"A migraine is an abnormal state of the brain where the brain has become hyperexcitable to stimuli," said Dr. Amy Gelfand, assistant professor of neurology at the University of California, San Francisco.
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As this channel is important for action potential generation in neurons, the Q1489K mutant is expected to result in hyperexcitable neurons.
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There was no good animal test to screen for the ataraxic effects, because the antihistamines made laboratory animals hyperexcitable, not calm.
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Plasticity in CA1 pyramidal cells and interneurons has been related to CA1 roles in epileptogenesis. CA1 is hyperexcitable when the CA3 region is damaged. Reduction of both GABAA and GABAB IPSPs occurs. GABA interneurons, though intact, become less easily activated.
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Seizures in the developing brain are more common than in a mature brain for several reasons. First, the developing brain is hyperexcitable due to excess in excitatory glutaminergic neurons and immaturity of inhibitory gamma-amino butyric acid (GABA) neurons. Preterm infants are at especially high risk for seizures for this reason.
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Evidence supports the theory that amyotrophic lateral sclerosis causes anterograde dengeneration of corticomotoneurons. The hyperexcitable corticomotoneurons drive anterior horn cells into metabolic deficit, resulting in cell degeneration and death. If this exocitotoxic process occurs rapidly, it results in a more rapid death of anterior horn cells resulting in lower motor neuron disease.
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This reorganization of neural networks may make them more excitable. Neurons that are in a hyperexcitable state due to trauma may create an epileptic focus in the brain that leads to seizures. In addition, an increase in neurons' excitability may accompany loss of inhibitory neurons that normally serve to reduce the likelihood that other neurons will fire; these changes may also produce PTE.
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1995–1996 (died of heart attack). "Whizzer" aka "Hetherbull", also owned by Chris Getman, was donated by Yale alumnus and bulldog breeder Bob Hetherington and was a descendant of 52 time best-in-show winner Hetherbull Arrogant Frigott; unfortunately, he possessed a temperament so hyperexcitable that he died in office from a heart attack, and was succeeded by his predecessor and housemate.
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Her work is also relevant to understanding the mechanisms of schizophrenia and amyotrophic lateral sclerosis (Lou Gehrig's disease).Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. van Zundert B, Peuscher MH, Hynynen M, Chen A, Neve RL, Brown RH Jr, Constantine-Paton M, Bellingham MC. J Neurosci. 2008 Oct 22;28(43):10864-74.
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Changes that occur during epileptogenesis are poorly understood but are thought to include cell death, axonal sprouting, reorganization of neural networks, alterations in the release of neurotransmitters, and neurogenesis. These changes cause neurons to become hyperexcitable and can lead to spontaneous seizures. Brain regions that are highly sensitive to insults and can cause epileptogenesis include temporal lobe structures such as the hippocampus, the amygdala, and the piriform cortex.
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G9a and ΔFosB share many of the same gene targets. Figure 4: Epigenetic basis of drug regulation of gene expression In addition to its role in the nucleus accumbens, G9a play a critical role in the development and the maintenance of neuropathic pain . Following peripheral nerve injury, G9a regulates the expression of +600 genes in the dorsal root ganglia. This transcriptomic change reprograms the sensory neurons to a hyperexcitable state leading to mechanical pain hypersensitivity.
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Lacosamide administration results in the inhibition of repetitive neuronal firing, the stabilization of hyperexcitable neuronal membranes, and the reduction of long-term channel availability, but does not affect physiological function. Lacosamide has a dual mechanism of action. It also modulates collapsin response mediator protein 2 (CRMP-2), preventing the formation of abnormal neuronal connections in the brain. Lacosamide does not affect AMPA, kainate, NMDA, GABAA, GABAB or a variety of dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid receptors and does not block potassium or calcium currents.
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Absence of this reflex in instances where spinal shock is not suspected could indicate a lesion or injury of the conus medullaris or sacral nerve roots. There is an association between hyperexcitable bulbocavernosus reflex resulting from stimulation of the prostatic urethra and premature ejaculation. The bulbocavernosus reflex has been found to be delayed or absent at a higher rate than the general population in diabetic men with complaints of erectile impotence, and men whose penises have been circumcised or have permanent retraction of the foreskin behind the glans penis.
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After a brain injury occurs, there is frequently a "silent" or "latent period" lasting months or years in which seizures do not occur; Canadian neurosurgeon Wilder Penfield called this time between injury and seizure "a silent period of strange ripening". During this latent period, changes in the physiology of the brain result in the development of epilepsy. This process, during which hyperexcitable neural networks form, is referred to as epileptogenesis. If researchers come to better understand epileptogenesis, the latent period may allow healthcare providers to interfere with the development of epilepsy or to reduce its severity.
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In addition to chemical processes, the physical structure of neurons in the brain may be altered. In acquired epilepsy in both humans and animal models, pyramidal neurons are lost, and new synapses are formed. Hyperexcitability, a characteristic feature of epileptogenesis in which the likelihood that neural networks will be activated is increased, may be due to loss of inhibitory neurons, such as GABAergic interneurons, that would normally balance out the excitability of other neurons. Neuronal circuits that are epileptic are known for being hyperexcitable and for lacking the normal balance of glutamatergic neurons (those that usually increase excitation) and GABAergic ones (those that decrease it).
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Lowenstein's recent clinical and research interests include the genetic factors thought to underlie many forms of epilepsies (idiopathic epilepsies) and the management and treatment of patients with status epilepticus (unusually prolonged seizures). His laboratory studies (carried out from 1989 to 2002) have addressed the fundamental mechanisms of neuronal network remodeling that occur during epileptogenesis; i.e. the process in which a normal network transforms into a hyperexcitable network capable of producing or relaying seizure activity. The main efforts of his research group focused on the various forms of cellular reorganization that are observed in humans with temporal lobe epilepsy, and the parallels between reorganization in the adult nervous system and normal developmental processes.
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