The brain's septum helps prevent epileptic seizures by inducing rhythmical electrical activity in the circuits of another area of the brain known as the hippocampus, according to a new study in the Journal of Neurophysiology. The researchers found that, by imposing a normal "theta" rhythm on chronically epileptic rats, they could reduce epileptic seizures by 86-97 percent.
The study "Septo-hippocampal networks in chronically epileptic rats: Potential antiepileptic effects of theta rhythm generation," by Luis V. Colom, Antonio García-Hernández, Maria T. Castañeda, Miriam G. Perez-Cordova and Emilio R. Garrido-Sanabria, The University of Texas at Brownsville/Texas Southmost College, appears in the June issue of the Journal of Neurophysiology, published by The American Physiological Society.
The septum acts as the conductor, orchestrating brain impulses as they pass from the brain stem through the septum and on to the hippocampus, said the study's lead researcher, Luis V. Colom, of the University of Texas at Brownsville/Texas Southmost College. The hippocampus is a part of the brain that plays a role in memory, spatial navigation and sensory motor integration, among other functions.
Normally, the hippocampus oscillates at a frequency of 3-12 Hz, a frequency that is called the theta rhythm, Colom explained. Oscillations at theta frequency are important in processing and storing relevant sensory information and appears important to certain memory processes.
"My hypothesis is that the septum keeps the electrical activity of neurons within certain areas of the brain working within normal ranges," Colom said. "By keeping the neurons firing normally, the septum inhibits neuronal hyperexcitability, such as epilepsy, and hypoexcitablity, such as Alzheimer's disease." In addition, septal impulses may help to maintain the anatomical integrity of other brain structures.
The brain's neurons are constantly chatting with each other through electrical impulses but it's a chatter that has to be kept in check, or it can snowball into an electrical storm that marks an epileptic seizure, Colom explained. Epilepsy affects an estimated 4 million Americans, he said.
There are a variety of ways to induce neurons to fire rhythmically, including, interestingly, engaging in stimulating cognitive activities.
Scientists and medical providers know that brain lesions, skull fractures, and high fever are among the factors that can produce epilepsy. But in most cases, there is no obvious cause, Colom said.
Colom's lifelong interest in how the brain works has led him to study epilepsy and Alzheimer's disease. People who suffer Alzheimer's, a degenerative disorder that affects various brain regions including the septum, have a higher risk of epileptic seizures, in the 10-22 percent range, he noted.
Previous studies have suggested that the septum plays an antiepileptic role. But in this study, Colom et al. showed what happens among the septum's neurons during epilepsy, knowledge that is important to understanding the mechanism underlying seizure generation. This line of inquiry could one day lead to the development of anti-epileptic drugs, said Colom.
Theta disrupted in epileptic rats
In this study, the researchers induced epilepsy by injecting anesthetized rats with pilocarpine, a drug that excites the brain's neurons and activates the synapses between the neurons to produce status epilepticus, in which sustained seizures occur. The rats received diazepam three hours later to interrupt the seizures, but became chronically epileptic, experiencing 3-5 seizures weekly.
The researchers then used electrodes to record individual neurons within the septum of the anesthetized rats to see what happened within the nerve pathways. They found that the epileptic rats suffered significantly more epileptic episodes when the brain did not have the proper theta rhythm.
The researchers also found that when the theta rhythm was induced in the rats, it reduced epileptic discharges 86-97 percent. (The researchers induced theta in one of three ways – by regulating the rats' anesthesia, by stimulating the septum directly with an injection of carbachol, or by using the sensory stimulation method of pinching the tail.)
The amplitude and frequency of the theta rhythm of the epileptic rats was significantly altered compared to the control group. In effect, the theta rhythm became faster and more jittery. Also, the septal neurons of epileptic rats doubled their firing rates in relation to the controls, from about 14 spikes per second to about 29 spikes per second.
Two promising lines of research
Colom and his fellow researchers at the University of Texas at Brownsville/Texas Southmost College are looking at two different approaches to stopping epilepsy. One group is taking the approach of making the neurons less excitable (this effort is led by Emilio Garrido-Sanabria and Masoud Zarei). Colom's group is looking for a new treatment that will focus on inducing theta.
"The understanding of the theta rhythm's anti-epileptic effect at the cellular and molecular levels may result in novel therapeutic approaches dedicated to protect the brain against abnormal excitability states," the authors wrote.
Although this research gives more insight into how epilepsy occurs, a cure is still years away. "But I would say there is hope," Colom said. "We want to offer people with epilepsy new options," he said, but progress will depend upon funding, he added.
The researchers will repeat the study using animals that are awake and mobile, though it is more difficult to record the brain's discharges in freely moving animals. Then the research can move to humans.
Source and funding
"Septo-hippocampal networks in chronically epileptic rats: potential antiepileptic effects of theta rhythm generation," by Luis V. Colom, Antonio García-Hernández, Maria T. Castañeda, Miriam G. Perez-Cordova and Emilio R. Garrido-Sanabria, Department of Biological Sciences and Center for Biomedical Studies, The University of Texas at Brownsville/Texas Southmost College, Brownsville. The study appears in the June issue of the Journal of Neurophysiology published by The American Physiological Society.
The study was funded by National Institutes of Health grants to Colom, and to Colom and Garrido-Sanabria.
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