Brain circuits that trigger rare glycemic epilepsy

Positron emission tomography (PET) images of the brains of the mice in the study showed a decrease
in glucose in the brains of GLUT1 (G1D)-deficient mice compared to normal (controls).
The color scale on the right indicates the amount of glucose, the higher the scale, the higher the
glucose content.

DALLAS - November 16, 2022 - A study led by researchers at the University of Texas Southwestern has shown that in a rare epilepsy affected by blood sugar levels, a small group of brain cells is connected in a circuit, causing whole-brain seizures
.
The findings, published in Science Translational Medicine, could lead to new treatments
for other metabolic diseases in the brain, the authors said.

"This also has broad implications for other diseases because this circuit is linked to dementia, schizophrenia, sleep and cognition," said study leader Juan Pascual, MD, professor of neurology, pediatrics, and physiology at the Eugene McDermott Center for Human Growth and Development
.
"Our lab is now studying these effects
.
"

Dr.
Pascual is the director
of the Rare Brain Disorders Program.
He said he and his colleagues at UTSW have long been interested in a disease known as GLUT1 deficiency because of its unusual characteristics
.
The disease is caused by a congenital deficiency called glucose transporter type 1, which carries blood sugar into cells for use as fuel
.
Only a few hundred people worldwide have been diagnosed with the disease
.

People with GLUT1 deficiency syndrome experience hundreds of episodes of "absentness" a day during the first few months of life, some of which are characterized by a few seconds of inattention
.
Patients with the disease from North America and other parts of the world seek medical care
from the University of Texas Southwest.

Blood glucose levels can significantly affect the number of seizures a patient has, while raising blood sugar levels or keeping blood sugar stable on a therapeutic diet can greatly reduce the number of
seizures.
Why these epilepsy are affected by glucose levels is unclear
.

To answer this question, Dr.
Pascual and his colleagues traced the anatomical origins
of these seizures in human patients.
A combination of electroencephalogram (EEG), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET) revealed that seizures originated from a relatively small area
of the thalamus and somatosensory cortex in the brain.

When blood sugar levels drop, abnormal electrical activity in circuits formed by these areas spreads throughout the brain
.
Curiously, despite the EEG showing vigorous whole-brain epileptic activity, the patient remained awake at the time of the seizure and was able to complete cognitive tests
.

Using a mouse model with GLUT1 deficiency, the researchers demonstrated that the metabolic byproducts of glucose — including neurotransmitters and other chemicals needed for normal brain function — remained mostly in normal concentrations
in the animals' brains.
However, the electrical activity of brain cells responsible for inhibiting or slowing neural activity becomes dysponic, causing them to send far fewer signals than usual, allowing other connected excitatory cells to signal
uninhibited.
When the researchers gave the animals an anti-epileptic drug called perampanel, their seizures were significantly reduced
.

Pascual said the results may provide a new treatment for this unusual epilepsy, while also refuting the long-held idea that normal function of cells in the thalamus and cortical circuits is necessary
for consciousness.
"These findings disprove decades of speculation about the brain's role in consciousness," he said
.
"However, this is not entirely unexpected, as consciousness is an attribute of the human being, not the brain
.
"