Uncovering why some seizures cause loss of consciousness

Posted Yesterday

In temporal lobe epilepsy — a common and debilitating form of the disorder — seizures often cause those affected to lose consciousness. But why that happens has been unclear.

Brain stimulation – artistic interpretation.

In a new study, Yale researchers show that levels of acetylcholine, a neurotransmitter that plays a key role in keeping people awake, decrease in the brains of mice when they have seizures that disrupt their behavior. The finding points to new therapeutic opportunities for a disorder without widely effective existing treatment options.

“Available anti-seizure medicines don’t work for about a third of people with temporal lobe epilepsy,” said Dr. Hal Blumenfeld, the Mark Loughridge and Michele Williams Professor of Neurology at Yale School of Medicine. “And while some of those individuals may respond to surgery, others won’t. So there are a few hundred thousand people in the United States alone for whom treatment just doesn’t work.”

Temporal lobe epilepsy affects around 50 million people worldwide and loss of consciousness is among the most disabling aspects of the disorder, said Blumenfeld, senior author of the study, published recently in the journal Cell Reports. If the cause of loss of consciousness could be better understood, new treatments may be able to help prevent it.

For the study, the researchers developed a mouse model of temporal lobe epilepsy in which seizures could be triggered in the same area of the brain as they occur in humans with the disorder. To test whether the seizures affected consciousness, the researchers observed whether seizures changed the mice’s behavior.

They found that, after a seizure was triggered, mice trained to lick a water dispenser after hearing a particular tone licked far less and mice running on a wheel ran less.

“This is the first time that it has been shown in a mouse model that these kinds of seizures, which resemble temporal lobe seizures, have a similar effect on mice as they do in humans,” said Lim-Anna Sieu, lead author of the study and a research associate in Blumenfeld’s lab. “When people lose consciousness with these seizures, they’ll stop whatever they’re doing and won’t be able to respond to things happening in their environment. It’s what we saw in the mice as well.”

They also saw that when seizures were triggered in the mice, brain activity in the cortex resembled that of deep sleep — despite the cortex not being where the seizures occurred. This has also been observed in humans.

“We wanted to figure out why the cortex was going to sleep,” said Blumenfeld.

In people and in the mouse model, not every seizure leads to loss of consciousness or behavioral effects. In comparing the instances where seizures changed mouse behavior with those that didn’t, the researchers found that activity in the cortex more closely resembled a sleep state when seizures affected water licking and running than when they didn’t.

Further, the cortex had significantly lower levels of acetylcholine, a neurotransmitter that is critical for keeping people awake and alert, during and after seizures that affected mouse behavior. The seizures also reduced the short burst of acetylcholine that typically occurred when the tone signaled water was available, meaning acetylcholine was reduced on both short and long timescales.

“What this suggests is that, while these seizures are occurring in the temporal lobe, they are also shutting off circuits deep in the brain responsible for keeping us awake,” said Blumenfeld. “This gives us hope that if we can understand what causes loss of consciousness in temporal lobe seizures, then we can come up with treatments that prevent that loss and reduce some of the burden of this disorder.”

To that end, the researchers are working to uncover why the acetylcholine reduction occurs — is it because the brain isn’t hitting the gas pedal, as it were, or because it’s going too heavy on the brakes? They’re also conducting a clinical trial in which brain stimulation is triggered when patients with temporal lobe epilepsy experience a seizure — an effort to try to either stop a seizure once it starts or to prevent loss of consciousness during the seizure.

This work may also benefit those with other conditions in which attention can be affected, such as attention-deficit/hyperactivity disorder, Alzheimer’s disease, or traumatic brain injury, said Blumenfeld.

“Understanding these circuits on longer and shorter timescales could be very helpful for understanding disorders where arousal, attention, consciousness, and behavior are affected,” he said.

Source: Yale University