Efferent Activity Research Articles

Organizational principles of amygdalar input-output neuronal circuits

The amygdala, one of the most studied brain structures, integrates brain-wide heterogeneous inputs and governs multidimensional outputs to control diverse behaviors central to survival, yet how amygdalar input-output neuronal circuits are organized remains unclear. Using a simplified cell-type- and projection-specific retrograde transsynaptic tracing technique, we scrutinized brain-wide afferent inputs of four major output neuronal groups in the amygdalar basolateral complex (BLA) that project to the bed nucleus of the stria terminals (BNST), ventral hippocampus (vHPC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), respectively. Brain-wide input-output quantitative analysis unveils that BLA efferent neurons receive a diverse array of afferents with varied input weights and predominant contextual representation. Notably, the afferents received by BNST-, vHPC-, mPFC- and NAc-projecting BLA neurons exhibit virtually identical origins and input weights. These results indicate that the organization of amygdalar BLA input-output neuronal circuits follows the input-dependent and output-independent principles, ideal for integrating brain-wide diverse afferent stimuli to control parallel efferent actions. The data provide the objective basis for improving the virtual reality exposure therapy for anxiety disorders and validate the simplified cell-type- and projection-specific retrograde transsynaptic tracing method.

How Action Shapes Body Ownership Momentarily and Throughout the Lifespan.

Objects which a human agent controls by efferent activities (such as real or virtual tools) can be perceived by the agent as belonging to his or her body. This suggests that what an agent counts as “body” is plastic, depending on what she or he controls. Yet there are possible limitations for such momentary plasticity. One of these limitations is that sensations stemming from the body (e.g., proprioception) and sensations stemming from objects outside the body (e.g., vision) are not integrated if they do not sufficiently “match”. What “matches” and what does not is conceivably determined by long–term experience with the perceptual changes that body movements typically produce. Children have accumulated less sensorimotor experience than adults have. Consequently, they express higher flexibility to integrate body-internal and body-external signals, independent of their “match” as suggested by rubber hand illusion studies. However, children’s motor performance in tool use is more affected by mismatching body-internal and body-external action effects than that of adults, possibly because of less developed means to overcome such mismatches. We review research on perception-action interactions, multisensory integration, and developmental psychology to build bridges between these research fields. By doing so, we account for the flexibility of the sense of body ownership for actively controlled events and its development through ontogeny. This gives us the opportunity to validate the suggested mechanisms for generating ownership by investigating their effects in still developing and incomplete stages in children. We suggest testable predictions for future studies investigating both body ownership and motor skills throughout the lifespan.

Heightened respiratory-parasympathetic coupling to airways in the spontaneously hypertensive rat.

Carotid body (CB) chemoreceptors are hyperactive in hypertension, and their acute activation produces bronchoconstriction. We show that the respiratory-modulated bronchiolar tone, pulmonary parasympathetic efferent activity, and the firing frequency and synaptic excitation of bronchoconstrictor motoneurones in the nucleus ambiguus were all enhanced in spontaneous hypertensive (SH) rats. In SH rats, CB denervation reduced the respiratory-related parasympathetic-mediated bronchoconstrictor tone to levels seen in normotensive rats. Chemoreflex evoked bronchoconstrictor tone was heightened in SH versus normotensive rats. The intrinsic electrophysiological properties and morphology of bronchoconstrictor motoneurones were similar across rat strains. The heightened respiratory modulation of parasympathetic-mediated bronchoconstrictor tone to the airways in SH rats is caused by afferent drive from the CBs. Much research has described heightened sympathetic activity in hypertension and diminished parasympathetic tone, especially to the heart. The carotid body (CB) chemoreceptors exhibit hyperreflexia and are hyperactive, providing excitatory drive to sympathetic networks in hypertension. Given that acute CB activation produces reflex evoked bronchoconstriction via activation of parasympathetic vagal efferents, we hypothesised that the parasympathetic bronchoconstrictor activity is enhanced in spontaneously hypertensive (SH) rats and that this is dependent on CB inputs. In situ preparations of Wistar and SH rats were used in which bronchiolar tone, the pulmonary branch of the vagus (pVN) and phrenic nerves were recorded simultaneously; whole cell patch clamp recordings of bronchoconstrictor vagal motoneurones were also made from the nucleus ambiguus. Bronchiolar tone, pVN and bronchoconstrictor motoneurones were respiratory modulated and this modulation was enhanced in SH rats. These differences were all eliminated after CB denervation. Stimulation of the CBs increased the phrenic frequency that caused a summation of the respiratory-related increases in pVN, resulting in the development of bronchoconstrictor tone. This tone was exaggerated in SH rats. The enhanced respiratory-parasympathetic coupling to airways in SH rats was not due to differences in the intrinsic electrophysiological properties of bronchoconstrictor motoneurones but reflected heightened pre-inspiratory- and inspiratory-related synaptic drive. In summary, in SH rats the phasic respiratory modulation of parasympathetic tone to the airways is elevated and the greater development of this bronchoconstrictor tone is caused by the heightened afferent drive originating from the CBs. Thus, targeting the CBs may prove effective for increasing lower airway patency.

The medial olivocochlear reflex strength is modulated during a visual working memory task.

Top-down modulation of sensory responses to distracting stimuli by selective attention has been proposed as an important mechanism by which our brain can maintain relevant information during working memory tasks. Previous works in visual working memory (VWM) have reported modulation of neural responses to distracting sounds at different levels of the central auditory pathways. Whether these modulations occur also at the level of the auditory receptor is unknown. Here, we hypothesize that cochlear responses to irrelevant auditory stimuli can be modulated by the medial olivocochlear system during VWM. Twenty-one subjects (13 males, mean age 25.3 yr) with normal hearing performed a visual change detection task with different VWM load conditions (high load = 4 visual objects; low load = 2 visual objects). Auditory stimuli were presented as distractors and allowed the measurement of distortion product otoacoustic emissions (DPOAEs) and scalp auditory evoked potentials. In addition, the medial olivocochlear reflex strength was evaluated by adding contralateral acoustic stimulation. We found larger contralateral acoustic suppression of DPOAEs during the visual working memory period (n = 21) compared with control experiments (n = 10), in which individuals were passively exposed to the same experimental conditions. These results show that during the visual working memory period there is a modulation of the medial olivocochlear reflex strength, suggesting a possible common mechanism for top-down filtering of auditory responses during cognitive processes.NEW & NOTEWORTHY The auditory efferent system has been proposed to function as a biological filter of cochlear responses during selective attention. Here, we recorded electroencephalographic activity and otoacoustic emissions in response to auditory distractors during a visual working memory task in humans. We found that the olivocochlear efferent activity is modulated during the visual working memory period suggesting a common mechanism for suppressing cochlear responses during selective attention and working memory.

Exercise training rescues the electrical activity of liver-projecting DMNV neurones in response to oxytocin in spontaneously hypertensive rats.

A neural circuit between the paraventricular nucleus of the hypothalamus (PVN) and the dorsal motor nucleus of the vagus (DMNV) constitutes part of an important parasympathetic autonomic pathway that controls hepatic glucose production. Intracerebroventricular injection of insulin activates oxytocinergic neurones in the PVN and elicits the release of oxytocin into the circulation, which plays an important role in the metabolism of glucose. Moreover, the central action of insulin can reduce the concentration of glucose in blood taken from the hepatic vein of Wistar rats via activation of vagal efferent nerves to the liver. This mechanism is impaired in sedentary spontaneously hypertensive rats (SHR). Because aerobic exercise increases vagal tone, partly mediated by increasing the oxytocinergic connections between the PVN and DMNV, we hypothesised that oxytocin (OT) might alter the excitability of liver-projecting DMNV neurones. Thus, we investigated the effects of OT on electrical properties of the liver-projecting DMNV neurones from Wistar, SHR subjected to 4weeks of exercise training, as well sedentary controls, using whole cell patch-clamping. The results show that OT increased the resting membrane potential of DMNV neurones in Wistar rats, as well as the firing frequency of these cells, but not in sedentary SHR. However, in SHR subjected to 4weeks of exercise training, the effects of OT on liver-projecting DMNV neurones of were similar to those seen in Wistar rats. These findings show that OT elicits similar changes in the electrophysiological properties of liver-projecting DMNV neurones of Wistar and exercise-trained but not sedentary SHR. These results indicate that exercise training can restore the sensitivity of liver-projecting DMNV neurones of exercise-trained SHR to OT.

The Influence of OSA Treatment on Muscle Sympathetic Nerve Activity: A Systematic Review and Meta‐Analysis

Introduction Obstructive Sleep Apnea (OSA) is commonly treated with Continuous Positive Airway Pressure (CPAP) therapy, which reduces the number of airway obstructions while sleeping. Recently, diet and exercise interventions have been explored as a possible alternative treatment for OSA. Microneurography is a technique used to measure efferent postganglionic muscle sympathetic nerve activity (MSNA) via direct interneural recordings. CPAP therapy and diet and exercise interventions reduce disease severity, but their influence on MSNA is less clear. Purpose The present meta-analysis aims to examine the influence of type and length of treatment for OSA on MSNA. Methods A structured search of electronic databases was performed by a research librarian. Two reviewers independently assessed the titles of abstracts of articles; studies meeting eligibility criteria were selected for full-text review. Two reviewers independently extracted the data and assessed the quality of the studies using Joanna Briggs Institute Critical Appraisal of Evidence Effectiveness tool. Review Manager v5.3 was used to conduct the statistical analyses, and significance was set at P < 0.05. Results Evidence from 10 interventions (n=186) shows CPAP therapy significantly decreases MSNA burst frequency in individuals with OSA (Mean Difference, +12.6 bursts/min; 95% CI, 10.1-15.2 bursts/min; I2 = 39%). The same is shown for burst incidence in 6 studies (n=113) (MD, +21.5 bursts/100 hbs; 95% CI, 18.6-24.5 bursts/100 hbs; I2 = 0%). Reductions in MSNA (burst frequency and burst incidence) were seen for all time points of CPAP therapy: 1, 6, and 12 months. Data from 5 studies shows a significant decrease in burst frequency following diet and exercise intervention (n=68) (MD, +9.86 bursts/min; 95% CI, 5.37-14.35 bursts/min; I2 = 75%). A meta-regression analysis identified a relationship between CPAP therapy length and burst frequency (R2 = 0.329, p = 0.003). Conclusion CPAP therapy decreases MSNA in individuals with OSA, and a relationship exists between length of treatment and sympathetic activity. However, a significant reduction in sympathetic activity was also seen as a result of diet and exercise interventions; although, only burst frequency data was reported. More data is needed to determine optimal treatment type and length.

The Influence of OSA Severity on Muscle Sympathetic Nerve Activity: A Systematic Review and Meta‐Analysis

Introduction Microneurography has been used to measure efferent postganglionic muscle sympathetic nerve activity (MSNA) via direct interneural recordings in individuals with obstructive sleep apnea (OSA) to gain an understanding of the cardiovascular control and disease risk in this population. Purpose We conducted a meta-analysis to identify a relationship between OSA severity, determined by the apnea-hypopnea index (AHI), and MSNA. Methods A structured search of electronic databases was performed by a research librarian. Two reviewers independently assessed the titles of abstracts of articles; studies meeting eligibility criteria were selected for full-text review. Two reviewers independently extracted the data and assessed the quality of the studies using Joanna Briggs Institute Critical Appraisal of Evidence Effectiveness tool. Review Manager v5.3 was used to conduct the statistical analyses, and significance was set at P < 0.05. When 10 or more studies were included, meta-regression analyses were also performed in STATA 15.0. Results Data from 36 studies indicating higher burst frequency in individuals with OSA (n=622) when compared to author-defined controls (n=573) (Mean Differences, +15.1 bursts/min; 95% CI, 12.6-17.6 bursts/min; I2 = 81%). 26 studies showed higher burst incidence in individuals with OSA when compared to controls as well (MD, +23.2 bursts/100 hbs; 95% CI, 19.7-26.6 bursts/100 hbs; I2 = 66%). Higher burst frequency and burst incidence was seen for all OSA subgroups: obese, overweight and obese, lean, Metabolic Syndrome, and Heart Failure. Meta-regression analyses were performed for burst frequency and burst incidence, and a relationship was identified with OSA severity (AHI) for both (burst frequency, R2 = 0.294, p<0.001; burst incidence, R2 = 0.373, p<0.001). This relationship remained when other confounding variables were included (age, body-mass index [BMI], systolic, diastolic, and mean arterial pressure), suggesting this relationship is specific to OSA severity. Conclusion MSNA was significantly higher in individuals with OSA when compared to healthy controls. Furthermore, MSNA was higher when BMI and other common comorbidities (Metabolic Syndrome and Heart Failure) were accounted for, and a significant positive relationship was identified between OSA severity and metrics of sympathetic activity. These data are clinically important for understanding cardiovascular disease risk in patients with OSA.

Absence of reliable physiological signature of illusory body ownership revealed by fine-grained autonomic measurement during the rubber hand illusion.

The neural representation of a 'biological self' is linked theoretically to the control of bodily physiology. In an influential model, selfhood relates to internal agency and higher-order interoceptive representation, inferred from the predicted impact of efferent autonomic nervous activity on afferent viscerosensory feedback. Here we tested if an altered representation of physical self (illusory embodiment of an artificial hand) is accompanied by sustained shifts in autonomic activity. Participants (N = 37) underwent procedures for induction of the rubber hand illusion (synchronous stroking of own unseen hand and observed stroking of artificial hand) and a control condition (asychronous stroking). We recorded electrocardiography, electrodermal activity, and a non-invasive measure of multiunit skin sympathetic nerve activity (SKNA) from the chest. We compared these autonomic indices between task conditions, and between individuals who did and did not experience the illusion. Bayes factors quantified the strength of evidence for and against null hypotheses. Observed proprioceptive drift and subjective reports confirmed the efficacy of the synchronous (vs asynchronous) condition in inducing illusory hand ownership. Stringent discriminant analysis classified 24/37 individuals as experiencing the rubber hand illusion. Surprisingly, heart rate, heart rate variability, electrodermal activity, and SKNA measures revealed no autonomic differences between synchronous vs asynchronous conditions, nor between individuals who did or did not experience the rubber hand illusion. Bayes factors indicated substantial evidence for no physiological differences. In contrast to earlier reports, our autonomic data show the absence of a reliable change in physiological state during the rubber hand illusion. More encompassing perturbations of self-experience, for example in full body illusions, may nevertheless be coupled to, or facilitated by, changes in efferent autonomic activity and afferent viscerosensory feedback. Our findings suggest that such changes in bodily physiology are not sustained as an obligatory component of the rubber hand illusion.

Pre-surgical heart-rate variability strongly predicts less post-operative pain in patients with epilepsy

ObjectivesPost-operative pain is a common clinical problem after surgery, yet its predictors are inconsistent and unclear. This study examined whether pre-surgical vagal cardiac efferent nerve activity, indirectly indexed by heart rate variability (HRV), predicts patients' pain after epileptic surgery. MethodsUsing a prospective design, HRV was measured at rest during 5 min in n = 30 patients, prior to undergoing epileptic surgery. Post-operative pain was assessed every 8 h during the first 2 days after surgery, and our analyses focused on the worse pain level. We used multiple regression analyses and statistically considered several confounders (age, surgical duration, and analgesics during various surgical phases). ResultsMultiple HRV indexes strongly and inversely predicted post-operative pain, with high-frequency HRV (HF-HRV) being the strongest predictor (r = −0.81, p < 0.001). In a hierarchical multiple regression, HF-HRV accounted for an additional and significant 18% of the variance in post-operative pain, after statistically considering effects of age, surgical duration and effects of two anaesthetics. ConclusionsPre-surgical HF-HRV independently, strongly and inversely predicts post-operative pain. These results are in line with a neuromodulatory role of the vagus nerve in pain and have clinical implications for predicting and managing post-operative pain.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity.

This study was designed to investigate whether transcutaneous auricular vagal nerve stimulation (taVNS) would be able to improve major pathophysiologies of functional dyspepsia (FD) in patients with FD. Thirty-six patients with FD (21 F) were studied in two sessions (taVNS and sham-ES). Physiological measurements, including gastric slow waves, gastric accommodation, and autonomic functions, were assessed by the electrogastrogram (EGG), a nutrient drink test and the spectral analysis of heart rate variability derived from the electrocardiogram (ECG), respectively. Thirty-six patients with FD (25 F) were randomized to receive 2-wk taVNS or sham-ES. The dyspeptic symptom scales, anxiety and depression scores, and the same physiological measurements were assessed at the beginning and the end of the 2-wk treatment. In comparison with sham-ES, acute taVNS improved gastric accommodation (P = 0.008), increased the percentage of normal gastric slow waves (%NSW, fasting: P = 0.010; fed: P = 0.007) and vagal activity (fasting: P = 0.056; fed: P = 0.026). In comparison with baseline, 2-wk taVNS but not sham-ES reduced symptoms of dyspepsia (P = 0.010), decreased the scores of anxiety (P = 0.002) and depression (P < 0.001), and improved gastric accommodation (P < 0.001) and the %NSW (fasting: P < 0.05; fed: P < 0.05) by enhancing vagal efferent activity (fasting: P = 0.015; fed: P = 0.048). Compared with the HC, the patients showed increased anxiety (P < 0.001) and depression (P < 0.001), and decreased gastric accommodation (P < 0.001) and %NSW (P < 0.001) as well as decreased vagal activity (fasting: P = 0.047). The noninvasive taVNS has a therapeutic potential for treating nonsevere FD by improving gastric accommodation and gastric pace-making activity via enhancing vagal activity.NEW & NOTEWORTHY Treatment of functional dyspepsia is difficult due to various pathophysiological factors. The proposed method of transcutaneous auricular vagal nerve stimulation improves symptoms of both dyspepsia and depression/anxiety, and gastric functions (accommodation and slow waves), possibly mediated via the enhancement of vagal efferent activity. This noninvasive and easy-to-implement neuromodulation method will be well received by patients and healthcare providers.

Medial olivocochlear reflex effects on amplitude growth functions of long- and short-latency components of click-evoked otoacoustic emissions in humans.

Functional outcomes of medial olivocochlear reflex (MOCR) activation, such as improved hearing in background noise and protection from noise damage, involve moderate to high sound levels. Previous noninvasive measurements of MOCR in humans focused primarily on otoacoustic emissions (OAEs) evoked at low sound levels. Interpreting MOCR effects on OAEs at higher levels is complicated by the possibility of the middle-ear muscle reflex and by components of OAEs arising from different locations along the length of the cochlear spiral. We overcame these issues by presenting click stimuli at a very slow rate and by time-frequency windowing the resulting click-evoked (CE)OAEs into short-latency (SL) and long-latency (LL) components. We characterized the effects of MOCR on CEOAE components using multiple measures to more comprehensively assess these effects throughout much of the dynamic range of hearing. These measures included CEOAE amplitude attenuation, equivalent input attenuation, phase, and slope of growth functions. Results show that MOCR effects are smaller on SL components than LL components, consistent with SL components being generated slightly basal of the characteristic frequency region. Amplitude attenuation measures showed the largest effects at the lowest stimulus levels, but slope change and equivalent input attenuation measures did not decrease at higher stimulus levels. These latter measures are less commonly reported and may provide insight into the variability in listening performance and noise susceptibility seen across individuals.NEW & NOTEWORTHY The auditory efferent system, operating at moderate to high sound levels, may improve hearing in background noise and provide protection from noise damage. We used otoacoustic emissions to measure these efferent effects across a wide range of sound levels and identified level-dependent and independent effects. Previous reports have focused on level-dependent measures. The level-independent effects identified here may provide new insights into the functional relevance of auditory efferent activity in humans.

Electroacupuncture regulates inflammatory cytokines by activating the vagus nerve to enhance antitumor immunity in mice with breast tumors

AimsThe aim of this study was to explore the potential effect of electroacupuncture (EA) at ST36 on mice bearing breast tumors by regulating inflammatory cytokines to enhance antitumor immunity via vagus nerve. Materials and methodsFemale BALB/c mice were implanted with 4T1-luc2 breast tumor cells to establish a murine mammary cancer model. Tumor growth was evaluated by tumor volume, weight and bioluminescence imaging. Inflammatory conditions in serum and tumor tissue were assessed by cytokines (IL-1β, TNF-α and IL-10) and HE staining. Proportions and functions of CD8+ T cells, NK cells and MDSCs were identified by flow cytometry and western blot. Involvement of vagal efferent components was confirmed by ChAT and c-Fos double labeling immunohistochemistry in dorsal motor nucleus of vagus (DMV). Subdiaphragmatic vagotomy was employed to determine if the effect of EA was mediated by vagus nerve. Key findingsEA at ST36 reduced the volume and weight of tumors within 22 days after implantation. Proinflammatory cytokines IL-1β and TNF-α in serum, tumor and local inflammatory infiltration were obviously attenuated after EA. Meanwhile, EA intervention significantly augmented the proportion and cytolytic function of CD8+ T cells and NK cells, along with a decline in the accumulation and immunosuppressive activities of MDSCs. Finally, c-Fos expression in ChAT+ neurons in DMV increased following EA, and the ameliorating effect of EA was obviously blocked by subdiaphragmatic vagotomy. SignificanceEA intervention relieved tumor progression in breast tumor-bearing mice by alleviating inflammation and enhancing antitumor immunity, which was mediated by eliciting efferent vagus nerve activity.

PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines.

Key points We have previously shown that carotid body stimulation by lysophosphatidic acid elicits a reflex stimulation of vagal efferent activity sufficient to cause bronchoconstriction in asthmatic rats.Here, we show that pathophysiological concentrations of asthma‐associated prototypical Th2 cytokines also stimulate the carotid bodies.Stimulation of the carotid bodies by these asthmakines involves a PKCε–transient receptor potential vanilloid 1 (TRPV1) signalling mechanism likely dependent on TRPV1 S502 and T704 phosphorylation sites.As the carotid bodies’ oxygen sensitivity is independent of PKCε–TRPV1 signalling, systemic blockade of PKCε may provide a novel therapeutic target to reduce allergen‐induced asthmatic bronchoconstriction.Consistent with the therapeutic potential of blocking the PKCε–TRPV1 pathway, systemic delivery of a PKCε‐blocking peptide suppresses asthmatic respiratory distress in response to allergen and reduces airway hyperresponsiveness to bradykinin. The autonomic nervous system orchestrates organ‐specific, systemic and behavioural responses to inflammation. Recently, we demonstrated a vital role for lysophosphatidic acid in stimulating the primary autonomic oxygen chemoreceptors, the carotid bodies, in parasympathetic‐mediated asthmatic airway hyperresponsiveness. However, the cacophony of stimulatory factors and cellular mechanisms of carotid body activation are unknown. Therefore, we set out to determine the intracellular signalling involved in carotid body‐mediated sensing of asthmatic blood‐borne inflammatory mediators. We employed a range of in vitro and rat in situ preparations, site‐directed mutagenesis, patch‐clamp, nerve recordings and pharmacological inhibition to assess cellular signalling. We show that the carotid bodies are also sensitive to asthma‐associated prototypical Th2 cytokines which elicit sensory nerve excitation. This provides additional asthmatic ligands contributing to the previously established reflex arc resulting in efferent vagal activity and asthmatic bronchoconstriction. This novel sensing role for the carotid body is mediated by a PKCε‐dependent stimulation of transient receptor potential vanilloid 1 (TRPV1), likely via TRPV1 phosphorylation at sites T704 and S502. Importantly, carotid body oxygen sensing was unaffected by blocking either PKCε or TRPV1. Further, we demonstrate that systemic PKCε blockade reduces asthmatic respiratory distress in response to allergen and airway hyperresponsiveness. These discoveries support an inflammation‐dependent, oxygen‐independent function for the carotid body and suggest that targeting PKCε provides a novel therapeutic option to abate allergic airway disease without altering life‐saving autonomic hypoxic reflexes.

No Change in Medial Olivocochlear Efferent Activity during an Auditory or Visual Task: Dual Evidence from Otoacoustic Emissions and Event-Related Potentials.

The medial olivocochlear (MOC) system is thought to be responsible for modulation of peripheral hearing through descending (efferent) pathways. This study investigated the connection between peripheral hearing function and conscious attention during two different modality tasks, auditory and visual. Peripheral hearing function was evaluated by analyzing the amount of suppression of otoacoustic emissions (OAEs) by contralateral acoustic stimulation (CAS), a well-known effect of the MOC. Simultaneously, attention was evaluated by event-related potentials (ERPs). Although the ERPs showed clear differences in processing of auditory and visual tasks, there were no differences in the levels of OAE suppression. We also analyzed OAEs for the highest magnitude resonant mode signal detected by the matching pursuit method, but again did not find a significant effect of task, and no difference in noise level or number of rejected trials. However, for auditory tasks, the amplitude of the P3 cognitive wave negatively correlated with the level of OAE suppression. We conclude that there seems to be no change in MOC function when performing different modality tasks, although the cortex still remains able to modulate some aspects of MOC activity.

A common variation in HCN1 is associated with heart rate variability in schizophrenia

BackgroundThere is growing evidence for a shared genetic basis between schizophrenia risk and cardiovascular disease. Reduced efferent vagal activity, indexed by reduced heart rate variability (HRV), has been consistently described in patients with schizophrenia and may potentially contribute to the increased cardiovascular risk in these patients. In this study, we tested the hypothesis whether the established schizophrenia risk variant HCN1 rs16902086 (A > G) is associated with reduced HRV. MethodsWe analyzed the risk status of HCN1 rs16902086 (AG/GG vs. AA genotype) in 83 unmedicated patients with schizophrenia and 96 healthy controls and investigated genotype-related impacts on various HRV parameters. ResultsWe observed significantly increased resting heart rates and a marked decrease of vagal modulation in our patient cohort. Strikingly, HCN1 rs16902086 (A > G) was associated with reduced HRV parameters in patients only. A trend towards more pronounced HRV deviations was observed in homozygous (GG) compared to heterozygous patients (AG). ConclusionWe present first evidence for a genetic risk factor that is associated with decreased vagal modulation in unmedicated patients with schizophrenia. Moreover, our findings suggest that HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients. Thus, our data indicate that reduced vagal modulation might be an endophenotype of schizophrenia.

Selective optogenetic stimulation of efferent fibers in the vagus nerve of a large mammal

BackgroundElectrical stimulation applied to individual organs, peripheral nerves, or specific brain regions has been used to treat a range of medical conditions. In cardiovascular disease, autonomic dysfunction contributes to the disease progression and electrical stimulation of the vagus nerve has been pursued as a treatment for the purpose of restoring the autonomic balance. However, this approach lacks selectivity in activating function- and organ-specific vagal fibers and, despite promising results of many preclinical studies, has so far failed to translate into a clinical treatment of cardiovascular disease. ObjectiveHere we report a successful application of optogenetics for selective stimulation of vagal efferent activity in a large animal model (sheep). Methods and resultsTwelve weeks after viral transduction of a subset of vagal motoneurons, strong axonal membrane expression of the excitatory light-sensitive ion channel ChIEF was achieved in the efferent projections innervating thoracic organs and reaching beyond the level of the diaphragm. Blue laser or LED light (>10 mW mm−2; 1 ms pulses) applied to the cervical vagus triggered precisely timed, strong bursts of efferent activity with evoked action potentials propagating at speeds of ∼6 m s−1. ConclusionsThese findings demonstrate that in species with a large, multi-fascicled vagus nerve, it is possible to stimulate a specific sub-population of efferent fibers using light at a site remote from the vector delivery, marking an important step towards eventual clinical use of optogenetic technology for autonomic neuromodulation.

Influences of GABAergic Inhibition in the Dorsal Medulla on Contralateral Swallowing Neurons in Rats

We aimed to examine the effect of unilateral inhibition of the medullary dorsal swallowing networks on the activities of swallowing-related cranial motor nerves and swallowing interneurons. In 25 juvenile rats, we recorded bilateral vagal nerve activity (VNA) as well as unilateral phrenic and hypoglossal activity (HNA) during fictive swallowing elicited by electrical stimulation of the superior laryngeal nerve during control and following microinjection of the GABA agonist muscimol into the caudal dorsal medulla oblongata in a perfused brainstem preparation. In 20 animals, swallowing interneurons contralateral to the muscimol injection side were simultaneously recorded extracellularly and their firing rates were analyzed during swallowing. Integrated VNA and HNA to the injection side decreased to 49.0 ± 16.6% and 32.3 ± 17.9%, respectively. However, the VNA on the uninjected side showed little change after muscimol injection. Following local inhibition, 11 out of 20 contralateral swallowing interneurons showed either increased or decreased of their respective firing discharge during evoked-swallowing, while no significant changes in activity were observed in the remaining nine neurons. The neuronal networks underlying the swallowing pattern generation in the dorsal medulla mediate the ipsilateral motor outputs and modulate the contralateral activity of swallowing interneurons, suggesting that the bilateral coordination of the swallowing central pattern generator regulates the spatiotemporal organization of pharyngeal swallowing movements. NA Laryngoscope, 131:2187-2198, 2021.

The involvement of renal afferents in the maintenance of cardiorenal diseases.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.

Thermoregulatory reflex control of cutaneous vasodilation in healthy aging

ABSTRACT Reflex cutaneous vasodilation during heating is attenuated in healthy human aging secondary to blunted increases in efferent skin sympathetic nervous system activity (SSNA) and reductions in end-organ sensitivity. Whether age-related alterations in the mean body temperature ( b) threshold for increasing SSNA and/or the sensitivity of responses are evident with aging have not been examined. We tested the hypotheses that the Tb threshold for SSNA and cutaneous vascular conductance (CVC) would be increased, but the sensitivity would be reduced, with aging. Reflex vasodilation was induced in 13 young (23 ± 3 y) and 13 older (67 ± 7 y) adults using a water-perfused suit to systematically increase mean skin and esophageal temperatures. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry) in the innervated dermatome were continuously measured. SSNA was normalized to baseline; CVC was normalized as a percentage of maximal CVC. Baseline b was lower in older adults (36.0 ± 0.4°C vs 36.4 ± 0.3°C; p = 0.005). During passive heating, the ∆ b thresholds for increasing SSNA and CVC were greater (1.3 ± 0.4°C vs 0.9 ± 0.3°C; p = 0.007 and 1.3 ± 0.4°C vs 0.8 ± 0.3°C; p = 0.002, respectively) in older adults. The slope of the relation between both SSNA (0.31 ± 0.23 vs 0.13 ± 0.10 V⋅s⋅°C −1; p = 0.01) and CVC (87.5 ± 50.1 vs 32.4 ± 18.1%max⋅°C−1; p = 0.002) vs b was lower in older adults. The relative b threshold for activation of SSNA and the initiation of reflex cutaneous vasodilation is higher in older adults, and once activated, the sensitivity of both responses is diminished, supporting the concept that the efferent component of the thermoregulatory reflex arc is impaired in healthy aging. Abbreviations: CI: confidence interval; CVC: cutaneous vascular conductance; SSNA: skin sympathetic nervous system activity; b: mean body temperature; Tes: esophageal temperature; sk: mean skin temperature.