Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a patient with adolescent-onset hypomyelinated leukodystrophy with atrophy of basal ganglia and cerebellum (H-ABC). METHODS: A patient who was diagnosed with H-ABC in March 2018 at the First Affiliated Hospital of Nanjing Medical University was selected as the study subject. Clinical data was collected. Peripheral venous blood samples of the patient and his parents were collected. The patient was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 31-year-old male, had manifested with developmental retardation, cognitive decline and abnormal gait. WES revealed that he has harbored a heterozygous c.286G>A variant of the TUBB4A gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Analysis with SIFT online software indicated the amino acid encoded by this variant is highly conserved among various species. This variant has been recorded by the Human Gene Mutation Database (HGMD) with a low population frequency. The 3D structure constructed by PyMOL software showed that the variant has a harmful effect on the structure and function of the protein. According to the guidelines formulated by the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. CONCLUSION The c.286G>A (p.Gly96Arg) variant of the TUBB4A gene probably underlay the hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum in this patient. Above finding has enriched the spectrum of TUBB4A gene variants and enabled early definitive diagnosis of this disorder.
Male ; Humans ; Adolescent ; Adult ; Magnetic Resonance Imaging ; Basal Ganglia/pathology* ; Cerebellum ; Atrophy/pathology* ; Mutation ; Tubulin/genetics*

OBJECTIVE: To summarize and analyze the clinical characteristics of children with basal ganglia germinoma and to improve the level of early clinical diagnosis. METHODS: The clinical data of children diagnosed with basal ganglia germinoma admitted to the Pediatric Surgery Ward of Peking University First Hospital from January 2013 to December 2020 were retrospectively analyzed, and descriptive statistics were used to analyze the clinical characteristics of children with basal ganglia germinoma. RESULTS: A total of 30 patients were included in the study, 28 were male, 2 were female, the mean age at onset was (9.7±2.2) years, the median disease duration was 7 months, 27 had unilateral disease, and 3 had bilateral disease. The clinical manifestations were decreased limb muscle strength, cognitive function disorders, polydipsia, precocious puberty, intracranial hypertension, dysphonia and swallowing dysfunction. The serum and cerebrospinal fluid tumor marker alpha-fetoprotein (AFP) were normal in the 30 patients, and the serum and cerebrospinal fluid tumor marker β-human chorionic gonadotropin (β-HCG) were normal in 8 patients.The serum β-HCG was normal in 11 patients but the cerebrospinal fluid β-HCG was slightly elevated, and the serum and cerebrospinal fluid β-HCG were slightly elevated in 11 patients. A total of 33 lesions with irregular shapes were found by imaging examination, including 15 (45.5%) patchy lesions, 10 (30.3%) patchy lesions, and 8 (24.2%) round-like high-density lesions. Tumors showed obvious high-density shadows on computed tomography (CT) scan. Magnetic resonance imaging (MRI) scan of the tumors showed low or isointensity on T1WI and isointensity on T2WI, accompanied by mild peritumoral edema, hemispheric atrophy, cerebral peduncle atrophy, calcification, cystic degeneration, ventricular dilatation and wallerian degeneration. On contrast-enhanced scans, the tumor showed no enhancement or heterogeneous enhancement. CONCLUSION The main age of onset of germ cell tumors in the basal ganglia in children is about 10 years old, and males are absolutely dominant. The clinical features and imaging manifestations have certain characteristics. With both combined, the early diagnosis of germ cell tumors in the basal ganglia can be improved.
Atrophy/pathology* ; Basal Ganglia/pathology* ; Biomarkers, Tumor ; Brain Neoplasms/diagnostic imaging* ; Child ; Chorionic Gonadotropin, beta Subunit, Human ; Female ; Germinoma/pathology* ; Humans ; Magnetic Resonance Imaging ; Male ; Neoplasms, Germ Cell and Embryonal ; Retrospective Studies

OBJECTIVE: To investigate the effect of bilateral superior cervical sympathetic ganglion occlusion (SCG) on aortic dissection and its possible mechanism. METHODS: Forty-five SD rats were randomly divided into three groups with 15 in each:blank control group, sham operation group and SCG group. β-aminopropione (666 mg·kg·d) was given by subcutaneous injection for 4 weeks to establish the aortic dissection model. Rats in SCG group were given SCG before the injection of β-aminopropione. Blood pressure and heart rate of the rats were monitored using noninvasive tail artery blood pressure measuring instrument; sympathetic activity was monitored using drug block method; the structure of aortic wall was observed using HE staining; collagen fibers in aortic wall was observed using Sirius red staining; protein expression of Apelin was detected by immunohistochemistry; and the protein expression of matrix metalloproteinase (MMP)-2, 9 was detected by Western blotting. RESULTS: During the experiment, the body mass of the sham operation group and SCG group was smaller than that of the blank control group (all <0.05), and the body mass of the SCG group was larger than that of the sham operation group (all <0.05). The heart rate and sympathetic activity of the sham operation group were higher than those of the blank control group (all <0.05), while the SCG group were lower (all <0.05). Compared with the blank control group, the aortic wall in the sham operation group was thickening, while that in the SCG group was improved. A large number of collagen-1 in the aortic wall of the blank control group was stained brown by Sirius red, which was lighter in SCG group, and the staining in the sham operation group was the lightest. Compared with the blank control group, the expression of Apelin, MMP-2 and MMP-9 protein in the sham operation group increased (all <0.05), while those in the SCG group decreased (all <0.05). CONCLUSIONS SCG can effectively reduce the incidence and mortality of aortic dissection in rats, which may be related to the inhibition of sympathetic activity and the decrease of collagen-1, Apelin, MMP-2 and MMP-9 expression.
Aneurysm, Dissecting ; pathology ; surgery ; Animals ; Aorta ; pathology ; Collagen Type I ; Ganglia, Sympathetic ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Lumbar foraminal pathology causing entrapment of neurovascular contents and radicular symptoms are commonly associated with foraminal stenosis. Foraminal neuropathy can also be derived from inflammation of the neighboring lateral recess or extraforaminal spaces. Conservative and interventional therapies have been used for the treatment of foraminal inflammation, fibrotic adhesion, and pain. This update reviews the anatomy, pathophysiology, clinical presentation, diagnosis, and current treatment options of foraminal neuropathy.
Constriction, Pathologic ; Decompression ; Diagnosis ; Electric Stimulation ; Fibrosis ; Foraminotomy ; Ganglia, Spinal ; Inflammation ; Lumbosacral Region ; Pain Management ; Pathology ; Radiculopathy ; Spinal Nerve Roots

BACKGROUND: Quantitative susceptibility mapping (QSM) has been used to measure iron accumulation in the deep nuclei of patients with Parkinson's disease (PD). This study examined the relationship between non-motor symptoms (NMSs) and iron accumulation in the deep nuclei of patients with PD. METHODS: The QSM data were acquired from 3-Tesla magnetic resonance imaging (MRI) in 29 patients with early PD and 19 normal controls. The Korean version of the NMS scale (K-NMSS) was used for evaluation of NMSs in patients. The patients were divided into high NMS and low NMS groups. The region-of-interest analyses were performed in the following deep nuclei: red nucleus, substantia nigra pars compacta, substantia nigra pars reticulata, dentate nucleus, globus pallidus, putamen, and head of the caudate nucleus. RESULTS: Thirteen patients had high NMS scores (total K-NMSS score, mean = 32.1), and 16 had low NMS scores (10.6). The QSM values in the deep were not different among the patients with high NMS scores, low NMS scores, and controls. The QSM values were not correlated linearly with K-NMSS total score after adjusting the age at acquisition of brain MRI. CONCLUSION: The study demonstrated that the NMS burdens are not associated with iron accumulation in the deep nuclei of patients with PD. These results suggest that future neuroimaging studies on the pathology of NMSs in PD should use more specific and detailed clinical tools and recruit PD patients with severe NMSs.
Basal Ganglia ; Brain ; Caudate Nucleus ; Cerebellar Nuclei ; Globus Pallidus ; Head ; Humans ; Iron* ; Magnetic Resonance Imaging ; Neuroimaging ; Parkinson Disease* ; Pars Compacta ; Pars Reticulata ; Pathology ; Putamen ; Red Nucleus

OBJECTIVES: Dopamine dysregulation has been regarded as one of the core pathologies in patients with schizophrenia. Since dopamine synthesis capacity has found to be inconsistent in patients with schizophrenia, current classification of patients based on clinical symptoms cannot reflect the neurochemical heterogeneity of the disease. Here we performed new subtyping of patients with first-episode psychosis (FEP) through biotype-based cluster analysis. We specifically suggested basal ganglia structural changes as a biotype, which deeply involves in the dopaminergic circuit. METHODS: Forty FEP and 40 demographically matched healthy participants underwent 3T T1 MRI. Whole brain parcellation was conducted, and volumes of total 6 regions of basal ganglia have been extracted as features for cluster analysis. We used K-means clustering, and external validation was conducted with Positive and Negative Syndrome Scale (PANSS). ResultsZZK-means clustering divided 40 FEP subjects into 2 clusters. Cluster 1 (n = 25) showed substantial volume decrease in 4 regions of basal ganglia compared to Cluster 2 (n = 15). Cluster 1 showed higher positive scales of PANSS compared with Cluster 2 (F = 2.333, p = 0.025). Compared to healthy controls, Cluster 1 showed smaller volumes in 4 regions, whereas Cluster 2 showed larger volumes in 3 regions. RESULTS: K-means clustering divided 40 FEP subjects into 2 clusters. Cluster 1 (n = 25) showed substantial volume decrease in 4 regions of basal ganglia compared to Cluster 2 (n = 15). Cluster 1 showed higher positive scales of PANSS compared with Cluster 2 (F = 2.333, p = 0.025). Compared to healthy controls, Cluster 1 showed smaller volumes in 4 regions, whereas Cluster 2 showed larger volumes in 3 regions. CONCLUSIONS: Two subgroups have been found by cluster analysis, which showed a distinct difference in volume patterns of basal ganglia structures and positive symptom severity. The result possibly reflects the neurobiological heterogeneity of schizophrenia. Thus, the current study supports the importance of paradigm shift toward biotype-based diagnosis, instead of phenotype, for future precision psychiatry.
Basal Ganglia* ; Brain ; Classification ; Cluster Analysis ; Diagnosis ; Dopamine ; Healthy Volunteers ; Humans ; Magnetic Resonance Imaging ; Pathology ; Phenotype ; Polytetrafluoroethylene ; Population Characteristics ; Psychotic Disorders* ; Schizophrenia ; Weights and Measures

Different physical and chemical stimuli are detected by the peripheral sensory receptors of dorsal root ganglion (DRG) neurons, and the generated inputs are transmitted via afferent fibers into the central nervous system. The gene expression profiles of DRG neurons contribute to the generation, transmission, and regulation of various somatosensory signals. Recently, the single-cell transcriptomes, cell types, and functional annotations of somatosensory neurons have been studied. In this review, we introduce our classification of DRG neurons based on single-cell RNA-sequencing and functional analyses, and discuss the technical approaches. Moreover, studies on the molecular and cellular mechanisms underlying somatic sensations are discussed.
Animals ; Ganglia, Spinal ; cytology ; Gene Regulatory Networks ; Humans ; Pain ; genetics ; metabolism ; pathology ; Sensory Receptor Cells ; metabolism ; Sequence Analysis, RNA ; Transcriptome

Injury to peripheral nerves can lead to neuropathic pain, along with well-studied effects on sensory neurons, including hyperexcitability, abnormal spontaneous activity, and neuroinflammation in the sensory ganglia. Neuropathic pain can be enhanced by sympathetic activity. Peripheral nerve injury may also damage sympathetic axons or expose them to an inflammatory environment. In this study, we examined the lumbar sympathetic ganglion responses to two rat pain models: ligation of the L5 spinal nerve, and local inflammation of the L5 dorsal root ganglion (DRG), which does not involve axotomy. Both models resulted in neuroinflammatory changes in the sympathetic ganglia, as indicated by macrophage responses, satellite glia activation, and increased numbers of T cells, along with very modest increases in sympathetic neuron excitability (but not spontaneous activity) measured in ex vivo recordings. The spinal nerve ligation model generally caused larger responses than DRG inflammation. Plasticity of the sympathetic system should be recognized in studies of sympathetic effects on pain.
Action Potentials ; physiology ; Animals ; Disease Models, Animal ; Female ; Ganglia, Sympathetic ; pathology ; Glial Fibrillary Acidic Protein ; metabolism ; Hyperalgesia ; etiology ; Ligation ; adverse effects ; Macrophages ; pathology ; Male ; Neurogenic Inflammation ; etiology ; Pain ; etiology ; pathology ; Patch-Clamp Techniques ; Peripheral Nerve Injuries ; complications ; Rats ; Rats, Sprague-Dawley ; Receptors, Antigen, T-Cell, alpha-beta ; metabolism

Due to the complex circuitry and plethora of cell types involved in somatosensation, it is becoming increasingly important to be able to observe cellular activity at the population level. In addition, since cells rely on an intricate variety of extracellular factors, it is important to strive to maintain the physiological environment. Many electrophysiological techniques require the implementation of artificially-produced physiological environments and it can be difficult to assess the activity of many cells simultaneously. Moreover, imaging Ca transients using Ca-sensitive dyes often requires in vitro preparations or in vivo injections, which can lead to variable expression levels. With the development of more sensitive genetically-encoded Ca indicators (GECIs) it is now possible to observe changes in Ca transients in large populations of cells at the same time. Recently, groups have used a GECI called GCaMP to address fundamental questions in somatosensation. Researchers can now induce GCaMP expression in the mouse genome using viral or gene knock-in approaches and observe the activity of populations of cells in the pain pathway such as dorsal root ganglia (DRG), spinal neurons, or glia. This approach can be used in vivo and thus maintains the organism's biological integrity. The implementation of GCaMP imaging has led to many advances in our understanding of somatosensation. Here, we review the current findings in pain research using GCaMP imaging as well as discussing potential methodological considerations.
Afferent Pathways ; physiology ; Animals ; Calcium ; metabolism ; Calcium Signaling ; drug effects ; genetics ; Ganglia, Spinal ; metabolism ; Humans ; Pain ; metabolism ; pathology