Central Nervous System Control Research Articles

Tyrosine kinase inhibitors with and without upfront CNS radiation for brain metastases in oncogene-driven non-small cell lung cancer (TURBO-NSCLC).

2019 Background: Newer generation tyrosine kinase inhibitors (TKI) for NSCLC with EGFR mutations and ALK rearrangements have demonstrated encouraging central nervous system (CNS) activity with CNS objective response rates, greatly improved from 1st generation TKIs. In response to these data, guideline statements have acknowledged a strategy of CNS-penetrant TKI +/- upfront stereotactic radiosurgery (SRS) for the treatment of select patients with BM. However, optimal use of upfront SRS for BM in these patients is controversial since upfront CNS radiation has been the historical standard of care, and there are limited data guiding patient management with upfront TKI alone. Additionally, results from a large multi-institutional series reported inferior overall survival (OS) with the omission of SRS in patients with EGFR-mutated NSCLC treated with first-generation TKI. Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs +/- upfront SRS were retrospectively collected from 7 centers in the United States. Time to CNS progression (PD), local CNS PD, and OS were analyzed, with multivariable adjustment (MVA) in Fine and Gray and Cox proportional hazards models for baseline factors including age, sex, performance status, mutation, extracranial metastases, prior therapy, neurologic symptoms, and number and size of BM. Results: We identified 317 patients (200 TKI only and 117 TKI+SRS). 250 (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients who received TKI+SRS were more likely to have BM ≥1 cm (p<0.001) and neurologic symptoms (p<0.001) at baseline. The median follow-up from treatment of BM was 23 months and 26 months in the TKI and TKI+SRS groups, respectively. Median OS was similar between the TKI and TKI+SRS groups (median 41 months [95% CI: 35-NR] vs 40 months [95% CI: 40-NR], respectively; p=0.5). On MVA, TKI+SRS was associated with a significant improvement in time to CNS PD (HR 0.63; 95% CI: 0.42-0.96; p=0.033). Local CNS control was significantly improved with TKI+SRS (HR 0.30, 95% CI: 0.16-0.55; p<0.001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated greater CNS control benefits with TKI+SRS in patients with BM ≥1 cm. Conclusions: This is the largest multi-institutional study comparing strategies of CNS-penetrant TKIs +/- upfront SRS in TKI-naïve patients with oncogene-driven NSCLC. The addition of SRS improved time to CNS PD and local CNS control but not OS. Patients with BM ≥1 cm may benefit the most from upfront integration of SRS. [Table: see text]

Gamma knife radiosurgery following whole-brain radiation

In this study, we aimed to determine outcomes for patients requiring salvage stereotactic radiosurgery (SRS) who have progression of brain metastatic disease after initial treatment with whole-brain radiation (WBRT). This is a retrospective analysis of a prospective database of 112 patients who were treated with salvage SRS after experiencing failure following WBRT treatment with salvage SRS. Collectively, the patients had a median overall survival of 7 months after salvage SRS. Patients who had more than two brain metastases had a significantly shorter median survival but were not subjected to increased risk for distant brain failure. We also found that a short intervening time between WBRT and central nervous system (CNS) failure did not seem to worsen the nervous system control or reduce patient survival. Small cell lung cancer (SCLC) was associated with decreased overall survival and CNS control. In conclusion, SRS use following WBRT is safe and effective in the majority of patients. Patients with rapid failure after WBRT can be successfully salvaged with SRS. The findings also shed light on the overall poor outcomes, coupled with low median survival and high rates of CNS failure, in patients suffering multiple metastases stemming from SCLC.

Pathophysiology of severe burn injuries: new therapeutic opportunities from a systems perspective.

Severe burn injury elicits a profound stress response with the potential for high morbidity and mortality. If polytrauma is present, patient outcomes appear to be worse. Sex-based comparisons indicate females have worse outcomes than males. There are few effective drug therapies to treat burn shock and secondary injury progression. The lack of effective drugs appears to arise from the current treat-as-you-go approach rather than a more integrated systems approach. In this review, we present a brief history of burns research and discuss its pathophysiology from a systems' perspective. The severe burn injury phenotype appears to develop from a rapid and relentless barrage of damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) and neural afferent signals, which leads to a state of hyperinflammation, immune dysfunction, coagulopathy, hypermetabolism and intense pain. We propose that if the central nervous system (CNS) control of cardiovascular function and endothelial-glycocalyx-mitochondrial coupling can be restored early, these secondary injury processes may be minimized. The therapeutic goal is to switch the injury phenotype to a healing phenotype by reducing fluid leak and maintaining tissue O2 perfusion. Currently, no systems-based therapies exist to treat severe burns. We have been developing a small-volume fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat hemorrhagic shock, traumatic brain injury and sepsis. Our early studies indicate that the ALM therapy holds some promise in supporting cardiovascular and pulmonary functions following severe burns. Future research will investigate the ability of ALM therapy to treat severe burns with polytrauma and sex disparities, and potential translation to humans.

Central Nervous System, Hormonal Regulation and Sensory Control of Schooling Behavior of Fish

Central Nervous System, Hormonal Regulation and Sensory Control of Schooling Behavior of Fish

Functional neuroimaging related to lower urinary tract sensations: Future directions for study designs and selection of patient groups: ICI-RS 2023.

Neuroimaging studies have advanced our understanding of the intricate central nervous system control network governing lower urinary tract (LUT) function, shedding light on mechanisms for urine storage and voiding. However, a lack of consensus in methodological approaches hinders the comparability of results among research groups and limits the translation of this knowledge to clinical applications, emphasizing the need for standardized methodologies and clinical utilization guidelines. This paper reports the discussions of a workshop at the 2023 meeting of the International Consultation on Incontinence Research Society, which reviewed uncertainties and research priorities to progress the field of neuroimaging in LUT control and dysfunction. Neuroimaging holds great potential for improving our understanding of LUT control and pathophysiological conditions. To date, functional neuroimaging techniques have not yet achieved sufficient strength to make a direct clinical impact. Potential approaches that can improve the clinical utilization of neuroimaging were discussed and research questions proposed. Neuroimaging offers a valuable tool for investigating LUT control, but it's essential to acknowledge the potential for oversimplification when interpreting brain activity due to the complex neural processing and filtering of sensory information. Moreover, technical limitations pose challenges in assessing key brain stem and spinal cord centers, particularly in cases of neurological dysfunction, highlighting the need for more reliable imaging of these centers to advance our understanding of LUT function and dysfunction.

Characteristics of multi-channel intermuscular directional coupling based on time-varying partial directional coherence analysis

The human body transmits directional information between muscles during upper limb movements, and this will be particularly evident when the dominant muscle changes during movement transitions. By capturing the electromyography (EMG) signals of wrist flexion and extension continuous transition movements, we investigated the characteristics of multichannel intermuscular directional coupling and directional information transmission, and consequently explored the control mechanism of Central nervous system (CNS) and the coordination mechanism of motor muscles. Multi-channel EMG was collected from 12 healthy subjects under continuous translational movements of wrist flexion and extension, and the time-varying biased directional coherence analysis (TVPDC) model was constructed using partial directional coherence analysis (PDC) frequency domain directionality to study the directional information transfer characteristics in the time–frequency domain, screen closely related muscle pairs and perform directional coupling significance analysis. Palmaris longus (PL) played a dominant role under wrist flexion movements(WF), Extensor Carpi Radialis (ECR) played a dominant role under wrist extension movements(WE), and the remaining muscles responded to them with information and Biceps Brachii (BB) played a responsive role throughout the movement; flexor pairs had the highest positive coupling values in the beta band during Conversion action1 (MC1) and WF phases, and extensor pairs had the highest positive coupling values in the gamma band during Conversion action2(MC2) phase and the highest coupling values in the beta band during WE phase. TVPDC can effectively analyze the multichannel intermuscular directional coupling and information transmission relationship of surface electromyography under wrist flexion and extension transition movements, providing a reference for exploring the control mechanism of CNS and abnormal control mechanism in patients with motor dysfunction in a new perspective.

Craniospinal Irradiation for CNS Leukemia: Rates of Response and Durability of CNS Control.

Craniospinal irradiation (CSI) is used in the management of leukemia patients with central-nervous-system (CNS) involvement, though the data on response and local control are limited. Given the radioresponsiveness of leukemia, we hypothesized that response to CSI would be high, but CNS control would be influenced by control of systemic disease. This retrospective, single-institution analysis included consecutive pediatric and adult patients between 2009-2021 with leukemia that underwent CSI for CNS involvement, defined as presence of blasts (i.e., >0%) on CSF flow cytometry. Endpoints included CNS response rate (RR), CNS local recurrence (LR), progression-free survival (PFS), and overall survival (OS), which were estimated from start of CSI. The probability of CNS LR was summarized using a cumulative incidence estimate, where death without LR was considered a competing risk. The probabilities of OS and PFS were obtained using Kaplan-Meier estimates. Among the 39 eligible patients (43% AML, 49% ALL, 8% blast-phase CML), most were male (59%). All had CSF confirmation of disease. Median age at CSI was 31 years (range 7-67). CSI (protons 54%, photons 46%) was utilized early within the CNS disease course (median 0 CNS relapses prior to CSI). Twenty-five patients (64%) received CSI immediately prior to a stem-cell transplant (SCT), of which 21 (84%) had TBI conditioning to a median dose of 12 Gy (range 2-13.2). Patients treated with CSI alone received a higher CSI dose (median 18 Gy; range 10.8-24) than those treated with SCT consolidation (median 12 Gy; range 10.8-24). Fifteen patients had CSF-positive disease immediately prior to CSI; all 14 of those assessed for response (RR 100%) had confirmed clearance of blasts at a median of 23 days (range 7-197) from CSI start. With a median follow-up of 48 months (range 0.4-123) for survivors, 2-year PFS and OS estimates were 32% and 43%, respectively. Only 5 CNS relapses were noted (2-year CNS LR of 14%). All CNS relapses either occurred after (n = 4) or concurrently (n = 1) with a systemic relapse. In Cox regression univariate models, age, sex, time to CNS disease, positive CSF immediately prior to CSI, and SCT did not show demonstrable evidence of association with CNS LR. However, systemic relapse after CSI (HR 5.9, 95% CI 2.5-13.8, P<0.0001) and systemic disease at the time of CSI (HR 3.9, 95% CI 1.6-9.5, P = 0.003) were associated with higher risk of CNS LR. No grade-3+ acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Though CNS local recurrence was modest, there was a high risk of systemic relapse and/or death. Control of systemic disease, both before and after CSI, may be important for CNS local control, and raises consideration that CNS recurrence may reflect reseeding from the systemic space.

CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC

Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi. We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier. We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease. Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.

Adenosine, lidocaine and Mg2+ update: teaching old drugs new tricks.

If a trauma (or infection) exceeds the body's evolutionary design limits, a stress response is activated to quickly restore homeostasis. However, when the injury severity score is high, death is often imminent. The goal of this review is to provide an update on the effect of small-volume adenosine, lidocaine and Mg2+ (ALM) therapy on increasing survival and blunting secondary injury after non-compressible hemorrhagic shock and other trauma and infective/endotoxemic states. Two standout features of ALM therapy are: (1) resuscitation occurs at permissive hypotensive blood pressures (MAPs 50-60 mmHg), and (2) the drug confers neuroprotection at these low pressures. The therapy appears to reset the body's baroreflex to produce a high-flow, hypotensive, vasodilatory state with maintained tissue O2 delivery. Whole body ALM protection appears to be afforded by NO synthesis-dependent pathways and shifting central nervous system (CNS) control from sympathetic to parasympathetic dominance, resulting in improved cardiovascular function, reduced immune activation and inflammation, correction of coagulopathy, restoration of endothelial glycocalyx, and reduced energy demand and mitochondrial oxidative stress. Recently, independent studies have shown ALM may also be useful for stroke, muscle trauma, and as an adjunct to Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). Ongoing studies have further shown ALM may have utility for burn polytrauma, damage control surgery and orthopedic surgery. Lastly, we discuss the clinical applications of ALM fluid therapy for prehospital and military far-forward use for non-compressible hemorrhage and traumatic brain injury (TBI).

Motor control differs for increasing and decreasing force production during ankle Isometric exercises in children

BackgroundPerformance of the central nervous system (CNS) in increased and decreasing muscle force around the ankle joint is essential for upright tasks of daily living. Previous studies have shown altered CNS control when they decrease force compared with when they increase force in young and older adults. But whether such alteration exists during childhood with incomplete maturation of CNS systems remain unclear. Therefore, this study aimed to evaluate the disparities in intramuscular EMG-EMG coherence, which serve as indicators of corticospinal drive to muscles during ankle isometric increasing and decreasing force generation in children.MethodsWe measured intramuscular EMG-EMG coherence activity of the tibialis anterior (TA) and the associated ability to perform isometric efforts at the ankle in 12 typically developing children (mean ± SD age = 5.91±1.37 years) and 12 healthy young adults (mean ± SD age = 23.16±1.52 years). The participants maintained isometric contractions at 20% of their maximal voluntary contractions (MVC) during ankle dorsiflexion to match a triangle trajectory for 7 s, including ramping up in 3.5 s (increasing force phase) and then linearly ramping down to rest in 3.5 s (decreasing force phase). The variability of force control was characterized by the coefficient of variance (CoV) of force output. Intramuscular EMG-EMG coherence from TA in two frequency bands, the beta band (15–30 Hz) and gamma band (30–45) that could reflect the corticospinal drive, were calculated for the comparison. A repeated measures ANOVA with the within-subjects factor of force generation phase (increasing force vs. decreasing force)x between-subjects factor of the group (children and young adults) was used for statistical analysis.ResultsRegarding the within-subjects difference, our results exhibited significantly higher CoV of force (p < 0.01) and lower EMG-EMG coherence of TA when they decrease force compared with when they increase force in both children and young adult groups. Regarding the between-subjects difference, the CoV of force was significantly higher (p < 0.01) in children compared to young adults, while the EMG-EMG coherence in children showed a significantly lower (p < 0.01) coherence compared with young adults. Furthermore, the EMG-EMG coherence measures were negatively correlated with the CoV of force.ConclusionsThe findings suggest that the age-related development would increase the corticospinal drive to TA muscle to deal with ankle isometric dorsiflexion during childhood, which could be also modulated with the force production phases, including increasing and decreasing force.

Stereotactic Radiosurgery for Brain Metastases in Patients With Small Cell Lung Cancer

Treatment of small cell lung cancer (SCLC) with brain metastatic disease has traditionally involved whole brain radiation therapy (WBRT). The role of stereotactic radiosurgery (SRS) is unclear. Our study was a retrospective review of an SRS database evaluating patients with SCLC who received SRS. A total of 70 patients and 337 treated brain metastases (BM) were analyzed. Forty-five patients had previous WBRT. The median number of treated BM was 4 (range, 1-29). Median survival was 4.9 months (range, 0.70-23.9). The number of treated BM was correlated with survival; patients with fewer BM had improved overall survival (P < .021). The number of treated BM was associated with different brain failure rates; 1-year central nervous system control rates were 39.2% for 1 to 2 BM, 27.6% for 3 to 5 BM, and 0% for >5 treated BM. Patients with previous WBRT had worse brain failure rates (P < .040). For patients without previous WBRT, the 1-year distant brain failure rate was 48%, and median time to distant failure was 15.3 months. SRS for SCLC in patients with <5 BM appears to offer acceptable control rates. Patients with >5 BM have high rates of subsequent brain failure and are not ideal candidates for SRS.

Brightness illusions evoke pupil constriction preceded by a primary visual cortex response in rats.

The mind affects the body via central nervous system (CNS) control of the autonomic nervous system (ANS). In humans, one striking illustration of the "mind-body" connection is that illusions, subjectively perceived as bright, drive pupil constriction. The CNS network driving this pupil response is unknown and requires an animal model for investigation. However, the pupil response to this illusion has long been thought to occur only in humans. Here, we report that the same brightness illusion that evokes pupil constriction in humans also does so in rats. We surveyed the role of most of rat cortex in this "mind-body" connection by recording cortex-wide EEG. These recordings revealed that, compared to a luminance-matched control stimulus, the illusion of brightness for a specific stimulus color and size, evoked a larger response in primary visual cortex (V1) and not in secondary visual, parietal, or frontal cortex. The response preceded pupil constriction suggesting a potential causal role of V1 on the pupil. Our results provide evidence that this "mind-body" connection is not confined to humans and that V1 may be part of a mammalian CNS network for bodily reactions to illusions.

IL-10-providing B cells govern pro-inflammatory activity of macrophages and microglia in CNS autoimmunity

B cells contribute to chronic inflammatory conditions as source of antibody-secreting plasma cells and as antigen-presenting cells activating T cells, making anti-CD20-mediated B cell depletion a widely used therapeutic option. B cells or B cell subsets may, however, exert regulatory effects, while to date, the immunological and/or clinical impact of these observations remained unclear. We found that in multiple sclerosis (MS) patients, B cells contain regulatory features and that their removal enhanced activity of monocytes. Using a co-culture system, we identified B cell-provided interleukin (IL)-10 as key factor in controlling pro-inflammatory activity of peripheral myeloid cells as well as microglia. Depleting B cells via anti-CD20 in a mouse model of MS unleashed the activity of myeloid cells and microglia and accelerated disease severity; in contrast, adoptive transfer of IL-10-providing B cells restored in vivo control of central nervous system (CNS) macrophages and microglia and reversed clinical exacerbation. These findings suggest that B cells exert meaningful regulatory properties, which should be considered when designing novel B cell-directed agents.

Characteristics analysis of muscle function network and its application to muscle compensatory in repetitive movement

In rehabilitation medicine, highly repetitive rehabilitation training can help patients recover their physical and cognitive abilities. When the patient undergoes rehabilitation training, the muscles that are supposed to function are unable to perform their functions properly, resulting in other muscles compensating or even replacing their functions, a phenomenon is known as muscle compensation. Analysis of muscle compensation allows the study of mechanisms of central nervous system control of movement. Muscle functional networks quantify the functional connectivity between synergistic muscles. They can identify the frequency characteristics between muscles regulated by standard neural inputs, which can be used as a valuable feature to analyze changes in muscle compensation. Therefore, this paper analyzes muscle compensation induced by repetitive fatiguing movements of the arm (with rest). Our work recruited 30 subjects to perform four bouts of isotonic exercise and collected Surface EMG and kinematic data. The muscle function network was used to extract the muscle compensatory characteristics of the subjects, and the neuromodulatory mechanisms of muscle compensation were explored at a macroscopic scale by linear fitting of the characteristics. The results showed that BOUT2 had the highest slope of the feature fit in the four bouts, with an average increase of 90.20% compared to BOUT1, an average decrease of 80.70% compared to BOUT3, and an average decrease of 71.56% compared to BOUT4.

Brain oscillatory activity in adolescent idiopathic scoliosis

Pathophysiology of Adolescent Idiopathic Scoliosis (AIS) is not yet completely understood. This exploratory study aims to investigate two aspects neglected in clinical practice: a defective postural central nervous system control in AIS, and alterations of body schema due to scoliosis spinal deformities. We recorded EEG data and balance data in four different standing positions in 14 adolescents with AIS and in 14 controls. A re-adaptation of the Image Marking Procedure (IMP) assessed body schema alterations on the horizontal (Body Perception Indices (BPIs)) and vertical direction (interacromial and bisiliac axes inclinations). Our results revealed no differences in balance control between groups; higher EEG alpha relative power over sensorimotor areas ipsilateral to the side of the curve and a significant increase of theta relative power localized over the central areas in adolescents with AIS. The difference in BPI shoulder and BPI waist significantly differed between the two groups. The inclinations of the perceived interacromial axes in adolescents with AIS was opposite to the real inclination. Increased theta activity and alpha lateralization observed may be a compensatory strategy to overcome sensorimotor dysfunction mirrored by altered body schema. Scoliosis onset might be preceded by sensorimotor control impairments that last during curve progression.

Detecting task-relevant spatiotemporal modules and their relation to motor adaptation.

How does the central nervous system (CNS) control our bodies, including hundreds of degrees of freedom (DoFs)? A hypothesis to reduce the number of DoFs posits that the CNS controls groups of joints or muscles (i.e., modules) rather than each joint or muscle independently. Another hypothesis posits that the CNS primarily controls motion components relevant to task achievements (i.e., task-relevant components). Although the two hypotheses are examined intensively, the relationship between the two concepts remains unknown, e.g., unimportant modules may possess task-relevant information. Here, we propose a framework of task-relevant modules, i.e., modules relevant to task achievements, while combining the two concepts mentioned above in a data-driven manner. To examine the possible role of the task-relevant modules, we examined the modulation of the task-relevant modules in a motor adaptation paradigm in which trial-to-trial modifications of motor output are observable. The task-relevant modules, rather than conventional modules, showed adaptation-dependent modulations, indicating the relevance of task-relevant modules to trial-to-trial updates of motor output. Our method provides insight into motor control and adaptation via an integrated framework of modules and task-relevant components.

The Influence of Energy Drinks on Lower Limb Muscle Fatigue and Recovery in Healthy Young Adults

Many studies have researched the influences of energy drinks (Edrinks) on the central nervous system, balance, and neuromuscular control. Understanding the neuromuscular adaptations that occur after drinking Celsius Edrinks on muscle fatigue and balance can be helpful when advising the use of Edrinks during physical activity. This study aims to understand the impact Celsius Edrinks has on neuromuscular adaptations in lower limb musculature during muscle fatigue, and balance in young, healthy adults. Two males and eighteen females were recruited for this study. The tibialis anterior, gastrocnemius, and Gluteus Medius neuromuscular data were captured with surface EMG electrodes. The number of single-leg heel raises repetitions and time to fatigue were recorded. Subjects were asked to perform single-leg heel raises to fatigue and single-leg balance activities pre-energy drink consumption, and the same tasks were repeated on the opposite not tested limb (post Edrinks consumption) to equate data points. Neuromuscular timing data suggested modifications on leg musculature. Although not significant, the amount of single-leg heel raises performed pre, and post-drink intake increased post-energy drink consumption. We infer that the ingredients in Celsius energy drinks, including caffeine, Taurine, and Guarana, alter nerve conduction velocity in lower limb musculature during exercise and balance activities. Future studies should research the influence of Celsius energy drinks in different scenarios and populations.

Targeting APC-Host Microbe interactions 2Robust control of a neurotropic parasite through MHC I presentation by infected neurons

Control of Central Nervous System (CNS) pathogens by CD8 T cells is pivotal to avoid fatal neuroinflammation. Yet the modalities of MHC I presentation in the brain are poorly understood. We analyzed the antigen presentation mechanisms underlying CD8 T cell-mediated brain restriction of Toxoplasma gondii, a neurotropic parasite that can chronically reside as cysts in the CNS and cause deadly encephalitis. First we engineered transgenic parasites expressing a model antigen that allows the establishment of latent toxoplasmosis in C57BL/6 mice, a mouse model that normally develops encephalitis following T. gondii infection. We show that MHC I presentation of that model antigen suffices to prevent encephalitis, even when restricted to the rapidly dividing tachyzoite stage. We find that improper parasite control in the context of encephalitis correlates with suboptimal MHC I presentation of T. gondii antigens by primary neuronal cultures. Using a new model of conditional MHC I-deficient mice, we finally demonstrate that brain parasite control requires neuronal MHC I presentation. Thus, MHC I presentation by CNS neurons is a crucial checkpoint that determines the clinical outcome of a prevalent and persisting brain infection.

Rotavirus Downregulates Tyrosine Hydroxylase in the Noradrenergic Sympathetic Nervous System in Ileum, Early in Infection and Simultaneously with Increased Intestinal Transit and Altered Brain Activities.

ABSTRACTWhile rotavirus diarrhea has been considered to occur only due to intrinsic intestinal effects within the enteric nervous system, we provide evidence for central nervous system control underlying the clinical symptomology. Our data visualize infection by large-scale three-dimensional (3D) volumetric tissue imaging of a mouse model and demonstrate that rotavirus infection disrupts the homeostasis of the autonomous system by downregulating tyrosine hydroxylase in the noradrenergic sympathetic nervous system in ileum, concomitant with increased intestinal transit. Interestingly, the nervous response was found to occur before the onset of clinical symptoms. In adult infected animals, we found increased pS6 immunoreactivity in the area postrema of the brain stem and decreased phosphorylated STAT5-immunoreactive neurons in the bed nucleus of the stria terminalis, which has been associated with autonomic control, including stress response. Our observations contribute to knowledge of how rotavirus infection induces gut-nerve-brain interaction early in the disease.

Neuroendocrine microRNAs linked to energy homeostasis: future therapeutic potential.

The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed andthe regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.