Onset Of Response Research Articles

Detection of β-Lactoglobulin by a Porous Silicon Microcavity Biosensor Based on the Angle Spectrum.

In this paper, carbon quantum dot-labelled β-lactoglobulin antibodies were used for refractive index magnification, and β-lactoglobulin was detected by angle spectroscopy. In this method, the detection light is provided by a He-Ne laser whose central wavelength is the same as that of the porous silicon microcavity device, and the light source was changed to a parallel beam to illuminate the porous silicon microcavity’ surface by collimating beam expansion, and the reflected light was received on the porous silicon microcavity’ surface by a detector. The angle corresponding to the smallest luminous intensity before and after the onset of immune response was measured by a detector for different concentrations of β-lactoglobulin antigen and carbon quantum dot-labelled β-lactoglobulin antibodies, and the relationship between the variation in angle before and after the immune response was obtained for different concentrations of the β-lactoglobulin antigen. The results of the experiment present that the angle variations changed linearly with increasing β-lactoglobulin antigen concentration before and after the immune response. The limit of detection of β-lactoglobulin by this method was 0.73 μg/L, indicating that the method can be used to detect β-lactoglobulin quickly and conveniently at low cost.

Identification of asthma phenotypes using blood cell count.

Asthma is a common disease characterized by chronic airway inflammation.1 Although clinical manifestations among asthmatic patients are quite similar, asthma is a heterogeneous and complex disease in which several phenotypes have been described, mainly related to the age of onset, type and severity of symptoms, airway inflammation and treatment response.2 Since the identification of asthmatic phenotypes is of great importance for providing the correct and most effective therapeutic intervention, the development of easy, non-invasive, and affordable biomarkers is still an unmet need.

CoSpar identifies early cell fate biases from single-cell transcriptomic and lineage information.

A goal of single-cell genome-wide profiling is to reconstruct dynamic transitions during cell differentiation, disease onset and drug response. Single-cell assays have recently been integrated with lineage tracing, a set of methods that identify cells of common ancestry to establish bona fide dynamic relationships between cell states. These integrated methods have revealed unappreciated cell dynamics, but their analysis faces recurrent challenges arising from noisy, dispersed lineage data. In this study, we developed coherent, sparse optimization (CoSpar) as a robust computational approach to infer cell dynamics from single-cell transcriptomics integrated with lineage tracing. Built on assumptions of coherence and sparsity of transition maps, CoSpar is robust to severe downsampling and dispersion of lineage data, which enables simpler experimental designs and requires less calibration. In datasets representing hematopoiesis, reprogramming and directed differentiation, CoSpar identifies early fate biases not previously detected, predicting transcription factors and receptors implicated in fate choice. Documentation and detailed examples for common experimental designs are available at https://cospar.readthedocs.io/ .

Nonlinearity in bone-conducted amplitude-modulated cervical vestibular-evoked myogenic potentials: harmonic distortion products.

Otolith organs of the balance system, the saccule and utricle, encode linear acceleration. Integrity of the saccule is commonly assessed using cervical vestibular-evoked myogenic potentials (cVEMPs) arising from an inhibitory reflex along the vestibulospinal pathway. Conventional approaches to eliciting these responses use brief, transient sounds to elicit onset responses. Here we used long-duration amplitude-modulated (AM) tones to elicit cVEMPs (AMcVEMPs) and analyzed their spectral content for evidence of nonlinear processing consistent with known characteristics of vestibular hair cells. Twelve young adults (ages 21-25) with no hearing or vestibular pathologies participated in this study. AMcVEMPs were elicited by bone-conducted AM tones with a 500-Hz carrier frequency. Eighteen modulation frequencies were used between 7 and 403 Hz. All participants had robust distortion products at harmonics of the modulation frequency. Total harmonic distortion ranged from approximately 10 to 80%. AMcVEMPs contain harmonic distortion products consistent with vestibular hair cell nonlinearities, and this new approach to studying the otolith organs may provide a noninvasive, in vivo method to study nonlinearity of vestibular hair cells in humans.NEW & NOTEWORTHY The otolith balance organs of humans are assessed for basic science and clinical applications by using vestibular-evoked myogenic potentials (VEMPs). Traditionally, VEMPs are elicited with brief, transient sounds to study onset responses. We used long-duration sounds to elicit steady-state VEMPs. This allowed us to measure nonlinear distortion products, consistent with nonlinear processing in vestibular hair cells. This new approach may help to better understand links between otolith organs and balance function.

Propofol anesthesia concentration rather than abrupt behavioral unresponsiveness linearly degrades responses in the rat primary auditory cortex.

Despite extensive knowledge of its molecular and cellular effects, how anesthesia affects sensory processing remains poorly understood. In particular, it remains unclear whether anesthesia modestly or robustly degrades activity in primary sensory regions, and whether such changes are linked to anesthesia drug concentration versus behavioral unresponsiveness, which are typically confounded. Here, we used slow gradual intravenous propofol anesthesia induction together with auditory stimulation and intermittent assessment of behavioral responsiveness while recording epidural electroencephalogram, and neuronal spiking activity in primary auditory cortex (PAC) of eight rats. We found that all main components of neuronal activity including spontaneous firing rates, onset response magnitudes, onset response latencies, postonset neuronal silence duration, late-locking to 40Hz click-trains, and offset responses, gradually changed in a dose-dependent manner with increasing anesthesia levels without showing abrupt shifts around loss of righting reflex or other time-points. Thus, the dominant factor affecting PAC responses is the anesthesia drug concentration rather than any sudden, dichotomous behavioral state changes. Our findings explain a wide array of seemingly conflicting results in the literature that, depending on the precise definition of wakefulness (vigilant vs. drowsy) and anesthesia (light vs. deep/surgical), report a spectrum of effects in primary regions ranging from minimal to dramatic differences.

Image-Based Learning Using Gradient Class Activation Maps for Enhanced Physiological Interpretability of Motor Imagery Skills

Brain activity stimulated by the motor imagery paradigm (MI) is measured by Electroencephalography (EEG), which has several advantages to be implemented with the widely used Brain–Computer Interfaces (BCIs) technology. However, the substantial inter/intra variability of recorded data significantly influences individual skills on the achieved performance. This study explores the ability to distinguish between MI tasks and the interpretability of the brain’s ability to produce elicited mental responses with improved accuracy. We develop a Deep and Wide Convolutional Neuronal Network fed by a set of topoplots extracted from the multichannel EEG data. Further, we perform a visualization technique based on gradient-based class activation maps (namely, GradCam++) at different intervals along the MI paradigm timeline to account for intra-subject variability in neural responses over time. We also cluster the dynamic spatial representation of the extracted maps across the subject set to come to a deeper understanding of MI-BCI coordination skills. According to the results obtained from the evaluated GigaScience Database of motor-evoked potentials, the developed approach enhances the physiological explanation of motor imagery in aspects such as neural synchronization between rhythms, brain lateralization, and the ability to predict the MI onset responses and their evolution during training sessions.

Metabolic syndrome and bladder cancer.

Metabolic syndrome (MetS) is a widely diffused dysmetabolism, well known to be associated with an increased cardiovascular risk. However, a growing burden of evidence links MetS with several malignancies, potentially influencing the onset, progression, and therapeutic response. In this work, we critically explored the relationship between MetS and bladder cancer through a narrative review, researching the most recent literature on the topic using PubMed, MEDLINE, and EMBASE. We found that the current evidence on the subject is heterogeneous and inconsistent, making it difficult to draw definitive conclusions. Furthermore, since MetS would be a modifiable oncological risk factor, more high-quality data is needed for tailored treatment of bladder cancer.

Contributed Session II: Attentional Modulation of Early Cortical Chromatic Responses

Prior research demonstrates that attention can modulate the amplitude of achromatic (black and white) pattern reversal stimuli. Similarly, MRI research has shown attentional modulation of BOLD responses to both chromatic and achromatic stimuli. However, prior research has also demonstrated that the chromatic onset visual evoked potential (VEP) is robust to attentional modulation (e.g., Highsmith & Crognale, 2010; Wang & Wade, 2011) with either spatially contiguous or spatially disparate manipulations. It is possible that more demanding attentional tasks than those that have been used previously, may reveal attentional modulation of the chromatic VEP. Here we report the results of experiments in which we recorded chromatic and achromatic VEPs while subjects performed multiple object tracking (MOT) tasks with several levels of difficulty. Steady-state onset responses were recorded at 3hz for stimuli modulated along the chromatic and achromatic axes. Our preliminary results suggest that the increased attentional demand provided by MOT can reveal a clear, but idiosyncratic modulation of chromatic VEP responses. The question remains whether or not chromatic and achromatic mechanisms share similar attentional gain processes as reflected in the VEP. We are currently characterizing the nature of these attentional gain mechanisms.

Onset of the humoral immune response of layer chicks vaccinated in ovo with strain F Mycoplasma gallisepticum vaccine and evidence of male-biased mortality

Previous trials in which layers were in ovo-vaccinated against strain F Mycoplasma gallisepticum (FMG) showed that nearly 50% of the birds produced IgM antibody against FMG at 6 wk of age (WOA). Standard FMG vaccination application at 9 or 10 woa, result in this percentage at approximately 15 woa. This study investigated when FMG in ovo-vaccinated birds initiate a humoral immune response prior to 6 wk, and if sex influences this response. Hy-Line W-36 embryonated eggs were either not vaccinated (controls) or in-ovo vaccinated with a 50 µL volume of a 10−6 dilution of Poulvac MycoF vaccine (Zoetis). For each treatment group, 384 straight-run chicks were reared. At hatch and at 2, 3, 5, 7, 14, 21, and 28 d post-hatch, 54 birds per treatment were individually weighed and a blood sample was collected for Mycoplasma gallisepticum (MG) IgM antibody detection. ELISA was run on blood samples at 14, 21, and 28 d to distinguish IgG antibody production. At each age, BW was not different between vaccinated and control chicks (all P > 0.19). Males, however, outweighed females starting at d 5 (P = 0.02). Mortality was 1.0% for the control birds and 12.2% for the FMG birds during the first 2 wk. The majority (72.3%) of the mortalities in the FMG group were male. The percentage of control and FMG in ovo-vaccinated birds with IgM antibody production was 0% and 1.9% on d 7, 0% and 31.5% on d 14, 1.9% and 55.9% on d 21, and 0% and 60.6% on d 28, respectively. IgG antibody production in the FMG in ovo-vaccinated birds was 0.0% at 14 d, 2.9% at 21 d, and 21.2% at 28 d of age. All control birds tested negative for FMG-IgG production. In conclusion, the earliest detection of MG antibodies after in ovo vaccination with live FMG occurred at 7 d. Male layer chickens were more susceptible to the effects of an in ovo FMG vaccine than females.

Ethanolic extract from Lepidium virginicum L. ameliorates DNBS-induced colitis in rats

Ethnopharmacological relevanceLepidium virginicum L. (Brassicaceae) is a plant widely used in traditional Mexican medicine as an expectorant, diuretic, and as a remedy to treat diarrhea and dysentery, infection-derived gastroenteritis. However, there is no scientific study that validates its clinical use as an anti-inflammatory in the intestine. Aim of the studyThis study aimed to investigate the anti-inflammatory properties of the ethanolic extract of Lepidium virginicum L. (ELv) in an animal model of inflammatory bowel disease (IBD)-like colitis. Materials and methodsThe 2,4-dinitrobenzene sulfonic acid (DNBS) animal model of IBD was used. Colitis was induced by intrarectal instillation of 200 mg/kg of DNBS dissolved vehicle, 50% ethanol. Control rats only received the vehicle. Six hours posterior to DNBS administration, ELv (3, 30, or 100 mg/kg) was administered daily by gavage or intraperitoneal injection. The onset and course of the inflammatory response were monitored by assessing weight loss, stool consistency, and fecal blood. Colonic damage was evaluated by colon weight/length ratio, histopathology, colonic myeloperoxidase (MPO) activity, and gene expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), chemokine C-X-C motif ligand 1 (CXCL-1), and interleukin-6 (IL-6). ResultsRats treated with DNBS displayed significant weight loss, diarrhea, fecal blood, colon shortening, a significant increase in immune cell infiltration and MPO activity, as well as increased proinflammatory cytokine expression. Intraperitoneal administration of ELv significantly reduced colon inflammation, whereas oral treatment proved to be ineffective. In fact, intraperitoneal ELv significantly attenuated the clinical manifestations of colitis, immune cell infiltration, MPO activity, and pro-inflammatory (CXCL-1, TNF-α, and IL-1β) gene expression in a dose-dependent manner. ConclusionTraditional medicine has employed ELv as a remedy for common infection-derived gastrointestinal symptoms; however, we hereby present the first published study validating its anti-inflammatory properties in the mitigation of DNBS-induced colitis.

Small Non-Coding RNAs in Leukemia.

Simple SummaryLeukemia is a group of blood cancers that arise when abnormal or underdeveloped blood cells accumulate in the bloodstream, bone marrow and lymphatic system. A driver event in the development of Chronic Lymphocytic Leukemia (CLL) is the deletion of the genomic region encoding for miR-15a/16-1. MicroRNAs are small non-coding RNAs involved in the regulation of gene expression, and loss of miR-15a/16-1 in CLL results in the accumulation of the antiapoptotic gene BCL2 and inhibition of the apoptotic process. This discovery was the first evidence that microRNAs have a role in the onset of cancer. Following this finding, several studies investigated the role of microRNAs and other small non-coding RNAs in different types of leukemia and cancers in general. This review summarizes the role of small non-coding RNAs in leukemia and describes their possible application in clinical settings as biomarkers and/or targets for therapy. In 2020, more than 60,500 people were diagnosed with leukemia in the USA, and more than 23,000 died. The incidence of leukemia is still rising, and drug resistance development is a serious concern for patients’ wellbeing and survival. In the past two decades, small non-coding RNAs have been studied to evaluate their functions and possible role in cancer pathogenesis. Small non-coding RNAs are short RNA molecules involved in several cellular processes by regulating the expression of genes. An increasing body of evidence collected by many independent studies shows that the expression of these molecules is tissue specific, and that their dysregulation alters the expression of genes involved in tumor development, progression and drug response. Indeed, small non-coding RNAs play a pivotal role in the onset, staging, relapse and drug response of hematological malignancies and cancers in general. These findings strongly suggest that small non-coding RNAs could function as biomarkers and possible targets for therapy. Thus, in this review, we summarize the regulatory mechanisms of small non-coding RNA expression in different types of leukemia and assess their potential clinical implications.

Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson\u2019s Disease

SummaryStearoyl-CoA desaturase (SCD) is a potential therapeutic target for Parkinson’s and related neurodegenerative diseases. SCD inhibition ameliorates neuronal toxicity caused by aberrant α-synuclein, a lipid-binding protein implicated in Parkinson’s disease. Its inhibition depletes monounsaturated fatty acids, which may modulate α-synuclein conformations and membrane interactions. Herein, we characterize the pharmacokinetic and pharmacodynamic properties of YTX-7739, a clinical-stage SCD inhibitor. Administration of YTX-7739 to rats and monkeys for 15 days caused a dose-dependent increase in YTX-7739 concentrations that were well-tolerated and associated with concentration-dependent reductions in the fatty acid desaturation index (FADI), the ratio of monounsaturated to saturated fatty acids. An approximate 50% maximal reduction in the carbon-16 desaturation index was observed in the brain, with comparable responses in the plasma and skin. A study with a diet supplemented in SCD products indicates that changes in brain C16 desaturation were due to local SCD inhibition, rather than to changes in systemic fatty acids that reach the brain. Assessment of pharmacodynamic response onset and reversibility kinetics indicated that approximately 7 days of dosing were required to achieve maximal responses, which persisted for at least 2 days after cessation of dosing. YTX-7739 thus achieved sufficient concentrations in the brain to inhibit SCD and produce pharmacodynamic responses that were well-tolerated in rats and monkeys. These results provide a framework for evaluating YTX-7739 pharmacology clinically as a disease-modifying therapy to treat synucleinopathies.

Acute Gravitational Stress Selectively Impairs Dynamic Cerebrovascular Reactivity in the Anterior Circulation Independent of Changes to the Central Respiratory Chemoreflex.

Cerebrovascular reactivity (CVR) to changes in the partial pressure of arterial carbon dioxide (PaCO2) is an important mechanism that maintains CO2 or pH homeostasis in the brain. To what extent this is influenced by gravitational stress and corresponding implications for the regulation of cerebral blood flow (CBF) remain unclear. The present study examined the onset responses of pulmonary ventilation (V̇E) and anterior middle (MCA) and posterior (PCA) cerebral artery mean blood velocity (Vmean) responses to acute hypercapnia (5% CO2) to infer dynamic changes in the central respiratory chemoreflex and cerebrovascular reactivity (CVR), in supine and 50° head-up tilt (HUT) positions. Each onset response was evaluated using a single-exponential regression model consisting of the response time latency [CO2-response delay (t0)] and time constant (τ). Onset response of V̇E and PCA Vmean to changes in CO2 was unchanged during 50° HUT compared with supine (τ: V̇E, p = 0.707; PCA Vmean, p = 0.071 vs. supine) but the MCA Vmean onset response was faster during supine than during 50° HUT (τ: p = 0.003 vs. supine). These data indicate that gravitational stress selectively impaired dynamic CVR in the anterior cerebral circulation, whereas the posterior circulation was preserved, independent of any changes to the central respiratory chemoreflex. Collectively, our findings highlight the regional heterogeneity underlying CBF regulation that may have translational implications for the microgravity (and hypercapnia) associated with deep-space flight notwithstanding terrestrial orthostatic diseases that have been linked to accelerated cognitive decline and neurodegeneration.

Attenuation and recovery of an avoidance response to a chemical antipredator cue in an invasive fish: implications for use as a repellent in conservation.

The detection of predation risk without direct engagement with a predator is an important driver of prey movement strategies. Consequently, the application of alarm cues may prove an effective tool in guiding the movements of fishes targeted for control or conservation. However, failure to contemplate the sensory, physiological and cognitive outcomes of repeated or persistent exposure to the cue will likely lead to poor performance of management practices. Using a series of behavioural tests and physiological recordings from the olfactory organ, we examined the timing of onset and recovery of the alarm response in sea lamprey (Petromyzon marinus L.) when exposed continuously or sporadically to its alarm cue. In the laboratory, sea lamprey exhibited short-term, reversible attenuation of the alarm response over 2-4h with continuous exposure. The alarm response spontaneously recovered after 30-60min of removal from the cue. In long-duration free-swimming tests, where the animals were allowed to move into and out of the odour plume volitionally, repeated but sporadic encounter with the alarm cue over 5h did not alter the alarm response. Electro-olfactogram recordings from the main olfactory epithelium indicated that olfactory sensory neurons quickly adapt to alarm cue and recovered within 15min. Our findings strongly implicate habituation as the mechanism that induces reduction in the alarm response and provide insight into the design of effective management practices that seek to use fish alarm cues as repellents.

SARS‐CoV‐2 memory B and T cell profiles in mild COVID‐19 convalescent patients

ObjectivesAntiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation. MethodsIn this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit. ResultsSeventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted. ConclusionsThe study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection.

Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling

Accurate chromosome segregation during cell division requires amphitelic chromosome attachment to the spindle apparatus. It is ensured by the combined activity of the spindle assembly checkpoint (SAC),1 a signaling mechanism that delays anaphase onset in response to unattached chromosomes, and an error correction mechanism that eliminates syntelic attachments.2 The SAC becomes active when Mps1 kinase sequentially phosphorylates the kinetochore protein Spc105/KNL1 and the signaling proteins that Spc105/KNL1 recruits to facilitate the production of the mitotic checkpoint complex (MCC).3-8 The error correction mechanism is regulated by the Aurora B kinase, but Aurora B also promotes SAC signaling via indirect mechanisms.9-12 Here we present evidence that Aurora B kinase activity directly promotes MCC production by working downstream of Mps1 in budding yeast and human cells. Using the ectopic SAC activation (eSAC) system, we find that the conditional dimerization of Aurora B in budding yeast and an Aurora B recruitment domain in HeLa cells with either Bub1 or Mad1, but not the phosphodomain of Spc105/KNL1, leads to ectopic MCC production and mitotic arrest.13-16 Importantly, Bub1 must recruit both Mad1 and Cdc20 for this ectopic signaling activity. These and other data show that Aurora B cooperates with Bub1 to promote MCC production, but only after Mps1 licenses Bub1 recruitment to the kinetochore. This direct involvement of Aurora B in SAC signaling may maintain SAC signaling even after Mps1 activity in the kinetochore is lowered.

P.0697 Exposure to an enriched environment shortens the onset of venlafaxine response which correlate with the remodeling of hippocampal parvalbumin interneurons

P.0697 Exposure to an enriched environment shortens the onset of venlafaxine response which correlate with the remodeling of hippocampal parvalbumin interneurons

Medullary vein architecture modulates the white matter BOLD cerebrovascular reactivity signal response to CO2: Observations from high-resolution T2* weighted imaging at 7T

Brain stress testing using blood oxygenation level-dependent (BOLD) MRI to evaluate changes in cerebrovascular reactivity (CVR) is of growing interest for evaluating white matter integrity. However, even under healthy conditions, the white matter BOLD-CVR response differs notably from that observed in the gray matter. In addition to actual arterial vascular control, the venous draining topology may influence the WM-CVR response leading to signal delays and dispersions. These types of alterations in hemodynamic parameters are sometimes linked with pathology, but may also arise from differences in normal venous architecture. In this work, high-resolution T2*weighted anatomical images combined with BOLD imaging during a hypercapnic breathing protocol were acquired using a 7 tesla MRI system. Hemodynamic parameters including base CVR, hemodynamic lag, lag-corrected CVR, response onset and signal dispersion, and finally ΔCVR (corrected CVR minus base CVR) were calculated in 8 subjects. Parameter maps were spatially normalized and correlated against an MNI-registered white matter medullary vein atlas. Moderate correlations (Pearson's rho) were observed between medullary vessel frequency (MVF) and ΔCVR (0.52; 0.58 for total WM), MVF and hemodynamic lag (0.42; 0.54 for total WM), MVF and signal dispersion (0.44; 0.53 for total WM), and finally MVF and signal onset (0.43; 0.52 for total WM). Results indicate that, when assessed in the context of the WM venous architecture, changes in the response shape may only be partially reflective of the actual vascular reactivity response occurring further upstream by control vessels. This finding may have implications when attributing diseases mechanisms and/or progression to presumed impaired WM BOLD-CVR.

Six-dimensional dynamic tractography atlas of language connectivity in the developing brain.

During a verbal conversation, our brain moves through a series of complex linguistic processing stages: sound decoding, semantic comprehension, retrieval of semantically coherent words, and overt production of speech outputs. Each process is thought to be supported by a network consisting of local and long-range connections bridging between major cortical areas. Both temporal and extratemporal lobe regions have functional compartments responsible for distinct language domains, including the perception and production of phonological and semantic components. This study provides quantitative evidence of how directly connected inter-lobar neocortical networks support distinct stages of linguistic processing across brain development. Novel six-dimensional tractography was used to intuitively visualize the strength and temporal dynamics of direct inter-lobar effective connectivity between cortical areas activated during each linguistic processing stage. We analysed 3401 non-epileptic intracranial electrode sites from 37 children with focal epilepsy (aged 5-20 years) who underwent extra-operative electrocorticography recording. Principal component analysis of auditory naming-related high-gamma modulations determined the relative involvement of each cortical area during each linguistic processing stage. To quantify direct effective connectivity, we delivered single-pulse electrical stimulation to 488 temporal and 1581 extratemporal lobe sites and measured the early cortico-cortical spectral responses at distant electrodes. Mixed model analyses determined the effects of naming-related high-gamma co-augmentation between connecting regions, age, and cerebral hemisphere on the strength of effective connectivity independent of epilepsy-related factors. Direct effective connectivity was strongest between extratemporal and temporal lobe site pairs, which were simultaneously activated between sentence offset and verbal response onset (i.e. response preparation period); this connectivity was approximately twice more robust than that with temporal lobe sites activated during stimulus listening or overt response. Conversely, extratemporal lobe sites activated during overt response were equally connected with temporal lobe language sites. Older age was associated with increased strength of inter-lobar effective connectivity especially between those activated during response preparation. The arcuate fasciculus supported approximately two-thirds of the direct effective connectivity pathways from temporal to extratemporal auditory language-related areas but only up to half of those in the opposite direction. The uncinate fasciculus consisted of <2% of those in the temporal-to-extratemporal direction and up to 6% of those in the opposite direction. We, for the first time, provided an atlas which quantifies and animates the strength, dynamics, and direction specificity of inter-lobar neural communications between language areas via the white matter pathways. Language-related effective connectivity may be strengthened in an age-dependent manner even after the age of 5.

Time to Onset of Response to Pitolisant for the Treatment of Excessive Daytime Sleepiness and Cataplexy in Patients With Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials.

BackgroundPitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy.ObjectiveAnalyses evaluated the time to onset of clinical response during treatment with pitolisant.MethodsData were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo.ResultsThe analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]).ConclusionsOnset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2–3 weeks of pitolisant treatment in patients with narcolepsy.ClinicalTrials.gov identifierNCT01067222 (February 2010), NCT01800045 (February 2013).