Crowd-sourcing a scientific study to understand autonomic disruption in epilepsy R Picard1,2, T Loddenkemper3, C Reinsberger4,5, R A Sarkis4, B Dworetzky4, M Lai2, S Tognettii2, L Picard2, R Surges6, D Friedman7, J A French7, O Devinsky7

1. Massachusetts Institute of Technology (MIT), email: picard@media.mit.edu 2. Empatica, Inc, Cambridge, MA and Milan, Italy 3. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 4. Edward B. Bromfield Epilepsy Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 5. Institute of Sports Medicine, University of Paderborn, Germany 6. Epileptology Clinic, University of Bonn, Germany 7. Department of Neurology, New York University Langone Medical Center

References [1] C A Mangina and J H Beuzeron-Mangina, “Direct electrical stimulation of specific human brain structures and bilateral electrodermal activity,” Int J of Psychophysiology, v. 22, no. 1–2, pp. 1–8, 1996. [2] M-Z. Poh et al., “Convulsive seizure detection using a wrist-worn electrodermal activity and accelerometry biosensor,” Epilepsia, v. 53, no. 5, pp. e93–7, May 2012. [3] M-Z Poh et al., “Autonomic changes with seizures correlate with postictal EEG suppression,” Neurology, v. 78, no. 23, pp. 1868–76, Jun. 2012. [4] P Ryvlin et al. “Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study.” Lancet Neurol. 2013 Oct; 12(10):966-77. doi: 10.1016/S1474-4422(13)70214-X. [5] RA Sarkis et al., “Autonomic Changes Following Generalized Tonic Clonic Seizures: An Analysis of Adult and Pediatric Patients with Epilepsy,” poster presented at AES, Washington DC, Dec. 2013. [6] R Surges and J W Sander. “Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention.” Curr Opin Neurol. 2012; 25:201-207. [7] E L So et al., “Postictal Central Apnea as a Cause of SUDEP: Evidence From Near-SUDEP Incident”, Epilepsia, 41(11):1494-1497, 2000. [8] Y Nagai et al., “Clinical efficacy of galvanic skin response biofeedback training in reducing seizures in adult epilepsy: a preliminary randomized controlled study,” Epilepsy & Behavior, v. 5, no. 2, pp. 216–223, 2004. With gratitude to the Epilepsy Foundation, the Nancy Lurie Marks Family Foundation, the Danny Did Foundation, and the members of the MIT Media Lab consortium for their generous support!

What could a wrist-worn sensor, measuring autonomic data and physical activity, tell us about seizures and SUDEP? There are two main branches of the Autonomic Nervous System, both of which can be measured from the wrist: §  The Sympathetic Nervous System “fight or flight” causes

electrodermal activity (EDA) changes in the skin, measured as skin conductance.

§  The Parasympathetic Nervous System “rest and digest” is measured from the high frequency component of heart-rate variability.

A crowd-sourced study could speed up the science of understanding autonomic changes in epilepsy. Would you pay to get a sensor (comfortable to wear 24/7) to participate? Tell us what you would value - some possibilities: §  Would you wear a sensor and log seizures in an e-diary for 6-18

months? §  If it detects that you have a GTCS, the sensor would alert you

and designated caregiver(s) – any preference how? §  Would you want to know the seizure’s autonomic disruption? §  Would you like to know how its severity compares to prior

seizures or to other people’s seizures? §  Do you want to know the seizure duration? §  How many “false alerts” could you tolerate? (It can be shut off.) §  OK to charge it daily, like a smartphone? §  OK if your data are encrypted and go to a secure server (over a

smartphone or iPod to the Internet) while you charge it? §  Would you give it corrective feedback so it could learn how to be

optimal at detecting your personal seizures? §  Note: It may be possible in some cases to detect that a seizure

is happening seconds or minutes in advance, but this is not proven and is not likely for most seizures.

§  Would you like to see your “autonomic stress” level? One study helping people control their EDA argued that this biofeedback reduced their number of seizures [8].

§  Would you want to track your sleep patterns and see if disrupted sleep relates to your seizures?

Fig 1. The “elephant” (or a seizure) shows changes not only in the EEG, but also in autonomic data that affects the heart, breathing, and more. Some seizures cause more severe autonomic changes than do others.

It is possible but not proven that autonomic disruption may lead to SUDEP [6]. §  PGES occurred in 100% of SUDEP cases in the

MORTEMUS study [4]. §  Pediatric [3] and adult [5] studies showed that duration of

PGES correlates with EDA. §  Respiratory arrest is inducible in humans by electrical

stimulation of the amygdala [7]. Amgydala stimulation gives rise to a strong EDA response (Fig 2). Note: a scalp EEG may not register this deep brain activation!

§  EDA is larger for most GTCS than for most CPS, and is not correlated with length of the seizure or with its motor component [2].

Fig 3. EDA+motion is better than motion alone for automated GTC seizure detection [2]. Also, larger EDA correlates with longer post-ictal generalized EEG suppression (PGES) [3].

Fig 2. Stimulating four brain regions on the left and four on the right (with depth electrodes) produces large skin conductance on the same side. Data from [1].

Fig 4. EDA provides a measure of seizure severity that correlates with duration of post-ictal Generalized EEG suppression (PGES), a biomarker for SUDEP.

PG

ES