Central Nervous System Mechanisms Research Articles

Status of Brain Imaging in Gastroparesis

The pathophysiology of nausea and vomiting in gastroparesis is complicated and multifaceted involving the collaboration of both the peripheral and central nervous systems. Most treatment strategies and studies performed in gastroparesis have focused largely on the peripheral effects of this disease, while our understanding of the central nervous system mechanisms of nausea in this entity is still evolving. The ability to view the brain with different neuroimaging techniques has enabled significant advances in our understanding of the central emetic reflex response. However, not enough studies have been performed to further explore the brain–gut mechanisms involved in nausea and vomiting in patients with gastroparesis. The purpose of this review article is to assess the current status of brain imaging and summarize the theories about our present understanding on the central mechanisms involved in nausea and vomiting (N/V) in patients with gastroparesis. Gaining a better understanding of the complex brain circuits involved in the pathogenesis of gastroparesis will allow for the development of better antiemetic prophylactic and treatment strategies.

Antioxidant and detoxycative mechanisms in central nervous system

Since the brain contains a large amount of polyunsaturated fatty acids, consumes up to 20% of oxygen used by the whole body and exhibits low antioxidants activity, it seems to be especially vulnerable to oxidative stress. The most important antioxidant enzymes are superoxide dismutase (SOD), which catalyze the dismutation of superoxide anion to hydrogen peroxide, catalase (CAT), which converts toxic hydrogen peroxide to water and oxygen, and glutathione peroxidase (Se-GSHPx), which reduces hydrogen peroxide and organic peroxides with glutathione as the cofactor. Among other detoxifying enzymes, the most significant is glutathione transferase (GST), which shows detoksyvarious catalytic activities allowing for removal of xenobiotics, reducing organic peroxides and oxidized cell components. One of the most important brain nonenzymatic antioxidants is reduced glutathione (GSH), which (individually or in cooperation with peroxidases) participates in the reduction of free radicals, repair of oxidative damage and the regeneration of other antioxidants, such as ascorbate or tocopherol. Glutathione as a cosubstrate of glutathione transferase scavenges toxic electrophilic compounds. Although the etiology of the major neurodegenerative diseases are unknown, numerous data suggest that reactive oxygen species play an important role. Even a small change in the level of antioxidants can leads to the many disorders in the CNS.

Neuroprotective Aspects of Cannabinoid Compounds

The accumulation of reliable data on the effects of cannabinoids is essential for understanding their possible beneficial effects on the central nervous system (CNS). Investigating individual substances along with the action of different combinations may show new possibilities for cannabinoids as neuroprotective agents. The data collected so far reveals the complexity of the mechanism of cannabinoids action on CNS, and even more complex and poorly understood are the effects when combined. Moreover, combining cannabinoids with different drugs and chemicals may lead to a decrease in beneficial effects. These characteristics of their action emphasize the complexity of the molecular mechanisms of neuroprotection and the lack of reliable information that may contribute to the safe and effective use of cannabinoids as medicines with valuable neuroprotective properties. The current brief review summarizes present data related to the protective effects of some cannabinoids on CNS and possible mechanisms involved in cannabinoid-mediated neuroprotection.

Prolonged nonobstructive urinary retention induced by tibial nerve stimulation in cats.

Nonobstructive urinary retention (NOUR) is a medical condition without an effective drug treatment, but few basic science studies have focused on this condition. In α-chloralose-anesthetized cats, the bladder was cannulated via the dome and infused with saline to induce voiding that could occur without urethral outlet obstruction. A nerve cuff electrode was implanted for tibial nerve stimulation (TNS). The threshold (T) intensity for TNS to induce toe twitch was determined initially. Repeated (6 times) application of 30-min TNS (5 Hz, 0.2 ms, 4-6T) significantly (P < 0.05) increased bladder capacity to 180% of control and reduced the duration of the micturition contraction to 30% of control with a small decrease in contraction amplitude (80% of control), which resulted in urinary retention with a low-voiding efficiency of 30% and a large amount of residual volume equivalent to 130% of control bladder capacity. This NOUR condition persisted for >2 h after the end of repeated TNS. However, lower frequency TNS (1 Hz, 0.2 ms, 4T) applied during voiding partially reversed the NOUR by significantly (P < 0.05) increasing voiding efficiency to 60% and reducing residual volume to 70% of control bladder capacity without changing bladder capacity. These results revealed that tibial nerve afferent input can activate either an excitatory or an inhibitory central nervous system mechanism depending on afferent firing frequencies (1 vs. 5 Hz). This study established the first NOUR animal model that will be useful for basic science research aimed at developing new treatments for NOUR.

Current evidence of neurological features, diagnosis, and neuropathogenesis associated with COVID-19.

Recent reports indicate that besides respiratory and systemic symptoms among coronavirus disease (COVID-19) patients, the disease has a wide spectrum of neurological manifestations (encephalitis, meningitis, myelitis, acute disseminated encephalomyelitis, metabolic and acute hemorrhagic necrotizing encephalopathy, cerebrovascular diseases, Guillain-Barré syndrome, polyneuritis cranialis, dysautonomia, and myopathies). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread from the respiratory system to the central nervous system, using transneuronal and hematogenous mechanisms. Although not every COVID-19 patient will test positive for the virus in the cerebrospinal fluid exam, the appearance of neurological symptoms associated with SARS-CoV-2 infection reveals the importance of understanding the neurologic manifestations and capacity for neural invasion associated with the pathogen. These aspects are relevant for correct diagnosis and treatment, and for the potential development of vaccines. This review highlights the latest evidence of SARS-CoV-2 infection with a focus on neurological involvement and potential neuropathogenesis mechanisms.

Data-driven adaptive optimal control for stochastic systems with unmeasurable state

This paper proposes a computational data-driven adaptive optimal control strategy for a class of linear stochastic systems with unmeasurable state. First, a data-driven optimal observer is designed to obtain the optimal state estimation policy. On this basis, an off-policy data-driven ADP algorithm is further proposed, yielding the stochastic optimal control in the absence of system model. An application example of the learning mechanism of central nervous system in arm movement control is given to illustrate the effectiveness and practicality of the strategy.

Liver sympathetic nerve activity and steatosis.

Liver sympathetic nerve activity and steatosis.

The dorsomedial hypothalamus and nucleus of the solitary tract as key regulators in a rat model of chronic obesity

The surging obesity epidemic calls for a deeper understanding of central nervous system (CNS) mechanisms underlying the biologically defended level of body weight. Here, we analyzed global gene expression in four hypothalamic and two brainstem nuclei involved in energy homeostatic control of body weight in diet-induced obese (DIO) and lean rats. Male Sprague-Dawley rats were offered ad libitum chow, or a two-choice diet consisting of a high palatable high sugar/fat diet and chow for 40 weeks. At termination, the hypothalamic arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), paraventricular nucleus (PVN) and lateral hypothalamus area (LHA), as well as the brainstem area postrema (AP) and nucleus of the solitary tract (NTS), were isolated by laser capture microdissection (LCM) followed by mRNA sequencing. Global gene expression analyses revealed a total of 88 differentially expressed genes (DEGs) in DIO rats. Transcriptome changes were mainly observed in the DMH and NTS and associated with neuropeptide signaling and regulation of signaling transduction pathways, suggesting a key role of these brain regions in body weight regulation.

Botulinum toxin A for refractory OAB and idiopathic urinary retention: Can phenotyping improve outcome for patients: ICI‐RS 2019?

Botulinum toxin A (BTX-A) is a well-established treatment for refractory idiopathic overactive bladder (OAB). It has also been used with short-term success in treating idiopathic urinary retention. However, efficacy and complication rates are variable and predicting those likely to benefit most from treatment would enable personalization of therapy and optimization of outcomes. At the International Consultation on Incontinence-Research Society (ICI-RS) meeting in 2019 a Think Tank addressed the question of how we can improve the way we phenotype patients undergoing BTX-A treatment. The Think Tank conducted a literature review and expert consensus meeting focussing on how advances in basic science research of the mechanism of action of BTX-A, as well as assessment of psychological comorbidity, can be translated into clinical practice to improve patient selection for therapy. Idiopathic OAB and idiopathic urinary retention are heterogenous conditions encompassing several phenotypes with multiple potential pathophysiological mechanisms. Animal models have demonstrated a central nervous system mechanism of action of intravesically injected BTX-A and this has been confirmed in human functional MRI studies, but whether this tool can be used to predict outcome from treatment remains to be determined. Phenotyping based on psychological comorbidity using validated screening tools should be studied as a way to potentially optimize patient selection for therapy. Advances in basic science research into the mechanism of action of BTX-A have improved our understanding of the pathophysiology of OAB and may lead to novel ways to phenotype patients. Psychological assessment is another way in which phenotyping may be improved. Areas for further research are proposed.

Effects of bariatric surgery on central nervous system regulation of obesity

As the incidence of obesity increases globally, treatment strategies of obesity emerge continuously. However, the weight loss effect varies between individuals without explicit explanations. In the recent years, many researchers have revealed regulation mechanisms of central nervous system on eating behavior, proposing that obese individuals exhibit brain functional abnormalities implicated in homeostatic regulation of food intake, central reward and motivation, emotion, memory, and attention system. Therefore, these scholars appeal that treating obesity cannot remain brainless . The most effective treatment currently available for obesity is bariatric surgery which lead to excess weight loss of 42%-67% in accompany with changes in brain activity. Functional magnetic resonance imaging showed a decreased activation in the central reward network and increased inhibitory control in the cognitive control system after bariatric surgeries. In this article, the authors introduce the central nervous system regulation of eating and investigate the effects of bariatric surgery on central nervous system. Key words: Obesity; Central nerve; Bariatric surgery; Bariatric and metabolic surgery; Regulation mechanisms

Central Nervous System Mechanisms of Nausea in Gastroparesis: An fMRI-Based Case-Control Study.

Nausea is a major complaint of gastroparesis (GP), and the pathophysiology of this condition is poorly understood. Therefore, this study utilized fMRI to investigate the possible central nervous system (CNS) mechanisms of nausea in 10GP patients versus 8 healthy controls (HCs). Nausea severity was assessed on a 0-10 scale and presented as mean ± SD. Nausea was increased from baseline utilizing up to 30min of visual stimulation (VS). Functional network connectivity was measured with fMRI at baseline and after 30 min of VS. fMRI data were preprocessed using statistical parametric mapping software. Thirty-four independent components were identified as meaningful resting-state networks (RSNs) by group independent component analysis. The Functional Network Connectivity (FNC) among 5 RSNs considered important in CNS nausea mechanisms was calculated as the Pearson's pairwise correlation. Baseline nausea scorein GP patients was 2.7 ± 2.0 and increased to 7.0 ± 1.5 after stimulation (P < 0.01). In HCs nausea scores did not increase from baseline after stimulus (0.3 ± 0.5). When comparing GP patients to HCs after VS, a significant reduction (P < 0.001) in bilateral insula network connectivity compared to the right insula network was detected. No significant differences in connectivity were noted among the other RSNs. Additionally, the average gray matter volume was non-significantly reduced in the insula in GP patients compared to HC. The insula connectivity network is impaired in nauseated GP patients. This phenomenon could explain the susceptibility of GP patients to nausea or may have resulted from a state of chronic nausea.

DARK Classics in Chemical Neuroscience: Gamma-Hydroxybutyrate (GHB).

Gamma-hydroxybutyrate (GHB) is a naturally occurring short-chain fatty acid that rose to prominence as a popular club drug in the 1990s. Originally developed as an anesthetic in the early 1960s, it was later sold as an over-the-counter dietary supplement before becoming a rising substance of abuse in the following decades as one of the "date rape" drugs. Despite its abuse potential, there has been a recent surge in therapeutic interest in the drug due to its clinical viability in the treatment of narcolepsy and alcohol abuse/withdrawal. Its interactions with the GABAergic framework of higher mammals has made it the prototypical example for the study of the chief inhibitory mechanism in the human central nervous system. Though relatively obscure in terms of popular culture, it has a storied history with widespread usage in therapeutic, recreational ("Chemsex"), and some disturbingly nefarious contexts. This Review aims to capture its legacy through review of the history, synthesis, pharmacology, drug metabolism, and societal impact of this DARK classic in chemical neuroscience.

Protection of Primary Dopaminergic Midbrain Neurons Through Impact of Small Molecules Using Virtual Screening of GPR139 Supported by Molecular Dynamic Simulation and Systems Biology.

GPCR share a common structural feature, i.e., the presence of seven trans-membrane helices having three intracellular and three extracellular loops. The carboxyl terminal is intracellular whereas amino terminal is extracellular. Various conformational changes are observed in structure of GPCR during the binding with ligand, coupling with G protein and interaction with other proteins. In Rhodopsin class of GPCR the basic structure of GPCR is resolved by X-ray crystallography. Ligand acts as an extracellular stimulus for GPCRs to bring physiological changes in organisms. GPR139 has been found to have effective physiological role in primary dopaminergic midbrain neurons and in central nervous system. Recent reports suggested that the ligand of GPR139 protein inhibits the growth of primary dopaminergic midbrain neurons in central nervous system. These discoveries indicated the potential involvement and influence of GPR139 protein in central nervous system METHOD: Therefore, we used multi-approach analysis to investigate the role of GPR139 in the molecular mechanisms of central nervous system. In silico screening was performed to study compound 1 binding with GPR139 protein in their predicted three-dimensional structures. Compound 1 was subjected to molecular dynamics (MD) simulation and stability analysis. The results of MD analysis suggested that the loop region in GPR139 protein structure could affect its binding with drugs. Finally, we cross-validated the predicted compound 1 through systems biology approach. Our results suggested that GPR139 might play an important role in primary dopaminergic midbrain neurons therapy.

CHARACTERIZATION OF EXPRESSION PATTERN OF SOMATOSTATIN 4 RECEPTOR IN THE MOUSE BRAIN

Somatostatin is a cyclic neuropeptide which is expressed in brain regions related to pain‐ and mood regulation. It has 5 inhibitory G‐protein coupled receptors, and subtype 4 (sst4) mediates analgesic, anti‐inflammatory and antidepressant effects without endocrine actions. It was suggested to be a novel drug target for chronic neuropathic pain. However, its central nervous system distribution and mechanism of the inhibitory actions are not known due to the lack of specific antibody.We mapped sst4 expression using β‐galactosidase immunohistochemistry in the brain of Sst4 knockout (KO) mice where sst4 was replaced by the lacZ gene. Since KO mice are not appropriate for determining functional changes and co‐localization, we also performed ultrasensitive RNAscope‐based in situ hybridization and neurochemical characterization on formalin‐fixed, paraffin‐embedded coronal sections of wild type mice. Sst4 mRNA was also quantified by qPCR in the positive regions.Strong sst4‐related β‐galactosidase immunopositivity was detected in the hippocampus, moderate in the medial septum, amygdala, habenula in both sexes. Remarkably more intensive signal was seen in the primary somatosensory cortex of male mice compared to females. Sst4 mRNA was abundant in the hippocampal CA1 region, amygdala, spinal cord, sensory and motor cortices (layer 5). It was co‐localized with vesicular glutamate transporter 1 in most regions and choline‐acetyl transferase in the habenula. Sst4 mRNA was significantly higher in the dorsal root ganglia compared the spinal cord. These are the first data for sst4 expression in glutamatergic and cholinergic excitatory neurons of the nociceptive pathway. This might explain its unique value to simultaneously inhibit chronic pain and depression.Support or Funding InformationÚNKP17‐3‐III‐PTE‐166, GINOP‐2.3.3.‐15‐2016‐00050, GINOP‐2.3.3.‐15‐2016‐00048, EFOP‐3.6.2‐16‐2017‐00008, KTIA_NAP_13‐2‐2014‐0022, KTIA_NAP_13‐1‐2013‐0001, 207653/2018/FEKUTSTRATThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Management Education in teaching and learning a Foreign Language, in particular English language

Brain is the most important part of the body in order to achieve goals. It’s important to have clear goals to clarify mind duty and tasks. It’s a difficult life to go on when you have many problems to face, but you can succeed if you make clear intention in what you do.&#x0D; Everything is to face life and find coherence in what you are able to do. Try to make a strategy list to find the right way to give the right time to every point and activity in your life.&#x0D; So you can find the explanation in neuroscience and quantum physic about all phenomena happen around you. Brain areas involve many processes as learning, memorization, in order to achieve better knowledge and skills in getting a foreign language. So brain working is related to neuropsychological research in order to explain process of learning a foreign language.&#x0D; All brain processes are connected with the central nervous system mechanisms that make working all the cerebral mechanisms used.&#x0D; A professional teacher knows how it works in mind process when he teaches a foreign language as English or. French or German or Russian etc

Resistant Hypertension: Diagnosis and Management.

Resistant hypertension is defined as high blood pressure requiring 3 or more medications for adequate control or controlled blood pressure requiring 4 or more medications. Considering the growing prevalence of hypertension and the strong link with cardiovascular disease, it is vital to understand the causes and treatment of resistant hypertension. This review article starts with an overview of the prevalence and little-known pathophysiology of resistant hypertension. Afterward, we discuss the evaluation and management of suspected secondary resistant hypertension in 2 broad categories: pseudoresistant hypertension and true resistant hypertension. Strategies for the identification and management of pseudoresistant hypertension are addressed. In addition, causes of true resistant hypertension, such as obstructive sleep apnea, primary aldosteronism, and renal artery stenosis, are examined along with their respective treatments. Finally, treatment of resistant hypertension is reviewed including pharmacologic treatments and novel procedural interventions for resistant hypertension. Overall, the review hopes to provide practitioners with a cohesive approach for the diagnosis and treatment of resistant hypertension.

Rel-Dependent Immune and Central Nervous System Mechanisms Control Viral Replication and Inflammation during Mouse Herpes Simplex Encephalitis.

Herpes simplex encephalitis (HSE), caused by HSV type 1 (HSV-1) infection, is an acute neuroinflammatory condition of the CNS and remains the most common type of sporadic viral encephalitis worldwide. Studies in humans have shown that susceptibility to HSE depends in part on the genetic make-up of the host, with deleterious mutations in the TLR3/type I IFN axis underlying some cases of childhood HSE. Using an in vivo chemical mutagenesis screen for HSV-1 susceptibility in mice, we identified a susceptible pedigree carrying a causal truncating mutation in the Rel gene (RelC307X ), encoding for the NF-κB transcription factor subunit c-Rel. Like Myd88-/- and Irf3-/- mice, RelC307X mice were susceptible to intranasal HSV-1 infection. Reciprocal bone marrow transfers into lethally irradiated hosts suggested that defects in both hematopoietic and CNS-resident cellular compartments contributed together to HSE susceptibility in RelC307X mice. Although the RelC307X mutation maintained cell-intrinsic antiviral control, it drove increased apoptotic cell death in infected fibroblasts. Moreover, reduced numbers of CD4+CD25+Foxp3+ T regulatory cells, and dysregulated NK cell and CD4+ effector T cell responses in infected RelC307X animals, indicated that protective immunity was also compromised in these mice. In the CNS, moribund RelC307X mice failed to control HSV-1 viral replication in the brainstem and cerebellum, triggering cell death and elevated expression of Ccl2, Il6, and Mmp8 characteristic of HSE neuroinflammation and pathology. In summary, our work implicates c-Rel in both CNS-resident cell survival and lymphocyte responses to HSV-1 infection and as a novel cause of HSE disease susceptibility in mice.

Quantitative assessment of nonpelvic pressure pain sensitivity in urologic chronic pelvic pain syndrome: a MAPP Research Network study.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in participants with UCPPS was compared with healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from 6 participating MAPP testing sites were pooled for analysis. Participants with UCPPS (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in patients with UCPPS was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in participants with UCPPS revealed that pain sensitivity increased during periods of urologic symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement 1 year later. The finding that individuals with UCPPS demonstrate nonpelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

Central nervous system mechanisms involved in inhibition of micturition reflex by gentle mechanical skin stimulation

Central nervous system mechanisms involved in inhibition of micturition reflex by gentle mechanical skin stimulation

Sex differences in the central and peripheral manifestations of ischemia-induced heart failure in rats.

Sex differences in the presentation, outcome, and responses to treatment of systolic heart failure (HF) have been reported. In the present study, we examined the effect of sex on central neural mechanisms contributing to neurohumoral excitation and its peripheral manifestations in rats with HF. Male and female Sprague-Dawley rats underwent coronary artery ligation (CL) to induce HF. Age-matched rats served as controls. Ischemic zone and left ventricular function were similar 24 h and 4 wk after CL. Female rats with HF had a lower mortality rate and less hemodynamic compromise, pulmonary congestion, and right ventricular remodeling 4 wk after CL. Plasma angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine levels were increased in HF rats in both sexes, but AVP and norepinephrine levels increased less in female rats. In the hypothalamic paraventricular nucleus, a key cardiovascular-related nucleus contributing to neurohumoral excitation in HF, mRNA levels for the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β as well as cyclooxygenase-2 and the ANG II type 1a receptor were increased in HF rats of both sexes, but less so in female rats. Angiotensin-converting enzyme 2 protein levels increased in female HF rats but decreased in male HF rats. mRNA levels of AVP were lower in female rats in both control and HF groups compared with the respective male groups. Activation of extracellular signal-regulated protein kinases 1 and 2 increased similarly in both sexes in HF. The results suggest that female HF rats have less central neural excitation and less associated hemodynamic compromise than male HF rats with the same degree of initial ischemic cardiac injury. NEW & NOTEWORTHY Sex differences in the presentation and responses to treatment of heart failure (HF) are widely recognized, but the underlying mechanisms are poorly understood. The present study describes sex differences in the central nervous system mechanisms that drive neurohumoral excitation in ischemia-induced HF. Female rats had a less intense central neurochemical response to HF and experienced less hemodynamic compromise. Sex hormones may contribute to these differences in the central and peripheral adaptations to HF.