shown. Complex therapy of the patients with CVD taking into account chronobiological disorders allows to eliminate the adverse effect of sleep disorders and CR on the regulation of the cardiovascular system and improve the efficiency of rehabilitation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/61140",risUrl:"/chapter/ris/61140",book:{id:"6628",slug:"circadian-rhythm-cellular-and-molecular-mechanisms"},signatures:"Elena Kostenko and Liudmila Petrova",authors:[{id:"233858",title:"Mrs.",name:"Liudmila",middleName:null,surname:"Petrova",fullName:"Liudmila Petrova",slug:"liudmila-petrova",email:"ludmila.v.petrova@yandex.ru",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"233861",title:"Prof.",name:"Elena",middleName:null,surname:"Kostenko",fullName:"Elena Kostenko",slug:"elena-kostenko",email:"ekostenko58@mail.ru",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Morphofunctional, molecular, genetic and biochemical basis of circadian rhythm regulation",level:"1"},{id:"sec_2_2",title:"2.1. Morphofunctional features of suprachiasmatic nuclei and their connections with epiphysis",level:"2"},{id:"sec_3_2",title:"2.2. Molecular mechanisms of circadian oscillations",level:"2"},{id:"sec_4_2",title:"2.3. Melatonin involvement in the circadian rhythms regulation",level:"2"},{id:"sec_6",title:"3. Violation of CR and cerebrovascular diseases (CVD)",level:"1"},{id:"sec_6_2",title:"3.1. Desynchronosis as a risk factor for stroke",level:"2"},{id:"sec_7_2",title:"3.2. Stroke and sleep disorders",level:"2"},{id:"sec_7_3",title:"3.2.1. Characteristics of sleep disorders in patients with stroke",level:"3"},{id:"sec_8_3",title:"3.2.2. Features of sleep disorders depending on the type, localization of the focus, stage of stroke and development time of the stroke",level:"3"},{id:"sec_9_3",title:"3.2.3. Sleep disorders and recovery from stroke",level:"3"},{id:"sec_12",title:"4. CR disorders in patients with DVB and development of cognitive disorders",level:"1"},{id:"sec_13",title:"5. Conclusion",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"},{id:"sec_17",title:"Conflicts of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Rapoporta SI, Frolova VA, Khetagurova LG. Khronobiologiya i khronomeditsina: Rukovodstvo/Pod red. M.: OOO “Meditsinskoe informatsionnoe agentstvo”, 2012. 480 p. (in Russian)\n'},{id:"B2",body:'Agadzhanyan NA, Gubin DG. Desinkhronoz: mekhanizmy razvitiya ot molekulyarno-geneticheskogo do organizmennogo urovnya. Uspekhi fiziologicheskikh nauk. 2004;35(2):57-72 (in Russian)\n'},{id:"B3",body:'Sergey MC, Rapoport SI, Agarval RK, et al. Potential chronobiological triggering factors of acute heart attack~!2009-12-29~!2010-01-11~!2010-04-22~!. The Open Nutraceuticals Journal [Internet]. May 20, 2010;3(3):166-173. 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RMZh. 2008;12:1677-1681 (in Russian)\n"},{id:"B88",body:'Chen X, Bi H, Zhang M, Liu H, Wang X, Zu R. Research of sleep disorders in patients with acute cerebral infarction. Journal of Stroke and Cerebrovascular Diseases [Internet]. Nov 2015;24(11):2508-2513. DOI: 10.1016/j.jstrokecerebrovasdis.2015.06.033\n'},{id:"B89",body:'Kerkhof GA. Epidemiology of sleep and sleep disorders in the Netherlands. Sleep Medicine [Internet]. Feb 2017;30:229-239. DOI: 10.1016/j.sleep.2016.09.015\n'},{id:"B90",body:'Suh M, Choi-Kwon S, Kim JS. Sleep disturbances at 3 months after cerebral infarction. European Neurology [Internet]. 2016;75(1-2):75-81. DOI: 10.1159/000443763\n'},{id:"B91",body:'Ruppert E, Kilic-Huck U, Wolff V, et al. Brainstem stroke-related restless legs syndrome: Frequency and anatomical considerations. European Neurology [Internet]. Nov 26, 2014;73(1-2):113-118. DOI: 10.1159/000366416\n'},{id:"B92",body:'Silber MH, Ehrenberg BL, Allen RP, et al. An algorithm for the management of restless legs syndrome. Mayo Clinic Proceedings [Internet]. Jul 2004;79(7):916-922. DOI: 10.4065/79.7.916\n'},{id:"B93",body:'Walters AS, Rye DB. Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease, and stroke. Sleep [Internet]. May 2009;32(5):589-597. DOI: 10.1093/sleep/32.5.589\n'},{id:"B94",body:'Polujektov MG, Bahrevskij IE, Koshelev IJ i dr. Rasstrojstva dyhanija vo sne pri cerebral\'nom insul\'te. Zhurn. nevrol. i psihiat. 2002;5:22-26 (in Russian)\n'},{id:"B95",body:'Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of sleep apnea to functional capacity and length of hospitalization following stroke. Sleep. 2003;26:293-297. DOI: 10.1093/sleep/26.3.293\n'},{id:"B96",body:'Dognin C, Stana L, Jousse M, et al. Lack of repercussions of sleep apnea syndrome on recovery and attention disorders at the subacute stage after stroke: A study of 45 patients. Annals of Physical and Rehabilitation Medicine. 2014 Dec;57(9-10):618-628. DOI: 10.1016/j.rehab.2014.09.008\n'},{id:"B97",body:'Hermann DM, Bassetti CL. Role of sleep-disordered breathing and sleep-wake disturbances for stroke and stroke recovery. Neurology. Sep 27, 2016;87(13):1407-1416. DOI: 10.1212/WNL.0000000000003037\n'},{id:"B98",body:'Koehler U, Cassel W, Hildebrandt O, et al. Obstructive sleep apnea in neurological diseases: Specially as a risk factor for stroke. Nervenarzt. 2014;85(1):35-42. ISSN: 1433-0407\n'},{id:"B99",body:'Menon D, Sukumaran S, Varma R, Radhakrishnan A. Impact of obstructive sleep apnea on neurological recovery after ischemic stroke: A prospective study. Acta Neurologica Scandinavica. Feb 15, 2017. DOI: 10.1111/ane.12740\n'},{id:"B100",body:'Zhang Y, Wang W, Cai S, Sheng Q, Pan S, Shen F, Tang Q, Liu Y.Obstructive sleep apnea exaggerates cognitive dysfunction in stroke patients. SleepMed. Feb 4, 2017. pii: S1389-9457(17)30033-3. DOI: 10.1016/j.sleep.2016.11.028\n'},{id:"B101",body:'Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: Findings from the Global Burden of Disease Study 2010. The Lancet Global Health [Internet]. Nov 2013;1(5):e259-e281. DOI: 10.1016/s2214-109x(13)70089-5\n'},{id:"B102",body:'Joa K-L, Kim W-H, Choi H-Y, et al. The effect of sleep disturbances on the functional recovery of rehabilitation inpatients following mild and moderate stroke. American Journal of Physical Medicine & Rehabilitation [Internet]. Oct 2017;96(10):734-740. DOI: 10.1097/phm.0000000000000744\n'},{id:"B103",body:'Kovaleva NS. Ispol\'zovanie kolichestvennoj jelektrojencefalografii pri ishemicheskom insul\'te v uslovijah primenenija melatonina. Diss. … kand. med. nauk. Pjatigorsk. 2011 (in Russian). Available from: http://medical-diss.com/medicina/ispolzovanie-kolichestvennoy-elektroentsefalografii-pri-ishemicheskom-insulte-v-usloviyah-primeneniya-melatonina [Accessed: Feb 1, 2018]\n'},{id:"B104",body:'Shi L, Chen S-J, Ma M-Y, Bao Y-P, Han Y, Wang Y-M, et al. Sleep disturbances increase the risk of dementia: A systematic review and meta-analysis. Sleep Medicine Reviews [Internet]. Jul 2017. DOI: 10.1016/j.smrv.2017.06.010\n'},{id:"B105",body:'Pase MP, Himali JJ, Grima NA, Beiser AS, Satizabal CL, Aparicio HJ, et al. Sleep architecture and the risk of incident dementia in the community. Neurology [Internet]. Aug 23, 2017;89(12):1244-1250. DOI: 10.1212/wnl.0000000000004373\n'},{id:"B106",body:'Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: Quality of sleep and next-day alertness outcomes. Current Medical Research and Opinion [Internet]. Sep 14, 2007;23(10):2597-2605. DOI: 10.1185/030079907x233098\n'},{id:"B107",body:'Jean-Louis G, Gizycki H, Zizi F. Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. Journal of Pineal Research [Internet]. Nov 1998;25(3):177-183. Available from: 10.1111/j.1600-079x.1998.tb00557.x\n'},{id:"B108",body:'Peck JS, LeGoff DB, Ahmed I, Goebert D. Cognitive effects of exogenous melatonin administration in elderly persons. The American Journal of Geriatric Psychiatry [Internet]. Jul 2004;12(4):432-436. DOI: 10.1097/00019442-200407000-00011\n'},{id:"B109",body:'Cardinali D, Vidal V. New developments in the treatment of primary insomnia in elderly patients: Focus on prolonged-release melatonin. ChronoPhysiology and Therapy [Internet]. Oct 2012;67. DOI: 10.2147/cpt.s15514\n'},{id:"B110",body:'Zharkovskiy A. Study of the effect of memantine + melatonin combination on memory disorder and brain cell death after administration of beta-amyloid (25-35) peptide fragment into lateral brain ventricle of mice. 2012. Study Report. Institute of Pharmacology Biomedical Center, University of Tartu, Estonia. Available from: https://elibrary.ru/download/elibrary_21080831_33108041.pdf at 01.02.2018\n\n'},{id:"B111",body:'McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database of Systematic Reviews [Internet]. Nov 16, 2016. DOI: 10.1002/14651858.cd009178.pub3\n'},{id:"B112",body:'Riemann D, Baglioni C, Bassetti C, Bjorvatn B, et al. European guideline for the diagnosis and treatment of insomnia. Journal of Sleep Research. 26:675-700. DOI: 10.1111/jsr.12594\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Elena Kostenko",address:"ekostenko58@mail.ru",affiliation:'
Pirogov Russian National Research Medical University, Russia
Restorative and Sports Medicine of Moscow Healthcare Department, Moscow Centre for Research and Practice in Medical Rehabilitation, Russia
Restorative and Sports Medicine of Moscow Healthcare Department, Moscow Centre for Research and Practice in Medical Rehabilitation, Russia
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1. Introduction
A stroke is defined by the abrupt and sudden onset of neurological signs and symptoms that occur due to a disorder in cerebral blood circulation. It can be due to an excess of blood in the cranial cavity, which is in expansible, called hemorrhagic stroke; or due to insufficient blood supply of oxygen and nutrients to the parenchyma: an ischemic stroke. Strokes usually have symptoms related to a focal brain lesion, an abrupt onset followed by stabilization with a tendency to regress, and predisposing risk factors.
We should suspect it when the following symptoms suddenly appear: weakness or numbness of a half body; difficulty speaking or understanding language; vision difficulty in one or both eyes having ruled out ophthalmological pathology, vertigo, or instability associated with other neurological symptoms or signs.
Cerebrovascular diseases are the second cause of morbidity and mortality in the world [1].
There is an estimated prevalence of about 80 million people with stroke worldwide. In 2016, of the 80.1 million affected, 41.1 were women and 39 were men [1].
The highest risk of stroke is found in populations in East Asia, Central Europe, and Eastern Europe. In terms of race, the incidence per 100.000 inhabitants of ischemic stroke is higher in black than in Hispanic, and higher in Hispanic than in white; being all the etiologies of stroke more frequent in black, except cardioembolic [2, 3].
In the last 30 years, a decrease in the incidence and mortality from stroke has been observed due to the better control of vascular risk factors, health education, and advances in the treatment of the acute phase of stroke. This improvement, unfortunately, is not universal and is highly influenced by the economic situation and the educational background of the population in each geographic area. In recent years, a decrease in the incidence of stroke has been observed in whites, remaining constant in blacks [4].
Hand in hand with the global decrease in incidence and mortality rates is the increase in the prevalence of stroke and its social health impact, due to a longer life expectancy and increased survival rate of patients suffering from cerebrovascular events.
Stroke patients have a high risk of poor prognosis during the first year after the event, including rehospitalization (33%), recurrence (7–13%), dementia (7–23%), mild cognitive disorder (35–47%), depression (30–50%) and fatigue (35–92%), all contributing to affect health-related quality of life [5, 6].
Stroke units and revascularization therapies have changed the stroke prognosis [7]. The role of rehabilitation is to help improve deficits, regain functionality and define the needs and care in patients with permanent disabilities. Disability in stroke varies according to the initial severity, the location of the injury, the patient’s pre-morbid state, the degree of neurological recovery, and the support system that surrounds the patient [7, 8].
It is evidenced that comprehensive rehabilitation after stroke has a prognostic impact that is maintained in the long term, in the form of a better functional situation for the patients who access it. Functional recovery through comprehensive rehabilitation allows patients to remain in their usual environment, perform their work duties and carry out activities of daily life autonomously, reducing the need for institutionalization in long-term care facilities [9].
The recommendations of the King’s College research team, in collaboration with the European Alliance Against Stroke, which presented the document “The impact of stroke in Europe to the European Parliament”, indicate that multidisciplinary evaluations should be carried out in the stroke unit and the rehabilitation should start as soon as the patient is medically stable. People who start rehabilitation within the first week after admission have better long-term results than those who start their rehabilitation later [10].
2. Stroke rhabilitation
2.1 Pathophysiology and principles of neurological rehabilitation
The cells of the nervous system and the endothelial cells are continuously interacting with each other and with the extracellular matrix in order to maintain continuous cerebral homeostasis, forming a functional unit called the neurovascular unit. It is made up of neurons, interneurons, astrocytes, basal lamina lined with smooth muscle cells and pericytes, endothelial cells, and an extracellular matrix [11]. All these elements, interconnected with each other, constitute a highly efficient system for regulating cerebral blood flow [11]. Cerebrovascular events alter the correct molecular communication between each of the elements of the neurovascular unit, generating a functional dysregulation that leads to the damage of the tissue. In the functional recovery phase after an ischemic stroke, compensatory neurovascular signaling at this level favors the repair mechanisms that involve angiogenesis and neurogenesis, thus intervening in achieving the most complete functional recovery possible [12].
Astrocytes play a fundamental role in cerebrovascular events, both in the establishment of the definitive lesion and in the process of tissue repair. During ischemia, the first morphological change observed is the edema of astrocytes, being one of the responsible factors for the decrease in glutamate reuptake. The edema may be surrounding the lesion up to 8 weeks after the stroke, which may alter the functioning of nearby neurons by blocking neuronal conduction [10].
Glial cells that survive the ischemic episode undergo a process of hypertrophy and proliferation, known as reactive gliosis, which has been related to mechanisms of neuroprotection and repair of ischemic injuries [13].
Recovery after stroke is associated with cortical reorganization [8]. After a cerebrovascular event, the tissue recovery that takes place during weeks, months, or years after the acute event is related to different physiological phenomena: dendritic growth, formation of new synapses (synaptogenesis), functional reorganization in the injured area or participation of other neighboring or homologous areas of the contralateral hemisphere in the process. These phenomena can occur spontaneously and they can be facilitated and directed by rehabilitative therapeutic interventions [13].
In ischemic stroke, the obstruction of a cerebral artery generates local changes in cerebral blood flow (CBF). Under normal conditions, CBF through adult brain tissue is >50 ml/100 g of brain parenchyma/minute. When the CBF is reduced in a certain area of the brain below 10 ml/100 g/min, a severe cerebral dysfunction is produced. This leads to a complete neuronal, structural and functional loss in that location in a short time; it is called the core of the infarction. Between this nucleus of ischemic infarction and the normally perfused brain parenchyma, there is a moderately vascularized region, the extent of which depends on the functioning of the collateral circulation, called the penumbra zone, in which two zones with different prognosis are differentiated: oligohemia zone (22–0 ml/100 g/min) and ischemic penumbra zone (10–22 ml/100 g/min) [14, 15]. The oligohemia zone is a hypoperfused zone that still maintains its functionality, while the ischemic penumbra is a hypoperfused and functionally inactive zone that limits the edges of the infarcted area but is still viable if CBF is recovered early [11]. Current strategies for acute reperfusion in ischemic stroke are aimed at restoring cerebral perfusion in the ischemic penumbra [11]. The therapeutic window in ischemic stroke is the time that elapses between the onset of ischemia and the moment in which the neuron located in the ischemic penumbra loses its ability to survive. After this time, reperfusion of the ischemic zone will be useless [13].
The tissue that survives a cerebrovascular event has the ability to adapt and reorganize itself anatomically and functionally to rebuild or replace synaptic connections that have been injured and reinforce neural networks that have remained after injury. This phenomenon is known as neuroplasticity [15], and neurological rehabilitation therapies play a fundamental role in its enhancement [16]. The key to activating neuronal plasticity is the repetition of the affected function, so all those treatment techniques that favor the performance of a function and its repetition will promote brain plasticity and the recovery of patients [9, 10].
The functional reassignment of the different healthy cortical areas to supply the deficit in the damaged area is called brain remapping [12].
The neuroanatomical, neurochemical, and functional changes that occur during the reorganization by neuroplasticity will facilitate, in some cases, the recovery of the affected functions (adaptive neuroplasticity). On other occasions, as a consequence of this reorganization in favor of some functions, the development of others may be hindered (maladaptive neuroplasticity) [17].
The most important cortical functions are not linked to specific anatomical regions, but rather depend on neural networks made up of neurons of diverse cortical locations interconnected with each other and distributed throughout the cerebral cortex [15, 18].
Although some functions of a neural network are specifically ascribed to a region of the same (e.g.: the execution of language to Broca’s area), the lesion in that specific area may have little clinical translation if the remaining structures that makeup that network take over functional relief and thus compensate for the defect.
If the damage to a functional system is partial, recovery within the system itself is possible. On the other hand, if the damage is complete, replacement by a functionally related system is the only alternative for the functional recovery of the injured area. Each of the mechanisms involved in the post-injury functional recovery process will depend on the magnitude of the brain damage [16].
Although the basic mechanisms of neuroplasticity are common to the entire cerebral cortex, the pattern of cortical reorganization in the functional recovery of the different capacities is not the same, and the peculiarities in these patterns support the different modalities of therapeutic intervention for the different deficits: motor, sensory and cognitive (Table 1) [17, 19].
Mechanisms of plasticity in neural networks
Mechanisms of plasticity in synapse
Recovery of neuronal excitability
Changes in intracellular signaling
Activation of neural pathways partially unscathed
Generation of axonal sprouting and dendritic from uninjured collaterals
Plasticity with assembly type neurons
Axonal regeneration
Synaptic unmasking dependent on neural activity.
Unmasking of networks previously existing but functionally inactive
Recruitment of neural network components
Long-term potentiation
Modulation by neurotransmitters of the excitability of subnetworks.
Motor recovery is a complex process that combines intrinsic or spontaneous neurological recovery and functional recovery. Intrinsic neurological recovery is the recovery of normal movement patterns, being the severity of the initial deficit inversely proportional to the recovery prognosis. It occurs generally within the first 1–3 months after the event. Functional recovery is the regaining of basic tasks or activities of daily life through learned compensatory movements (new movement patterns), which depends on motivation, learning capacity, family support, and the quality and intensity of the rehabilitative therapy [8].
The structures that help restore motor activity and function after a brain injury can be gathered into three groups: intact perilesional areas of the ipsilateral primary motor cortex, ipsilateral and contralesionally auxiliary motor systems together with the structures responsible for executive control and contralateral motor system [20].
In addition to neuroplasticity phenomena, the post-injury recovery process involves mechanisms of regeneration, differentiation, and maturation of new neurons and support cells that facilitate the creation of new neural networks, thus allowing the replacement of damaged ones [16]. Neurogenesis, gliogenesis, and angiogenesis refer to the development and formation of new neurons, supporting glial cells, and blood vessels respectively [14, 15]. Neurogenesis takes place throughout life, although it is attenuated with age. In adults, it is discrete and basically restricted to two neurogenic areas: the subventricular zone close to the third ventricle and the infragranular area of the dentate gyrus of the hippocampus [15]. Several studies have shown that ischemic lesions of the central nervous system lead to an increase in the proliferation of neural stem cells located in the subventricular zone, which will subsequently differentiate into mature cells that will travel to the damaged brain areas through different biochemical mechanisms and molecular cell signaling. Neuronal death is a strong stimulus for neurogenesis after ischemic stroke, even when it occurs in brain territories that are located at a distance from neurogenic niches. However, the vast majority of these newly generated cells have low survival once they reach the damaged area, a fact that could be favored by detrimental factors in the perilesional environment, lack of neurotrophic support, and molecular signaling which is necessary for proper development [16].
Both in the phenomena of neuroplasticity and cell regeneration, epigenetic regulation through mechanisms that include DNA methylation, histone modification and the action of micro-RNAs (miRNA) play a fundamental role [16].
2.2 Disability measurement scales
2.2.1 Disability of basic activities of daily living
2.2.1.1 Barthel scale
The most widely used and the fastest index of functional independence. Its completion time is 5 min. The maximum score is 100 points (complete functional independence for activities of daily living) and a score below 20 points will show a great dependency level. It rates the level of dependency with feeding, movement, personal grooming, getting on and off the toilet, bathing, walking on a level surface, ascend and descend stairs, dressing and undressing, and bowel and bladder continence [21].
2.2.1.2 Functional Independence Measure (FIM)
Assesses physical and cognitive disability according to the level of assistance required to carry out activities of daily life. Its completion time is 30–40 min. It consists of 18 items that assess 6 areas of function that are summarized in 2 basic domains: physical and cognitive. Each item scores on a scale of 1–7 (1 = total dependence and 7 = total independence), with a maximum score of 126 points. An unfavorable prognostic factor of function is considered a score less than 40 or a score less than 60 in people older than 75 years [9].
2.2.2 Motor disability
2.2.2.1 Motor index
It is a simple, fast scale: its completion time is 5 min and it is useful to assess voluntary motor activity in three basic movements of the upper limb (shoulder abduction, elbow flexion, and handgrip) and another three in the lower limb (hip flexion, knee extension, and foot dorsiflexion). 0 represents total paralysis and 100 represents normality [9].
2.2.2.2 Fugl-Meyer scale
It is used to assess the function and control of the musculoskeletal system, including balance, sensitivity, and joint pain in patients who have suffered a stroke. It has the disadvantage that it requires training for the evaluators, and its application is very slow, taking about 30–40 min. It consists of 155 items, each of which is scored on a three-point ordinal scale. The maximum motor performance score is 66 points for the upper limb, 34 points for the lower limb, 14 points for balance, 24 points for sensitivity, and 44 points each for passive joint movement and joint pain. A maximum of 266 points can be reached [9, 10].
2.2.3 Cognitive disability
2.2.3.1 Mini Mental State Examination (MMSE)
It is a brief test for the detection and quantitative evaluation of cognitive impairment. Its maximum score is 30 and the threshold value for cognitive impairment is 23. It consists of 11 questions that assess orientation in time and space, fixation, attention and calculation, memory, nomination, repetition, understanding, reading, writing, and replication of a drawing. The test is valid as a screening tool and is sensitive to detect moderate/severe impairment, but not mild impairment [10].
2.2.3.2 Montreal Cognitive Assessment (MoCA)
It is a short test that can be performed in 12 min to detect mild cognitive impairment. It consists of 30 questions, the score ranges from 0 to 30. A score above 26 is considered normal. It evaluates different types of cognitive abilities, including orientation, short-term memory, delayed recovery, executive function, visuospatial ability, language skills, abstraction, object naming, and attention [22].
2.2.4 Disability for communication
2.2.4.1 Boston aphasia test
It requires 1–4 h to do and consists of 16 slides for the diagnosis of aphasia and 60 graphic elements for the vocabulary test. 1 point is awarded for each correct answer, the maximum score being 60. A score above 50 is considered normal [23].
Sagunto Hospital Functional Gait Categories (FACHS) allows a quick, valid, sensitive, and reliable assessment of ambulation, allowing to determine the walking speed of stroke patients. It has 6 self-exclusive and self-explanatory function levels. Level 0: impossible; 1: completely dependent; 2: dependent hand; 3: free; 4: prolonged and 5: normal [10].
2.2.6 Stroke severity
2.2.6.1 Modified Rankin scale
It is a scale to measure functional outcomes in post-stroke patients. Assigns a score of 1–5 based on the level of independence from pre-stroke activities. 0: Asymptomatic; 1: No significant disability, able to carry out all usual duties and activities; 2: Mild disability, unable to carry out all previous activities but able to look after own activities without assistance; 3: Moderate disability, requiring some help, but able to walk without assistance; 4: Moderately severe disability, unable to walk and to attend to own bodily needs without assistance; 5: Severe disability: bedridden, incontinent, and requiring constant nursing care and attention [24].
2.2.6.2 National Institutes of Health Stroke Scale (NIHSS)
It is a measure of somatosensory function used in the acute phase with patients who have suffered a stroke. It is made up of 11 items: level of consciousness, conjugate look, visual fields, facial paresis, paresis of upper extremities, lower extremity paresis, limb ataxia, sensitivity, language, dysarthria, extinction/neglect/inattention. It determines the severity of the stroke: Mild <4, Moderate <16, Severe <25, Very severe ≥25 [10].
2.2.6.3 Canadian Neurological Scale (CNS)
It is also used in the acute phase to assess the neurological status of stroke patients. Ten clinical domains are measured, including mental state: level of consciousness, orientation, language, and motor functions: face, proximal arm, distal arm, leg [10].
2.3 Upper and lower limb motor rehabilitation
Stroke is one of the main causes of disability in adults, and the demand for rehabilitation services after suffering a cerebrovascular event is very high.
Motor deficit is the main cause of physical disability in stroke and the area in which rehabilitation works as a priority. It is usually unilateral, although in more severe patients bilaterally innervated muscle functions, such as trunk control, may be affected [25, 26].
Hemiparesis or hemiplegia is the most prevalent deficit in stroke, being the symptom that is more worrying for the patient and their relatives, and the main indicator of treatment expectations [27]. The rehabilitation program consists of different phases.
2.3.1 Rehabilitation in the acute phase
It covers the first 2 weeks after a stroke and it must be started soon when they are still in the stroke unit [25, 27]. All patients with acute stroke should be evaluated by the rehabilitation physician in the first 24–48 h to assess the deficit and initiate measures to prevent future complications, grade of recommendation A [27].
It is necessary to correctly align the patient in bed, make frequent postural changes, and place the joints in a functional position, with the help of orthoses and pillows. Adduction and internal rotation of the shoulder and flexion of the wrist and hands, as well as hips, knees, and ankles, which tend to extension and varus should be avoided [27].
The immobilization of the muscles in a shortened position is the initial mechanism for the development of contractures, which are objectified as an increase in resistance to passive movement, a situation that, if maintained, will decrease the joint range [26].
Therefore, once the patient is hemodynamically stable, passive kinesitherapy of the affected hemi body will be started [27], performing passive exercises of the full joint arch on a daily basis in the routes susceptible to muscle shortening. Prolonged muscle stretching is more effective than a brief passive exercise. It is also necessary to stimulate the mobility of the unaffected side since immobility weakens its strength [26].
Likewise, the patient will receive instruction to perform functional tasks, such as getting up in the bed and recovering adequate trunk control, which later allows sitting, self-mobilization, and transfers, as well as standing and walking depending on the degree of involvement [27].
In addition, respiratory physiotherapy treatment and global stimulation of the patient should be started [25].
Early mobilization and immediate rehabilitation appear to be the main variables associated with getting the best results in stroke units, by reducing bed-ridden complications (such as aspiration pneumonia, deep vein thrombosis, and pulmonary embolism as a consequence of immobility, contractures and pressure ulcers, potentially avoidable through frequent postural changes) [26].
Current evidence confirms that the more intensive the stroke rehabilitation treatment after the first 24 h, the better the functional results [27].
2.3.2 Rehabilitation in the subacute phase
From 2 weeks to 4 months after the stroke. Patients should be treated both during their hospital stay and after discharge, by units that are specialized in stroke rehabilitation treatment, recommendation grade A [27].
The objective during this phase is to gain the maximum degree of functionality possible by adapting to the deficits [25]. Recovery of motor activity usually follows a proximal to distal order. In cases of partial motor recovery, synergistic mobility patterns may develop. Proximal muscle contraction may induce distal contraction with the mass movement of the limb. The predominant synergies are antigravity: flexor in the upper limb and extensor in the lower [26].
The patient will learn new motor skills through experience and training for the phenomenon that constitutes brain plasticity. This brain reorganization substrate can be modulated by different rehabilitation therapies [26]. These therapies are very varied, and each physiotherapist applies them according to their knowledge and experience. There is no evidence that any type of physiotherapy shows superior results to the others [25].
2.3.2.1 Compensation techniques
They seek to reeducate residual capacities, especially of the unaffected hemi body, to improve function [26]. They are indicated in severe patients with a poor prognosis or in the stabilization phase [25].
2.3.2.2 Neuromotor techniques or facilitating techniques
Their objective is to improve the quality of movement on the affected side. There are different methods [26, 27]:
Bobath method: inhibition techniques (which reduce spasticity, synergies, and abnormal patterns), facilitation techniques (favor the development of normal posture patterns) are applied and the incorporation of the plegic side in therapeutic activities is promoted [25].
Brunnstrom method: It is based on the stimulation of synergies for the performance of analytical movements that the patient does not perform voluntarily [26].
Proprioceptive neuromuscular facilitation (Kabat): its main objective is to improve muscle weakness. It uses peripheral stimuli of superficial (touch) or deep origin (joint position, stretching) to improve muscle strength and coordination. It is based on movement patterns in which weak muscles are aided by stronger agonists [25].
2.3.2.3 Motor relearning techniques or task-oriented rehabilitation
It aimed at improving the execution of specific tasks that have a practical meaning in the patient’s life [27]. Learning requires repetitive and intense training, progressive in its difficulty, with feedback on what is being done and motivation strategies [26].
2.3.2.4 Therapy of movement induced by restraint of the healthy side
It is based on experimental studies carried out by Taub in 1977 with monkeys that had undergone a dorsal rhizotomy, showing that they were able to use the affected limb by immobilizing the healthy side [27].
2.3.2.5 Technology applied to task-oriented rehabilitation programs
For example, functional electrical stimulation (FES) applied to the lower extremity as an alternative to an antiequine orthosis or biofeedback to the patient (FES-EMG). Technology can facilitate the automation of the activity to be trained [26].
In this phase, the assessment and treatment of spasticity are also important, and the prescription of drugs or the application of botulinum toxin on the spastic muscles and/or orthoses that maintain muscle stretching may be necessary [25].
Rehabilitative treatment of the upper extremity: Unlike the lower limb, only a minority of patients achieve satisfactory functional use of the upper limb. The purpose of the rehabilitation treatment will be to reach the maximum possible functionality of the affected upper limb [25]. The specific techniques used for its treatment are [27]:
Assisted passive and active kinesitherapy of the affected upper limb, as well as muscle strengthening.
Mental imagery: Mental practice of movements and activities helps the functional recovery of the affected side.
Induced movement therapy with suppression of the healthy side: The best results with this therapy have been obtained when applied 3–9 months after cerebrovascular disease and it has been shown to be superior to conventional therapies in the motor recovery of the paretic upper limb, improving grip and speed of movement in carrying out activities of daily living.
Mirror therapy: It is effective in the motor recovery of the affected limb as well as in the reduction of pain. Visual feedback is used through a mirror, mobilizing both extremities, but observing the healthy side reflected.
Virtual reality: A simulation of the real environment is produced, generating human-computer feedback, while the patient performs the programmed exercises. Currently, it has been shown to be superior to conventional occupational therapy in improving the disability of the affected limb, also enhancing the effects of the latter.
Functional electrical stimulation and simultaneous performance of task-oriented exercises:The synchronization between the increase in sensory inputs to the CNS and muscle contraction stimulates motor recovery.
Robot-assisted therapy in the upper limb: It is used when the patient lacks sufficient strength. As an adjuvant therapy to physiotherapy, it makes it possible to increase the intensity of treatment, improving motor function in the shoulder, elbow and wrist, although it has not been shown to improve ADL performance.
Transcranial stimulation: It favors neuroplasticity phenomena, interfering with the patient’s learning and motor function in a noninvasive and safe way.
Rehabilitative treatment of the lower extremity: It should start in the first days. A good mastery of orthostasis and some motor coordination should be achieved as soon as possible [25]. The main objective is to improve mobility and restore motor control of standing and walking (recommendation grade A) [26], to achieve greater independence and reduce energy costs [25]. In general, patients who are capable of performing transfers and standing safely in the subacute phase recover ambulation, in some cases requiring the use of technical aids such as anti-equine orthoses, canes, or a walker [26].
Normally the following phases are followed: initiation of standing, balance re-education, parallel standing, and walking [25]. The following techniques are used [27]:
Passive, assisted and active kinesitherapy, as well as muscle strength training, being the strength of the quadriceps essential for dynamic stability during the support phase of walking.
Re-education of balance: Affected in patients with stroke due to impaired motor control in the trunk and lower extremity, as well as the sensitivity of the corresponding hemibody and a perception disorder, which makes it difficult for the patient to achieve correct maintenance of balance. Its treatment is essential since it can reduce the risk of falls.
Physical reconditioning: It is necessary to carry out an individualized aerobic training program that involves large muscle groups, to combat fatigue and increase cardiovascular resistance. Monitoring of heart rate and blood pressure is recommended during the performance of the same.
Treadmill gait training with or without body weight offloading: It improves gait parameters, increasing monopodal support on the affected side and step alternation, as well as physiological activation of the spinal erectors [25].
FES of the affected lower limb: It improves strength and deformity, but the effect is not maintained over time [25].
Rehabilitation is a time-limited process. Beyond the sixth month after the stroke, there is a stabilization phase in functional recovery. To indicate additional intervention in the chronic phase, it is necessary to set a realistic goal, have a rehabilitation technique with evidence of being effective in achieving that goal, and objectify progress towards the planned goal on a practical scale [26].
There are different studies about motor limb rehabilitation.
The AMOBES trial [28] found that additional physical therapy aimed at reducing complications of immobility had similar benefits at a lower dose of physical therapy. Studies performed in the early subacute stage of stroke, treating patients with neuromuscular electrical stimulation, functional stretch training, and task-oriented training, showed similar benefits to routine care for upper extremity functional capacity [29].
The EXPLICIT trial [30] found that restricted movement therapy led to an increase in upper limb capacity in the first 12 weeks after stroke, without maintaining this benefit at 26 weeks.
The VIRTUES [31] and EVREST [32] studies carried out an investigation on the effects of virtual reality and video games on the motor capacity of the upper extremities during the subacute stage of stroke.
The RATULS trial [33] investigated the effects of robot-assisted therapy on upper limb motor ability in the chronic stage of stroke. All of these trials illustrate the feasibility of using these technologies on a large scale and report benefits similar to those produced by an equivalent dose of recreational activities or conventional therapies [29].
2.4 Aphasia and apraxia rehabilitation
Aphasia is an alteration of oral (comprehension and/or expression) or written (reading/writing) language as a consequence of a brain injury. 21–38% of stroke patients will present with some type of aphasia.
Dysarthria is the alteration that occurs in speech as a consequence of muscular dyscontrol in the buccophonatory organs due to the lesion, affecting its clarity.
It is necessary to differentiate it from apraxia, which is the decrease in the ability to voluntarily plan and execute the appropriate movements for the articulation of speech, without affecting the muscles involved in speech [34].
In the subacute and chronic phases, recovery from language and speech disabilities will depend on neuroplasticity processes, so specific assessment by specialized professionals and the start of speech therapy treatment during the subacute phase will be essential [27].
The period of recovery is variable, it is considered that during the first 6 months the speed of recovery is much higher and later it slows down, until almost stabilizing after the first year [26].
The treatment of these patients aims to increase the patient’s linguistic capacity, providing them with tools to deal with the situation and make up for the deficit. It should be individualized, early (as soon as the patient is stable, able to cooperate with an acceptable level of care, and not excessively fatigued), and intensive [34]. There is an inverse relationship between the time elapsed from the onset of the deficit to the start of treatment and the magnitude of its effect. The magnitude of the effect is directly related to the frequency and intensity of treatment. The therapies usually offered in our environment, which are usually 2 h/week in the best of cases, have effects that are barely superior to those of spontaneous recovery [27]. Its efficacy has been demonstrated with RCTs with frequencies of 3 h/week or 5 h/week [26].
The speech therapist can opt for three treatment strategies, not mutually exclusive, and that depends on the severity, the evolutionary moment, and the characteristics of each patient [26]:
2.4.1 Recovery of specific linguistic deficits
Recovering the norm, the function is recovered. For example, in Wernicke’s aphasia, working on phonological discrimination with specific exercises to differentiate phonemes [26].
2.4.2 Reorganization of the function
Starting from the intact skills. It would be applied to the same patient trying to improve oral comprehension by promoting the use of more preserved semantic comprehension. The important thing is that he understands the messages, not that he maintains certain linguistic skills. It is usually the most used and effective strategy, especially in moderate or severe aphasia [26].
2.4.3 Substitution of lost linguistic abilities by any other mechanism that ensures communication
In the same patient, his or her close environment is taught to increase expressiveness and to increase the gestural code used. It is usually necessary for patients with global or very severe aphasia, in addition to technical aids and augmentative or alternative communication [26].
As long as identifiable goals exist and progress persists, the aphasic patient should continue to receive treatment with regular and objective assessment of progress [25].
2.5 Cognitive and perceptual rehabilitation
Cognitive impairment secondary to stroke is a frequent complication, with a prevalence ranging between 20 and 80%. The risk of cognitive impairment is related to demographic factors (age, education, or occupation of the patient) and vascular factors, although it can be stated in general terms that this risk is increased between 5 and 8 times more after suffering a stroke [35, 36]. Its presence is associated with a lower quality of life 12 months after the stroke, an increased risk of dementia (vascular dementia), mortality and institutionalization rates, as well as an augmented burden on the caregiver and bigger health expenses [37]. However, despite being a common and serious complication that carries a poor prognosis in the medium and long term, it is an underdiagnosed entity [38]. Assessment of cognitive functions should always be done routinely in the clinical care of stroke patients prior to discharge home [39]. To reduce cognitive consequences after stroke, the cognitive impairment must be properly characterized, the underlying causes of cognitive decline understood, and the efficacy of different treatment and rehabilitation approaches determined [40].
Cognition is an aggregate of different cognitive domains that are not independent of each other but are interrelated through neural networks. These cognitive domains could be outlined as follows [40]: attention (focusing, shifting, dividing, or maintaining attention on a particular stimulus or task); executive functions (work planning, organization of thoughts, capacity for inhibition, control, and monitoring of responses, instrumental adaptation); visuospatial skills (visual search, drawing, construction); praxic function and perceptual/recognition skills (gnosis); memory (recall and recognition of visual and verbal information) and language (expressive and receptive, verbal and non-verbal, reading and writing).
A common finding in patients with cognitive impairment secondary to cerebrovascular lesions, and one that appears to be a consistent pattern, it is deficits in attention, executive functions, and processing speed [41]. Memory impairment, highly compromised in patients with Alzheimer’s Disease, is not usually the most obvious cognitive deficit after a stroke; only about half of the people with vascular cognitive impairment present amnesic signs, and approximately 30% of patients with vascular cognitive impairment will progress to a phase of dementia [42].
The location of the lesion constitutes a determining factor in the clinic of cognitive deterioration after stroke [43]. Strategic infarcts in specific locations in the brain are capable of causing a postictal cognitive deficit, sometimes of acute/subacute onset. The first evidence in this regard was obtained after observing symptoms of cognitive impairment in the context of acute vascular thalamic lesions.
Some typical locations of strategic infarcts and their most characteristic clinical manifestations are described below (Table 2) [44].
Memory impairment, dysexecutive, speed of attention, and mental processing
Fornix
Severe anterograde memory impairment
Caudate Nucleus
Pronounced abulia, disinhibition, and affective disorders
Corpus Callosum
Pure alexia, visual agnosia, unilateral apraxia
Table 2.
Cognitive disorders after strategic strokes.
The most widely recognized neuropathological substrates include infarcts, hemorrhages, and global hypoxic-ischemic brain injury. White matter injury, including demyelination with or without axonal loss, is also common in people with vascular dementia, but is nonspecific and can also occur in the setting of neurodegenerative dementia, such as in AD. Similarly, cortical atrophy and hippocampal sclerosis may be related to both focal and diffuse hypoxic brain injury, but are also not specific to VD, and are also seen in neurodegenerative diseases [41].
Cognitive rehabilitation plays a fundamental role in multidisciplinary stroke rehabilitation and should be started as soon as possible in order to obtain the best functional results. It should not be done in isolation, but rather combined with physical measures and training in activities of daily living. Furthermore, physical activity by itself protects against cognitive decline by increasing cerebral blood flow and the expression of neurotrophic factors [45]. Interventions carried out in cognitive rehabilitation are broadly classified as direct repair/cognitive skills training to restore previously learned behavior patterns and training of compensatory strategies establishing new patterns of cognitive activity through internal compensatory cognitive mechanisms, or establishing new patterns of activity through external compensatory mechanisms such as external aids, environmental structuring, and support [45].
The objectives of cognitive rehabilitation are to reinforce previously learned behavior patterns, establish new patterns of cognitive activity through internal compensatory cognitive mechanisms for impaired neurological systems, establish new patterns of activity through external compensatory mechanisms such as external aid, or structuring and environmental support and to allow people to adapt to their cognitive disability [45].
2.5.1 Rehabilitation in attention, working memory, and processing speed
Rehabilitation in attention, working memory, and processing speed are three cognitive domains that constitute the cognitive triad that must be addressed first for the rehabilitation to be successful. Most exercises are based on the stimulus–response paradigm. The repeated activation and stimulation of the attentional systems facilitate changes in cognitive capacity, progressively increasing the attentional demand. Transcranial magnetic stimulation over the left dorsolateral prefrontal cortex can improve attention [46, 47].
2.5.2 Memory rehabilitation
In mild memory problems, compensatory strategies may be considered [45]. The use of internal strategies (visual images, semantic organization, and spaced practice) is an option for patients with a high degree of functional independence. Non-electronic external strategies (use of notebooks, wall calendars, notes, to-do lists) will be another valid option in patients with preserved executive functions. In more serious deficits, the use of external compensations through assisted technology (e.g., tablets, laptops) is recommended, as well as specific interventions aimed at facilitating the acquisition of specific skills (e.g., error-free learning). Virtual reality games could improve attention and visuospatial memory, while music therapy improves verbal memory.
2.5.3 Rehabilitation of executive functions
Executive dysfunction is the main component of neurobehavioral disorders in these patients [45]. It causes disruptive behaviors that have a great impact on the autonomy, functional independence, and social interaction of the patient. Intervention in groups constitutes a work tool of great value in these cases. It represents an opportunity to observe and work on cognitive and behavioral functioning and interpersonal interaction. The great variety of frontal symptoms (cognitive and behavioral) and the theoretical complexity of the exercises constitute some obstacles to which the designs of executive functional rehabilitation programs are exposed, which is why it is necessary to use different non-exclusive techniques such as modifications of the environment, restoration techniques, compensatory strategies, and educational interventions.
2.5.4 Dual-task training
Dual-task training requires subjects to perform complex cognitive and motor activities simultaneously, improving the coordination of various tasks. Dual tasks are important for different daily activities, such as walking while having a conversation [46].
2.5.5 Pharmacological treatments
Pharmacological treatments (acetylcholinesterase inhibitors, antidepressants, atomoxetine, methylphenidate, and modafinil) have not been shown to improve cognitive impairment in patients with cognitive impairment secondary to stroke, so their use must always be individualized [45].
2.5.6 Rehabilitation of perceptual and constructive abilities
Cortical perceptual abilities are defined as the ability to organize, process and interpret visual, tactile, or kinesthetic afferent information or both, and the capacity to act appropriately on the information received [47]. Some symptoms in relation to the compromise of perceptual activities are unilateral spatial neglect (the lack of information, response, or orientation to sensory stimuli presented on the contralateral side of the lesion, usually related to right parietal lesions. These patients can ignore food on one side of the plate, or attend only to stimuli on one side of the body) [48] and anosognosia (lack of awareness of the loss of an important bodily function, mainly hemiplegia. It is also more common in right parietal lesions) [49]. The left hemisphere is responsible for modulating arousal and attention in the right visual field, while the right hemisphere controls these processes in the left and right visual fields. Rehabilitative interventions must be implemented repeatedly, training the patient to voluntarily compensate for its deficits: seeking adaptation to the external environment with strategies that do not require the patient to be aware of the deficit [49], modifying behavioral conditions to affect the execution of observable tasks, trying to correct hemineglect without the conscious participation of the patient, or with the top-down strategies, in which the voluntary effort of the patient seeks to reduce or compensate the negligent side, following the indications given by the rehabilitator [50].
2.6 Behavior and psychological rehabilitation
The psychological and behavioral changes due to stroke are in most cases devastating, causing a marked decline in quality of life, which can be improved with neurorehabilitation. Anxiety is common during the first year after stroke, with one in three experiencing it, and it gets significantly less attention compared to other psychological problems after stroke. Anxiety significantly influences the quality of life and could be a predictor of depression [51]. Post-stroke depression occurs in 1 in 3 stroke patients and more than half of all cases are neither diagnosed nor treated. Symptoms usually occur within the first three months after the event [52]. These patients experience sleep disturbances, vegetative symptoms, and social withdrawal. In some patients, depression can be accompanied by suicidal thoughts or tendencies. Irritability is a very common symptom after stroke and a source of a great deal of distress to patients and caretakers [53]. All these psychological and behavioral problems can be tackled with group rehabilitation, psychological therapy, and drugs such as selective serotonin reuptake inhibitors.
There are other techniques that can help in mental health recovery and psychological rehabilitation after strokes, such as yoga and meditation. Both are known to reduce anxiety, fear, anger, stress, and depression in patients and caregivers, promote cardio-respiratory health, and reduce stroke-related risk factors such as carotid atherosclerosis, dyslipidemia, hypertension, diabetes, and coronary artery disease. Also, it was demonstrated that following practice of yoga and meditation made significant improvement in muscle power and range of movements in hemiplegic limbs and some positive effects in the Berg Balance Scale, Timed Movement Battery, and quality of life as assessed with the Stroke Impact Scale [54].
2.7 Rehabilitation technologies and remote rehabilitation
Rehabilitation technologies are defined as ‘those whose primary purpose is to maintain or improve an individual’s functioning and independence, to facilitate participation and to enhance overall well-being’ [54]. Such devices are quite helpful in engaging patient’s interests and motivation. A wide range of such applications are available:
2.7.1 Robotic devices and virtual reality
Robotic devices are machines capable of carrying out a series of complex actions automatically. Virtual reality consists of machines that produce interactive simulations to allow users to engage in environments that closely resemble the real world. Both techniques use visual and multisensory stimuli and facilitate joint movements, walking, improving muscle strength and motor function. Electromechanically assisted gait training combined with conventional physiotherapy is more effective than training without these devices [54].
To regain motor function after stroke, rehabilitation robots are increasingly integrated into clinics. The devices fall into two main classes: robots developed to train lost motor function after stroke: therapy devices, and robots designed to compensate for lost skills: assistive devices [55].
2.7.2 Electrical stimulation
Electrical stimulation is one of the most widely used therapy and its reported benefits include spasticity reductions, improvements in range of motion, improved sensation, and reduced pain, but its benefit in stroke rehabilitation has not been adequately demonstrated [54].
Remote rehabilitation is very useful after a stroke. Tele-rehabilitation, also known as e-rehabilitation, is the delivery of rehabilitation services over telecommunication networks and the internet, which provides access to rehabilitation services in a remote area using communication technology, minimizing the problem of living far away from these centers where rehabilitation can be offered.
Wearable sensor technology can also address many of these limitations, being able to offer home-based therapies which can be monitored remotely. Brain-computer interface or brain-machine interface is an upcoming technology in stroke rehabilitation, in which brain signals are recorded through a sensor, transmitted to a computer processor to decode it, and formulate a signal for intended actions with a robotic limb or wheelchair [54].
2.8 Predictive factors of recovery
The factors with the greatest weight in the functional prognosis after a stroke are the initial severity, the functionality before the event, the time between the stroke and the start of rehabilitation, and the cognitive status. The two most important predictors of functional recovery are initial stroke severity and age.
The patients who benefit the most from a rehabilitation program are usually those with better baseline functionality. Classification of patients can be made based on the severity of the stroke [8, 10].
2.8.1 Mild stroke
Mild deficits: FIM score > 80. NIHSS <5. There are no assessable cognitive deficits. Barthel >80.
2.8.2 Moderate stroke
Moderate deficits: FIM score 40–80. FIM engine 38–62. NIHSS 5–9. Normal level of consciousness with significant hemiparesis. Barthel 60–80.
2.8.3 Severe stroke
Severe deficits: FIM < 40 or motor FIM < 37. NIHSS >9. It is usually associated with severe motor deficits, impaired level of consciousness, and/or medical comorbidities. Barthel <60.
2.9 Community reintegration
Hospital discharge should never lead to an interruption in rehabilitation, and it is the responsibility of the healthcare organization and the professionals of the rehabilitation teams to ensure the continuity of the process. Hospital discharge planning should be approached from the initial stages of admission and should involve the professionals, the patients themselves, and their families or caregivers. Knowing possible problems and needs in advance facilitates reintegration into the community [51].
The perception of health among people with stroke sequelae 2 years after the stroke is lower than the general population. The factors that determine a lower quality of life are depression, having to depend on a third person, and the need for social help.
Rehabilitation programs are most effective when carried out at an early stage. Late rehabilitation is the one performed when most of the deficits have stabilized and the objective is to maintain recovered functionality, continue the adaptation process, and improve the performance of basic activities of daily life [51].
In patients undergoing rehabilitation programs, improvements in deficits, social participation, and quality of life can be seen even years after the event that generated the initial injury. It is important to make a selection of the appropriate approach to continue the rehabilitation treatment according to the type of patient [9].
2.9.1 Long term care facilities
Patients who continue to need hospitalization and have a moderate or severe disability in more than two functional areas such as mobility, swallowing, or communication, but whose medical and cognitive conditions do not allow them to participate in therapies of high intensity, and without sufficient social and family support to foresee a return home in the medium term.
2.9.2 Outpatient rehabilitation
If patients have a mild or moderate disability and meet the medical and cognitive conditions that allow them to travel to a rehabilitation center, and have good social and family support, they will continue with high-intensity treatment (1–3 h daily) in outpatient rehabilitation centers or by going to the referral hospital on an outpatient basis.
2.9.3 Home rehabilitation
In those patients who continue with a moderate or severe disability and good cognitive conditions but whose medical or social situation does not allow them to travel to a rehabilitation center. For patients with very severe disabilities in the chronic phase, as long as there are functional objectives to be achieved, home rehabilitation can help to avoid long-term complications, readmissions and moderate the impact of the disability on the quality of life of patients and caregivers.
Regarding social support after the stroke, it will be necessary to report on aspects such as labor reintegration, changes, and strategies to minimize sexual dysfunction, the possibility of driving vehicles again, or the access to adapted transport systems that would make it possible to increase the level of occupational, social and leisure activities, improving the quality of life of the patients. In addition, after a stroke, family training and emotional support are highly important, especially for those who are going to become caregivers [51].
Conflict of interest
The authors declare no conflict of interest.
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The role of rehabilitation is to help improve deficits to regain functionality and to define the needs and care in patients with permanent disabilities. Stroke rehabilitation must start early and intensively and it must be carried out by a multidisciplinary team made up of neurologists, rehabilitation doctors, nurses, physiotherapists, occupational therapists, speech therapists, neuropsychologists, neurophysiologists, and social workers. Patients and families should be actively involved with this team, if possible, from the beginning and throughout the rehabilitation process. 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Restorative Neurology and Neuroscience. 2009;27:645-650'},{id:"B48",body:'Liu KP, Chan CC. Pilot randomized controlled trial of self-regulation in promoting function in acute poststroke patients. Archives of Physical Medicine and Rehabilitation. 2014;95(7):1262-1267'},{id:"B49",body:'Titus MN, Gall NG, Yerxa EJ, Roberson TA, Mack W. Correlation of perceptual performance and activities of daily living in stroke patients. The American Journal of Occupational Therapy. 1991;45(5):410-418'},{id:"B50",body:'Wee JYM, Hopman WM. Comparing consequences of right and left unilateral neglect in a stroke rehabilitation population. American Journal of Physical Medicine and Rehabilitation. 2008;87(11):910-920'},{id:"B51",body:'Rafsten L, Danielsson A, Sunnerhagen KS. Anxiety after stroke: A systematic review and meta-analysis. Journal of Rehabilitation Medicine. 2018;50(9):769-778'},{id:"B52",body:'Llorca GE, Castilla-Guerra L, Moreno MF, Doblado SR, Hernández MJ. Post-stroke depression: An update. Neurología. 2015;30(1):23-31'},{id:"B53",body:'Mimentza N, González-Fraile E, Arango-Lasprilla JC, Ortiz-Marqués N, Berrios GE, González-Pinto A, et al. Assessing irritability in patients with stroke: Psychometric properties of the irritability questionnaire. Brain Injury. 2020;34(1):115-121'},{id:"B54",body:'Sanchetee P. Current trends in stroke rehabilitation. En: Ischemic Stroke. IntechOpen: London; 2021'},{id:"B55",body:'Klamroth-Marganska A. Stroke rehabilitation: Therapy robots and assistive devices. Advances in Experimental Medicine and Biology. 2018;1065:579-587'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Iria Beltrán-Rodríguez",address:"iriabeltranrodriguez@gmail.com",affiliation:'
'},{corresp:null,contributorFullName:"Rebeca de la Fuente Blanco",address:null,affiliation:'
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Military Reserve Officer serving with the 100 Support Command, 100 Troop Command, 40 Infantry Division, CA National Guard.",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"6925",title:"Endoplasmic Reticulum",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6925.jpg",slug:"endoplasmic-reticulum",publishedDate:"April 17th 2019",editedByType:"Edited by",bookSignature:"Angel Català",hash:"a9e90d2dbdbc46128dfe7dac9f87c6b4",volumeInSeries:2,fullTitle:"Endoplasmic Reticulum",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",institutionURL:null,country:{name:"Argentina"}}}]},{type:"book",id:"6924",title:"Adenosine Triphosphate in Health and Disease",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6924.jpg",slug:"adenosine-triphosphate-in-health-and-disease",publishedDate:"April 24th 2019",editedByType:"Edited by",bookSignature:"Gyula Mozsik",hash:"04106c232a3c68fec07ba7cf00d2522d",volumeInSeries:3,fullTitle:"Adenosine Triphosphate in Health and Disease",editors:[{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",institutionURL:null,country:{name:"Hungary"}}}]},{type:"book",id:"8008",title:"Antioxidants",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/8008.jpg",slug:"antioxidants",publishedDate:"November 6th 2019",editedByType:"Edited by",bookSignature:"Emad Shalaby",hash:"76361b4061e830906267933c1c670027",volumeInSeries:5,fullTitle:"Antioxidants",editors:[{id:"63600",title:"Prof.",name:"Emad",middleName:null,surname:"Shalaby",slug:"emad-shalaby",fullName:"Emad Shalaby",profilePictureURL:"https://mts.intechopen.com/storage/users/63600/images/system/63600.png",biography:"Dr. Emad Shalaby is a professor of biochemistry on the Biochemistry Department Faculty of Agriculture, Cairo University. He\nreceived a short-term scholarship to carry out his post-doctoral\nstudies abroad, from Japan International Cooperation Agency\n(JICA), in coordination with the Egyptian government. Dr.\nShalaby speaks fluent English and his native Arabic. He has 77\ninternationally published research papers, has attended 15 international conferences, and has contributed to 18 international books and chapters.\nDr. Shalaby works as a reviewer on over one hundred international journals and is\non the editorial board of more than twenty-five international journals. He is a member of seven international specialized scientific societies, besides his local one, and\nhe has won seven prizes.",institutionString:"Cairo University",institution:{name:"Cairo University",institutionURL:null,country:{name:"Egypt"}}}]}]},openForSubmissionBooks:{},onlineFirstChapters:{},subseriesFiltersForOFChapters:[],publishedBooks:{},subseriesFiltersForPublishedBooks:[],publicationYearFilters:[],authors:{paginationCount:617,paginationItems:[{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"12",type:"subseries",title:"Human Physiology",keywords:"Anatomy, Cells, Organs, Systems, Homeostasis, Functions",scope:"Human physiology is the scientific exploration of the various functions (physical, biochemical, and mechanical properties) of humans, their organs, and their constituent cells. The endocrine and nervous systems play important roles in maintaining homeostasis in the human body. Integration, which is the biological basis of physiology, is achieved through communication between the many overlapping functions of the human body's systems, which takes place through electrical and chemical means. Much of the basis of our knowledge of human physiology has been provided by animal experiments. Because of the close relationship between structure and function, studies in human physiology and anatomy seek to understand the mechanisms that help the human body function. The series on human physiology deals with the various mechanisms of interaction between the various organs, nerves, and cells in the human body.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/12.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11408,editor:{id:"195829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Sakuma",slug:"kunihiro-sakuma",fullName:"Kunihiro Sakuma",profilePictureURL:"https://mts.intechopen.com/storage/users/195829/images/system/195829.jpg",biography:"Professor Kunihiro Sakuma, Ph.D., currently works in the Institute for Liberal Arts at the Tokyo Institute of Technology. He is a physiologist working in the field of skeletal muscle. He was awarded his sports science diploma in 1995 by the University of Tsukuba and began his scientific work at the Department of Physiology, Aichi Human Service Center, focusing on the molecular mechanism of congenital muscular dystrophy and normal muscle regeneration. His interest later turned to the molecular mechanism and attenuating strategy of sarcopenia (age-related muscle atrophy). His opinion is to attenuate sarcopenia by improving autophagic defects using nutrient- and pharmaceutical-based treatments.",institutionString:null,institution:{name:"Tokyo Institute of Technology",institutionURL:null,country:{name:"Japan"}}},editorTwo:null,editorThree:{id:"331519",title:"Dr.",name:"Kotomi",middleName:null,surname:"Sakai",slug:"kotomi-sakai",fullName:"Kotomi Sakai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000031QtFXQA0/Profile_Picture_1637053227318",biography:"Senior researcher Kotomi Sakai, Ph.D., MPH, works at the Research Organization of Science and Technology in Ritsumeikan University. She is a researcher in the geriatric rehabilitation and public health field. She received Ph.D. from Nihon University and MPH from St.Luke’s International University. Her main research interest is sarcopenia in older adults, especially its association with nutritional status. Additionally, to understand how to maintain and improve physical function in older adults, to conduct studies about the mechanism of sarcopenia and determine when possible interventions are needed.",institutionString:null,institution:{name:"Ritsumeikan University",institutionURL:null,country:{name:"Japan"}}},series:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261"},editorialBoard:[{id:"213786",title:"Dr.",name:"Henrique P.",middleName:null,surname:"Neiva",slug:"henrique-p.-neiva",fullName:"Henrique P. Neiva",profilePictureURL:"https://mts.intechopen.com/storage/users/213786/images/system/213786.png",institutionString:null,institution:{name:"University of Beira Interior",institutionURL:null,country:{name:"Portugal"}}},{id:"39275",title:"Prof.",name:"Herbert Ryan",middleName:null,surname:"Marini",slug:"herbert-ryan-marini",fullName:"Herbert Ryan Marini",profilePictureURL:"https://mts.intechopen.com/storage/users/39275/images/9459_n.jpg",institutionString:null,institution:{name:"University of Messina",institutionURL:null,country:{name:"Italy"}}},{id:"196218",title:"Dr.",name:"Pasquale",middleName:null,surname:"Cianci",slug:"pasquale-cianci",fullName:"Pasquale Cianci",profilePictureURL:"https://mts.intechopen.com/storage/users/196218/images/system/196218.png",institutionString:null,institution:{name:"University of Foggia",institutionURL:null,country:{name:"Italy"}}}]},onlineFirstChapters:{},publishedBooks:{},testimonialsList:[{id:"18",text:"It was great publishing with IntechOpen, the process was straightforward and I had support all along.",author:{id:"71579",name:"Berend",surname:"Olivier",institutionString:"Utrecht University",profilePictureURL:"https://mts.intechopen.com/storage/users/71579/images/system/71579.png",slug:"berend-olivier",institution:{id:"253",name:"Utrecht University",country:{id:null,name:"Netherlands"}}}},{id:"27",text:"The opportunity to work with a prestigious publisher allows for the possibility to collaborate with more research groups interested in animal nutrition, leading to the development of new feeding strategies and food valuation while being more sustainable with the environment, allowing more readers to learn about the subject.",author:{id:"175967",name:"Manuel",surname:"Gonzalez Ronquillo",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/175967/images/system/175967.png",slug:"manuel-gonzalez-ronquillo",institution:{id:"6221",name:"Universidad Autónoma del Estado de México",country:{id:null,name:"Mexico"}}}},{id:"8",text:"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality.",author:{id:"202192",name:"Catrin",surname:"Rutland",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",slug:"catrin-rutland",institution:{id:"134",name:"University of Nottingham",country:{id:null,name:"United Kingdom"}}}}]},submityourwork:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],subseriesList:[],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:null},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"ofsBook.detail",path:"/welcome/9885534183ae520bcc63a91d4d083390",hash:"",query:{},params:{hash:"9885534183ae520bcc63a91d4d083390"},fullPath:"/welcome/9885534183ae520bcc63a91d4d083390",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()