Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,whic...Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.展开更多
Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management ...Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.展开更多
Oxaliplatin is a novel platinum compound with clinical activity against several solid tumors. It has been associated with sensory neuropathies and, rarely, a neuromyotonia-like hyperexcitability syndrome;a form of per...Oxaliplatin is a novel platinum compound with clinical activity against several solid tumors. It has been associated with sensory neuropathies and, rarely, a neuromyotonia-like hyperexcitability syndrome;a form of peripheral neuropathy manifested by tremor and twitching activity of muscles. We present a case of hyperexcitability syndrome developed during the treatment of stage III appendiceal adenocarcinoma with oxaliplatin-containing regimen and was successfully treated with Pregabalin.展开更多
Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of...Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of overexcited networks.Recent evidence has confirmed that thrombospondin-1(TSP-1),mainly secreted by astrocytes,is a critical cytokine that regulates synaptogenesis during epileptogenesis.Furthermore,numerous studies have reported that TSP-1 is also involved in other processes,such as angiogenesis,neuroinflammation,and regulation of Ca^(2+)homeostasis,which are closely associated with the occurrence and development of epilepsy.In this review,we summarize the potential contributions of TSP-1 to epilepsy development.展开更多
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. N...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.展开更多
Insomnia is one of the most frequently observed sleep disorders, affecting nearly 10% of the general population. It has multiple etiological factors. Recently, it has been reported that EEG abnormalities are associate...Insomnia is one of the most frequently observed sleep disorders, affecting nearly 10% of the general population. It has multiple etiological factors. Recently, it has been reported that EEG abnormalities are associated with insomnia in patients previously diagnosed as idiopathic insomniacs. In addition, transcranial magnetic stimulation (TMS) has shown to be effective in the treatment of disorders characterized by neural hyper-excitability. Method: In the present study, patients with insomnia and EEG abnormalities were submitted to slow repetitive trans-cranial magnetic stimulation, for 15 minutes daily during 10 days. Polysomnographic recordings were performed before and after TMS. Results: The results indicate that the presence of EEG abnormalities significantly decreased after TMS. In addition, most of the sleep parameters showed significant improvement. Conclusions: These data support the notion that TMS is a reliable therapeutic tool for patients affected with abnormalities linked to neuronal hyper-excitability.展开更多
Neuromyotonia is a neuromuscular hyperexitability disorder characterized by muscle stiffness caused by continuous muscle fiber activity. It is an immune mediated disorder with elevated antibody level against presynapt...Neuromyotonia is a neuromuscular hyperexitability disorder characterized by muscle stiffness caused by continuous muscle fiber activity. It is an immune mediated disorder with elevated antibody level against presynaptic, voltage gated potassium channels, either as isolation or as a paraneoplastic process. Symptoms usually include muscle twitching during rest (myokymia), cramps, peudomyotonia (delayed relaxation), increased sweating, and sometimes motor weakness. In this case report, we present a seventy-two years old man who presented with pain in both thighs for one month. It gradually became worse to involve feet and chest. His brain CT scan showed features of brain atrophy. EMG showed fasciculation along neuromyotonic discharges with characteristic wave in frequency and amplitude typical of Isaacs’ syndrome. Potassium channel antibodies were very high. Diagnosis of Isaacs’ syndrome was made. He was followed up for two months with treatment by three-day course of methyl prednisolone followed by oral steroid and methotrexate with much improvement. This is the first case of Isaacs’ syndrome in Kurdistan.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that is characterized by the selectivedegeneration of upper motor neurons and lower spinal motor neurons, resulting in the progressive paralysi...Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that is characterized by the selectivedegeneration of upper motor neurons and lower spinal motor neurons, resulting in the progressive paralysis of allvoluntary muscles. Approximately 10 % of ALS cases are linked to known genetic mutations, with the remaining 90 %of cases being sporadic. While the primary pathology in ALS is the selective death of upper and lower motor neurons,numerous studies indicate that an imbalance in whole body and/or cellular metabolism influences the rate ofprogression of disease. This review summarizes current research surrounding the impact of impaired metabolicphysiology in ALS. We extend ideas to consider prospects that lie ahead in terms of how metabolic alterations mayimpact the selective degeneration of neurons in ALS and how targeting of adenosine triphosphate-sensitive potassium(K_(ATP)) channels may represent a promising approach for obtaining neuroprotection in ALS.展开更多
Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC);however, post-progression survival (PPS) has not been well characteriz...Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC);however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment. Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment. Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥+1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the Child-Pugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months(HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00). Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.展开更多
Isaacs' syndrome is a disease characterized by nerve hyperexcitability. The patients are commonly treated with symptomatic therapies and immunomodulatory approaches, but no clinical trials are available to date. H...Isaacs' syndrome is a disease characterized by nerve hyperexcitability. The patients are commonly treated with symptomatic therapies and immunomodulatory approaches, but no clinical trials are available to date. Here, we report the case of an anti-Caspr2-positive patient, presenting with continuous muscle twitches and diffuse muscle pain. He experienced a nearly complete clinical response to intravenous high-dose steroids combined with plasma exchange, sustained for at least 1 year. Our experience suggests that methylprednisolone 1000 mg/day × 5 days and consecutive tapering followed by plasma exchange may be efficient and well tolerated in patient with Isaacs' syndrome due to anti-Caspr2 antibodies.展开更多
基金supported by the National Natural Science Foundation of China(81901119 and 81901142)Special Project on Innovation and Generation of Medical Support Capacity,and the Natural Science Foundation of Tibet(XZ2019ZRG-119),China.
文摘Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus(LEC-DG)are considered responsible for the chronification of pain.However,the underlying alterations in fan cells,which are the predominant neurons in the LEC that project to the DG,remain elusive.Here,we investigated possible mechanisms using a rat model of complete Freund’s adjuvant(CFA)-induced inflammatory pain.We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents(Ih),which led to the hyperexcitability of LEC fan cells of CFA slices.This phenomenon was attenuated in CFA slices by activating dopamine D2,but not D1,receptors.Chemogenetic activation of the ventral tegmental area-LEC projection had a D2 receptor-dependent analgesic effect.Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity,and this effect was attenuated by pre-activation of the Ih.Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.
基金supported in part by the NIH DA039530(to XJ)a grant from the CURE Epilepsy Foundation(to XJ)
文摘Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.
文摘Oxaliplatin is a novel platinum compound with clinical activity against several solid tumors. It has been associated with sensory neuropathies and, rarely, a neuromyotonia-like hyperexcitability syndrome;a form of peripheral neuropathy manifested by tremor and twitching activity of muscles. We present a case of hyperexcitability syndrome developed during the treatment of stage III appendiceal adenocarcinoma with oxaliplatin-containing regimen and was successfully treated with Pregabalin.
基金supported by the Natural Science Foundation of Shandong Province(ZR2021MH034 and ZR2022MH059)the National Natural Science Foundation of China(81573412).We’d like to thank Editage for English language editing.
文摘Epilepsy is a neural network disorder caused by uncontrolled neuronal hyperexcitability induced by an imbalance between excitatory and inhibitory networks.Abnormal synaptogenesis plays a vital role in the formation of overexcited networks.Recent evidence has confirmed that thrombospondin-1(TSP-1),mainly secreted by astrocytes,is a critical cytokine that regulates synaptogenesis during epileptogenesis.Furthermore,numerous studies have reported that TSP-1 is also involved in other processes,such as angiogenesis,neuroinflammation,and regulation of Ca^(2+)homeostasis,which are closely associated with the occurrence and development of epilepsy.In this review,we summarize the potential contributions of TSP-1 to epilepsy development.
基金supported in part by National Institutes of Health Grants NS045594,NS055860,and AR068989 to J.M.Z.
文摘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.
文摘Insomnia is one of the most frequently observed sleep disorders, affecting nearly 10% of the general population. It has multiple etiological factors. Recently, it has been reported that EEG abnormalities are associated with insomnia in patients previously diagnosed as idiopathic insomniacs. In addition, transcranial magnetic stimulation (TMS) has shown to be effective in the treatment of disorders characterized by neural hyper-excitability. Method: In the present study, patients with insomnia and EEG abnormalities were submitted to slow repetitive trans-cranial magnetic stimulation, for 15 minutes daily during 10 days. Polysomnographic recordings were performed before and after TMS. Results: The results indicate that the presence of EEG abnormalities significantly decreased after TMS. In addition, most of the sleep parameters showed significant improvement. Conclusions: These data support the notion that TMS is a reliable therapeutic tool for patients affected with abnormalities linked to neuronal hyper-excitability.
文摘Neuromyotonia is a neuromuscular hyperexitability disorder characterized by muscle stiffness caused by continuous muscle fiber activity. It is an immune mediated disorder with elevated antibody level against presynaptic, voltage gated potassium channels, either as isolation or as a paraneoplastic process. Symptoms usually include muscle twitching during rest (myokymia), cramps, peudomyotonia (delayed relaxation), increased sweating, and sometimes motor weakness. In this case report, we present a seventy-two years old man who presented with pain in both thighs for one month. It gradually became worse to involve feet and chest. His brain CT scan showed features of brain atrophy. EMG showed fasciculation along neuromyotonic discharges with characteristic wave in frequency and amplitude typical of Isaacs’ syndrome. Potassium channel antibodies were very high. Diagnosis of Isaacs’ syndrome was made. He was followed up for two months with treatment by three-day course of methyl prednisolone followed by oral steroid and methotrexate with much improvement. This is the first case of Isaacs’ syndrome in Kurdistan.
基金The authors dedicate this manuscript in memory of Mr Bob DelaneySTN acknowledges the support of the Queensland Brain Institute,the Royal Brisbane and Women’s Hospital,the MND and Me Foundation+1 种基金the School of Biomedical Sciences,and a Bob Delaney MND research grant from the MNDRIAFJS acknowledges the support of the University of Queensland Centre for Clinical Research,the School of Biomedical Sciences,and a Cunningham Collaboration research grant from the MNDRIA.
文摘Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that is characterized by the selectivedegeneration of upper motor neurons and lower spinal motor neurons, resulting in the progressive paralysis of allvoluntary muscles. Approximately 10 % of ALS cases are linked to known genetic mutations, with the remaining 90 %of cases being sporadic. While the primary pathology in ALS is the selective death of upper and lower motor neurons,numerous studies indicate that an imbalance in whole body and/or cellular metabolism influences the rate ofprogression of disease. This review summarizes current research surrounding the impact of impaired metabolicphysiology in ALS. We extend ideas to consider prospects that lie ahead in terms of how metabolic alterations mayimpact the selective degeneration of neurons in ALS and how targeting of adenosine triphosphate-sensitive potassium(K_(ATP)) channels may represent a promising approach for obtaining neuroprotection in ALS.
文摘Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC);however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment. Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment. Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥+1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the Child-Pugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months(HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00). Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.
文摘Isaacs' syndrome is a disease characterized by nerve hyperexcitability. The patients are commonly treated with symptomatic therapies and immunomodulatory approaches, but no clinical trials are available to date. Here, we report the case of an anti-Caspr2-positive patient, presenting with continuous muscle twitches and diffuse muscle pain. He experienced a nearly complete clinical response to intravenous high-dose steroids combined with plasma exchange, sustained for at least 1 year. Our experience suggests that methylprednisolone 1000 mg/day × 5 days and consecutive tapering followed by plasma exchange may be efficient and well tolerated in patient with Isaacs' syndrome due to anti-Caspr2 antibodies.
