March 29, 2022

CURE Epilepsy Discovery: Investigating Spreading Depolarization in SUDEP

Key Points:

  • Dr. Stuart Cain’s CURE Epilepsy Taking Flight Award received while at the University of British Columbia, explored the mechanisms underlying Sudden Unexpected Death in Epilepsy (SUDEP).
  • SUDEP occurs when the heart and respiration both stop in a process called “cardiorespiratory arrest.” An area of the brain called the brainstem is critical in maintaining both heart function and respiration and is, therefore, an important brain area for researchers to study in order to understand the biological process through which SUDEP occurs. The brainstem is also connected to areas called the superior and inferior colliculus.
  • A phenomenon known as “spreading depolarization” is known to contribute to respiratory arrest. Dr. Cain’s team investigated mechanisms underlying spreading depolarization in the areas of the brain connected to the brain stem called the superior and inferior colliculus. Their research showed the specific role of the superior colliculus in spreading depolarization to the brainstem, causing SUDEP.
  • This study establishes a foundation for continued study on the superior colliculus to ultimately develop preventative approaches for SUDEP.

 


Deep Dive:

Sudden Unexpected Death in Epilepsy (SUDEP) is one of the most tragic consequences of epilepsy. SUDEP occurs when a seemingly healthy person with epilepsy dies unexpectedly for no known reason. The biological causes of SUDEP are still not fully understood [1, 2]. Research suggests that SUDEP occurs because of the effects of seizures on the cardiovascular and respiratory systems resulting in “cardiorespiratory arrest”. Given that the brainstem is the part of the brain that controls heart rate and respiration, scientists have investigated the role of this region of the brain in causing SUDEP [3]. One phenomenon that has emerged as a possible explanation for SUDEP is called “spreading depolarization.” Spreading depolarization can be described as a wave of abnormal brain activity that travels through the layers of the brain in an organized fashion. Earlier work done by Dr. Cain and other researchers showed that spreading depolarization that engages the brainstem can be fatal. They also observed that additional areas in the brain called the superior and inferior colliculus are susceptible to spreading depolarization, but only during seizures, and that spreading depolarization that traveled into the brainstem during seizures was fatal [4]. 

Past research studies have shown that the superior and inferior colliculus may be involved in epilepsy [5]. Dr. Cain’s research, funded by the CURE Epilepsy Taking Flight Award, sought to investigate if the superior and inferior colliculus may play a role in spreading depolarization to the brainstem [6]. In this study, Dr. Cain’s team used a genetic mouse model that is susceptible to seizures and SUDEP and has been previously shown to be a good model to understand activity in the brainstem during fatal seizures [4]. The team did several experiments using these mice, called Cacna1aS218L mice, and state-of-the-art techniques. Using these techniques, Dr. Cain’s team first showed that when they stimulated the superior or the inferior colliculus, the mice experienced severe seizures, interrupted breathing (respiratory depression), and ultimately, death. Stimulation of the superior or the inferior colliculus started a wave of spreading depolarization that reached the brainstem in Cacna1aS218L mice, but not in normal mice. This wave of spreading depolarization that started in the superior and inferior colliculus traveled to several other brain regions, and then finally to the brainstem. Previous work done by Dr. Cain and other researchers also suggested the potential role of an additional brain structure called the thalamus in spreading depolarization that reaches the brainstem [4, 7]. By performing an additional experiment, the team observed that while stimulation of the thalamus initiated spreading depolarization in the Cacna1aS218L mice, the wave of activity did not reach the brainstem, and hence, was not associated with arresting breathing. The thalamus, therefore, does not appear to be involved in  spreading depolarization that leads to SUDEP.

To dive deeper into whether the superior or the inferior colliculus is important in spreading depolarization in the brainstem, Dr. Cain’s team used electrophysiology to measure electrical signals in these regions. They found that brain cells (neurons) of the superior colliculus of the Cacna1aS218L mice were inherently more excitable compared to superior colliculus neurons from normal mice. This finding suggests that the superior colliculus is what is critical for the brainstem spreading depolarization to occur which may in turn lead to SUDEP.  

Taken together, these novel results suggest the critical role of the superior colliculus in seizures that may lead to SUDEP. The results also strengthen the understanding of the sequence of events that may cause SUDEP. Spreading depolarization in the superior and inferior colliculus reaching the brainstem was associated with respiratory arrest, followed by cardiac arrest that is seen in SUDEP (as seen in the chart below). While more studies are necessary to understand the role of these brain structures in SUDEP, these data help envision methods to target and address brainstem spreading depolarization as a way to prevent SUDEP.

Literature Cited:

  1. Buchanan, G.F., Impaired CO(2)-Induced Arousal in SIDS and SUDEP. Trends Neurosci, 2019. 42(4): p. 242-250.
  2. Massey, C.A., et al., Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention. Nat Rev Neurol, 2014. 10(5): p. 271-82.
  3. Ryvlin, P., et al., Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol, 2013. 12(10): p. 966-77.
  4. Loonen, I.C.M., et al., Brainstem spreading depolarization and cortical dynamics during fatal seizures in Cacna1aS218L mice. Brain, 2019. 142(2): p. 412-425.
  5. Faingold, C.L., Neuronal networks in the genetically epilepsy-prone rat. Adv Neurol, 1999. 79: p. 311-21.
  6. Cain, S.M., et al., Hyperexcitable superior colliculus and fatal brainstem spreading depolarization in a model of sudden unexpected death in epilepsy. Brain Communications, 2022: p. fcac006.
  7. Cain, S.M., et al., In vivo imaging reveals that pregabalin inhibits cortical spreading depression and propagation to subcortical brain structures. Proc Natl Acad Sci U S A, 2017. 114(9): p. 2401-2406.