Vagal sensory neurons mediate the Bezold-Jarisch reflex and induce syncope.

Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders1. The Bezold-Jarisch reflex (BJR), first described2,3 in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing4 to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses-hypotension, bradycardia and suppressed respiration-and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push-pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.

Feasibility and value of salivary cortisol sampling to reflect distress in head and neck cancer patients undergoing chemoradiation: A proof-of-concept study.

Background: Head and neck cancer (HNC) patients undergoing chemo/radiation commonly experience severe and persistent distress associated with treatment related fear and physical side effects such as xerostomia, dysphagia, and dryness of mouth. Cortisol, a stress sensitive hormone, can be easily measured in saliva to reflect biobehavioral responses to such stressors. Unfortunately, it has not been used in this population due to concerns associated with chemoradiation (C/RT) related xerostomia. Methods: In a proof-of-concept study, we explored the feasibility of collecting salivary cortisol as a marker of fear and distress in HNC patients. Ten HNC subjects undergoing C/RT provided saliva samples for 3 consecutive days across three timepoints (pre-treatment, 3-weeks and 1-month post-treatment) and completed concurrent depression, anxiety and swallowing related fear measures. Results: Salivary cortisol collection adherence was between 80-60%. It was not impacted by xerostomia. Diurnal cortisol pattern demonstrated dysregulation at pretreatment in 62%, and flattened aberrant slopes continued at 3-weeks and beyond in 50% of subjects. Conclusions: Our study supports the feasibility and utility of salivary cortisol measurement in HNC patients across the treatment trajectory. Diurnal cortisol measures may be a valuable tool to detect and monitor treatment distress during C/RT in this population.

Zebrafish vascular quantification: a tool for quantification of three-dimensional zebrafish cerebrovascular architecture by automated image analysis.

Zebrafish transgenic lines and light sheet fluorescence microscopy allow in-depth insights into three-dimensional vascular development in vivo. However, quantification of the zebrafish cerebral vasculature in 3D remains highly challenging. Here, we describe and test an image analysis workflow for 3D quantification of the total or regional zebrafish brain vasculature, called zebrafish vasculature quantification (ZVQ). It provides the first landmark- or object-based vascular inter-sample registration of the zebrafish cerebral vasculature, producing population average maps allowing rapid assessment of intra- and inter-group vascular anatomy. ZVQ also extracts a range of quantitative vascular parameters from a user-specified region of interest, including volume, surface area, density, branching points, length, radius and complexity. Application of ZVQ to 13 experimental conditions, including embryonic development, pharmacological manipulations and morpholino-induced gene knockdown, shows that ZVQ is robust, allows extraction of biologically relevant information and quantification of vascular alteration, and can provide novel insights into vascular biology. To allow dissemination, the code for quantification, a graphical user interface and workflow documentation are provided. Together, ZVQ provides the first open-source quantitative approach to assess the 3D cerebrovascular architecture in zebrafish.

Preliminary development and validation of a measure of fear of swallowing and swallowing-related movement injury in head and neck cancer: Swallowing Kinesiophobia Scale.

BACKGROUND: Fear is an under-recognized issue in intervention adherence in head and neck cancer (HNC). We developed and validated a patient reported outcome for swallowing fear in HNC patients. METHODS: Items were adapted from the Tampa Scale for Kinesiophobia to swallowing function. A beta version was completed by 51 HNC patients undergoing chemo +/- radiotherapy at baseline and post-treatment. Psychometric and factor structure analyses were applied. RESULTS: Swallowing Kinesiophobia Scale (SWKS) demonstrated strong face and content validity, internal consistency, and test-retest reliability. Factor analysis revealed three-factors: somatic factor, swallow avoidance, and fear of harm. Factors correlated positively with depression score, worry scale, and anxiety and pain scales. Score differences between patient subgroups (dysphagic vs nondysphagic) confirmed discriminative validity. CONCLUSION: The SWKS is a psychometrically valid tool to identify patients with fear of swallowing and swallowing-related movement. It can help identify patients early in treatment who may need additional support.

The Assessment of Supportive Accountability in Adults Seeking Obesity Treatment: Psychometric Validation Study.

BACKGROUND: Technology-mediated obesity treatments are commonly affected by poor long-term adherence. Supportive Accountability Theory suggests that the provision of social support and oversight toward goals may help to maintain adherence in technology-mediated treatments. However, no tool exists to measure the construct of supportive accountability. OBJECTIVE: This study aimed to develop and psychometrically validate a supportive accountability measure (SAM) by examining its performance in technology-mediated obesity treatment. METHODS: Secondary data analyses were conducted in 2 obesity treatment studies to validate the SAM (20 items). Study 1 examined reliability, criterion validity, and construct validity using an exploratory factor analysis in individuals seeking obesity treatment. Study 2 examined the construct validity of SAM in technology-mediated interventions involving different self-monitoring tools and varying amounts of phone-based interventionist support. Participants received traditional self-monitoring tools (standard, in-home self-monitoring scale [SC group]), newer, technology-based self-monitoring tools (TECH group), or these newer technology tools plus additional phone-based support (TECH+PHONE group). Given that the TECH+PHONE group involves more interventionist support, we hypothesized that this group would have greater supportive accountability than the other 2 arms. RESULTS: In Study 1 (n=353), the SAM showed strong reliability (Cronbach α=.92). A factor analysis revealed a 3-factor solution (representing Support for Healthy Eating Habits, Support for Exercise Habits, and Perceptions of Accountability) that explained 69% of the variance. Convergent validity was established using items from the motivation for weight loss scale, specifically the social regulation subscale (r=0.33; P<.001) and social pressure for weight loss subscale (r=0.23; P<.001). In Study 2 (n=80), the TECH+PHONE group reported significantly higher SAM scores at 6 months compared with the SC and TECH groups (r2=0.45; P<.001). Higher SAM scores were associated with higher adherence to weight management behaviors, including higher scores on subscales representing healthy dietary choices, the use of self-monitoring strategies, and positive psychological coping with weight management challenges. The association between total SAM scores and percent weight change was in the expected direction but not statistically significant (r=-0.26; P=.06). CONCLUSIONS: The SAM has strong reliability and validity across the 2 studies. Future studies may consider using the SAM in technology-mediated weight loss treatment to better understand whether support and accountability are adequately represented and how supportive accountability impacts treatment adherence and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01999244; https://clinicaltrials.gov/ct2/show/NCT01999244.

Gastrostomy Utilization by Oropharyngeal Cancer Patients Is Partially Driven by Swallowing Function.

OBJECTIVE: Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rapidly increasing, as are survival rates, in large part due to the human papillomavirus (HPV). Treatment intensity, however, has remained unchanged, making treatment-related toxicity (i.e., dysphagia) a critical problem for an increasing number of patients. The primary objective of this study was to determine whether pretreatment objective swallowing measures can predict percutaneous fluoroscopic guided gastrostomy tube (PFG) utilization during OPSCC treatment. METHODS: Forty-one newly diagnosed OPSCC patients treated with radiation underwent evaluation of swallow function with modified barium swallow study (MBSS) prior to and at completion of radiation treatment using the Dynamic Imaging Grade of Swallowing Toxicity (DIGEST); a subset of patients were evaluated using the MD Anderson Dysphagia Inventory (MDADI). RESULTS: Patients were male (100%), primarily Caucasian (85.4%) and p16 positive (85.4%) with mean age of 65.7 years. PFG were placed in 70.7% patients (n = 29) and used by 63.4% (n = 26). Pre- and post-treatment DIGEST scores were associated with T-classification (t = -2.9, p = .001, t = -2.7, p = .01) and indicated deteriorating swallow function during treatment (mean change = 0.46 [t = -2.7, p = .01]). DIGEST and MDADI scores were generally not associated with patient PFG utilization. DIGEST and MDADI scores were significantly correlated prior to, but not following completion of treatment. CONCLUSION: Pre-treatment DIGEST and patient reported swallowing outcomes (MDADI) can be useful in identifying patients with unsafe and/or grossly inefficient swallowing function. However, objectively measured swallow function was not associated with PFG utilization. Development of PFG placement algorithms (reactive vs. prophylactic) therefore require additional inputs/metrics. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2153-2159, 2020.

The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish.

Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow non-invasive quantification of cerebrovascular anatomy, neural activation, and cerebral vessel haemodynamics. We therefore established a novel non-invasive, non-anaesthetised zebrafish larval model of neurovascular coupling, in which visual stimulus evokes neuronal activation in the optic tectum that is associated with a specific increase in red blood cell speed in tectal blood vessels. We applied this model to the examination of the effect of glucose exposure on cerebrovascular patterning and neurovascular coupling. We found that chronic exposure of zebrafish to glucose impaired tectal blood vessel patterning and neurovascular coupling. The nitric oxide donor sodium nitroprusside rescued all these adverse effects of glucose exposure on cerebrovascular patterning and function. Our results establish the first non-mammalian model of neurovascular coupling, offering the potential to perform more rapid genetic modifications and high-throughput screening than is currently possible using rodents. Furthermore, using this zebrafish model, we reveal a potential strategy to ameliorate the effects of hyperglycemia on cerebrovascular function.

Sodium nitroprusside prevents the detrimental effects of glucose on the neurovascular unit and behaviour in zebrafish.

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.

Cerebrovascular endothelial cells form transient Notch-dependent cystic structures in zebrafish.

We identify a novel endothelial membrane behaviour in transgenic zebrafish. Cerebral blood vessels extrude large transient spherical structures that persist for an average of 23 min before regressing into the parent vessel. We term these structures "kugeln", after the German for sphere. Kugeln are only observed arising from the cerebral vessels and are present as late as 28 days post fertilization. Kugeln do not communicate with the vessel lumen and can form in the absence of blood flow. They contain little or no cytoplasm, but the majority are highly positive for nitric oxide reactivity. Kugeln do not interact with brain lymphatic endothelial cells (BLECs) and can form in their absence, nor do they perform a scavenging role or interact with macrophages. Inhibition of actin polymerization, Myosin II, or Notch signalling reduces kugel formation, while inhibition of VEGF or Wnt dysregulation (either inhibition or activation) increases kugel formation. Kugeln represent a novel Notch-dependent NO-containing endothelial organelle restricted to the cerebral vessels, of currently unknown function.

Dyadic Interventions for Cancer Survivors and Caregivers: State of the Science and New Directions.

OBJECTIVES: To describe caregiving and relationship challenges in cancer and the state of the science of dyadic interventions that target survivors and caregivers. DATA SOURCES: Narrative review. CONCLUSION: Viewing the survivor-caregiver dyad as the unit of care may improve multiple aspects of survivor and caregiver quality of life. However, several questions remain regarding how, why, and for whom dyadic interventions are effective. IMPLICATIONS FOR NURSING PRACTICE: Nurses should consider survivor, caregiver, and relationship needs when formulating supportive care protocols. Screening for survivor distress and extending distress screening to caregivers is an important first step in providing comprehensive psychosocial care.

tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis.

Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.

Self-management intervention for head and neck cancer couples: Results of a randomized pilot trial.

BACKGROUND: Patients with head and neck cancer (HNC) experience significant physical and psychological morbidity during radiotherapy (RT) that contributes to treatment interruptions and a poor quality of life. Although spouses/partners can help by encouraging patient self-management (eg, self-care) during RT, they often experience high psychological distress rates, lack basic health care knowledge and skills, and report increased marital conflict regarding patient self-management. The current pilot study examined the feasibility and acceptability of a 6-session telephone-based intervention called Spouses coping with the Head And neck Radiation Experience (SHARE), which teaches self-management, communication, and coping skills to patients with HNC and their spouses. The treatment effects of SHARE compared with usual medical care (UMC) in controlling patient physical symptoms and improving patient/spouse psychological and marital functioning also were examined. METHODS: Thirty patients who initiated RT and their spouses (60 participants; 40% of whom were racial/ethnic minorities) were randomized to SHARE or UMC, and preintervention and postintervention assessments were completed. RESULTS: Solid recruitment (70%) and low attrition rates (7%) demonstrated feasibility. Strong program evaluations and homework completion rates (72%) supported acceptability. Significant treatment effects (medium in magnitude) were observed for SHARE compared with UMC with regard to HNC-specific physical symptom burden (Cohen's d, -0.89) and symptom interference (Cohen's d, -0.86). Medium to large effects favoring SHARE also were found for patient and spouse depressive symptoms (Cohen's d, -0.84) and cancer-specific distress (Cohen's d, -1.05). CONCLUSIONS: The findings of the current study support the feasibility, acceptability, and preliminary efficacy of SHARE. They also suggest that programs that empower HNC couples with the necessary skills to coordinate care and manage the challenges of RT together hold great promise for controlling a patient's physical symptoms and improving the psychological functioning of both partners.

Preliminary Development of a Screening Tool for Pre-Clinical Dysphagia in Community Dwelling Older Adults.

Evidence suggests that community dwelling older adults (CDOA) are at risk for dysphagia (swallowing difficulties). Dysphagia is often unidentified until related morbidities like under nutrition or pneumonia occur. These cases of unidentified dysphagia, prior to any clinical intervention, may be termed 'pre-clinical dysphagia'. Identifying pre-clinical dysphagia is challenged by the lack of validated tools appropriate for CDOA. This study addresses preliminary development of a novel patient reported outcome (PRO) screening tool for pre-clinical dysphagia. Initially, 34 questions were developed from literature review and expert opinion. Following pilot testing (n = 53), the questionnaire was revised and tested on 335 additional CDOA. Face validity, content validity, item analysis, reliability (internal consistency), and construct validity (exploratory factor analysis) measures were completed. Psychometric validation resulted in a 17-question PRO tool. Construct analysis identified a three-factor model that explained 67.345% of the variance. Emergent factors represented swallowing effort, physical function, and cognitive function. The results revealed strong construct validity and internal consistency (Cronbach's α = 0.90). A novel, simple PRO incorporating multiple function domains associated with aging demonstrated strong preliminary psychometric properties. This tool is more comprehensive and aging-focused than existing dysphagia screening tools. Inclusion of multiple domains may be key in early identification of pre-clinical dysphagia.

Low-Dimensional Models of "Neuro-Glio-Vascular Unit" for Describing Neural Dynamics under Normal and Energy-Starved Conditions.

The motivation of developing simple minimal models for neuro-glio-vascular (NGV) system arises from a recent modeling study elucidating the bidirectional information flow within the NGV system having 89 dynamic equations (1). While this was one of the first attempts at formulating a comprehensive model for neuro-glio-vascular system, it poses severe restrictions in scaling up to network levels. On the contrary, low--dimensional models are convenient devices in simulating large networks that also provide an intuitive understanding of the complex interactions occurring within the NGV system. The key idea underlying the proposed models is to describe the glio-vascular system as a lumped system, which takes neural firing rate as input and returns an "energy" variable (analogous to ATP) as output. To this end, we present two models: biophysical neuro-energy (Model 1 with five variables), comprising KATP channel activity governed by neuronal ATP dynamics, and the dynamic threshold (Model 2 with three variables), depicting the dependence of neural firing threshold on the ATP dynamics. Both the models show different firing regimes, such as continuous spiking, phasic, and tonic bursting depending on the ATP production coefficient, ɛp, and external current. We then demonstrate that in a network comprising such energy-dependent neuron units, ɛp could modulate the local field potential (LFP) frequency and amplitude. Interestingly, low-frequency LFP dominates under low ɛp conditions, which is thought to be reminiscent of seizure-like activity observed in epilepsy. The proposed "neuron-energy" unit may be implemented in building models of NGV networks to simulate data obtained from multimodal neuroimaging systems, such as functional near infrared spectroscopy coupled to electroencephalogram and functional magnetic resonance imaging coupled to electroencephalogram. Such models could also provide a theoretical basis for devising optimal neurorehabilitation strategies, such as non-invasive brain stimulation for stroke patients.

Vascular Dynamics Aid a Coupled Neurovascular Network Learn Sparse Independent Features: A Computational Model.

Cerebral vascular dynamics are generally thought to be controlled by neural activity in a unidirectional fashion. However, both computational modeling and experimental evidence point to the feedback effects of vascular dynamics on neural activity. Vascular feedback in the form of glucose and oxygen controls neuronal ATP, either directly or via the agency of astrocytes, which in turn modulates neural firing. Recently, a detailed model of the neuron-astrocyte-vessel system has shown how vasomotion can modulate neural firing. Similarly, arguing from known cerebrovascular physiology, an approach known as "hemoneural hypothesis" postulates functional modulation of neural activity by vascular feedback. To instantiate this perspective, we present a computational model in which a network of "vascular units" supplies energy to a neural network. The complex dynamics of the vascular network, modeled by a network of oscillators, turns neurons ON and OFF randomly. The informational consequence of such dynamics is explored in the context of an auto-encoder network. In the proposed model, each vascular unit supplies energy to a subset of hidden neurons of an autoencoder network, which constitutes its "projective field." Neurons that receive adequate energy in a given trial have reduced threshold, and thus are prone to fire. Dynamics of the vascular network are governed by changes in the reconstruction error of the auto-encoder network, interpreted as the neuronal demand. Vascular feedback causes random inactivation of a subset of hidden neurons in every trial. We observe that, under conditions of desynchronized vascular dynamics, the output reconstruction error is low and the feature vectors learnt are sparse and independent. Our earlier modeling study highlighted the link between desynchronized vascular dynamics and efficient energy delivery in skeletal muscle. We now show that desynchronized vascular dynamics leads to efficient training in an auto-encoder neural network.