May 24, 2022

CURE Epilepsy Discovery: Identifying Human Brain Regions that Regulate Breathing as Eventual Targets for Direct SUDEP Intervention

Key Points:

  • CURE Epilepsy Award grantee Dr. Nuria Lacuey and her team sought to identify specific parts of the brain essential for regulating breathing, a fundamental function whose failure following a seizure is primarily responsible for Sudden Unexpected Death in Epilepsy (SUDEP).
  • The team recruited patients who were being evaluated for epilepsy surgery and who formally agreed to enroll in a study that had them perform various breathing exercises while having different areas of their brain electrically stimulated with varying intensities.
  • Quantitative analyses of the data revealed that four specific areas of the cortex of the brain affected the patients’ breathing responses, depending on the strength and frequency of the electrical stimulation. Two of these areas resulted in enhanced respiratory activity.
  • Additional data from more patients is needed, but Dr. Lacuey hopes to use these valuable results to develop a device that will stimulate critical areas of the brain following seizures to enhance breathing and avoid its cessation, thereby preventing SUDEP.

Deep Dive:

SUDEP is the most frequent cause of death among people with drug-resistant epilepsy [1,2]. Although different biological processes may contribute to SUDEP, the most prominent appears to be a phenomenon known as central apnea, a condition in which breathing repeatedly stops and starts, usually while sleeping, during or immediately after a severe seizure [3,4]. There is compelling evidence that breathing irregularities are an underlying cause of SUDEP. Research to date has almost exclusively concentrated on the role of an area of the brain called the brainstem [5], which ultimately connects higher cortical regions of the brain to the spinal cord. Although the brainstem plays a crucial role in maintaining respiratory activity, it may not be the only contributing area. Indeed, areas of the cortex have also been implicated [6], but the specific roles different areas of the cortex play in modulating breathing is unclear. Most importantly, there are currently no strategies for directly improving respiratory function during the dangerous period between seizure-induced central apnea and death.

One possible approach would be to electrically stimulate specific areas of the brain to maintain respiratory function during this critical period. As a first step, it is vital to assess the role of specific areas of the brain and what intensity and frequency of the electrical current might have beneficial or detrimental effects on breathing. Developing such an innovative method requires a detailed understanding of the relationship between brain electrical activity and breathing responses, specifically how brain regions are structurally and functionally linked through their neuronal connections, collectively known as the connectome [7,8].

Research on this approach was conducted by Dr. Lacuey and her team in the Department of Neurology at the University of Texas Health Science Center  in Houston, TX. Nineteen patients who suffered from drug-resistant epilepsy and who were being evaluated for epilepsy surgery consented to be enrolled in the study [9]. Pinpointing the exact seizure focus without damaging surrounding healthy tissue necessitated placing electrodes directly on the brains of these patients and then, electrically stimulating various brain regions for clinical mapping.

Electrodes were implanted in seven brain regions common to all 19 participants, and thus, these were the regions selected for comprehensive investigation. The goal was to ascertain whether electrical stimulation of each of these seven regions would affect breathing responses and, if so, whether the resulting respiratory activity would be enhanced or inhibited. Equally important was to determine the stimulation intensity as well as frequency necessary to elicit such responses. Electrical stimulation was carried out at a current of 1-10 milliamps (mA) and a frequency of 50 Hertz for 0.2 milliseconds [9].

Quantitative analyses of the data showed that electrical stimulation affected breathing responses in four of the seven different brain regions tested. Stimulation of two of these regions, specifically within the frontal portions of areas called the temporal lobe and cingulate gyrus, promoted breathing enhancement at a relatively low current (less than 3 mA) but not at the higher electrical current conditions tested [9]. Future experiments will require a larger group of patients, finer mapping of the identified brain regions, and exploration of brain regions other than the seven examined in the current study. Subsequent experiments will also include an evaluation of electric current and frequency as well as how any observed changes in respiratory control interact with the breathing mechanisms of the brainstem.

The fact that electrical stimulation of four cortical regions affected respiration, and that two of these areas enhanced breathing is an exciting finding. Significantly, this CURE Epilepsy funded research supports the idea that an implantable device capable of electrically stimulating pre-identified cortical regions of the brain to enhance breathing at critical times to prevent SUDEP may eventually be possible.


Literature Cited:

  1. Jones, L.A. & Thomas, R.H. Sudden unexpected death in epilepsy: insights from the last 25 years. Seizure 2017; 44: 232-236.
  2.   Devinsky, O. et al. Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention. Lancet Neurol. 2016; 15(10): 1075-1088.
  3.   Vilella, L. et al. Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP). Neurology 2019; 92(3): e171-e182.
  4.   So, E.L., Sam, M.C., & Lagerlund, T.L. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 2000; 41(11): 1494-1497.
  5.   Patodia, S. et al. The ventrolateral medulla and medulla raphe in sudden unexpected death in epilepsy. Brain 2018; 141(6): 1719-1733.
  6.   Herrero, J.L. Breathing above the brain stem: volitional control and attentional modulation in humans. J. Neurophysiol. 2018; 119(1): 145-159.
  7.   Bethlehem, R.A.J. et al. Brain charts for the human lifespan. Nature 2022; 604(7906): 525-533.
  8.   Fan, Q. et al. Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact. Neuroimage 2022; 254:118958.
  9.   Ganne, C. et al. Limbic and paralimbic respiratory modulation: from inhibition to enhancement. Epilepsia 2022; Epub