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Journal of Neuropsychology Sep 2023Tourette syndrome (TS) and chronic tic disorder (CTD) are neurological disorders of childhood onset characterized by the occurrence of tics; repetitive, purposeless,... (Randomized Controlled Trial)
Randomized Controlled Trial
A double-blind, sham-controlled, trial of home-administered rhythmic 10-Hz median nerve stimulation for the reduction of tics, and suppression of the urge-to-tic, in individuals with Tourette syndrome and chronic tic disorder.
Tourette syndrome (TS) and chronic tic disorder (CTD) are neurological disorders of childhood onset characterized by the occurrence of tics; repetitive, purposeless, movements or vocalizations of short duration which can occur many times throughout a day. Currently, effective treatment for tic disorders is an area of considerable unmet clinical need. We aimed to evaluate the efficacy of a home-administered neuromodulation treatment for tics involving the delivery of rhythmic pulse trains of median nerve stimulation (MNS) delivered via a wearable 'watch-like' device worn at the wrist. We conducted a UK-wide parallel double-blind sham-controlled trial for the reduction of tics in individuals with tic disorder. The device was programmed to deliver rhythmic (10 Hz) trains of low-intensity (1-19 mA) electrical stimulation to the median nerve for a pre-determined duration each day, and was intended to be used by each participant in their home once each day, 5 days each week, for a period of 4 weeks. Between 18th March 2022 and 26th September 2022, 135 participants (45 per group) were initially allocated, using stratified randomization, to one of the following groups; active stimulation; sham stimulation or to a waitlist (i.e. treatment as usual) control group. Recruited participants were individuals with confirmed or suspected TS/CTD aged 12 years of age or upward with moderate to severe tics. Researchers involved in the collection or processing of measurement outcomes and assessing the outcomes, as well as participants in the active and sham groups and their legal guardians were all blind to the group allocation. The primary outcome measure used to assess the 'offline' or treatment effect of stimulation was the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTSS) assessed at the conclusion of 4 weeks of stimulation. The primary outcome measure used to assess the 'online' effects of stimulation was tic frequency, measured as the number of tics per minute (TPM) observed, based upon blind analysis of daily video recordings obtained while stimulation was delivered. The results demonstrated that after 4-week stimulation, tic severity (YGTSS-TTSS) had reduced by 7.1 points (35 percentile reduction) for the active stimulation group compared to 2.13/2.11 points for the sham stimulation and waitlist control groups. The reduction in YGTSS-TTSS for the active stimulation group was substantially larger, clinically meaningful (effect size = .5) and statistically significant (p = .02) compared to both the sham stimulation and waitlist control groups, which did not differ from one another (effect size = -.03). Furthermore, blind analyses of video recordings demonstrated that tic frequency (tics per minute) reduced substantially (-15.6 TPM) during active stimulation compared to sham stimulation (-7.7 TPM). This difference represents a statistically significant (p < .03) and clinically meaningful reduction in tic frequency (>25 percentile reduction: effect size = .3). These findings indicate that home-administered rhythmic MNS delivered through a wearable wrist-worn device has the potential to be an effective community-based treatment for tic disorders.
Topics: Humans; Child; Tourette Syndrome; Tics; Median Nerve; Tic Disorders; Treatment Outcome; Severity of Illness Index
PubMed: 37133932
DOI: 10.1111/jnp.12313 -
Osteoarthritis and Cartilage Dec 2023TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-β1 (TGF-β1), has...
TissueGene-C induces long-term analgesic effects through regulation of pain mediators and neuronal sensitization in a rat monoiodoacetate-induced model of osteoarthritis pain.
OBJECTIVE
TissueGene-C (TG-C), a combination of human allogeneic chondrocytes and irradiated GP2-293 cells engineered to overexpress transforming growth factor-β1 (TGF-β1), has been developed as a novel cell-based gene therapy and a candidate for disease modifying osteoarthritis drug (DMOAD). We aim to investigate analgesic mechanism of TG-C in a pre-clinical animal model with monoiodoacetate (MIA)-induced pain.
DESIGN
We used a rat MIA model of osteoarthritis (OA) pain. We examined that TG-C can regulate pain by inhibiting the upregulation of various pain mediators in both knee joint tissue and dorsal root ganglia (DRG) (n = 112) and alleviating pain behavior (n = 41) and neuronal hyperexcitability in DRG (n = 60), afferent nerve fiber (n = 24), and spinal cord (n = 35).
RESULTS
TG-C significantly alleviated pain-related behavior by restoring altered dynamic weight bearing and reduced mechanical threshold of the affected hindlimb. TG-C significantly suppressed the expression of nerve growth factor (NGF) and calcitonin gene-related peptide (CGRP) in inflamed joint tissue. TG-C significantly suppressed the upregulation of tropomyosin receptor kinase A (TrkA) and nerve injury/regeneration protein (GAP43) and activation of Iba1-positive microglial cells in DRG. TG-C significantly recovered neuronal hyperexcitability by restoring RMP and firing threshold and frequency of DRG neurons, attenuating firing rates of mechanosensitive C- or Aδ-nerve fiber innervating knee joint, and lowering increased miniature and evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) in the spinal cord.
CONCLUSION
Our results demonstrated that TG-C exerted potent analgesic effects in a rat MIA model of OA pain by inhibiting the upregulation of pain mediators and modulating neuronal sensitization.
Topics: Rats; Humans; Animals; Rats, Sprague-Dawley; Pain; Osteoarthritis; Analgesics; Neurons; Ganglia, Spinal; Disease Models, Animal
PubMed: 37544583
DOI: 10.1016/j.joca.2023.07.008 -
ELife Jan 2024Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and...
Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics. Moreover, we compared the human findings with previously published single-nucleus data of the adult mouse spinal cord, which revealed an overall similarity in the neuronal composition of the spinal cord between the two species while simultaneously highlighting some degree of heterogeneity. Additionally, we examined the sex differences in the spinal neuronal subclusters. Several genes, such as and , showed sex differences in motor neurons. Finally, we classified human dorsal root ganglia (DRG) neurons using spatial transcriptomics and explored the putative interactions between DRG and spinal cord neuronal subclusters. In summary, these results illustrate the complexity and diversity of spinal neurons in humans and provide an important resource for future research to explore the molecular mechanisms underlying spinal cord physiology and diseases.
Topics: Mice; Animals; Adult; Humans; Female; Male; Transcriptome; Spinal Cord; Motor Neurons; Gene Expression Profiling; Ganglia, Spinal; Sequence Analysis, RNA
PubMed: 38289829
DOI: 10.7554/eLife.92046 -
Neuroreport Dec 2023In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of...
In acute inflammatory demyelinating polyneuropathy (AIDP), myelin vesiculation mediated by complement activation contributes to nerve injury. Macrophage infiltration of the spinal roots has been demonstrated in AIDP, but its pathological significance remains uncertain. The present study aimed to investigate the role of macrophages in the pathogenic sequence of AIDP. A rabbit model of AIDP was induced by immunization with galactocerebroside. Immunostaining was performed to localize the macrophages and myelin injury. The rabbit developed tetraparesis with electrophysiological and pathological features of peripheral nerve demyelination. Immunostaining demonstrated colocalization of IgG antibodies, complement deposition and myelin injury apart from macrophages. Immunostaining and electron microscopy showed myelin injury preceded macrophage infiltration. There was significant disruption of voltage-gated sodium channel clusters at the nodes of Ranvier in the spinal roots. Macrophages acted may as scavengers to remove myelin debris following complement activation-mediated demyelination in the AIDP rabbit. Lesions at the node of Ranvier contribute to conduction failure and muscle weakness.
Topics: Animals; Rabbits; Myelin Sheath; Guillain-Barre Syndrome; Macrophages; Peripheral Nervous System Diseases; Spinal Nerve Roots
PubMed: 37942737
DOI: 10.1097/WNR.0000000000001964 -
Brain : a Journal of Neurology Apr 2024The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in...
The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer's disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.
Topics: Humans; Supranuclear Palsy, Progressive; tau Proteins; Pick Disease of the Brain; Alzheimer Disease; Tauopathies; Spinal Nerves; Biomarkers
PubMed: 37972275
DOI: 10.1093/brain/awad381 -
The Journal of Neuroscience : the... Jul 2023Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly...
Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP) and growth associated protein 43 (GAP43) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP. Multiple myeloma (MM) is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population.
Topics: Humans; Mice; Male; Animals; Multiple Myeloma; Quality of Life; Pain; Bone Diseases; Nerve Tissue; Ganglia, Spinal
PubMed: 37286351
DOI: 10.1523/JNEUROSCI.0404-23.2023 -
International Journal of Molecular... Mar 2024With the development of single-cell sequencing technology, the cellular composition of more and more tissues is being elucidated. As the whole nervous system has been... (Review)
Review
With the development of single-cell sequencing technology, the cellular composition of more and more tissues is being elucidated. As the whole nervous system has been extensively studied, the cellular composition of the peripheral nerve has gradually been revealed. By summarizing the current sequencing data, we compile the heterogeneities of cells that have been reported in the peripheral nerves, mainly the sciatic nerve. The cellular variability of Schwann cells, fibroblasts, immune cells, and endothelial cells during development and disease has been discussed in this review. The discovery of the architecture of peripheral nerves after injury benefits the understanding of cellular complexity in the nervous system, as well as the construction of tissue engineering nerves for nerve repair and axon regeneration.
Topics: Humans; Axons; Endothelial Cells; Nerve Regeneration; Schwann Cells; Sciatic Nerve; Peripheral Nerve Injuries
PubMed: 38542483
DOI: 10.3390/ijms25063511 -
Arquivos de Neuro-psiquiatria Sep 2023The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is...
BACKGROUND
The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is important for etiologic investigation and prognosis estimation. However, this task is often challenging in clinical practice. We hypothesize that F-wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP and SM, but not in SN.
OBJECTIVE
The aim of the present study was to determine whether F-waves are useful to distinguish SN from SP and SM.
METHODS
We selected 21 patients with SP (12 diabetes mellitus, 4 transthyretin familial amyloid polyneuropathy, 4 others), 22 with SM (22 leprosy), and 26 with SN (13 immune-mediated, 10 idiopathic, 3 others) according to clinical-electrophysiological-etiological criteria. For every subject, we collected data on height and performed 20 supramaximal distal stimuli in median, ulnar, peroneal, and tibial nerves, bilaterally, to record F-waves. Latencies (minimum and mean) and persistences were compared across groups using the Kruskal-Wallis and Bonferroni tests. -values < 0.05 were considered significant.
RESULTS
All groups were age, gender, and height-matched. Overall, there were no significant between-group differences regarding F-wave latencies. In contrast, F-wave persistence was able to stratify the groups. Peroneal F-wave persistence was higher, bilaterally, in the SN group compared to SM and SP ( < 0.05). In addition, F-waves persistence of the ulnar and tibial nerves was also helpful to separate SN from SP ( < 0.05).
CONCLUSION
F-wave persistence of the peroneal nerves might be an additional and useful diagnostic tool to differentiate peripheral sensory syndromes.
Topics: Humans; Neural Conduction; Median Nerve; Ulnar Nerve; Tibial Nerve; Peroneal Nerve; Polyneuropathies; Syndrome; Peripheral Nerves
PubMed: 37793400
DOI: 10.1055/s-0043-1772599 -
ARP Rheumatology 2023In this study, our primary aim was to compare ultrasound (US) findings of the median nerve between rheumatoid arthritis (RA) with carpal tunnel syndrome (CTS)...
AIM
In this study, our primary aim was to compare ultrasound (US) findings of the median nerve between rheumatoid arthritis (RA) with carpal tunnel syndrome (CTS) (RA(+)CTS), RA without CTS (RA(-)CTS) and healthy controls (HC) and to determine the optimal US parameters to detect the presence of CTS in RA patients.
METHODS
65 RA patients and 25 HC patients were included in this study. The diagnosis of CTS was made according to the clinical history and physical examination of the participants. Median nerve cross-sectional area(CSA) was measured at the carpal tunnel inlet(CTI), outlet(CTO), and forearm level by the US. In addition, anteroposterior(AP) and mediolateral(ML) diameters of the median nerve were measured. After the measurements, wrist-to-forearm ratio, wrist-to-forearm difference, and flattening ratio were calculated. The presence of tenosynovitis was investigated.
RESULTS
CTS was detected in 26(40.0%) of 65 RA patients who participated in the study. CTS was detected in 43(35.2%) of 122 wrists of 65 RA patients. CTI CSA, CTO CSA, forearm CSA, anteroposterior/mediolateral diameter, wrist-to-forearm ratio, wrist-to-forearm difference, and flattening ratio were significantly higher in RA(+)CTS than in RA(-)CTS and HC(p<0.01). In addition, CDAI and CTI CSA(r=0.322, p<0.01), CTO CSA(r=0.301, p<0.01), CTI-to-forearm ratio(r=0.345, p<0.001), CTI-to-forearm difference(r=0.362, p<0.01) and CTO-Forearm difference(r=0.304, p<0.01) moderate correlation was found between. The frequency of tenosynovitis was higher in wrists with CTS than in wrists without CTS (p<0.05).
CONCLUSION
While the presence of CTS in RA patients is sonographically evaluated, it may be useful to evaluate parameters such as CTI-to-forearm difference, ratio, and CTI ML diameter rather than just sticking to CTI CSA during diagnosis. Correlations of these parameters with disease activity can also be noted.
Topics: Humans; Carpal Tunnel Syndrome; Tenosynovitis; Ultrasonography; Median Nerve; Arthritis, Rheumatoid
PubMed: 38174753
DOI: No ID Found