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•taVNS effects on brainstem activity are assessed during fMRI.•taVNS modulates activity in brainstem vagal afferent targets (including the NTS).•The signal dynamics over time indicates both acute, persistent and delayed effects of taVNS. Our increasing knowledge about gut-brain interaction is revolutionising the understanding of the links between digestion, mood, health, and even decision making in our everyday lives. In support of this interaction, the vagus nerve is a crucial pathway transmitting diverse gut-derived signals to the brain to monitor of metabolic status, digestive processes, or immune control to adapt behavioural and autonomic responses. Hence, neuromodulation methods targeting the vagus nerve are currently explored as a treatment option in a number of clinical disorders, including diabetes, chronic pain, and depression. The non-invasive variant of vagus nerve stimulation (VNS), transcutaneous auricular VNS (taVNS), has been implicated in both acute and long-lasting effects by modulating afferent vagus nerve target areas in the brain. The physiology of neither of those effects is, however, well understood, and evidence for neuronal response upon taVNS in vagal afferent projection regions in the brainstem and its downstream targets remain to be established. Therefore, to examine time-dependent effects of taVNS on brainstem neuronal responses in healthy human subjects, we applied taVNS during task-free fMRI in a single-blinded crossover design. During fMRI data acquisition, we either stimulated the left earlobe (sham), or the target zone of the auricular branch of the vagus nerve in the outer ear (cymba conchae, verum) for several minutes, both followed by a short ‘stimulation OFF’ period. Time-dependent effects were assessed by averaging the BOLD response for consecutive 1-minute periods in an ROI-based analysis of the brainstem. We found a significant response to acute taVNS stimulation, relative to the control condition, in downstream targets of vagal afferents, including the nucleus of the solitary tract, the substantia nigra, and the subthalamic nucleus. Most of these brainstem regions remarkably showed increased activity in response to taVNS, and these effect sustained during the post-stimulation period. These data demonstrate that taVNS activates key brainstem regions, and highlight the potential of this approach to modulate vagal afferent signalling. Furthermore, we show that carry-over effects need to be considered when interpreting fMRI data in the context of general vagal neurophysiology and its modulation by taVNS.

The output from a motor nucleus is determined by the synaptic input to the motor neurons and their intrinsic properties. Here, we explore whether the source of synaptic inputs to the motor neurons (cats) and the age or post-stroke conditions (humans) may change the recruitment gain of the motor neuron pool. In cats, the size of Ia EPSPs in triceps surae motor neurons (input) and monosynaptic reflexes (MSRs; output) was recorded in the soleus and medial gastrocnemius motor nerves following graded stimulation of dorsal roots. The MSR was plotted against the EPSP thereby obtaining a measure of the recruitment gain. Conditioning stimulation of sural and peroneal cutaneous afferents caused significant increase in the recruitment gain of the medial gastrocnemius, but not the soleus motor neuron pool. In humans, the discharge probability of individual soleus motor units (input) and soleus H-reflexes (output) was performed. With graded stimulation of the tibial nerve, the gain of the motor neuron pool was assessed as the slope of the relation between probability of firing and the reflex size. The gain in young subjects was higher than in elderly subjects. The gain in post-stroke survivors was higher than in age-matched neurologically intact subjects. These findings provide experimental evidence that recruitment gain of a motor neuron pool contributes to the regulation of movement at the final output stage from the spinal cord and should be considered when interpreting changes in reflex excitability in relation to movement or injuries of the nervous system.

Although the effects of cannabis on perception are well documented, little is known about their neural basis or how these may contribute to the formation of psychotic symptoms. We used functional magnetic resonance imaging (fMRI) to assess the effects of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during visual and auditory processing in healthy volunteers. In total, 14 healthy volunteers were scanned on three occasions. Identical 10 mg THC, 600 mg CBD, and placebo capsules were allocated in a balanced double-blinded pseudo-randomized crossover design. Plasma levels of each substance, physiological parameters, and measures of psychopathology were taken at baseline and at regular intervals following ingestion of substances. Volunteers listened passively to words read and viewed a radial visual checkerboard in alternating blocks during fMRI scanning. Administration of THC was associated with increases in anxiety, intoxication, and positive psychotic symptoms, whereas CBD had no significant symptomatic effects. THC decreased activation relative to placebo in bilateral temporal cortices during auditory processing, and increased and decreased activation in different visual areas during visual processing. CBD was associated with activation in right temporal cortex during auditory processing, and when contrasted, THC and CBD had opposite effects in the right posterior superior temporal gyrus, the right-sided homolog to Wernicke's area. Moreover, the attenuation of activation in this area (maximum 61, −15, −2) by THC during auditory processing was correlated with its acute effect on psychotic symptoms. Single doses of THC and CBD differently modulate brain function in areas that process auditory and visual stimuli and relate to induced psychotic symptoms.

Apnea of Prematurity (AOP) is common, affecting the majority of infants born at <34 weeks gestational age. Apnea and periodic breathing are accompanied by intermittent hypoxia (IH). Animal and human studies demonstrate that IH exposure contributes to multiple pathologies, including retinopathy of prematurity (ROP), injury to sympathetic ganglia regulating cardiovascular action, impaired pancreatic islet cell and bone development, cerebellar injury, and neurodevelopmental disabilities. Current standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and methylxanthine therapy; these interventions are inadequate, and not optimal for early development. The objective is to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements trigger reflexive facilitation of breathing. Premature infants (23-34 wks gestational age), with clinical evidence of AOP/IH episodes were enrolled 1 week after birth. Caffeine treatment was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in 6 hour ON/OFF sequences for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2), and breathing pauses were continuously collected. Fewer respiratory pauses occurred during vibration periods, relative to baseline (p<0.005). Significantly fewer SpO2 declines occurred with vibration (p<0.05), relative to control periods. Significantly fewer bradycardic events occurred during vibration periods, relative to no vibration periods (p<0.05). In premature neonates, limb proprioceptive stimulation, simulating limb movement, reduces breathing pauses and IH episodes, and lowers the number of bradycardic events that accompany aberrant breathing episodes. This low-cost neuromodulatory procedure has the potential to provide a non-invasive intervention to reduce apnea, bradycardia and intermittent hypoxia in premature neonates. ClinicalTrials.gov NCT02641249.

It is generally assumed that primary sensory neurons transmit information by their firing rates. However, during natural object manipulations, tactile information from the fingertips is used faster than can be readily explained by rate codes. Here we show that the relative timing of the first impulses elicited in individual units of ensembles of afferents reliably conveys information about the direction of fingertip force and the shape of the surface contacting the fingertip. The sequence in which different afferents initially discharge in response to mechanical fingertip events provides information about these events faster than the fastest possible rate code and fast enough to account for the use of tactile signals in natural manipulation.

Background: Sensory amplitude electrical stimulation (SES) and repetitive task practice reduce impairments and arm dysfunction when delivered separately following stroke. Objective: To determine if home-based, task-specific arm exercise was more effective when administered concurrent with SES. Methods: Thirty-eight subjects with chronic stroke and mean Fugl-Meyer Assessment (FMA) score 28/66 (15–45) participated. Subjects were randomly assigned to an SES (n = 20) or sham stimulation (n = 18) group. Subjects engaged in task-based home exercise for 30 minutes, twice daily, for four weeks while wearing a glove electrode on the impaired hand. Experimental subjects received SES while control subjects received sham stimulation during exercise. Primary outcome measures: FMA and Arm Motor Ability Test (AMAT). Results: There were no significant between-group differences for outcome measures. There was a significant difference between the pre- and post-test scores in the SES group AMAT median time (P = 0.003 95% confidence interval (CI): −14.304, −6.365; effect size: 0.84). Practice time was not associated with changes in outcomes. Subjects with more sensorimotor dysfunction had significantly greater improvements on AMAT median time (P = 0.037). There was a significant relationship between baseline FMA score and FMA change score (r = 0.402; P = 0.006). Conclusions: This study describes a unique SES delivery system via glove electrode that enabled delivery of SES during home-based arm task practice in stroke survivors. Task practice with concurrent SES did not demonstrate significantly better effects than task practice with sham stimulation, however there was a trend for greater improvement in one activity measure.

Key Points Locomotion is a complex motor act that, to a large degree, is controlled by neuronal circuits in the spinal cord. Using a systems neuroscience approach in several model systems of non-limbed and limbed animals, important advances have been made in revealing the functional organization of the spinal locomotor networks. The key circuit elements in the spinal locomotor networks are the rhythm-generating circuits and the pattern-generating circuits, which include circuits that control bilateral muscle activity, and circuits that control flexor–extensor muscles in limbed animals. Comparison of the network organization of the key circuit elements in limbed and non-limbed animals reveals both commonalities and differences in organization. The commonalities extend to the basic components of inhibitory left–right alternating circuits and excitatory neurons involved in rhythm generation. The differences include left–right alternating circuitries that have multiple components in legged animals compared with the control of axial muscles in fish where one component dominates, rhythm-generating neurons that originate from developmentally diverse progenitors in fish and mice, and elaborated reciprocal network circuits involved in the flexor–extensor coordination that is found in legged animals, which do not have direct counterparts in non-legged animals. Locomotor networks, whether they control swimming or over-ground locomotion, are built around modules of rhythm- and pattern-generating modules. Functional network reorganization occurs with changes in the speed of locomotion or changes in gait. This reconfiguration takes places both at the level of rhythm generation and at the level of pattern generation. The exact mechanisms of rhythm generation are not generally understood across phyla but seem to depend on an interplay between active membrane properties and network properties. Proprioception suggests an important role for phase switching during locomotion. The combination of electrophysiological and molecular genetic approaches has revealed details of the organization of large-scale spinal networks in limbed animals in considerably different ways than previous research has suggested and has allowed for comparison with network organization in leg-less animals with more limited numbers of cells in the spinal cord. Although these fundamental motor networks have begun to be decoded, there are still unresolved issues regarding their functional organization. In vertebrates, assemblies of neurons in the spinal cord generate the precise timing and patterning of locomotor movements. In this Review, Ole Kiehn examines the organization and operation of these spinal locomotor networks in limbed and non-limbed animals. Unravelling the functional operation of neuronal networks and linking cellular activity to specific behavioural outcomes are among the biggest challenges in neuroscience. In this broad field of research, substantial progress has been made in studies of the spinal networks that control locomotion. Through united efforts using electrophysiological and molecular genetic network approaches and behavioural studies in phylogenetically diverse experimental models, the organization of locomotor networks has begun to be decoded. The emergent themes from this research are that the locomotor networks have a modular organization with distinct transmitter and molecular codes and that their organization is reconfigured with changes to the speed of locomotion or changes in gait.

Current models of active vision emphasize the role of intracortical feedback projections. The authors report that thalamocortical projections, in particular from the higher order lateral posterior nucleus, provide an alternative pathway by which contextual sensory and motor information, as well as putative visuomotor error signals, are conveyed to primary visual cortex. Sensory perception depends on the context in which a stimulus occurs. Prevailing models emphasize cortical feedback as the source of contextual modulation. However, higher order thalamic nuclei, such as the pulvinar, interconnect with many cortical and subcortical areas, suggesting a role for the thalamus in providing sensory and behavioral context. Yet the nature of the signals conveyed to cortex by higher order thalamus remains poorly understood. Here we use axonal calcium imaging to measure information provided to visual cortex by the pulvinar equivalent in mice, the lateral posterior nucleus (LP), as well as the dorsolateral geniculate nucleus (dLGN). We found that dLGN conveys retinotopically precise visual signals, while LP provides distributed information from the visual scene. Both LP and dLGN projections carry locomotion signals. However, while dLGN inputs often respond to positive combinations of running and visual flow speed, LP signals discrepancies between self-generated and external visual motion. This higher order thalamic nucleus therefore conveys diverse contextual signals that inform visual cortex about visual scene changes not predicted by the animal's own actions.

Key Points Brainstem vagovagal neurocircuits modulate the functions of the upper gastrointestinal tract Neuronal communications between vagal sensory (nucleus tractus solitarius, NTS) and motor (dorsal motor nucleus of the vagus, DMV) nuclei are highly specialized and probably specific for function and target organ NTS–DMV synaptic contacts are not static but undergo plastic changes to ensure that vagally regulated gastrointestinal functions respond appropriately to ever-changing physiological conditions or derangements Gastrointestinal peptides influence vagovagal circuits via actions on both vagal afferent fibres and brainstem nuclei Neurodegenerative alterations of the vagal neurocircuitry induce marked impairments of gastrointestinal functions Upper gastrointestinal tract function is regulated by vagovagal neurocircuits, comprising brainstem nuclei that integrate visceral sensory information and provide vagal motor output. Here, Travagli and Anselmi describe the organization of these neurocircuits and their plasticity in response to stressors. The influence of gastrointestinal peptides on vagovagal neurons is also discussed. A large body of research has been dedicated to the effects of gastrointestinal peptides on vagal afferent fibres, yet multiple lines of evidence indicate that gastrointestinal peptides also modulate brainstem vagal neurocircuitry, and that this modulation has a fundamental role in the physiology and pathophysiology of the upper gastrointestinal tract. In fact, brainstem vagovagal neurocircuits comprise highly plastic neurons and synapses connecting afferent vagal fibres, second order neurons of the nucleus tractus solitarius (NTS), and efferent fibres originating in the dorsal motor nucleus of the vagus (DMV). Neuronal communication between the NTS and DMV is regulated by the presence of a variety of inputs, both from within the brainstem itself as well as from higher centres, which utilize an array of neurotransmitters and neuromodulators. Because of the circumventricular nature of these brainstem areas, circulating hormones can also modulate the vagal output to the upper gastrointestinal tract. This Review summarizes the organization and function of vagovagal reflex control of the upper gastrointestinal tract, presents data on the plasticity within these neurocircuits after stress, and discusses the gastrointestinal dysfunctions observed in Parkinson disease as examples of physiological adjustment and maladaptation of these reflexes.

Key Points Taste buds are composed of two excitable cell types and a glia-like cell; each type of cell has distinct functions. Basic taste qualities are detected by G protein-coupled type 1 and type 2 taste receptors, by other receptors and ion channels, and possibly by transporters. ATP is an afferent taste transmitter and is secreted by taste bud cells through an unconventional, non-vesicular release mechanism. ATP, serotonin and GABA mediate cell–cell interactions in the taste bud that may shape transmission to sensory afferent fibres. Controversy remains regarding whether peripheral taste coding follows a labelled-line or combinatorial pattern. Taste preferences and appetites seem to have a genetic component that is being revealed by molecular and population studies. Mammals detect the nutrient content, palatability and potential toxicity of food through taste buds that are present mainly in the tongue. In this Review, Roper and Chaudhari discuss the taste bud cells, receptors and transmitters that are involved in taste detection, how these cells communicate with sensory afferent fibres, and peripheral taste coding. The past decade has witnessed a consolidation and refinement of the extraordinary progress made in taste research. This Review describes recent advances in our understanding of taste receptors, taste buds, and the connections between taste buds and sensory afferent fibres. The article discusses new findings regarding the cellular mechanisms for detecting tastes, new data on the transmitters involved in taste processing and new studies that address longstanding arguments about taste coding.