A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy

Abstract

BACKGROUND. Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown. METHODS. We studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine-learning algorithm was used to delineate brain regions that inhibit respiration. RESULTS. In 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 subjects (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine-learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons. CONCLUSIONS. A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.

Electrical Stimulation-Induced Seizures and Breathing Dysfunction: A Systematic Review of New Insights Into the Epileptogenic and Symptomatogenic Zones

“…Studies indicate that ICA is a semiological phenomenon, hypothesized to arise from seizure activity in symptomatogenic brain regions, including mesial temporal structures (Lacuey et al, 2017;Vilella et al, 2019a). Recent investigations have shown that ictal activity that spreads to the amygdala elicits ICA (Nobis et al, 2020;Rhone et al, 2020). This finding supports previous observations that report that ICA preceded surface electroencephalographic onset of temporal lobe seizures, representing the first sign in 69% and occasionally the only clinical seizure manifestation (in 16% of the seizures) (Nadkarni et al, 2012;Lacuey et al, 2019a).…”

“…However, we find recent evidence to suggest that with appropriate multimodal monitoring, these structures are highly symptomatogenic in both spontaneous seizures and ES, thus opening up a whole new aspect to epilepsy surgery assessments. From ES studies in animals and humans, we know that mesial temporal structures have a modulatory effect on breathing (Bailey and Sweet, 1940;Kaada et al, 1949;Kaada and Jasper, 1952;Dlouhy et al, 2015;Nobis et al, 2018;Lacuey et al, 2019b;Rhone et al, 2020). The mechanism underlying ICA is due to seizure discharge induced impairment of involuntary, suprapontine (amygdalohippocampal) breathing control through disruption of brainstem-driven inspiration (Lacuey et al, 2018c).…”

Enhanced Synaptic Transmission in the Extended Amygdala and Altered Excitability in an Extended Amygdala to Brainstem Circuit in a Dravet Syndrome Mouse Model

“…Electrical stimulation of the human amygdala reliably produces apneas ( Dlouhy et al, 2015 ; Lacuey et al, 2019 ; Nobis et al, 2018 , 2019 ). This is likely related to the stimulation of structures of the extended amygdala rather than the lateral regions ( Nobis et al, 2018 ; Rhone et al, 2020 ). Similarly, seizure spread to these regions may be driving ictal apneas ( Dlouhy et al, 2015 ; Nobis et al, 2019 ).…”

Neuronal activity in the human amygdala and hippocampus enhances emotional memory encoding

“…To localize the depth electrodes to the different subregions of the amygdala, we used the CIT168 atlas 77, 78 . Due to the bipolar reference scheme we utilized, we localized the resulting “virtual” electrodes using the averaged MNI coordinates of the two referenced electrodes.…”