Authors :
Presenting Author: Sukhbinder Kumar, PhD – University of Iowa
Hiroyuki Oya, MD – University of Iowa; Ariane Rhone, PhD – University of Iowa; Christoph Kovach, PhD – University of Iowa; Md Rakib Mowla, PhD – University of Iowa; Aubrey Chan, MD – University of Iowa; John Wemmie, MD – University of Iowa; George Richerson, MD – University of Iowa; Brian Dlouhy, MD – University of Iowa
Rationale:
Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsy. Animal models and human studies suggest impaired breathing following seizures as one of the leading causes of SUDEP. In our previous work (Dlouhy et al, J Neurosci 2015 35:10281-10289; Rhone et al, JCI Insight 2020 5(6): e134852), we identified a focal circumscribed site in the amygdala, referred to as the amygdala inhibition of respiration (AIR) site, whereby activation by spread of seizure activity or by electrical stimulation causes cessation of respiration (apnea) without air hunger or alarm. The AIR site, therefore, is posited as a brain region that mediates seizure-induced inhibition of breathing which may lead to SUDEP. However, the pathways via which the AIR site inhibits respiration are unknown. To determine these neural circuits in humans, we combined electrical stimulation of the AIR site while simultaneously acquiring whole brain fMRI BOLD signal to assess its causal influence on other brain areas (electrical stimulation fMRI: esfMRI).
Methods:
We conducted esfMRI in seven patients with intractable epilepsy undergoing intracranial EEG for seizure focus localization. Electrical stimulation (current range: 6-12mA, biphasic pulse duration: 1.25ms, frequency: 100Hz) was applied in blocks of 30s, with a stimulation OFF block following every stimulation ON block in a 3T MRI scanner. After pre-processing of the fMRI data using standard pipeline (realignment, normalization to MNI space and smoothing with a Gaussian kernel of 8 mm), data were analyzed within the general linear modelling framework using SPM toolbox. A fixed effect group analysis was performed to summarize the results across subjects.
Results:
Strikingly, AIR site stimulation caused reduced (negative) BOLD signal in the dorsal brainstem (pons and medulla) Figure 2(a), thalamus/hypothalamus (Figure 2b), posterior cingulate/precuneus and cerebellum (Figure 2c). Although the significance of negative BOLD is debated, multiple studies suggest it represents suppression of neural activity. Thus, reduction of BOLD activity following AIR site stimulation suggests inhibition of sites in the pons and medulla, a region of the brainstem previously implicated in the control of breathing. We also found increased BOLD activity in ventral insula (Figure 1a) which is known to process interoceptive physiological changes in breathing, including air hunger. Increased BOLD activity was also observed in medial orbital gyrus (Figure 1b) and hippocampus/parahippocampus (Figure 1c), brain regions previously found to respond to resting automatic breathing.
Conclusions:
In conclusion, the AIR site has excitatory causal influence on a network of brain areas involved in representing and processing respiration. It exerts inhibitory causal influence on pontomedullary sites in the brainstem which may be the putative pathway via which respiration is inhibited in SUDEP. The lack of air hunger or alarm associated with such loss of breathing may be due to the disruption of neural processing in the ventral insula.
Funding:
National Institute of Neurological Disorders and Stroke Grant K08 NS112573 01 (BJD)