Study identifies neuronal basis of impaired consciousness in ‘absence’ epilepsy

by Yale University

BOLD fMRI signals associated with SWDs in GAERS resemble human absence epilepsy. a Statistical Parametric Mapping (SPM) analysis of spike-wave discharge (SWD)-associated changes in blood-oxygen-level-dependent (BOLD) signal. Cortex shows mainly functional magnetic resonance imaging (fMRI) decreases (cool colors), whereas the thalamus shows fMRI increases (warm colors). Values on both color scales indicate the magnitude of increases (upper scale) and decreases (lower scale). T maps are superimposed on coronal anatomical images from the template animal, with FDR corrected threshold p < 0.05. AP coordinates are in millimeters relative to bregma. b Regions of interest overlaid on a reference anatomical MRI image. Structures are taken from the Paxinos & Watson Rat Brain Atlas after alignment of image sections with approximate rostrocaudal locations from bregma. Somatosensory cortex (ctx, cyan) includes all S1 regions from bregma +1 mm to bregma −3.6 mm; Ventrobasal thalamus (thal, orange) includes VPM and VPL from bregma −2.3 mm to bregma −4.16 mm. Note that these are representative sections only and do not constitute the full extent of the regions in question. c Mean percent-change time courses of BOLD signals (±SEM) in each of the regions described in b (including medial (pink) and lateral (green) caudate putamen (CPU)) aligned to SWD onset and offset in 1 s time bins. N = 18 animals, 670 SWDs in all of these analyses. Credit: Nature Communications (2023). DOI: 10.1038/s41467-022-35535-4

Imagine slipping in and out of consciousness hundreds of times per day, staying awake the whole time but having no sense of awareness during these lapses.

In children with absence epilepsy, these highly disruptive episodes are known as absence seizures. Children experience brief staring spells, during which they temporarily lose consciousness. Absence seizures can be captured by abnormal rhythms on EEG recordings, but their neuronal cause has never before been identified.

Using a genetic model known as Genetic Absence Epilepsy Rats of Strasbourg (GAERS), Yale researchers have identified the neuronal basis for this condition. Their findings were published Jan. 10 in Nature Communications.

“First, we studied behavior during seizures using an auditory response task, and a spontaneous motivated licking liquid reward task,” said senior author Dr. Hal Blumenfeld, the Mark Loughridge and Michele Williams Professor of Neurology and professor of neuroscience and neurosurgery at Yale School of Medicine. 

“Next, we imaged the rats using functional magnetic resonance imaging [fMRI] to map brain activity during seizures. Finally, we recorded electrical signals from the brain using EEG and electrical signal from single neurons using multi-contact silicon probes.”

The experiments were led by Cian McCafferty, who at the time was a postdoctoral fellow at Yale and is now a lecturer and principal investigator at University College Cork. The team observed that not only do the rats’ response to external stimuli mimic those of children with absence epilepsy, but the rats also revealed four different types of neuronal activity during seizures.

“Most neurons showed sustained decreases in activity during seizures, explaining the decreased brain function and the impaired consciousness seen during absence seizures in both rats and children,” Blumenfeld said. “However, some neurons showed sustained increases during seizures, some showed transient increases at seizure onset only, and others showed no change.”

Defining four types of neuronal activity could result in more customized treatment for children with absence epilepsy, selectively targeting a certain type of neuron and causing fewer side effects.

Perhaps most importantly, Blumenfeld said, the recordings of electrical brain signals from this study could help epilepsy specialists prevent seizures in the first place and treat patients before their onset.

Having completed this first-of-its-kind study with a rat model, Blumenfeld and his team hope that children whose everyday lives are disrupted by losses of consciousness during absence epilepsy seizures will be able to regain a sense of normalcy and return to the activities they enjoy.