Peripheral nerve hyperexcitability syndromes / 中华神经科杂志

Peripheral nerve hyperexcitability syndromes (PNHS) encompass a spectrum of a heterogeneous condition with clinical as well as electrophysiological manifestations of peripheral nerve hyperexcitability. The PNHS consist of Isaacs syndrome, Morvan syndrome and Cramp-fasciculation syndrome, which cause widespread symptoms and signs while without evident peripheral nerve disease. Probably the most well-known condition of PNHS is Isaacs syndrome, often called acquired neuromyotonia. Clinical symptoms of PNHS are characterized by muscle twitching, cramps, stiffness, and neuropathic pain. The electrophysiological findings that are very useful in the diagnosis of PNHS are spontaneous myokymic, neuromyotonic, and cramp discharges. An overview of the history, clinical manifestations, pathophysiology, electrophysiological findings and management of PNHS is presented.

Inflammatory Changes in Paravertebral Sympathetic Ganglia in Two Rat Pain Models / 神经科学通报·英文版

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.

The Puzzling Case of Hyperexcitability in Amyotrophic Lateral Sclerosis

The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na+ conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research.

La abstinencia al GABA: 20 años de un modelo de hiperexcitabilidad neuronal / The GABA withdrawal: 20 years of a hyperexcitability neuronal model

The sudden interruption of increase in the concentration of the synaptic cleft of the inhibitory neurotransmitter in the cerebral cortex, the γ-amino butyric acid (GABA), determines an increase in the neuronal activity. GABA withdrawal is a heuristic analogy with withdrawal symptoms developed by other GABA receptor-agonists such as benzodiazepines, barbiturates, neurosteroids and alcohol. GABA withdrawal is a model of neuronal hyperexcitability in complete animal validated by EEG, in which complex spikes-wide of high- frequency and amplitude appear. In brain slices, GABA withdrawal was identified by increased firing synchronization of pyramidal neurons and by changes in the active properties of the neuronal membrane. The increase in neuronal excitability of this model is the result of dynamic changes in consecutive pre- and post-synaptic components such as: a) the decrease in the synthesis/release of GABA; b) the decrease in the expression and composition of GABA A receptors associated with increased calcium entry into the cell. This model is an excellent bioassay to study partial epilepsy, epilepsy refractory to drug treatment and a model to reverse or prevent the generation of abstinence from different drugs.

La interrupción abrupta del incremento de la concentración en el espacio sináptico del neurotransmisor inhibitorio de la corteza cerebral, el ácido γ-amino butírico (GABA), condiciona un incremento en la actividad de las neuronas. La abstinencia al GABA es una analogía heurística con los síndromes de abstinencia desarrollados por otros agonistas del receptor GABA A como: las benzodiacepinas, los barbitúricos, los neuroesteroides y el alcohol. La abstinencia a GABA es un modelo de hiperexcitabilidad neuronal validado en animal íntegro por medio del EEG, en el cual aparecen complejos espigas-onda de amplia frecuencia y amplitud. En rebanadas de cerebro se identifica por incremento en la sincronización de disparo de neuronas piramidales y por cambios en las propiedades activas de la membrana neuronal. El incremento de la excitabilidad neuronal de este modelo es la consecuencia de cambios dinámicos y consecutivos en los componentes presinápticos y postsinápticos como son: a) la disminución en la síntesis/liberación de GABA; b) la disminución en la expresión y la composición de receptores GABA asociado al incremento en la entrada de calcio a la célula. Este modelo es un excelente bioensayo para estudiar epilepsias parciales, epilepsias refractarias a tratamiento farmacológico y un modelo para revertir o prevenir la generación de la abstinencia de diferentes drogas.

Epilepsia del lóbulo temporal y las neuronas hipocampales de las áreas CA1 y CA3 / Temporal lobe epilepsy and hippocampal neurons from areas CA1 and CA3

La epilepsia del lóbulo temporal es la forma más común de epilepsia que padece el ser humano. El sustrato fisiopatológico que la caracteriza es la esclerosis del hipocampo, que se distingue por pérdida neuronal, gliosis y disminución del volumen del hipocampo y áreas vecinas como la amígdala, el giro parahipocámpico y la corteza entorrinal. Lo anterior ocasiona atrofia y esclerosis del hilus del giro dentado y de las áreas CA1 y CA3 del hipocampo. Además se establece cierta reorganización de las vías neuronales que favorecen la neoespinogénesis, la morfogénesis, la neosinaptogénesis y la neurogénesis, con desarrollo aberrante de células y fibras, que contribuyen a la formación de un foco cuyo componente neuronal muestra un significativo aumento en la excitabilidad. El interés por entender el proceso de la epileptogénesis ha motivado al diseño de modelos de este tipo de epilepsia en animales de experimentación. La epileptogénesis evoluciona en el tiempo y muestra que la reorganización dinámica de las vías neuronales establece una red neuronal con cambios funcionales y anatómicos muy significativos. En este trabajo se realiza una revisión de la información obtenida por estudios electrofisiológicos que combinan el marcaje celular mediante el registro intra o extracelular en el hipocampo y en particular de las áreas CA1 y CA3 involucradas estrechamente con la epileptogénesis.

Temporal Lobe Epilepsy is the most common form of human epilepsy. Hippocampal sclerosis, neuronal loss, gliosis and hippocampal volume reduction are the representative changes of this pathology. Also some other near areas like amygdala, gyrus parahipocampal and entorrinal cortex are affected. Furthermore the neural circuits undergo activity-dependent reorganization during epileptogenesis. This brain circuits remodeling include neuronal loss (acute and delayed), neurogenesis, gliosis, plasticity (axonal and dendritic), inflammation and molecular reorganization. Two significant changes are evident, aberrant sprouting of granule cell axons in the dentate gyrus and hilar ectopic granular cells. Because temporal lobe epilepsy commonly develops after brain injury, most experimental animal models involve use of this factor. The pilocarpine-induced status epilepticus rat model may be the most widely used model of temporal lobe epilepsy. In the present work, we review the experimental support for seizure-induced plasticity in neural circuits, and then turn to evidence that seizure-induced plasticity occurs in human temporal-lobe.

Neuronal Hyperexcitability Mediates Below-Level Central Neuropathic Pain after Spinal Cord Injury in Rats / 한국실험동물학회지

Spinal cord injury often leads to central neuropathic pain syndromes, such as allodynic and hyperalgesic behaviors. Electrophysiologically, spinal dorsal horn neurons show enhanced activity to non-noxious and noxious stimuli as well as increased spontaneous activity following spinal cord injury, which often called hyperexcitability or central sensitization. Under hyperexcitable states, spinal neurons lose their ability of discrimination and encoding somatosensory information followed by abnormal somatosensory recognition to non-noxious and noxious stimuli. In the present review, we summarize a variety of pathophysiological mechanisms of neuronal hyperexcitability for treating or preventing central neuropathic pain syndrome following spinal cord injury.

Cerebrovascular Reactivity According to Migraine Subtypes: with or without Aura

BACKGROUND: In migraine studies, the cerebrovascular reactivity (CVR) using a transcranial Doppler (TCD) has been investigated to elucidate the nature and role of the vascular response. However, past studies have not comprised the posterior circulation including functionally important brainstem structures. The purpose of this study was to compare the simultaneous CVRs between the middle cerebral artery (MCA) and basilar artery (BA) in migraine patients with and without aura, by means of a power motion mode Doppler (PMD) with an anterior-posterior probes fixating device. METHODS: Thirty-six consecutive patients with migranes [15 migraine patients with aura (MA) and 21 migraine patients without aura (MWA)] were compared with 29 healthy volunteers. CVR [(Vmax-Vbase)x100/Vbase] was evaluated by the re-breathing technique. TCD was performed as two steps. First, the velocities and spectra of the MCAs through both temporal windows were simultaneously monitored. Second, those were simultaneously monitored between MCA and BA. RESULT: There were no significant differences in age, sex, baseline hemodynamic values (blood pressure, heart rate), and those of the baseline mean flow velocity and CVR of TCD between the migraine patients and the controls. However, the CVR of the BA significantly differed between the MA and the MWA (39.4+/-13.7 vs 64.6+/-25.4%; p=0.001), among MA, MWA, and controls (39.4+/-13.7, 64.6+/-25.4, 45.6+/-14.9%; p<0.001). CONCLUSIONS: CVR of BA was entirely different according to migraine subtypes: with or without aura. Our study suggests that MWA and MWOA seem to be distinct disorders in terms of different vascular responses of the BA during the interictal period.

Effects of the Divalproex Sodium on Cortical Hyperexcitability in Migraine Patients Chung-Ang University,Pildong Hospital

BACKGROUND: Cortical hyperexcitability is proposed to be the putative basis for the physiological disturbances in migraine. Recent studies have demonstrated that divalproex sodium effectively prevents migraine. The cortical silent period (CSP) elicited by transcranial magnetic stimulation (TMS) reflects the cortical inhibition of the central motor pathway. METHODS: We studied the CSP of both first dorsal interossei muscles evoked by TMS in 15 migraine patients and 15 normal subjects. As a prophylactic therapy, 15 migraine patients were treated with divalproex sodium 500~750 mg/day. After 3 months, we studied the CSP in migraine patients for the purpose of comparing with results before medication. RESULTS: The CSP was shorter in migraine patients than in controls (135.8+/-27.8 msec vs 203.7+/-32.2 msec, p<0.001). After treatment with divalproex sodium, the CSP was significantly prolonged in migraine patients (196.9+/-31.0msec, p=0.001). CONCLUSIONS: The shortened CSP in migraine patients suggests increased excitability of the cortical neuron in migraine. The prolonged CSP after medication in migraine patients suggests that the divalproex sodium may play a role in the prophylaxis of migraine by decreasing cortical neuronal hyperexcitability. (J Korean Neurol Assoc 19(5):489~493, 2001)

A Study on Synkinetic Behavior in Hemifacial Spasm Using Blink Reflex Methodology

BACKGROUND AND PURPOSE: Hemifacial spasm is clinically characterized by involuntary co-contraction of unilateral facial muscles innervated by facial nerve and presence of synkinetic response between facial muscles innervated by different branches of facial nerve is considered as the electrophysiological hallmark of this disease. We performed this study in order to analyse and thereby to approach the pathogenesis of these synkinetic responses in detail. METHODS: Blink reflex test was applied to the 21 patients with hemifacial spasm. With some modification of conventional blink reflex methodology, synkinetic responses between orbicularis oculi and orbicularis oris muscles were recorded on both affected and unaffected sides. RESULTS: Among 21 patients, 10( 47.6% ) showed synkinetic responses both on affected and unaffected side, 8( 38.1% ) only on affected side, and 3( 14.3% ) did not show any evidence of synkinesis on either side. CONCLUSION: These findings could be considered as additional supportive evidence that the facial neuronal hyperexcitability is working in hemifacial spasm as synkinesis on unaffected side cannot be explained solely by peripheral mechanism. Further research on change of synkinetic behavior after microvascular decompression surgery seems to be needed.

Somatosensory Evoked Potential (SEP) in Patients with Primary Premature Ejaculation / 대한비뇨기과학회지

Premature ejaculation (PE) has been thought to be psychological in the majority of patients. With few exceptions, organic conditions are rarely implicated. We investigated the possible role of sensory function in patients with primary PE to determine whether or not there is an etiologic basis for PE: We performed somatosensory evoked potentials (SEP) from the penis in 34 patients with primary PE and in 30 normally potent men. The latencies and amplitudes of the evoked potentials were measured by two different places in stimuli, with one at penile shaft (DNSEP) and the other at the glans penis (GPSEP). The mean latency of DNSEP was 1.51 msec. shorter in the patient group than the normal subjects, and the mean latency of GPSEP was significantly shorter (6.80 msec.) in the patient group than the normal subjects. The mean amplitude of GPSEP was lower than that of DNSEP in both groups. However, the mean amplitudes of DNSEP and GPSEP in patients with PE were significantly higher than that of normal subjects. With these results we conclude that patients with PE have a glans penile hyperexcitability. A glans penile hyperexcitability may give rise to an uncontrolled ejaculation, which is thought to be an organic implication for PE.

Sensory evoked potential and effect of SS-cream in premature ejaculation

The cause of premature ejaculation (PE) has been thought to be psychological in the majority of patients but we investigated penile hypersensitivity for an organic basis of PE. For another organic basis of PE, we have suggested hyperexcitability of the ejaculation center. SS-cream is a topical agent containing 9 oriental herbs for treating PE. Clinically SS-cream has been effective in the treatment of PE. Therefore, in order to implicate the organic basis of PE and realize the effect of SS-cream on PE, we investigated the somatosensory evoked potential (SEP) in patients with PE(16 cases) and the effects of SS-cream on SEP for treating PE. The latencies and amplitudes of the evoked responses were measured by two different places in stimuli, one was on the penile shaft with ring electrode and the other on the glans penis with a surface electrode. The latency of SEP stimulated at the glans penis was significantly longer than that stimulated at the penile shaft (p 0.05). The amplitudes of the evoked responses stimulated at the glans penis were significantly higher than those stimulated at penile shaft (p< 0.05). And both these amplitudes were significantly reduced with the application of SS-cream (p< 0.05). With these result, we can suggest that the patients with PE have glans penile hyperexcitability and it provides further implications for an organic basis of PE, SEP stimulated at the glans penis can be a very useful method to evaluate PE, along with SEP stimulated a penile shaft and SS-cream prolongs the sensory conduction and reduces the penile hyperexcitability of the patient with PE.