Neuroinflammatory activation in sensory and motor regions of the cortex is related to sensorimotor function in individuals with low back pain maintained by nociplastic mechanisms: A preliminary proof-of-concept study.

BACKGROUND: Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function. METHODS: Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered. RESULTS: Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41). CONCLUSION: This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype. SIGNIFICANCE STATEMENT: Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation.

Brainstem processing of cough sensory inputs in chronic cough hypersensitivity.

BACKGROUND: Chronic cough is a prevalent and difficult to treat condition often accompanied by cough hypersensitivity, characterised by cough triggered from exposure to low level sensory stimuli. The mechanisms underlying cough hypersensitivity may involve alterations in airway sensory nerve responsivity to tussive stimuli which would be accompanied by alterations in stimulus-induced brainstem activation, measurable with functional magnetic resonance imaging (fMRI). METHODS: We investigated brainstem responses during inhalation of capsaicin and adenosine triphosphate (ATP) in 29 participants with chronic cough and 29 age- and sex-matched controls. Psychophysical testing was performed to evaluate individual sensitivities to inhaled stimuli and fMRI was used to compare neural activation in participants with cough and control participants while inhaling stimulus concentrations that evoked equivalent levels of urge-to-cough sensation. FINDINGS: Participants with chronic cough were significantly more sensitive to inhaled capsaicin and ATP and showed a change in relationship between urge-to-cough perception and cough induction. When urge-to-cough levels were matched, participants with chronic cough displayed significantly less neural activation in medullary regions known to integrate airway sensory inputs. By contrast, neural activations did not differ significantly between the two groups in cortical brain regions known to encode cough sensations whereas activation in a midbrain region of participants with chronic cough was significantly increased compared to controls. INTERPRETATION: Cough hypersensitivity in some patients may occur in brain circuits above the level of the medulla, perhaps involving midbrain regions that amplify ascending sensory signals or change the efficacy of central inhibitory control systems that ordinarily serve to filter sensory inputs. FUNDING: Supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Pty Ltd. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme (Australia) Pty Ltd.

Two-point discrimination responses in children with idiopathic toe walking: A feasibility fMRI study.

Idiopathic toe walking (ITW) is a diagnosis given to children who walk with an absence or limitation of heel strike in the contact phase of the gait cycle, that are otherwise typically developing. There is emerging evidence that this gait pattern may occur in children who experience tactile sensory processing challenges. This feasibility study aimed to determine if children were able to respond to a sensory stimulus during a fMRI. Children aged between 8-16 years of age, with and without idiopathic toe walking were recruited from general public advertising. Participants were required to perform a two-point discrimination test (task block) and press a button without being tested (control block) during an fMRI using a standard block design. Activation differences were examined in the left frontal pole, left supramarginal gyrus, left parahippocampal gyrus, left paracingulate gyrus and the right superior temporal. Five children were in the typically developing (TD) group and three were in the ITW group. There were between-group activation differences in the decision-making block compared to the control block in the left frontal lobe, parahippocampal gyrus and the right superior temporal gyrus. There was greater variation in activation in the left supramarginal gyrus and the left paracingulate gyrus in the ITW group compared to the typically developing group. Based on this study a future sample size of 15 children per group will be required to detect an adequate effect across chosen regions of interest Conducting fMRI using two-point discrimination testing on this population is feasible. Further research is required with larger population sizes to determine if brain activation patterns during the sensory input decision-making process are different in this population.

Mini Review: Central Organization of Airway Afferent Nerve Circuits.

Airway afferents monitor the local chemical and physical micro-environments in the airway wall and lungs and send this information centrally to regulate neural circuits involved in setting autonomic tone, evoking reflex and volitional respiratory motor outflows, encoding perceivable sensations and contributing to higher order cognitive processing. In this mini-review we present a current overview of the central wiring of airway afferent circuits in the brainstem and brain, highlighting recent discoveries that augment our understanding of airway sensory processing. We additionally explore how advances in describing the molecular diversity of airway afferents may influence future research efforts aimed at defining central mesoscale connectivity of airway afferent pathways. A refined understanding of how functionally distinct airway afferent pathways are organized in the brain will provide deeper insight into the physiology of airway afferent-evoked responses and may foster opportunities for targeted modulation of specific pathways involved in disease.

Behavioral and Regional Brain Responses to Inhalation of Capsaicin Modified by Painful Conditioning in Humans.

BACKGROUND: Cough is a defense mechanism that protects the airways and lungs in response to airway irritation. The sensory neurons involved in detecting airway irritants and the neural pathways mediating cough share similarities with those that encode pain from the body. Painful conditioning stimuli applied to one body site are known to reduce the perception of pain at another. However, whether the neural regulation of cough is influenced by painful stimuli is not known. RESEARCH QUESTION: What are the behavioral and neural outcomes of painful conditioning stimuli on urge-to-cough (UTC) and cough evoked by inhaled capsaicin? STUDY DESIGN AND METHODS: Sixteen healthy participants underwent psychophysical testing and functional MRI while completing a series of capsaicin inhalations to induce UTC and cough. The responses associated with capsaicin inhalation without pain were compared with those after the application of painful conditioning stimuli. RESULTS: Significant decreases were seen behaviorally of 18.7% ± 17.3% (P < .001) and 47.0% ± 30.8% (P < .001) in participants' UTC ratings and cough frequencies, respectively, during the application of pain. UTC ratings were reduced by 24.2% ± 36.5% (P < .005) and increased by 67% ± 40% (P < .001) for capsaicin and saline inhalation, respectively, during the scanning session. Painful conditioning stimuli were associated with widespread decreases in regional brain responses to capsaicin inhalation (P < .001). Several brain regions showed levels of reduced activation attributable to painful conditioning that correlated with related changes in behavioral responses during scanning (R2 = 0.53). INTERPRETATION: Pain-related decreases of cough and UTC are accompanied by widespread changes in brain activity during capsaicin inhalation, suggesting that pain can modify the central processing of inputs arising from the airways. A mechanistic understanding of how cough and pain processing interact within the brain may help develop more effective therapies to reduce unwanted coughing.

"Phantom Kicks": Women's Subjective Experience of Fetal Kicks After the Postpartum Period.

Background: During pregnancy, a woman will attribute increased abdominal sensations to fetal movement. Surprisingly, many women report that they feel kick sensations long after the pregnancy; however, this experience has never been reported in the scientific literature. Materials and Methods: We used a qualitative approach to survey n = 197 women who had previously been pregnant. We calculated the number of women who had experienced phantom kicks after their first pregnancy, and explored subjective experiences of kick-like sensations in the post-partum period. Results: In this study, we show that almost 40% of women in our sample experienced phantom fetal kicks after their first pregnancy, up to 28 years (average 6.4 years) post-partum. Women described the phantom sensations as "convincing," "real kicks," or "flutters." Twenty-seven percent of women described the experience as nostalgic or comforting, and 25.7% reported felt confused or upset by the experience. Conclusions: Our results demonstrate that phantom kicks in the postpartum period are a widely experienced sensation, which may have implications for a woman's postpartum mental health. The mechanism behind the phantom kick phenomenon is unknown, but may be related to changes in the somatosensory homunculus or proprioception during pregnancy.

Waiting in Pain II: An Updated Review of the Provision of Persistent Pain Services in Australia.

OBJECTIVE: To provide an update on Australian persistent pain services (number, structure, funding, wait times, activity). METHODS: An updated national search was conducted. Of those identified, 74 persistent pain services provided detailed responses between July 2016 and February 2018 (64 adult, seven pediatric, two pelvic pain, and one cancer pain). A similar structure to the original Waiting in Pain (WIP) survey was used, and participants chose online or telephone completion. RESULTS: Pediatric pain services had more than doubled but remained limited. Adult services had also increased, with a concurrent decrease in median wait times and an increase in the number of new referrals seen each year. Despite this, some lengthy wait times (≥3 years) persisted. Wait times were longest at clinics using public or combined funding models and offering pain management group programs (PMGPs). Although clinical activity had increased, medical staffing had not, suggesting that clinics were operating differently. Privately funded clinics performed more procedures than publicly funded services. Use of PMGPs had increased, but program structure remained diverse. CONCLUSIONS: Specialist pain services have expanded since the original WIP survey, facilitating treatment access for many. However, wait time range suggested that the most disadvantaged individuals still experienced the longest wait times, often far exceeding the recommended 6-month maximum wait. More needs to be done. Numerous developments (e.g., National Strategic Action Plan for Pain Management, health system changes as a result of the COVID-19 pandemic) will continue to influence the delivery of pain services in Australia, and repeated analysis of service structures and wait times will optimize our health system response to the management of this condition.

Peripheral and central mechanisms of cough hypersensitivity.

Chronic cough is a difficult to treat symptom of many respiratory and some non-respiratory diseases, indicating that varied pathologies can underpin the development of chronic cough. However, clinically and experimentally it has been useful to collate these different pathological processes into the single unifying concept of cough hypersensitivity. Cough hypersensitivity syndrome is reflected by troublesome cough often precipitated by levels of stimuli that ordinarily don't cause cough in healthy people, and this appears to be a hallmark feature in many patients with chronic cough. Accordingly, a strong argument has emerged that changes in the excitability and/or normal regulation of the peripheral and central neural circuits responsible for cough are instrumental in establishing cough hypersensitivity and for causing excessive cough in disease. In this review, we explore the current peripheral and central neural mechanisms that are believed to be involved in altered cough sensitivity and present possible links to the mechanism of action of novel therapies that are currently undergoing clinical trials for chronic cough.

Evidence for multiple bulbar and higher brain circuits processing sensory inputs from the respiratory system in humans.

KEY POINTS: Unpleasant respiratory sensations contribute to morbidity in pulmonary disease. In rodents, these sensations are processed by nodose and jugular vagal sensory neurons, two distinct cell populations that differentially project to the airways and brainstem. Whether similar differences exist in bronchopulmonary sensory pathways in humans is unknown. We use functional magnetic resonance imaging during inhalation of capsaicin and ATP, showing that airway nodose pathways project centrally to the nucleus of the solitary tract, whereas jugular pathways input into the trigeminal brainstem nuclei. We also show differences between the efficacy of nodose and jugular stimuli to evoke cough and activity in motor control regions of the brain. Our data suggest that humans have two distinct vagal sensory neural systems governing airway sensations and this may have implications for the development of new antitussive therapies. ABSTRACT: In rodents, nodose vagal sensory neurons preferentially innervate the distal airways and terminate centrally in the nucleus of the solitary tract. By contrast, jugular vagal sensory neurons preferentially innervate the proximal airways and terminate in the paratrigeminal nucleus in the dorsolateral medulla. This differential organization suggests distinct roles for nodose and jugular pathways in respiratory sensory processing. However, it is unknown whether bronchopulmonary afferent pathways are similarly arranged in humans. We set out to investigate this using high resolution brainstem and whole brain functional magnetic resonance imaging in healthy human participants when they were inhaling stimuli known to differentially activate nodose and jugular pathways. Inhalation of capsaicin or ATP evoked respiratory sensations described as an urge-to-cough, although ATP was significantly less effective compared to capsaicin at evoking the motor act of coughing. The nodose and jugular neuron stimulant capsaicin increased blood oxygen level-dependent (BOLD) signals extending across the dorsomedial and dorsolateral medulla, encompassing regions containing both the nucleus of the solitary tract and the paratrigeminal nucleus. By contrast, at perceptually comparable stimulus intensities, the nodose-selective stimulant ATP resulted in BOLD signal intensity changes that were confined to the area of the nucleus of the solitary tract. During whole brain imaging, capsaicin demonstrated a wider distributed network of activity compared to ATP, with significantly increased activity in regions involved with motor control functions. These data suggest that functional and neuroanatomical differences in bronchopulmonary nodose and jugular sensory pathway organization are conserved in humans and also that this has implications for understanding the neurobiological mechanisms underpinning cough.

Descending Modulation of Laryngeal Vagal Sensory Processing in the Brainstem Orchestrated by the Submedius Thalamic Nucleus.

The nodose and jugular vagal ganglia supply sensory innervation to the airways and lungs. Jugular vagal airway sensory neurons wire into a brainstem circuit with ascending projections into the submedius thalamic nucleus (SubM) and ventrolateral orbital cortex (VLO), regions known to regulate the endogenous analgesia system. Here we investigate whether the SubM-VLO circuit exerts descending regulation over airway vagal reflexes in male and female rats using a range of neuroanatomical tracing, reflex physiology, and chemogenetic techniques. Anterograde and retrograde neuroanatomical tracing confirmed the connectivity of the SubM and VLO. Laryngeal stimulation in anesthetized rats reduced respiration, a reflex that was potently inhibited by activation of SubM. Conversely, inhibition of SubM potentiated laryngeal reflex responses, while prior lesions of VLO abolished the effects of SubM stimulation. In conscious rats, selective chemogenetic activation of SubM neurons specifically projecting to VLO significantly inhibited respiratory responses evoked by inhalation of the nociceptor stimulant capsaicin. Jugular vagal inputs to SubM via the medullary paratrigeminal nucleus were confirmed using anterograde transsynaptic conditional herpes viral tracing. Respiratory responses evoked by microinjections of capsaicin into the paratrigeminal nucleus were significantly attenuated by SubM stimulation, whereas those evoked via the nucleus of the solitary tract were unaltered. These data suggest that jugular vagal sensory pathways input to a nociceptive thalamocortical circuit capable of regulating jugular sensory processing in the medulla. This circuit organization suggests an intersection between vagal sensory pathways and the endogenous analgesia system, potentially important for understanding vagal sensory processing in health and mechanisms of hypersensitivity in disease.SIGNIFICANCE STATEMENT Jugular vagal sensory pathways are increasingly recognized for their important role in defensive respiratory responses evoked from the airways. Jugular ganglia neurons wire into a central circuit that is notable for overlapping with somatosensory processing networks in the brain rather than the viscerosensory circuits in receipt of inputs from the nodose vagal ganglia. Here we demonstrate a novel and functionally relevant example of intersection between vagal and somatosensory processing in the brain. The findings of the study offer new insights into interactions between vagal and spinal sensory processing, including the medullary targets of the endogenous analgesia system, and offer new insights into the central processes involved in airway defense in health and disease.

Regional brain responses associated with using imagination to evoke and satiate thirst.

In response to dehydration, humans experience thirst. This subjective state is fundamental to survival as it motivates drinking, which subsequently corrects the fluid deficit. To elicit thirst, previous studies have manipulated blood chemistry to produce a physiological thirst stimulus. In the present study, we investigated whether a physiological stimulus is indeed required for thirst to be experienced. Functional MRI (fMRI) was used to scan fully hydrated participants while they imagined a state of intense thirst and while they imagined drinking to satiate thirst. Subjective ratings of thirst were significantly higher for imagining thirst compared with imagining drinking or baseline, revealing a successful dissociation of thirst from underlying physiology. The imagine thirst condition activated brain regions similar to those reported in previous studies of physiologically evoked thirst, including the anterior midcingulate cortex (aMCC), anterior insula, precentral gyrus, inferior frontal gyrus, middle frontal gyrus, and operculum, indicating a similar neural network underlies both imagined thirst and physiologically evoked thirst. Analogous brain regions were also activated during imagined drinking, suggesting the neural representation of thirst contains a drinking-related component. Finally, the aMCC showed an increase in functional connectivity with the insula during imagined thirst relative to imagined drinking, implying functional connectivity between these two regions is needed before thirst can be experienced. As a result of these findings, this study provides important insight into how the neural representation of subjective thirst is generated and how it subsequently motivates drinking behavior.

A role for neurokinin 1 receptor expressing neurons in the paratrigeminal nucleus in bradykinin-evoked cough in guinea-pigs.

KEY POINTS: Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor. This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses. Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation. The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex. These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease. ABSTRACT: Jugular vagal ganglia sensory neurons innervate the large airways and are thought to mediate cough and associated perceptions of airway irritations to a range of chemical irritants. The central terminals of jugular sensory neurons lie within the brainstem paratrigeminal nucleus, where postsynaptic neurons can be differentiated based on the absence or presence of the neurokinin 1 (NK1) receptor. Therefore, in the present study, we set out to test the hypothesis that NK1 receptor expressing paratrigeminal neurons play a role in cough evoked by inhaled chemical irritants. To test this, we performed selective neurotoxin lesions of NK1 receptor expressing neurons in the paratrigeminal nucleus in guinea-pigs using substance P conjugated to saporin (SSP-SAP). Sham lesion control or SSP-SAP lesion guinea-pigs received nebulised challenges, with the pan-nociceptor stimulant bradykinin or the nodose ganglia specific stimulant adenosine 5'-triphosphate (ATP), in conscious whole-body plethysmography to study cough and associated behaviours. Laryngeal apnoea reflexes and cough evoked by mechanical stimulation of the trachea were additionally investigated in anaesthetised guinea-pigs. SSP-SAP significantly and selectively reduced the number of NK1 receptor expressing neurons in the paratrigeminal nucleus. This was associated with a significant reduction in bradykinin-evoked cough, but not ATP-evoked cough, mechanical cough or laryngeal apnoeic responses. These data provide further evidence for a role of jugular vagal pathways in cough, and additionally suggest an involvement of NK1 receptor expressing neurons in the paratrigeminal nucleus. Therefore, this neural pathway may provide novel therapeutic opportunities to treat conditions of chronic cough.

Altered neural activity in brain cough suppression networks in cigarette smokers.

Cough is important for airway defence, and studies in healthy animals and humans have revealed multiple brain networks intimately involved in the perception of airway irritation, cough induction and cough suppression. Changes in cough sensitivity and/or the ability to suppress cough accompany pulmonary pathologies, suggesting a level of plasticity is possible in these central neural circuits. However, little is known about how persistent inputs from the lung might modify the brain processes regulating cough.In the present study, we used human functional brain imaging to investigate the central neural responses that accompany an altered cough sensitivity in cigarette smokers.In nonsmokers, inhalation of the airway irritant capsaicin induced a transient urge-to-cough associated with the activation of a distributed brain network that included sensory, prefrontal and motor cortical regions. Cigarette smokers demonstrated significantly higher thresholds for capsaicin-induced urge-to-cough, consistent with a reduced sensitivity to airway irritation. Intriguingly, this was accompanied by increased activation in brain regions known to be involved in both cough sensory processing (primary sensorimotor cortex) and cough suppression (dorsolateral prefrontal cortex and the midbrain nucleus cuneiformis). Activations in the prefrontal cortex were highest among participants with the least severe smoking behaviour, whereas those in the midbrain correlated with more severe smoking behaviour.These outcomes suggest that smoking-induced sensitisation of central cough neural circuits is offset by concurrently enhanced central suppression. Furthermore, central suppression mechanisms may evolve with the severity of smoke exposure, changing from initial prefrontal inhibition to more primitive midbrain processes as exposure increases.

Are neural pathways processing airway inputs sensitized in patients with cough hypersensitivity?

Patients with cough hypersensitivity exhibit unusually low thresholds for responses to tussive stimuli, exaggerated responses to suprathreshold tussive stimuli, and report spontaneous experiences of urge-to-cough in the absence of exogenous stimulation. These aberrant responses to tussive challenge have the hallmark features of behaviours associated with a sensitized sensory system. Searching for further evidence to implicate neural sensitization in the symptomatology of cough hypersensitivity warrants consideration. If up-regulation of neural circuits involved in processing of airways inputs can be demonstrated in patients with cough hypersensitivity, then strategies to reverse this dysfunctional plasticity can be contemplated and assessed. This review considers the implications of neural sensitization as a factor in the cough hypersensitivity syndrome, reflects on the limited data available in this field, and suggests prospective directions for future research.

Heterogeneity of cough neurobiology: Clinical implications.

Cough is an important protective mechanism for clearing the airways but becomes a troublesome, and often difficult to treat, symptom in respiratory disease. Although cough can be produced as a reflex in response to the presence of irritants within the airways, emerging research demonstrates an unappreciated complexity in the peripheral and central neural systems that regulate cough. This complexity includes multiple primary sensory neurons that can induce or facilitate reflex coughing, different ascending central circuits in the brain that contribute to cough sensory discrimination and the perception of the urge-to-cough, and several descending brain systems for inducing, facilitating and inhibiting cough responses. Consequently, the mechanisms responsible for cough becoming dysregulated in disease are not likely homogeneous across all patients with chronic cough. The available data suggests that changes in primary sensory neuron excitability, altered central nervous system integration of sensory inputs and changes in descending control mechanisms may each contribute to the development of cough hypersensitivity.

Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans.

Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation ("urge to cough") accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated ( r2 = 0.47, 0.48) with participants' subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. NEW & NOTEWORTHY Functional brain imaging in humans was optimized for the brain stem. We provide the first detailed description of brain stem sites activated in response to airway irritation. The results are consistent with findings in animal studies and extend our foundational knowledge of brain processing of airway irritation in humans.

Reflex regulation of breathing by the paratrigeminal nucleus via multiple bulbar circuits.

Sensory neurons of the jugular vagal ganglia innervate the respiratory tract and project to the poorly studied medullary paratrigeminal nucleus. In the present study, we used neuroanatomical tracing, pharmacology and physiology in guinea pig to investigate the paratrigeminal neural circuits mediating jugular ganglia-evoked respiratory reflexes. Retrogradely traced laryngeal jugular ganglia neurons were largely (> 60%) unmyelinated and expressed the neuropeptide substance P and calcitonin gene-related peptide, although a population (~ 30%) of larger diameter myelinated jugular neurons was defined by the expression of vGlut1. Within the brainstem, vagal afferent terminals were confined to the caudal two-thirds of the paratrigeminal nucleus. Electrical stimulation of the laryngeal mucosa evoked a vagally mediated respiratory slowing that was mimicked by laryngeal capsaicin application. These laryngeal reflexes were modestly reduced by neuropeptide receptor antagonist microinjections into the paratrigeminal nucleus, but abolished by ionotropic glutamate receptor antagonists. D,L-Homocysteic acid microinjections into the paratrigeminal nucleus mimicked the laryngeal-evoked respiratory slowing, whereas capsaicin microinjections evoked a persistent tachypnoea that was insensitive to glutamatergic inhibition but abolished by neuropeptide receptor antagonists. Extensive projections from paratrigeminal neurons were anterogradely traced throughout the pontomedullary respiratory column. Dual retrograde tracing from pontine and ventrolateral medullary termination sites, as well as immunohistochemical staining for calbindin and neurokinin 1 receptors, supported the existence of different subpopulations of paratrigeminal neurons. Collectively, these data provide anatomical and functional evidence for at least two types of post-synaptic paratrigeminal neurons involved in respiratory reflexes, highlighting an unrecognised complexity in sensory processing in this region of the brainstem.

Determining Brain Mechanisms that Underpin Analgesia Induced by the Use of Pain Coping Skills.

Objective: Cognitive behavioral therapies decrease pain and improve mood and function in people with osteoarthritis. This study assessed the effects of coping strategies on the central processing of knee pain in people with osteoarthritis of the knees. Methods: Mechanical pressure was applied to exacerbate knee pain in 28 people with osteoarthritis of the knee. Reports of pain intensity and functional magnetic resonance imaging measures of pain-related brain activity were recorded with and without the concurrent use of pain coping skills. Results: Coping skills led to a significant reduction in pain report (Coping = 2.64 ± 0.17, Not Coping = 3.28 ± 0.15, P < 0.001). These strategies were associated with increased activation in pain modulatory regions of the brain (medial prefrontal and rostral anterior cingulate cortices, Pcorrected < 0.05) and decreased pain-related activation in regions that process noxious input (midcingulate cortex, supplementary motor area, secondary somatosensory cortex, and anterior parietal lobule, Pcorrected < 0.05). The magnitude of the decrease in pain report during the use of pain coping strategies was found to be proportional to the decrease in pain-related activation in brain regions that code the aversive/emotional dimension of pain (anterior insula, inferior frontal gyrus, orbitofrontal cortex, Pcorrected < 0.05) but did not differ between groups with and without training in coping skills. However, training in coping skills reduced the extent to which brain responses to noxious input were influenced by anxiety. Conclusions: The results of this study support previous reports of pain modulation by cognitive pain coping strategies and contribute to the current understanding of how analgesia associated with the use of pain coping strategies is represented in the brain.

Influence of anterior midcingulate cortex on drinking behavior during thirst and following satiation.

In humans, activity in the anterior midcingulate cortex (aMCC) is associated with both subjective thirst and swallowing. This region is therefore likely to play a prominent role in the regulation of drinking in response to dehydration. Using functional MRI, we investigated this possibility during a period of "drinking behavior" represented by a conjunction of preswallow and swallowing events. These events were examined in the context of a thirsty condition and an "oversated" condition, the latter induced by compliant ingestion of excess fluid. Brain regions associated with swallowing showed increased activity for drinking behavior in the thirsty condition relative to the oversated condition. These regions included the cingulate cortex, premotor areas, primary sensorimotor cortices, the parietal operculum, and the supplementary motor area. Psychophysical interaction analyses revealed increased functional connectivity between the same regions and the aMCC during drinking behavior in the thirsty condition. Functional connectivity during drinking behavior was also greater for the thirsty condition relative to the oversated condition between the aMCC and two subcortical regions, the cerebellum and the rostroventral medulla, the latter containing nuclei responsible for the swallowing reflex. Finally, during drinking behavior in the oversated condition, ratings of swallowing effort showed a negative association with functional connectivity between the aMCC and two cortical regions, the sensorimotor cortex and the supramarginal gyrus. The results of this study provide evidence that the aMCC helps facilitate swallowing during a state of thirst and is therefore likely to contribute to the regulation of drinking after dehydration.

A neuroanatomical framework for the central modulation of respiratory sensory processing and cough by the periaqueductal grey.

Sensory information arising from the airways is processed in a distributed brain network that encodes for the discriminative and affective components of the resultant sensations. These higher brain networks in turn regulate descending motor control circuits that can both promote or suppress behavioural responses. Here we explore the existence of possible descending neural control pathways that regulate airway afferent processing in the brainstem, analogous to the endogenous descending analgesia system described for noxious somatosensation processing and placebo analgesia. A key component of this circuitry is the midbrain periaqueductal grey, a region of the brainstem recently highlighted for its altered activity in patients with chronic cough. Understanding the nature and plasticity of descending neural control may help identify novel central therapeutic targets to alleviate the neuronal hypersensitivity underpinning many symptoms of respiratory disease.