Supplementary Table 1. Preclinical Studies Combining Acute Stress and Epilepsy

Species Stress timing and du‐ Epilepsy model Stage of epilepsy Stressor(s) ration progression being Relevant outcomes Reference studied Conspecific alarm Zebrafish Zebrafish in experi‐ Pentylenetetrazol ex‐ Epileptogenesis CAS exposure increased seizure Canzian et al., substance (CAS) mental group were ex‐ posure intensity, decreased latency to 2021 posed to 3.5 ml/L of developing clonic‐like seizure be‐ CAS skin extract prep‐ haviors after PTZ exposure, and aration for 5 mins. im‐ decreased the number of clonic‐ mediately before expo‐ like seizure behaviors in sure to pentylene‐ CAS/PTZ zebrafish. tetrazol Single and repetitive CBA Mice Experiment #1: Picrotoxin, bicuculline, Epileptogenesis Single acute swim stress Pericic et al., acute swim stress Mice exposed to 10 pentylenetetrazol, increased dose threshold for 2001 strychnine, kainic acid, minutes of swim stress convulsant signs and death for or 4‐aminopyridine in‐ at 18‐19 degrees jections picrotoxin, pentylenetetrazol, Celsius 15 mins. before strychnine, and 4‐aminopyridine‐ chemoconvulsant induced seizures. injection Single acute swim stress did not Experiment #2: affect dose threshold for Mice exposed to 10 producing kainic‐acid induced minutes of swim stress convulsions.

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at 25 degrees Celsius (room temperature) 15 Picrotoxin mice subject to room mins. before temperature swimming chemoconvulsant experienced a less robust stress injection. effect than picrotoxin mice subjected to swimming in 18‐19 Experiment #3: degrees Celsius water. Mice exposed to repeti‐ tive swim stress two Repetitive stress was less times a day for four effective in reducing convulsive consecutive days with one extra stress proce‐ potency of picrotoxin than single dure on the fifth day; acute stress. the last stress proce‐ dure was completed 25‐15 mins. before chemoconvulsant injec‐ tion. Acute restraint NMRI mice Plastic tube restraint Pentylenetetrazol infu‐ Epileptogenesis Mice exposed to 2 hours of Homayoun et stress stress lasting 30 mins., sion restraint stress exhibited higher al., 2004 1 hours, or 2 hours; seizure thresholds than restraint stress unstressed mice. procedure completed 15 minutes before chemically induced seizure

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Acute foot shock NMRI Mice Prolonged intermittent Pentylenetetrazol infu‐ Epileptogenesis Foot‐shock stressed mice Shirzadian et stress foot shock (lasting 30 sion exhibited significantly higher al., 2018 mins., 1‐second‐long seizure thresholds than non‐ shocks every 5 stressed mice when given seconds) administered pentylenetetrazol infusion within 1 min., 15 mins., 30 30 minutes after foot shock. mins., and 60 mins. before chemically induced seizure Acute restraint C7BL/6 Mice Plastic tube restraint Pilocarpine injection Epileptogenesis Mice stressed before pilocarpine Maggio et al., stress stress lasting 3 hours; injection exhibited a smaller 2017 [ One group of mice was reduction in paired pulse subject to restraint potentiation and long‐term stress prior to potentiation as compared to chemically induced unstressed mice treated with seizure and the other pilocarpine. group of mice subjected to restraint Mice stressed after pilocarpine stress immediately injection exhibited a larger after chemically reduction in paired pulse induced seizure potentiation as compared to unstressed mice treated with pilocarpine.

Mice stressed after pilocarpine injection exhibited a rise in blood

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corticosterone that lasted much longer than the rise seen in mice stressed before pilocarpine.

Pre‐administration of a mineralocorticoid receptor agonist to unstressed pilocarpine‐ treated mice mimicked the effects of stress priming and decreased the reduction of LTP and paired pulse potentiation associated with pilocarpine.

Pre‐administration of a mineralocorticoid antagonist to mice stressed before pilocarpine resulted in levels of reduction in long term potentiation and paired pulse potentiation that were similar to those of unstressed pilocarpine‐treated mice. Repetitive acute Adult mice 7 consecutive days of Pentylenetetrazol; Epileptogenesis Repetitive swim stress mice Weizman et swim stress acute swim stress; each Clonazepam pre‐treat‐ caused for less efficient binding al., 1989 ment for one group of acute swim stress of the benzodiazepine [3H]Ro15‐ mice session lasted either 2 1788 to its receptors in the

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or 10 mins. and the last hippocampus, cerebral cortex, session was completed hypothalamus, midbrain, and 30 minutes before striatum but not in the pentylenetetrazol cerebellum, pons, and medulla. infusion Repetitive swim stressed mice exhibited reduced maximal binding capacity of benzodiazepine receptors when compared to unstressed mice.

The ED50 dose of clonazepam for protection against PTZ‐induced seizures was higher for mice subjected to repeated swim stress.

None of the differences stated above were found using in vitro binding techniques. Acute repetitive Wild‐type Gro‐ 4 days of repetitive Kainic acid Epileptogenesis One half of social defeat stressed Becker et al., social defeat stress ningen (WTG) social defeat stress mice exhibited a sustained 2019 rats ending 4 weeks prior reduction in BDNF levels. to chemically induced seizure Social defeat stressed mice with low BDNF levels exhibited

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reduction of seizure threshold and accelerated epileptogenesis than social defeat stressed mice with normal BDNF levels and unstressed mice. Acute repetitive Wild‐type Gro‐ 4 days of repetitive Kainic acid Epileptogenesis Social defeat stressed mice with Becker et al., social defeat stress ningen (WTG) social defeat stress low BDNF levels exhibited 2015 rats ending 4 weeks prior reduction of seizure threshold to chemically induced and accelerated epileptogenesis, seizure both of which were not observed in social defeat stressed mice with normal BDNF levels and unstressed mice. Handling stress, Hooded rats Unspecified frequency Repetitive infusions of Chronic phase Sporadic handling stress, Cain & Corco‐ immobilization and duration of beta‐endorphin and immobilization stress, and ran, 1984 met‐enkephalin stress, and stressors conspecific threat stress conspecific threat exacerbated frequency and stress intensity of convulsive seizures. Handling stress, Hooded rats Unspecified frequency Repetitive infusions of Chronic phase Sporadic conspecific threat stress Cain & Corco‐ conspecific threat and duration of beta‐endorphin and and handling stress exacerbated ran, 1985 met‐enkephalin stress stressors epileptiform spiking and convulsive signs for some, but not all epileptic rats. Immobilization Wistar Rats Rats were subjected to Hippocampal kindling Chronic phase interictal discharges in the dorsal Takeshita et stress immobilization by wire hippocampus were significantly al., 1991

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netting for 1 hour more frequent during starting 24 hours after immobilization stress. This effect electrical stimulation. disappeared during the 10 minutes after cessation of immobilization stress but returned during 10 to 60 minutes after stress cessation.

None of the hippocampal kindled rats exhibited generalized convulsions; however, some displayed behavioral arrest less than a minute after cessation of immobilization stress. Inter‐male agonistic TMD‐S3 rats Rats were subject to a Amygdala kindling Chronic phase Social defeat stressed rats had Beldhuis et al., experience resident/intruder social shorter and less severe motor 1992 defeat paradigm seizures than unstressed animals. during which an experienced “fighter” The duration of postictal rat was introduced into inhibition was also reduced by the experimental rat’s social defeat stress. cage for 15 minutes.

Tail suspension El mice and ddY One group of mice was El mice (Genetic model Chronic phase El mice had higher CRF peptide Forcelli et al., stress control mice suspended by the tail of idiopathic epilepsy) content in the paraventricular 2007

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for 2, 30 second thalamic nucleus in response to Foot shock stress periods, with a brief tail suspension stress than ddY 15‐minute break in controls treated with the same between suspension stressor. sessions. Plasma corticosterone levels for Another group of mice El mice were higher than ddY was subject to 2, 90‐ controls 60 min following second‐long foot‐shock handling and foot‐shock stress. sessions, with 2‐ minutes in between the El mice displayed greater EEG two sessions. activity (1‐4 Hz) in reaction to tail suspension stress than ddY controls.

Acute restraint Scn8a mutant 20‐minute acute Scn8a mutation Chronic phase Even before restraint stress, Sawyer et al., stress mice restraint stress using (Genetic model of Scn8a mutants exhibited greatest 2014 polypropylene absence epilepsy) seizure activity around time of restrainer immediately peak corticosterone release (1700‐ before chemically + 1900 h). induced seizure Picrotoxin or Kainic Scn8a mutants showed more acid induced seizures frequent spike wave discharges (SWDs) in response to chemoconvulsant injection

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immediately after restraint stress; however, wild type mice did not exhibit changes in SWD responses to chemoconvulsant after stress exposure.

Restraint stressed Scn8a mutants experienced more severe and longer lasting seizures in response to picrotoxin/kainic acid injection as compared to wild‐ type mice subject to the same stressor and chemoconvulsant.

Repetitive foot WAG/Rij rats, Experiment 1: WAG/Rij rats (Genetic Chronic phase WAG/Rij and ACI rats had Tolmacheva et shock stress ACI rats, and One day of foot shock model of absence higher baseline levels of al., 2012 Wistar rats stress with three epilepsy) corticosterone as well as a electrical foot shocks quicker corticosterone response delivered to rats with to foot shock stress. randomized inter‐ shock intervals lasting WAG/Rij rats reached basal 1‐10 seconds. corticosterone levels more quickly than ACI and Wistar rats Experiment 2:

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Three consecutive days after exposure to foot shock of foot shock stress stress. with one, three, or ten scrambled electrical WAG/Rij rats initially exhibited shocks presented each less spike wave discharges in day; each shock series response to foot shock stress, but (1,3,10) had an inter‐ eventually displayed exacerbated shock interval of 1‐10 spike wave discharges preceding seconds. the third consecutive presentation of stressor.

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Suplemmentary Table 2. Clinical Studies Combining Acute Stress and Epilepsy

Patient popula‐ Relevant methodology Relevant findings Stressor(s) Reference tion Patients surveyed 266 patients at Patients were asked 219/266 participants Privitera et al., for acute (lasting tertiary epilepsy whether they experienced stress‐ 2014 minutes‐hours) center experienced acute or precipitated seizures. and/or chronic (last‐ ing days‐months) chronic stress‐ 68% of these 219 stress precipitated precipitated seizures, participants reported seizures. and whether any stress acute stress as a reduction activities precipitant and 85% they’ve tried had been reported chronic stress. effective in limiting stress‐precipitated 57% of the 219 seizures. participants who experience stress‐ precipitated seizures tried stress reduction activities and 88% found them to be effective.

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Strong emotional 39 participants EEG recordings were No significant change Stevens, 1959 stimuli by way of a total. done for all in the EEG was noted stressful interview participants before and during the stressful 22 patients with during the stressful interview in 5 patients. psychomotor or interview. psychosensory 20 patients showed epilepsy. The stressful interview abnormal EEG activity was led by the patient’s after the interview; for 8 patients who physician and its 9 of these 20 patients, had previously contents were highly the abnormal EEG experienced individualized. Each activity included grand mal interview included exaggerated spiking or seizures. interrogations, recordings indicative criticisms, accusations, of seizure activity. 9 non‐epileptic laudatory comments, controls. and apologies. Unprecedented pathological EEG The authors noted that activity was recorded they were not com‐ in 11 patients. pletely successful in

eliciting visibly emo‐ tional responses from all participants. Personalized audio Patients with Patients were Video and audio re‐ Feldman et al., and video tapes of complex partial interviewed at length plays of stress triggers 1976 seizures (n = 5) were sufficient to in‐ problematic social about their duce seizures in all 5 interactions neurological patients.

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background, the nature of their seizures, and whether or not they felt their seizures were precipitated by stressful stimuli. Additional background information on each patient was collected by means of contacting previous healthcare providers and family members, as well as by collecting current EEG data.

Patients are shown a series of personalized “stressor tapes” based on the stressful interpersonal relationships/situations they identified as triggers during the interview.

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High‐intensity Case report: A Patient attended 60 After 6 months of van der Kop et fitness program patient with minute long high‐ engaging in weekly al., 2020 [33] drug‐resistant fo‐ (CrossFit) intensity CrossFit high‐intensity exercise cal epilepsy (n =

1) classes three times a classes, the patient’s week. seizure frequency dropped by 33%.

The patient’s severity and duration of sei‐ zures did not change

after starting high‐in‐

tensity fitness pro‐ gram.