Central Nervous System Disruption Research Articles

Plenary A: Presidential Address: Anesthesia: A Wake-Up Call. Part 2. Developmental Risk or Resilience?

Abstract & Learning Objectives:This presentation is a clarion call to neuropsychologists to contribute their specialized knowledge to help answer a critical question: Is there a Fetal Anesthesia Syndrome that results in subtle and persistent adverse effects over an individual’s lifespan? Neuropsychologists are uniquely positioned to make substantial contributions to conceptualization, methodology, and interpretation in studies of human exposure to general anesthesia (GA). Part 1, presented at the 2022 INS Barcelona meeting, reviewed preclinical data that documented effects on the central nervous system and long-term behavioral adversities of GA exposure during an animal’s critical growth spurt developmental period. Studies of human adult exposure were also summarized, and attention directed to the absence of prospective studies from childhood to adulthood. Part 2 extends the conversation to GA exposure during the highly vulnerable in utero and early childhood developmental periods. Human retrospective study results began to be published in the early 2000s, and prospective studies only within the last decade. Reports of associations between GA and attentional problems, learning disorder, neuropsychological deficit, and neuropsychiatric disorder are emerging. Yet, due to methodological weaknesses and multiple confounders, clear evidence of causality remains lacking in this nascent literature. A 'developmentalistic’ way forward for neuropsychologists will be suggested, one using neuropsychological expertise along with the application of innovative technologies that is informed by the extensive preclinical data showing cellular, synaptic, and neural circuitry disruption during critical growth periods and short- and long-termeuropsychological effects. Upon conclusion of this course, learners will be able to: 1.Describe types of central nervous system disruption that result in animals following exposure to general anesthesia2.Identify neuropsychological domains at high potential risk following exposure to general anesthesia during the human critical growth spurt period3.Explain what is meant by 'vertical transfer'

Post-COVID depression and its multiple factors, does Favipiravir have a protective effect? A longitudinal study of indonesia COVID-19 patients.

Coronavirus disease (COVID-19) not only has a long-term effect on its survivors, it also affects their quality of life, including inducing depression as a possible manifestation of central nervous system disruption. Favipiravir shows promising efficacy as an antiviral drug for the treatment of COVID-19. However, its effect on the sequelae of COVID-19 has not been explored. Therefore, this study aims to assess the impact of Favipiravir and address the factors associated with post-COVID depression in Indonesia. This cohort study conducted a post-COVID-19 survey on Indonesian patients who were diagnosed by using real-time polymerase chain reaction (RT-PCR) and antigen tests until January 2022. An online questionnaire was distributed to obtain information on demographics, comorbidities, health behavior, symptoms, and treatment. The propensity technique was used to allocate the participants into the favipiravir and nonrecipient groups (1:1). The Patient Health Questionnaire-9 (PHQ-9) was used for outcome measurement. The cohort was followed up biweekly for 60 days after onset/diagnosis to determine the occurrence of depression. Cox regression analysis with an adjusted odds ratio and 95% confidence interval was used to estimate the effect of favipiravir on post-COVID-19 depression. The data included the information of 712 participants, of whom 18.54% had depression within 60 days after onset/diagnosis. Depression was higher in the nonrecipient group (21.06%) than in the favipiravir group (16.01%). After adjustment by other factors, favipiravir prescription was found to be associated with depression (aOR 0.488, 95% CI 0.339-0.701 p < 0.001). In accordance with the PHQ-9 subset, favipiravir exerted a significant protective effect against depressive mood and loss of interest. However, patients living alone were prone to experiencing loss of interest (aOR 2.253, 95% CI 1.329-3.818, p = 0.003). The data obtained in this preliminary survey suggested that favipiravir may be useful for preventing post-COVID depression. However, further study is needed. Moreover, the provision of mental health support, particularly to those who live alone, must be ensured. Registry NCT05060562.

Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer's Disease.

Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

Central Nervous System Complaint in Worker Exposed to Air Toluene in Car Painting Workshop in Surabaya

The existence of toluene in air work environment can affect in health worker, such as disruption of Central Nervous System (CNS), lung, kidney, eye, skin and complaint. Therefore, the aim of this research was to learn CNS complaint in workers in car painting workshop in Surabaya. The sample research was taken from total population that was appropriate with inclusion criteria. The sample total was 12 people. Air sampling was conducted by using NIOSH method number 1501 with pipe absorption material activated carbon (charcoal) that use Gas Chromatography (GC) technique. Hipurric acid was measure by NIOSH method number 8301. CNS complaint in workers was known by using Q18 questionnaire. It was standardized questionnaire to determine CNS complaint in people exposed to toluene. The result showed air toluene in painting room still in threshold level that was 18.5726 ppm. Urine hipurric acid level in painter worker showed still in threshold level with the highest urine hipurric acid in worker 0.32 g hippuric acid/g urine creatinine. It can be concluded that toluene level in air and urine hippuric acid were still in threshold level, painter workers showed a trend CNS complaint compired with administration workers. It is suggested to wear Personal Protective Equipment (PPE), such as mask for gas, gloves, glasses, special clothes and boots for working.

Altered Permeability Of The Blood‐CSF Barrier In Chronic Migraine

BackgroundMolecular communication from blood circulation to brain is tightly regulated at multiple biological barriers, but is disrupted in a variety of diseases, disorders, and infections. Recent human and animal data in migraine research has shown conflicting results regarding barrier disruption. These contradictions require resolution because a leaky barrier will expose the brain to potentially harmful components with diverse deleterious effects on brain function.MethodsSince blood‐to‐CSF transfer studies have not yet been performed in migraineurs, we studied surrogate biomarkers of barrier disruption in blood and CSF from non‐headache suffering controls and chronic migraine sufferers.ResultsWhen compared to controls, study participants with chronic migraine had clear evidence of barrier leak based on their higher CSF—blood albumin ratio, CSF fibrinogen levels, and CSF levels of the pericyte biomarker, soluble platelet‐derived growth factor receptor β. To test if other blood components were leaking through this barrier, we examined how CSF and blood lipids relate to the CSF—blood albumin ratio. The CSF—blood ratios of trans palmitoleic acid, linoleic acid, and ceramide were higher in chronic migraine and these lipid ratios correlated significantly with the CSF—blood albumin index, consistent with their derivation, at least partly, from a leaking barrier.ConclusionWe conclude that individuals with chronic migraine have distinct disruption of central nervous system (CNS) barriers that allows leakage into the CNS of multiple blood components, including proteins and lipids, and which likely results from, and contributes to the pathophysiology of migraine. The blood‐brain barrier and molecules that leak into the CNS are potential treatment targets.Support or Funding InformationThe National Institutes of Health, R01 NS043295, Higgins Family TrustsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Oligodendrocyte morphology in the developing brain of the African giant rat (Cricetomys gambianus, Waterhouse): Histology, immunohistochemistry and electron microscopy.

Oligodendrocyte and myelin-related studies have been pivotal in understanding disruption of central nervous system (CNS) myelin through injury, toxicological, pathological degeneration or genetic intervention. The African giant rat (AGR) has been postulated as an indigenous wild-type model within the African context. This work thus describes oligodendrocyte morphologies and myelin components of the developing African giant rat brain using histological, immunohistochemical and ultrastructural techniques. Five types, precursor-progenitor oligodendrocytes, pre-oligodendrocytes, immature oligodendrocytes, mature non-myelinating oligodendrocytes and mature myelinating oligodendrocytes, were identified. The first four types were observed in neonates while juvenile and adult AGR had predominantly mature myelinating oligodendrocytes with evidence of myelin sheath deposition. All cell types identified showed positive CNPase-positive immunosignalling across all age groups. This suggests CNPase as a suitable, sensitive and reliable biomarker for studying CNS neurodegenerative/demyelinating disorders in the AGR. This baseline study has given detailed insight into the morphology of oligodendrocytes and myelin in the AGR. It may be useful for anatomical studies and detection of alterations in neurocellular profile of oligodendrocytes and myelin in the AGR in real-life or in experimental models.

The role of the immunoproteasome in interferon-\u03b3-mediated microglial activation

Microglia regulate the brain microenvironment by sensing damage and neutralizing potentially harmful insults. Disruption of central nervous system (CNS) homeostasis results in transition of microglia to a reactive state characterized by morphological changes and production of cytokines to prevent further damage to CNS tissue. Immunoproteasome levels are elevated in activated microglia in models of stroke, infection and traumatic brain injury, though the exact role of the immunoproteasome in neuropathology remains poorly defined. Using gene expression analysis and native gel electrophoresis we characterize the expression and assembly of the immunoproteasome in microglia following interferon-gamma exposure. Transcriptome analysis suggests that the immunoproteasome regulates multiple features of microglial activation including nitric oxide production and phagocytosis. We show that inhibiting the immunoproteasome attenuates expression of pro-inflammatory cytokines and suppresses interferon-gamma-dependent priming of microglia. These results imply that targeting immunoproteasome function following CNS injury may attenuate select microglial activity to improve the pathophysiology of neurodegenerative conditions or the progress of inflammation-mediated secondary injury following neurotrauma.

Animal and cellular models of familial dysautonomia.

Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.

A Hydrogel Bridge Incorporating Immobilized Growth Factors and Neural Stem/Progenitor Cells to Treat Spinal Cord Injury.

Spinal cord injury (SCI) causes permanent, often complete disruption of central nervous system (CNS) function below the damaged region, leaving patients without the ability to regenerate lost tissue. To engineer new CNS tissue, a unique spinal cord bridge is created to deliver stem cells and guide their organization and development with site-specifically immobilized growth factors. In this study, this bridge is tested, consisting of adult neural stem/progenitor cells contained within a methacrylamide chitosan (MAC) hydrogel and protected by a chitosan conduit. Interferon-γ (IFN-γ) and platelet-derived growth factor-AA (PDGF-AA) are recombinantly produced and tagged with an N-terminal biotin. They are immobilized to streptavidin-functionalized MAC to induce either neuronal or oligodendrocytic lineages, respectively. These bridges are tested in a rat hemisection model of SCI between T8 and T9. After eight weeks treatments including chitosan conduits result in a significant reduction in lesion area and macrophage infiltration around the lesion site (p < 0.0001). Importantly, neither immobilized IFN-γ nor PDGF-AA increased macrophage infiltration. Retrograde tracing demonstrates improved neuronal regeneration through the use of immobilized growth factors. Immunohistochemistry staining demonstrates that immobilized growth factors are effective in differentiating encapsulated cells into their anticipated lineages within the hydrogel, while qualitatively reducing glial fibrillary acid protein expression.

Absence of galectin-3 attenuates neuroinflammation improving functional recovery after spinal cord injury.

After spinal cord injury (SCI), a cascade of events begins. At first, there is physical damage with disruption of the blood-brain barrier (BBB) and the integrity of the nervous tissue. The disruption of central nervous system (CNS) BBB alters the endothelial permeability, the protein and chemokines expression and the propensity to release in situ inflammatory cytokines, overcoming anti-inflammatory signals, facilitating the attraction and entry of immune system cells into the injured spinal cord parenchyma (Gaudet et al., 2011). As a result, there is a neuroinflammatory response with changes in blood flow, edema, cell infiltration, apoptosis and release of axonal growth inhibitory factors. Nerve function loss occurs when the nerve impulse propagation is interrupted and do not reach its target. This disorder encompasses neuron and glia apoptosis, accompanied by Wallerian degeneration of disconnected axons, and CNS cells exposure to a hostile microenvironment that hampers axon regeneration (Mautes et al., 2000; Harkey et al., 2003). Additionally, the damage spreads further in a phenomenon called progressive hemorrhagic necrosis – PHN, with the appearance of petechial hemorrhagic foci and deterioration in areas outside the lesion epicenter during the next 2 – 24 hours after the trauma (Simard et al., 2007). Our laboratory investigates the role of galectin-3, a protein linked to mechanisms of inflammation, behind the cellular mechanisms of neural degeneration/regeneration with perspectives of a novel treatment (Mostacada et al., 2015).

Injury pattern and mortality of noncompressible torso hemorrhage in UK combat casualties

Hemorrhage following traumatic injury is a leading cause of military and civilian mortality. Noncompressible torso hemorrhage (NCTH) has been identified as particularly lethal, especially in the prehospital setting. All patients sustaining NCTH between August 2002 and July 2012 were identified from the UK Joint Theatre Trauma Registry. NCTH was defined as injury to a named torso axial vessel, pulmonary injury, solid-organ injury (Grade 4 or greater injury to the liver, kidney, or spleen) or pelvic fracture with ring disruption. Patients with ongoing hemorrhage were identified using either a systolic blood pressure of less than 90 mm Hg or the need for immediate surgical hemorrhage control. Data on injury pattern and location as well as cause of death were analyzed using univariate and multivariate analyses. During 10 years, 296 patients were identified with NCTH, with a mortality of 85.5%. The majority of deaths occurred before hospital admission (n = 222, 75.0%). Of patients admitted to hospital, survivors (n = 43, 14.5%) had a higher median systolic blood pressure (108 [43] vs. 89 [46], p = 0.123) and Glasgow Coma Scale (GCS) (14 [12] vs. 3 [0], p < 0.001) compared with in-hospital deaths (n = 31, 10.5%). Hemorrhage was the more common cause of death (60.1%), followed by central nervous system disruption (30.8%), total body disruption (5.1%), and multiple-organ failure (4.0%). On multivariate analysis, major arterial and pulmonary hilar injury are most lethal with odds ratio (95% confidence interval) of 16.44 (5.50-49.11) and 9.61 (1.06-87.00), respectively. This study demonstrates that the majority of patients sustaining NCTH die before hospital admission, with exsanguination and central nervous system disruption contributing to the bulk cause of death. Major arterial and pulmonary hilar injuries are independent predictors of mortality.

Effect of rat brain tissue extracts on osteoblast proliferation and differentiation

The reason for enhanced fracture healing in traumatic brain injury patients is not clearly understood. It is possible that factors inherent in the brain passing through the blood-brain barrier to the peripheral circulation, or a disruption of central nervous system (CNS) control of the sympathetic nervous system (SNS), stimulates the process of fracture healing. In this study, we assessed proliferation [using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay] and differentiation [using alkaline phosphatase (ALP)] in rat osteoblasts incubated with gray matter or other tissue extracts with and without the addition of an α- or β-adrenergic receptor blocker (phentolamine or propranolol). Gray matter extract from normal brain caused a dose-dependent increase in osteoblast proliferation and differentiation. Serum from normal rats enhanced differentiation but not proliferation. Alpha-receptor blockade had no effect on proliferation or differentiation. Beta-receptor blockade caused a partial, but statistically significant, decrease in gray matter stimulation of osteoblast differentiation. The results of this study indicate that gray matter extract from normal brain increases osteoblast proliferation and differentiation and that β receptors may be involved in differentiation under these conditions.

Caring for the Infant of a Diabetic Mother

In the United States, approximately 100,000 infants are born to diabetic mothers each year. If diabetes in pregnancy is uncontrolled, the diversity of resulting health problems can have a profound effect on the embryo, the fetus, and the neonate. These infants are at risk for a multitude of physiologic, metabolic, and congenital complications such as macrosomia, asphyxia, respiratory distress, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia and hyperviscosity, cardiomegaly, and central nervous system disruption. Preconception control of glucose metabolism throughout the trajectory of a woman's pregnancy is a significant factor in decreasing the adverse impact of diabetes on the fetus and newborn. Meticulous attention to neonatal glucose levels, thorough physical examination, and precise diagnosis are prerequisites to appropriate care for the neonate.

Environmental endocrine disruption: an effects assessment and analysis.

This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter.

Eye movement dysfunctions in psychiatric patients: a review.

Impairments of smooth pursuit eye movements occur in a high proportion of schizophrenic patients and in a lower but significant percentage of patients with affective psychoses, as well as patients with structural and metabolic disorders of the central nervous system. These findings have been confirmed using a wide range of tracking tasks, recording techniques, and scoring procedures, and therefore cannot be attributed to measurement artifact. The eye movement disruption in schizophrenics does not seem to result from drug treatment or simple inattention. Eye tracking pattern appears to be under genetic control and some impairments may reflect a predisposition to functional psychosis. The smooth pursuit eye movement impairment has been attributed to a central nervous system dysfunction that manifests itself in a disorder of nonvoluntary attention. The study of other oculomotor functions, such as the oculocephalic reflex, optokinetic and vestibular nystagmus, and saccadic eye movements, suggests that the locus of the central nervous system disruption is above the brainstem.