Rostral Medulla Research Articles

Rostral ventral medulla circuits regulate both the sensory and affective dimensions of neuropathic pain: a commentary on Dogrul et al.

Rostral ventral medulla circuits regulate both the sensory and affective dimensions of neuropathic pain: a commentary on Dogrul et al.

Open-Label Placebo Injection for Chronic Back Pain With Functional Neuroimaging

Chronic back pain (CBP) is a leading cause of disability. Placebo treatments often provide as much pain relief as bona fide treatments, such as steroid injections. Open-label (honestly prescribed) placebos (OLPs) may relieve CBP without deception, but OLP mechanisms remain poorly understood. To investigate the long-term efficacy and neurobiological mechanisms of OLP for CBP. A randomized clinical trial of CBP with longitudinal functional magnetic resonance imaging (MRI) comparing OLP with usual care, with 1-year follow-up, was conducted in a university research setting and a community orthopedic clinic. Participants were individuals aged 21 to 70 years with CBP. The trial was conducted from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Data analysis was performed from April 2020 to May 2024. The primary analysis was conducted on an intention-to-treat sample. Participants randomized to OLP received a 1-time subcutaneous lumbar saline injection presented as placebo accompanied by information about the power of placebo to relieve pain, alongside their ongoing care. Usual care participants continued their ongoing care. The primary outcome was pain intensity (0-10, with 0 indicating no pain and 10 the most intense) at 1 month posttreatment. Secondary outcomes included pain interference, depression, anxiety, anger, and sleep quality. Functional MRI was performed before and after treatment during evoked and spontaneous back pain. A total of 101 adults (52 [51.4%] females; mean [SD] age, 40.4 [15.4] years) with moderate severity CBP (mean [SD], 4.10 [1.25] intensity; duration, 9.7 [8.5] years) were enrolled. Compared with usual care, OLP reduced CBP intensity posttreatment (relative reduction, 0.61; Hedges g = 0.45; 95% CI, -0.89 to 0.04; P = .02). Through 1-year follow-up, pain relief did not persist, although significant benefits were observed for depression, anger, anxiety, and sleep disruption (Hedges g = 0.3-0.5; all P < .03). Brain responses to evoked back pain for OLP vs usual care increased in rostral anterior cingulate and ventromedial prefrontal cortex and decreased in somatomotor cortices and thalamus. During spontaneous pain, functional connectivity analyses identified OLP vs usual care increases in ventromedial prefrontal cortex connectivity to the rostral ventral medulla, a pain-modulatory brainstem nucleus. No adverse effects of treatment were reported by participants. In this randomized clinical trial of OLP vs usual care, a single nondeceptive placebo injection reduced CBP intensity for 1 month posttreatment and provided benefits lasting for at least 1 year posttreatment. Brain mechanisms of OLP in a clinical population overlap with those of deceptive placebos in healthy volunteers, including engagement of prefrontal-brainstem pain modulatory pathways. ClinicalTrials.gov Identifier: NCT03294148.

RNA sequencing of the thalamus and rostral ventral medulla in rats with chronic orofacial pain.

Diagnosing and treating chronic orofacial pain is challenging due to its complex structure and limited understanding of its causes and mechanisms. In this study, we used RNA sequencing to identify differentially expressed genes (DEGs) in the rostral ventral medulla (RVM) and thalamus of rats with persistent orofacial pain, aiming to explore its development. DEGs were functionally analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results showed a significant association between immune response and pain in this model. Key DEG mRNA expression trends were further validated using real-time quantitative polymerase chain reaction (RT-PCR), confirming their crucial roles in chronic orofacial pain. After injecting complete Freund's adjuvant (CFA) into the bilateral temporomandibular joint cavity for 14 days, we observed 293 upregulated genes and 14 downregulated genes in the RVM, and 1086 upregulated genes and 37 downregulated genes in the thalamus. Furthermore, we identified 27 common DEGs with altered expression (upregulation) in both the thalamus and RVM, including Cd74, C3, Cxcl13, C1qb, Itgal, Fcgr2b, C5ar1, and Tlr2, which are pain-associated genes. Protein-protein interaction (PPI) analysis using Cytoscape revealed the involvement of Toll-like receptors, complement system, differentiation clusters, and antigen presentation-related proteins in the interaction between the thalamus and RVM. The results of this study show that the immune system seems to have a more significant influence on chronic orofacial pain. There may be direct or indirect influence between the thalamus and RVM, which may participate in the regulation of chronic orofacial pain.

Elevated Serotonin in Mouse Spinal Dorsal Horn Is Pronociceptive.

Serotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathologic pain states, but whether changes in serotonergic mechanisms are pro- or antinociceptive is debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naive mice produces mechanical hypersensitivity and conditioned place aversion (CPA). Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin (5HT) concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase in sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain.

SAT596 Evidence That Corticotropin-releasing Hormone Receptor 2 Activation Mediates Stress-induced Hyperglycemia

Abstract Disclosure: R.B. McCosh: None. M.J. Kreisman: None. J. Jang: None. J. Jung: None. K.M. Breen Church: None. Stress-induced hyperglycemia refers to the transient increase in blood glucose (BG) levels during stress, which occurs in healthy and diabetic patients. In critically ill patients, stress-induced hyperglycemia is associated with a 2-fold increase in risk of incident diabetes. Thus, stress-induced hyperglycemia is a predictor of or may contribute to glucose dysregulation. In mice, activation of catecholamine neurons in the rostral ventral lateral medulla (rVLM) is necessary for stress-induced hyperglycemia; however, the mechanism by which these cells become activated during stress is not clear. Here, we tested the possibility that corticotropin-releasing hormone receptor 2 (CRHR2) signaling mediates stress-induced hyperglycemia in adult, ovariectomized mice. First, BG levels and rVLM cell activation were examined in two stress models. For psychosocial stress, BG levels were not altered by control treatment. In contrast, placement in a restraint device increased BG levels ∼2-fold, within 30 min, from pretreatment values and BG remained elevated for an additional 90 min. For immune stress, BG was significantly elevated (21% increase) at 30 min post IP injection of lipopolysaccharide (LPS, 10ng/g bw), then returned to baseline levels whereas BG levels were not altered from pretreatment levels in saline injected mice. In tissue collected 2 hr after initiation of restraint stress, the percentage of tyrosine hydroxylase (TH, marker of catecholamine cells) neurons in the rVLM that contained c-Fos (a marker of neural activation) was significantly greater than control mice. Next, we assessed the sufficiency of CRHR2 activation to induce hyperglycemia using the CRHR2 agonist urocortin 2 (UCN2), injected intracerebroventricular (ICV). BG was significantly increased 30 min after injection of both saline and UCN2 (60-80%); however, BG subsequently returned to baseline in saline-treated mice, but remained elevated in mice that received UCN2, similar to restraint stress. To test necessity of CRHR2 activation to induce hyperglycemia, we delivered ICV either the specific CRHR2 antagonist Astressin 2B (A2B) or saline 1 hr before psychosocial or immune stress. In no stress controls, A2B did not alter BG levels compared to saline, yet, BG levels in both groups decreased over time. BG levels were elevated in saline-treated controls 30 min after restraint stress; and, this increase was delayed, although not prevented, by 30 min by A2B pre-treatment. Following LPS injection, BG was increased at 30 min then decreased relative to baseline in saline-treated controls; yet, A2B pre-treatment blocked these changes. Together these data support the hypothesis that CRHR2 signaling is an important mediator of stress-induced hyperglycemia. Assessment of rVLM TH cells is ongoing. Presentation: Saturday, June 17, 2023

Measurement of brainstem diameter in small-breed dogs using magnetic resonance imaging.

Measurement of brainstem diameters (midbrain, pons, and medulla oblongata)is of potential clinical significance, as changes in brainstem size may decrease or increase due to age, neurodegenerative disorders, or neoplasms. In human medicine, numerous studies have reported the normal reference range of brainstem size, which is hitherto unexplored in veterinary medicine, particularly for small-breed dogs. Therefore, this study aims to investigate the reference range of brainstem diameters in small-breed dogs and to correlate the measurements with age, body weight (BW), and body condition score (BCS). Herein, magnetic resonance (MR) images of 544 small-breed dogs were evaluated. Based on the exclusion criteria, 193 dogs were included in the midbrain and pons evaluation, and of these, 119 dogs were included in the medulla oblongata evaluation. Using MR images, the height and width of the midbrain, pons, and medulla oblongata were measured on the median and transverse plane on the T1-weighted image. For the medulla oblongata, two points were measured for each height and width. The mean values of midbrain height (MH), midbrain width (MW), pons height (PH), pons width (PW), medulla oblongata height at the fourth ventricle level (MOHV), medulla oblongata height at the cervicomedullary (CM) junction level (MOHC), rostral medulla oblongata width (RMOW), and caudal medulla oblongata width (CMOW) were 7.18 ± 0.56 mm, 17.42 ± 1.21 mm, 9.73 ± 0.64 mm, 17.23 ± 1.21 mm, 6.06 ± 0.53 mm, 5.77 ± 0.40 mm, 18.93 ± 1.25 mm, and 10.12 ± 1.08 mm, respectively. No significant differences were found between male and female dogs for all the measurements. A negative correlation was found between age and midbrain diameter, including MH (p < 0.001) and MW (p = 0.002). All brainstem diameters were correlated positively with BW (p < 0.05). No significant correlation was found between BCS and all brainstem diameters. Brainstem diameters differed significantly between breeds (p < 0.05), except for MW (p = 0.137). This study assessed linear measurements of the brainstem diameter in small-breed dogs. We suggest that these results could be useful in assessing abnormal conditions of the brainstem in small-breed dogs.

Altered brain connectivity in Long Covid during cognitive exertion: a pilot study.

Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection. Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores. Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI. Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.

The chronification mechanism of orofacial inflammatory pain: Facilitation by GPER1 and microglia in the rostral ventral medulla.

Chronic orofacial pain is a common and incompletely defined clinical condition. The role of G protein-coupled estrogen receptor 1 (GPER1) as a new estrogen receptor in trunk and visceral pain regulation is well known. Here, we researched the role of GPER1 in the rostral ventral medulla (RVM) during chronic orofacial pain. A pain model was established where rats were injected in the temporomandibular joint with complete Freund's adjuvant (CFA) to simulate chronic orofacial pain. Following this a behavioral test was performed to establish pain threshold and results showed that the rats injected with CFA had abnormal pain in the orofacial regions. Additional Immunostaining and blot analysis indicated that microglia were activated in the RVM and GPER1 and c-Fos were significantly upregulated in the rats. Conversely, when the rats were injected with G15 (a GPER1 inhibitor) the abnormal pain the CFA rats were experiencing was alleviated and microglia activation was prevented. In addition, we found that G15 downregulated the expression of phospholipase C (PLC) and protein kinase C (PKC), inhibited the expression of GluA1, restores aberrant synaptic plasticity and reduces the overexpression of the synapse-associated proteins PSD-95 and syb-2 in the RVM of CFA rats. The findings indicate that GPER1 mediates chronic orofacial pain through modulation of the PLC-PKC signal pathway, sensitization of the RVM region and enhancement of neural plasticity. These results of this study therefore suggest that GPER1 may serve as a potential therapeutic target for chronic orofacial pain.

PS-BPB07-2: AFFERENT RENAL NERVES CONTRIBUTE TO LEFT VENTRICULAR DYSFUNCTION THROUGH HYPOTHALAMIC VASOPRESSIN-MEDIATED CENTRAL SYMPATHOEXCITATION IN HYPERTENSIVE HEART FAILURE MODEL

Objective: Afferent renal nerves may contribute to the development and progression of heart failure, which, however, has not been well investigated. This study aimed to examine whether the afferent renal nerve input contributes to hypertensive cardiac dysfunction. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt diet (LS) or 8% high-salt diet (HS) from 6 weeks of age. HS-fed rats were divided into selective afferent renal denervation (HS-ARDN) or sham operation (HS-Sham) at 9 weeks. The effects of ARDN on central sympathetic regulation were investigated at 12 weeks. In another cohort, its effects on the cardiac phenotypes were evaluated at 16 weeks, with adding total renal denervation (HS-TRDN) group. Results: At 12 weeks, systolic blood pressure (SBP) measured by tail-cuff method was significantly increased in HS-Sham compared to LS, while there was no significant difference between HS-Sham and HS-ARDN. Plasma norepinephrine concentration was increased in HS-Sham compared to LS and was attenuated in HS-ARDN. The c-Fos expression, a neuronal activation marker, in presympathetic neurons within hypothalamic paraventricular nucleus (PVN) and rostral ventral lateral medulla (RVLM) was also increased in HS-Sham and attenuated in HS-ARDN, which was in parallel with the c-Fos expression in vasopressin-expressing neurons within PVN. At 16 weeks, SBP was similarly increased in HS-Sham, HS-ARDN, and HS-TRDN compared to LS. Although the parameters of left ventricular (LV) hypertrophy, such as LV wall thickness by echocardiography and LV weight, were significantly increased in HS-Sham, HS-ARDN, and HS-TRDN compared to LS, there was no significant difference between HS-fed three groups. Echocardiographic LV fractional shortening was significantly decreased in HS-Sham compared to LS, and was attenuated to the same extent in HS-ARDN and HS-TRDN. Histological LV fibrosis determined by Masson trichrome staining and mRNA expression of ANP and CTGF in LV were significantly increased in HS-Sham compared to LS; these changes were similarly ameliorated in both HS-ARDN and HS-TRDN. Conclusion: The input from renal afferent nerves contributes to sympathoexcitation and cardiac dysfunction independently of SBP in Dahl salt-sensitive hypertensive heart failure model. Vasopressin production in PVN may be involved in the renal afferents-mediated sympathetic regulation.

Brainstem Damage Underlies Changes in Hypoxic Ventilatory Response Following Cardiac Arrest and Resuscitation in Rats.

People resuscitated after sudden cardiac arrest remain at high risk for mortality, with treatment for survivors varying from monitoring to life support. With respect to assessing survivability post cardiac arrest and resuscitation (CAR), we previously demonstrated the potential of the hypoxic ventilatory response (HVR) as a reliable indicator for discerning between survivors and non-survivors in the early stages of recovery following CAR in rats. Since HVR describes the increase in ventilation in response to hypoxia, we hypothesize that damage to cardiorespiratory regulatory centers in the brainstem underlie the loss of HVR observed post resuscitation in nonsurvivors. Wistar rats underwent cardiac arrest (12-min) and resuscitation. At 1day post-resuscitation, rats were perfused transcardially and the brains were harvested and processed for immunohistostaining of caspase-3, a marker of apoptosis. Positive caspase-3 staining was observed in brainstem regions such as the rostral ventral lateral medulla (RVLM); Co-localization of caspase-3 and NeuN was observed in the RVLM as well, suggesting that apoptosis most likely occurs in neurons. Our results showed positive markers for neuronal apoptosis present in pathways of the brainstem involved in respiratory and cerebrovascular regulation, suggesting brain stem damage underlies changes in HVR following CAR.

Effect of cisplatin on respiratory activity in neonatal rats.

One side effect of cisplatin, a cytotoxic platinum anticancer drug, is peripheral neuropathy; however, its central nervous system effects remain unclear. We monitored respiratory nerve activity from the C4 ventral root in brainstem and spinal cord preparations from neonatal rats (P0-3) to investigate its central effects. Bath application of 10-100μM cisplatin for 15-20min dose-dependently decreased the respiratory rate and increased the amplitude of C4 inspiratory activity. These effects were not reversed after washout. In separate perfusion experiments, cisplatin application to the medulla decreased the respiratory rate, and application to the spinal cord increased the C4 burst amplitude without changing the burst rate. Application of other platinum drugs, carboplatin or oxaliplatin, induced no change of respiratory activity. A membrane potential analysis of respiratory-related neurons in the rostral medulla showed that firing frequencies of action potentials in the burst phase tended to decrease during cisplatin application. In contrast, in inspiratory spinal motor neurons, cisplatin application increased the peak firing frequency of action potentials during the inspiratory burst phase. The increased burst amplitude and decreased respiratory frequency were partially antagonized by riluzole and picrotoxin, respectively. Taken together, cisplatin inhibited respiratory rhythm via medullary inhibitory system activation and enhanced inspiratory motor nerve activity by changing the firing property of motor neurons.

The stroke mechanism, clinical presentation, and radiological feature of bilateral medial medullary infarction.

Bilateral medial medullary infarction (BMMI) is a rare type of posterior circulation stroke. The aim of this study is to characterize its stroke mechanisms, clinical manifestations, neuroradiological features, and prognosis. From January 2015 to June 2021, a retrospective review of 15 patients diagnosed with BMMI was conducted. The clinical and neuroradiological features were summarized by our experienced neurologists. Fifteen patients (12 male, 3 female), ranging in age from 48 to 72years, satisfied the inclusion criteria. The common clinical presentations included motor weakness (100%), deep sensory disturbance (93.3%), vertigo/dizziness (80%), dysarthria (93.3%), and dysphagia (66.7%). Vertically, infarct lesions in the rostral medulla were observed in all included patients. Horizontally, "heart appearance," "Y appearance," and "fan appearance" infarcts occurred in 9 cases (60%), 5 cases (33.3%), and 1 (6.7%) case, respectively. Patients (53.3%) had severe stenosis or occlusion in unilateral vertebral artery (VA), and 33.3% had normal findings in the vertebrobasilar artery. Patients (93.3%) achieved poor prognosis. BMMI is more frequently located in the rostral medulla and comprises three forms of infarction. The two main stroke etiologies of BMMI are large-artery atherosclerosis (LAA) and small vessel disease (SVD). BMMI is always associated with bad clinical outcome.

TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids.

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures.

Postsurgical Latent Pain Sensitization Is Driven by Descending Serotonergic Facilitation and Masked by µ-Opioid Receptor Constitutive Activity in the Rostral Ventromedial Medulla.

Following tissue injury, latent sensitization (LS) of nociceptive signaling can persist indefinitely, kept in remission by compensatory µ-opioid receptor constitutive activity (MORCA) in the dorsal horn of the spinal cord. To demonstrate LS, we conducted plantar incision in mice and then waited 3-4 weeks for hypersensitivity to resolve. At this time (remission), systemic administration of the opioid receptor antagonist/inverse agonist naltrexone reinstated mechanical and heat hypersensitivity. We first tested the hypothesis that LS extends to serotonergic neurons in the rostral ventral medulla (RVM) that convey pronociceptive input to the spinal cord. We report that in male and female mice, hypersensitivity was accompanied by increased Fos expression in serotonergic neurons of the RVM, abolished on chemogenetic inhibition of RVM 5-HT neurons, and blocked by intrathecal injection of the 5-HT3R antagonist ondansetron; the 5-HT2AR antagonist MDL-11 939 had no effect. Second, to test for MORCA, we microinjected the MOR inverse agonist d-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) and/or neutral opioid receptor antagonist 6β-naltrexol. Intra-RVM CTAP produced mechanical hypersensitivity at both hindpaws; 6β-naltrexol had no effect by itself, but blocked CTAP-induced hypersensitivity. This indicates that MORCA, rather than an opioid ligand-dependent mechanism, maintains LS in remission. We conclude that incision establishes LS in descending RVM 5-HT neurons that drives pronociceptive 5-HT3R signaling in the dorsal horn, and this LS is tonically opposed by MORCA in the RVM. The 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.SIGNIFICANCE STATEMENT Surgery leads to latent pain sensitization and a compensatory state of endogenous pain control that is maintained long after tissue healing. Here, we show that either chemogenetic inhibition of serotonergic neuron activity in the RVM or pharmacological inhibition of 5-HT3 receptor signaling at the spinal cord blocks behavioral signs of postsurgical latent sensitization. We conclude that MORCA in the RVM opposes descending serotonergic facilitation of LS and that the 5-HT3 receptor is a promising therapeutic target for the development of drugs to prevent the transition from acute to chronic postsurgical pain.

Clinical and radiological features of medullary infarction caused by spontaneous vertebral artery dissection

Background and purposeMedullary infarction (MI) caused by spontaneous vertebral artery dissection (sVAD) is an important type of stroke. It is important to distinguish sVAD from other causes of stroke since...

Laterality of Skin Temperature and Magnetic Resonance Imaging in Patients with Wallenberg Syndrome

Background: Recently, lateral differences in body surface temperature (BST) have been reported as a symptom of Wallenberg syndrome (WS), resulting from disturbances in the sympathetic nerve pathway. This study aimed to investigate the relationship between the laterality of BST and brain magnetic resonance imaging (MRI) findings in 12 patients with WS.Methods: BST was measured using an infrared thermal camera at 7±3 days and 90±30 days after symptom onset. The MRI findings were categorized as rostral, middle, and caudal medulla rostrocaudally and typical, ventral, large, dorsal, and lateral types in the horizontal direction.Results: MRI revealed medullary lesions on the right in five patients and on the left in seven patients. Two patients without lateralized BST had lateral caudal medullary infarction, and one patient had a dorsal middle medullary infarction. One patient with lateralized BST had a rostral medullary infarction and the other had a typical or large middle medulla infarction. Lateralized BST in patients with WS may disturb the sympathetic nervous system pathway that descends from the rostral ventrolateral medulla oblongata. Deficits in sweating and skin blood flow may cause BST laterality.Conclusion: This study showed that lateralized BST in patients with WS may be associated with disturbances in the sympathetic nervous pathway descending from the rostral ventrolateral medulla. These results support the assumption that autonomic dysfunction may be related to abnormal sensory symptoms in patients with WS.

Astrocytic contribution to glutamate-related central respiratory chemoreception in vertebrates

Central respiratory chemoreceptors play a key role in the respiratory homeostasis by sensing CO2 and H+ in brain and activating the respiratory neural network. This ability of specific brain regions to respond to acidosis and hypercapnia is based on neuronal and glial mechanisms. Several decades ago, glutamatergic transmission was proposed to be involved as a main mechanism in central chemoreception. However, a complete identification of mechanism has been elusive. At the rostral medulla, chemosensitive neurons of the retrotrapezoid nucleus (RTN) are glutamatergic and they are stimulated by ATP released by RTN astrocytes in response to hypercapnia. In addition, recent findings show that caudal medullary astrocytes in brainstem can also contribute as CO2 and H+ sensors that release D-serine and glutamate, both gliotransmitters able to activate the respiratory neural network. In this review, we describe the mammalian astrocytic glutamatergic contribution to the central respiratory chemoreception trying to trace in vertebrates the emergence of several components involved in this process.

The development of descending serotonergic modulation of the spinal nociceptive network: a life span perspective.

The nociceptive network, responsible for transmission of nociceptive signals that generate the pain experience, is not fully developed at birth. Descending serotonergic modulation of spinal nociception, an important part of the pain network, undergoes substantial postnatal maturation and is suggested to be involved in the altered pain response observed in human newborns. This review summarizes preclinical data of the development of descending serotonergic modulation of the spinal nociceptive network across the life span, providing a comprehensive background to understand human newborn pain experience and treatment. Sprouting of descending serotonergic axons, originating from the rostroventral medulla, as well as changes in receptor function and expression take place in the first postnatal weeks of rodents, corresponding to human neonates in early infancy. Descending serotonergic modulation switches from facilitation in early life to bimodal control in adulthood, masking an already functional 5-HT inhibitory system at early ages. Specifically the 5-HT3 and 5-HT7 receptors seem distinctly important for pain facilitation at neonatal and early infancy, while the 5-HT1a, 5-HT1b, and 5-HT2 receptors mediate inhibitory effects at all ages. Analgesic therapy that considers the neurodevelopmental phase is likely to result in a more targeted treatment of neonatal pain and may improve both short- and long-term effects. IMPACT: The descending serotonergic system undergoes anatomical changes from birth to early infancy, as its sprouts and descending projections increase and the dorsal horn innervation pattern changes. Descending serotonergic modulation from the rostral ventral medulla switches from facilitation in early life via the 5-HT3 and 5-HT7 receptors to bimodal control in adulthood. A functional inhibitory serotonergic system mainly via 5-HT1a, 5-HT1b, and 5-HT2a receptors at the spinal level exists already at the neonatal phase but is masked by descending facilitation.

Neuropathology of Perry Syndrome: Evidence of Medullary and Hypothalamic Involvement.

Perry syndrome is a rare genetic parkinsonian disorder with TAR DNA binding protein 43 (TDP-43) pathology clinically presenting with parkinsonism, neuropsychiatric features, weight loss, and central hypoventilation. As respiratory complications are often the cause of death, studies likely show the early stage of the neurodegenerative process. Because of the rarity of this condition, few studies exist, and each case provides insight into pathological findings in this neurodegenerative condition. To study the clinical and pathological correlations of an autopsy case of Perry syndrome. The patient was a woman in her 50s with Perry syndrome and a DCTN1 gene mutation. Between October 2016 and July 2019, she underwent postmortem and pathological examination at University Hospital in London, Ontario, Canada. Data were obtained through clinical pathological examination. Microscopy showed significant neuronal loss with pigmentary incontinence and gliosis in the substantia nigra. There was no atrophy elsewhere, including the frontal and cingulate cortex. Intraneuronal cytoplasmic TDP-43 inclusions and neurites were noticed in a moderate number in the substantia nigra and midbrain and were sparsely noticed in the basal ganglia, thalamus, thoracic motor neuron, posterior nucleus of the hypothalamus, and rostral ventral medulla. β-Amyloid, Lewy body, and tau pathologies were absent. Rare axonal swelling was identified at the rostral ventrolateral medulla. This study confirms that Perry syndrome is characterized by TDP-43 pathology with absent Lewy bodies or tau pathology. These findings support the hypothesis of dysfunctional neurons in the medulla and hypothalamus, which may respectively correlate to the clinical symptoms of hypoventilation and weight loss in Perry syndrome.

D2 Receptors in the Periaqueductal Gray/Dorsal Raphe Modulate Peripheral Inflammatory Hyperalgesia via the Rostral Ventral Medulla

Dopamine neurons in the periaqueductal gray (PAG)/dorsal raphe are key modulators of antinociception with known supraspinal targets. However, no study has directly tested whether these neurons contribute to descending pain inhibition. We hypothesized that PAG dopamine neurons contribute to the analgesic effect of D-amphetamine via a mechanism that involves descending modulation via the rostral ventral medulla (RVM). Male C57BL/6 mice showed increased c-FOS expression in PAG dopamine neurons and a significant increase in paw withdrawal latency to thermal stimulation after receiving a systemic injection of D-amphetamine. Targeted microinfusion of D-amphetamine, L-DOPA, or the selective D2 agonist quinpirole into the PAG produced analgesia, while a D1 agonist, chloro APB, had no effect. In addition, inhibition of D2 receptors in the PAG by eticlopride prevented the systemic D-amphetamine analgesic effect. D-amphetamine and PAG D2 receptor-mediated analgesia were inhibited by intra-RVM injection of lidocaine or the GABAA receptor agonist muscimol, indicating a PAG-RVM signaling pathway in this model of analgesia. Finally, both systemic D-amphetamine and local PAG microinjection of quinpirole, inhibited inflammatory hyperalgesia induced by carrageenan. This hyperalgesia was transiently restored by intra-PAG injection of eticlopride, as well as RVM microinjection of muscimol. We conclude that D-amphetamine analgesia is partially mediated by descending inhibition and that D2 receptors in the PAG are responsible for this effect via modulating neurons that project to the RVM. These results further our understanding of the antinociceptive effects of dopamine and elucidate a mechanism by which clinically available dopamine modulators produce analgesia.