On 2017 Jul 07, DANIEL BARTH commented:

The possible role of spike-wave discharges (SWDs) in epilepsy is a highly controversial. Although we expected our work to generate debate, the eLetter from Blumenfeld et al. is disappointing.

For a more detailed response to this eLetter, please see: https://www.dropbox.com/s/d8ut94ayf57f8pk/Response to responseBlumenfeld et al2017.pdf?dl=0

• Partial consciousness and maintenance of cognitive functions during SWD

eLetter: “Their logic appears to be based on the misperception that seizures in absence epilepsy (AE) are always associated with ‘profound impairment of consciousness,’ leading to the flawed premise of the study and its interpretation that anything less than full loss of consciousness must not be AE.”

Loss of conscious is stipulated as an inclusion criterion for diagnosis of typical childhood absence epilepsy, versus mild or no impairment of consciousness as an exclusion criterion (Loiseau and Panayiotopoulos, 2000; Engle, 2013). Accordingly, we characterized WAG/Rij rats as mild absence with partial impairment of consciousness during seizures.

eLetter: “The ‘ability’ to modulate SWD severity in rodent models is not demonstrated since the reduction in number and duration can be explained otherwise.” The alternative explanation put forward is “a sensory cue white noise, which may increase arousal and vigilance known to reduce SWD”.

We stated that operantly conditioned arousal is what terminates SWD bursts early. The possibility that the arousal is due only to the white noise cue, however, fails to account for the critical result that preemptive pellet checks occurred almost entirely in the seconds after each SWD burst, indicating awareness of the SWD, associative learning, and operant control over SWDs.

• SWDs occur in several rodent strains

eLetter: Blumenfeld et al. note SWDs are not observed in most laboratory rodent strains.

That is not correct. Observations of SWDs are common in outbred Sprague Dawley, Long Evans, Wistar and hooded rats. Unlike human absence epilepsy, SWDs become more prevalent with age). Our conclusion is not that SWDs cannot reflect absence epilepsy, but that their ubiquity in various outbred rat strains suggests their unreliability as a signature of absence epilepsy. We have no vested interest in whether SWDs are genetic epilepsy or part of normal rat behavior. We simply recommend caution that Blumenfeld et al. appear opposed to.

eLetter: Single gene mutations can lead to SWDs therefore absence epilepsy. We note that while genes can influence innate rhythms, this does not prove that all SWDs are epileptic or that all SWDs model genetic absence seizures. Furthermore, inbreeding does not seem to be a requirement for SWDs, since our outbred Sprague Dawley rats had the same amount of SWDs as our inbred WAG/Rij rats, and Long Evans rats had approximately four times this amount (Fig. 7).

• SWD/immobility as a model of absence epilepsy

Blumenfeld et al list characteristics that support SWDs as a model of absence epilepsy. We do not understand why they are raising this issue, since we clearly stated that inbred WAG/Rij rats model mild absence seizures in humans.

We believe, however, the case that all SWDs in outbred rats serve to model genetic absence seizures in humans is weak. We and others remain skeptical that most outbred rats have developed - or are developing - absence epilepsy; however, as we said, it is possible.

Conclusion

The eLetter by Blumenfeld et al. was written by experts with decades of publications in absence epilepsy. We have examined many of these papers, plus ones challenging the epileptic nature of SWDs (e.g. Kaplan, 1985; Wiest and Nicolelis, 2003). None of us have studied absence seizures or SWDs, except recently (Rodgers et al., 2015). The research history and publication record of Blumenfeld et al., however, could incline them toward an imbalanced interpretation of our results. We do not understand what specifically were the “overstatements” and inappropriate “assumptions” in Taylor et al. that Blumenfeld et al. claimed in the beginning of their eLetter. We urge readers to re-read our Significance Statement in the context of the eLetter by Blumenfeld et al.: “Our evidence that inbred and outbred rats learn to control the duration of spike–wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.”

While writing and revising this manuscript in response to successive peer reviews, we responded to the points of Blumenfeld et al. and tried to objectively incorporate reviewers’ suggestions and avoid misinterpretations of our data. We are disappointed that our efforts were either largely ignored or misrepresented in the eLetter, since this unnecessarily complicates an already controversial subject and detracts from what we believe is the importance of this work.

References

Engle, J, Jr. (2013) Seizures and Epilepsy, 2nd ed. New York ; London: Oxford University Press. Kaplan BJ (1985) The epileptic nature of rodent electrocortical polyspiking is still unproven. Exp Neurol 88:425–436. Loiseau, P, Panayiotopoulos, CP (2000) Childhood absence epilepsy. In: Neurobase. San Diego: Arbor. Rodgers KM, Dudek FE, Barth DS (2015) Progressive, seizure-Like, spike-Wave discharges are common in both Injured and uninjured Sprague-Dawley rats: Implications for the fluid percussion injury model of post-traumatic epilepsy. J Neurosci 35:9194–9204. Wiest MC, Nicolelis MAL (2003) Behavioral detection of tactile stimuli during 7-12 Hz cortical oscillations in awake rats. Nat Neurosci 6:913–914.

On 2017 Jun 29, Antoine Depaulis commented:

This study presents interesting behavioral observations during seizures in absence epilepsy (AE). However, there are many overstatements that could be misinterpreted. This begins with the flawed premise that anything less than full loss of consciousness during spike-wave discharges (SWD) is not AE. The broad group of experts in absence epilepsy who signed this response strongly disagree as outlined below. A more complete collective response can be found at: <https://dl.dropboxusercontent.com/u/3541791/Collective reply to Taylor et al_2017.pdf>

1. Partial consciousness during SWD The authors claim that patients with AE experience "profound loss of consciousness" during seizures. On the contrary, some preservation of consciousness is quite common in human AE. Many clinical studies have shown highly variable responsiveness depending both on task difficulty and vigilance level, even from one SWD to the next in the same individual (Blumenfeld, 2005, Guo et al., 2016). Perception of sensory stimuli, discrimination between relevant and irrelevant stimuli during absence seizures and preservation of some cortical processing has been shown in both rat models and human patients (e.g., Inoue et al, 1992, Chipaux et al., 2013, Berman et al., 2010, Drinkenburg et al., 2003, Guo et al., 2016). In addition, as the authors acknowledge, external stimuli like those in this study can increase vigilance and reduce SWD. Therefore, preserved ability to respond during a task or to modulate seizure severity is not a surprise; instead it provides further support for face validity of rodent SWD for human absence seizures.

2. SWD occur in several rodent strains The occurrence of SWD in some animals from outbred rodent strains has been published many times since the 60’s (Marescaux et al., 1992). However, SWDs are not observed in many individual animals in most inbred or outbred rodent strains (e.g., Letts et al., 2014). For example, when rats with SWD (about 30%) were selected from the initial Wistar colony of Strasbourg to produce the GAERS substrain, about 70 % of the colony did not have SWD and were bred as the non-epileptic control (NEC) strain. No NEC display SWD, even when over one year old (Depaulis et al., 2016). Why SWD are so prevalent in some outbred strains is unknown but might be due to preferential selection of dominantly inherited mutated AE genes in docile animals chosen for breeding. The many examples of single gene mutations in mice that lead to SWD/AE not seen in wild type littermates (Maheshwari and Noebels, 2014), provide further evidence that SWD are not normal in rodents. Some monogenic mutations likely result from genetic drift, such as the spontaneous Gria4 gene mutation causing SWD in C3H/HeJ mice, modulated by SWD suppressor mutations in other genes (Beyer et al., 2008, Frankel et al., 2014). Several additional differences between rodents with or without SWD make it very doubtful that SWD reflect “typical rodent behavior” (see PubMed commons for further details).

3. SWD/immobility as a model of absence epilepsy The authors disregard 4 decades of work firmly demonstrating the face validity, pharmacological predictivity and construct validity of rats and mice with SWD as models for AE (see Jarre et al., 2017 for a recent review).These animals fulfill many features relevant to the human AE (Guillemain et al., 2012). In addition to SWD, immobility and mild facial clonus, rodents models exhibit behavioral, structural, molecular and functional co-morbidities not seen in animals without SWD, but also observed in human patients (Shaw, 2007). Furthermore, the anti-epileptic drug profile in rodent AE models corresponds remarkably well with effects in human patients (Depaulis and van Luijtelaar, 2005, Shaw, 2007, Jarre et al., 2017). Over 20 single gene mutations associated with SWD, have been identified in mice and in rats that are consistent with findings in human AE (Powell et al., 2009, Noebels and Sidman, 1979) (Maheshwari and Noebels, 2014). Finally, many electrophysiological (see Depaulis et al., 2017 for a recent review), and fMRI studies (David et al., 2008, Mishra et al., 2011, 2013) in rat AE models agree with clinical data (Westmijse et al., 2009, Hamandi et al., 2008).

Based on these lines of evidence, we assert that SWD/immobility represents a form of epilepsy in rodents. In our view, these episodes are not a natural behavior nor do all individuals display this trait. Studying SWD, in both outbred and inbred strains as well as single gene mutations, has already enabled 1) the development of predictive models of the efficacy of antiepileptic drug efficacy (Tringham et al., 2012, Marks et al., 2016, Glauser et al., 2017), and 2) enhanced understanding of the pathophysiology of cortico-thalamic circuitry that generates and maintains SWD and the mechanisms underlying associated comorbidities.

Contributors and institutions (by alphabetical order) Hal Blumenfeld, Yale University, New Haven, CT, USA Stéphane Charpier, Pierre and Marie Curie University and INSERM, France Doug Coulter, University of Pennsylvania, Philadelphia, USA Vincenzo Crunelli, Cardiff University, Cardiff, UK. Antoine Depaulis, Grenoble Alpes University and INSERM, France Wayne Frankel, Columbia University, NY, USA Martin J. Gallagher, Vanderbilt University, Nashville, TN, USA John Huguenard, Stanford University, Stanford, CA, USA Cian McCafferty, Yale University, New Haven, CT, USA Richard Ngomba, University of Lincoln, UK Jeffrey Noebels, Baylor College of Medicine, TX, USA Jeanne T. Paz, Univ California & Gladstone Institute of Neurological Disease, San Francisco, USA Terence J. O’Brien, University of Melbourne, Melbourne, Australia Filiz Onat, Marmara University, Turkey Gilles van Luijtelaar, Donders Centre for Cognition, Radboud University, Nijmegen, the Netherlands Laurent Vercueil, Grenoble University Hospital, Neurology Department, Grenoble, France

REFERENCES Berman R et al. (2010) Epilepsia 51:2011–2022. Beyer B et al. (2008) Human Molecular Genetics 17:1738–1749. Blumenfeld H (2005) Epilepsia 46 Suppl 9:21–33. Chipaux M et al. (2013) PLoS One 8:e58180. David O et al. (2008) Plos Biol 6:e315–e2697. Depaulis A, Charpier S (2017) Neurosci Letters 17:30141-6. Depaulis A et al. (2016) J Neurosci Meth 260:159–174. Depaulis A, van Luijtelaar G (2005) In: Models of seizures and epilepsy (Pitkänen A, Schwartzkroin P, Moshe S, eds), pp 233–248. Amsterdam: Oxford: Elsevier Academic. Drinkenburg WHIM et al. (2003) Behavioural Brain Research 143:141–146. Frankel WN et al. (2014) PLoS Genet 10:e1004454. Glauser TA et al. (2017) Ann Neurol 81:444–453. Guillemain I et al. (2012) Epileptic Disord 14:217–225. Guo JN et al. (2016) The Lancet 15:1336-1345 Hamandi K et al. (2008) NeuroImage 39:608–618. Inoue M et al. (1992) Electroencephalogr Clin Neurophysiol. 84:172-9. Jarre G et al. (2017) In: Models of seizure and epilepsy. Second edition (Pitkänen A, Buckmaster P, Galanopoulou AS, Moshe SM, eds). Elsevier, in press. Letts VA et al. (2014) Genes, Brain and Behavior 13:519–526. Maheshwari A, Noebels JL (2014) Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits, 1st ed. Elsevier B.V. Marescaux C et al. (1992) J Neural Trans - S35:37–69. Marks WN et al. (2016) Eur J Neurosci 43:25–40. Mishra AM et al. (2013) Epilepsia 54:1214–1222. Mishra AM et al. (2011) J Neurosci 31:15053–15064. Noebels JL, Sidman RL (1979) Science 204:1334–1336. Powell KL et al. (2009) J Neurosci 29:371–380. Shaw FZ (2007) 7-12 Hz J Neurophysiol 97:238–247. Tringham E et al. (2012) Science Transl Med 4:121ra19–121ra19. Westmijse I et al. (2009) Epilepsia 50:2538–2548.

On 2017 Jun 29, Antoine Depaulis commented:

This study presents interesting behavioral observations during seizures in absence epilepsy (AE). However, there are many overstatements that could be misinterpreted. This begins with the flawed premise that anything less than full loss of consciousness during spike-wave discharges (SWD) is not AE. The broad group of experts in absence epilepsy who signed this response strongly disagree as outlined below. A more complete collective response can be found at: <https://dl.dropboxusercontent.com/u/3541791/Collective reply to Taylor et al_2017.pdf>

1. Partial consciousness during SWD The authors claim that patients with AE experience "profound loss of consciousness" during seizures. On the contrary, some preservation of consciousness is quite common in human AE. Many clinical studies have shown highly variable responsiveness depending both on task difficulty and vigilance level, even from one SWD to the next in the same individual (Blumenfeld, 2005, Guo et al., 2016). Perception of sensory stimuli, discrimination between relevant and irrelevant stimuli during absence seizures and preservation of some cortical processing has been shown in both rat models and human patients (e.g., Inoue et al, 1992, Chipaux et al., 2013, Berman et al., 2010, Drinkenburg et al., 2003, Guo et al., 2016). In addition, as the authors acknowledge, external stimuli like those in this study can increase vigilance and reduce SWD. Therefore, preserved ability to respond during a task or to modulate seizure severity is not a surprise; instead it provides further support for face validity of rodent SWD for human absence seizures.

2. SWD occur in several rodent strains The occurrence of SWD in some animals from outbred rodent strains has been published many times since the 60’s (Marescaux et al., 1992). However, SWDs are not observed in many individual animals in most inbred or outbred rodent strains (e.g., Letts et al., 2014). For example, when rats with SWD (about 30%) were selected from the initial Wistar colony of Strasbourg to produce the GAERS substrain, about 70 % of the colony did not have SWD and were bred as the non-epileptic control (NEC) strain. No NEC display SWD, even when over one year old (Depaulis et al., 2016). Why SWD are so prevalent in some outbred strains is unknown but might be due to preferential selection of dominantly inherited mutated AE genes in docile animals chosen for breeding. The many examples of single gene mutations in mice that lead to SWD/AE not seen in wild type littermates (Maheshwari and Noebels, 2014), provide further evidence that SWD are not normal in rodents. Some monogenic mutations likely result from genetic drift, such as the spontaneous Gria4 gene mutation causing SWD in C3H/HeJ mice, modulated by SWD suppressor mutations in other genes (Beyer et al., 2008, Frankel et al., 2014). Several additional differences between rodents with or without SWD make it very doubtful that SWD reflect “typical rodent behavior” (see PubMed commons for further details).

3. SWD/immobility as a model of absence epilepsy The authors disregard 4 decades of work firmly demonstrating the face validity, pharmacological predictivity and construct validity of rats and mice with SWD as models for AE (see Jarre et al., 2017 for a recent review).These animals fulfill many features relevant to the human AE (Guillemain et al., 2012). In addition to SWD, immobility and mild facial clonus, rodents models exhibit behavioral, structural, molecular and functional co-morbidities not seen in animals without SWD, but also observed in human patients (Shaw, 2007). Furthermore, the anti-epileptic drug profile in rodent AE models corresponds remarkably well with effects in human patients (Depaulis and van Luijtelaar, 2005, Shaw, 2007, Jarre et al., 2017). Over 20 single gene mutations associated with SWD, have been identified in mice and in rats that are consistent with findings in human AE (Powell et al., 2009, Noebels and Sidman, 1979) (Maheshwari and Noebels, 2014). Finally, many electrophysiological (see Depaulis et al., 2017 for a recent review), and fMRI studies (David et al., 2008, Mishra et al., 2011, 2013) in rat AE models agree with clinical data (Westmijse et al., 2009, Hamandi et al., 2008).

Based on these lines of evidence, we assert that SWD/immobility represents a form of epilepsy in rodents. In our view, these episodes are not a natural behavior nor do all individuals display this trait. Studying SWD, in both outbred and inbred strains as well as single gene mutations, has already enabled 1) the development of predictive models of the efficacy of antiepileptic drug efficacy (Tringham et al., 2012, Marks et al., 2016, Glauser et al., 2017), and 2) enhanced understanding of the pathophysiology of cortico-thalamic circuitry that generates and maintains SWD and the mechanisms underlying associated comorbidities.

Contributors and institutions (by alphabetical order) Hal Blumenfeld, Yale University, New Haven, CT, USA Stéphane Charpier, Pierre and Marie Curie University and INSERM, France Doug Coulter, University of Pennsylvania, Philadelphia, USA Vincenzo Crunelli, Cardiff University, Cardiff, UK. Antoine Depaulis, Grenoble Alpes University and INSERM, France Wayne Frankel, Columbia University, NY, USA Martin J. Gallagher, Vanderbilt University, Nashville, TN, USA John Huguenard, Stanford University, Stanford, CA, USA Cian McCafferty, Yale University, New Haven, CT, USA Richard Ngomba, University of Lincoln, UK Jeffrey Noebels, Baylor College of Medicine, TX, USA Jeanne T. Paz, Univ California & Gladstone Institute of Neurological Disease, San Francisco, USA Terence J. O’Brien, University of Melbourne, Melbourne, Australia Filiz Onat, Marmara University, Turkey Gilles van Luijtelaar, Donders Centre for Cognition, Radboud University, Nijmegen, the Netherlands Laurent Vercueil, Grenoble University Hospital, Neurology Department, Grenoble, France

REFERENCES Berman R et al. (2010) Epilepsia 51:2011–2022. Beyer B et al. (2008) Human Molecular Genetics 17:1738–1749. Blumenfeld H (2005) Epilepsia 46 Suppl 9:21–33. Chipaux M et al. (2013) PLoS One 8:e58180. David O et al. (2008) Plos Biol 6:e315–e2697. Depaulis A, Charpier S (2017) Neurosci Letters 17:30141-6. Depaulis A et al. (2016) J Neurosci Meth 260:159–174. Depaulis A, van Luijtelaar G (2005) In: Models of seizures and epilepsy (Pitkänen A, Schwartzkroin P, Moshe S, eds), pp 233–248. Amsterdam: Oxford: Elsevier Academic. Drinkenburg WHIM et al. (2003) Behavioural Brain Research 143:141–146. Frankel WN et al. (2014) PLoS Genet 10:e1004454. Glauser TA et al. (2017) Ann Neurol 81:444–453. Guillemain I et al. (2012) Epileptic Disord 14:217–225. Guo JN et al. (2016) The Lancet 15:1336-1345 Hamandi K et al. (2008) NeuroImage 39:608–618. Inoue M et al. (1992) Electroencephalogr Clin Neurophysiol. 84:172-9. Jarre G et al. (2017) In: Models of seizure and epilepsy. Second edition (Pitkänen A, Buckmaster P, Galanopoulou AS, Moshe SM, eds). Elsevier, in press. Letts VA et al. (2014) Genes, Brain and Behavior 13:519–526. Maheshwari A, Noebels JL (2014) Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits, 1st ed. Elsevier B.V. Marescaux C et al. (1992) J Neural Trans - S35:37–69. Marks WN et al. (2016) Eur J Neurosci 43:25–40. Mishra AM et al. (2013) Epilepsia 54:1214–1222. Mishra AM et al. (2011) J Neurosci 31:15053–15064. Noebels JL, Sidman RL (1979) Science 204:1334–1336. Powell KL et al. (2009) J Neurosci 29:371–380. Shaw FZ (2007) 7-12 Hz J Neurophysiol 97:238–247. Tringham E et al. (2012) Science Transl Med 4:121ra19–121ra19. Westmijse I et al. (2009) Epilepsia 50:2538–2548.

On 2017 Jul 07, DANIEL BARTH commented:

The possible role of spike-wave discharges (SWDs) in epilepsy is a highly controversial. Although we expected our work to generate debate, the eLetter from Blumenfeld et al. is disappointing.

For a more detailed response to this eLetter, please see: https://www.dropbox.com/s/d8ut94ayf57f8pk/Response to responseBlumenfeld et al2017.pdf?dl=0

• Partial consciousness and maintenance of cognitive functions during SWD

eLetter: “Their logic appears to be based on the misperception that seizures in absence epilepsy (AE) are always associated with ‘profound impairment of consciousness,’ leading to the flawed premise of the study and its interpretation that anything less than full loss of consciousness must not be AE.”

Loss of conscious is stipulated as an inclusion criterion for diagnosis of typical childhood absence epilepsy, versus mild or no impairment of consciousness as an exclusion criterion (Loiseau and Panayiotopoulos, 2000; Engle, 2013). Accordingly, we characterized WAG/Rij rats as mild absence with partial impairment of consciousness during seizures.

eLetter: “The ‘ability’ to modulate SWD severity in rodent models is not demonstrated since the reduction in number and duration can be explained otherwise.” The alternative explanation put forward is “a sensory cue white noise, which may increase arousal and vigilance known to reduce SWD”.

We stated that operantly conditioned arousal is what terminates SWD bursts early. The possibility that the arousal is due only to the white noise cue, however, fails to account for the critical result that preemptive pellet checks occurred almost entirely in the seconds after each SWD burst, indicating awareness of the SWD, associative learning, and operant control over SWDs.

• SWDs occur in several rodent strains

eLetter: Blumenfeld et al. note SWDs are not observed in most laboratory rodent strains.

That is not correct. Observations of SWDs are common in outbred Sprague Dawley, Long Evans, Wistar and hooded rats. Unlike human absence epilepsy, SWDs become more prevalent with age). Our conclusion is not that SWDs cannot reflect absence epilepsy, but that their ubiquity in various outbred rat strains suggests their unreliability as a signature of absence epilepsy. We have no vested interest in whether SWDs are genetic epilepsy or part of normal rat behavior. We simply recommend caution that Blumenfeld et al. appear opposed to.

eLetter: Single gene mutations can lead to SWDs therefore absence epilepsy. We note that while genes can influence innate rhythms, this does not prove that all SWDs are epileptic or that all SWDs model genetic absence seizures. Furthermore, inbreeding does not seem to be a requirement for SWDs, since our outbred Sprague Dawley rats had the same amount of SWDs as our inbred WAG/Rij rats, and Long Evans rats had approximately four times this amount (Fig. 7).

• SWD/immobility as a model of absence epilepsy

Blumenfeld et al list characteristics that support SWDs as a model of absence epilepsy. We do not understand why they are raising this issue, since we clearly stated that inbred WAG/Rij rats model mild absence seizures in humans.

We believe, however, the case that all SWDs in outbred rats serve to model genetic absence seizures in humans is weak. We and others remain skeptical that most outbred rats have developed - or are developing - absence epilepsy; however, as we said, it is possible.

Conclusion

The eLetter by Blumenfeld et al. was written by experts with decades of publications in absence epilepsy. We have examined many of these papers, plus ones challenging the epileptic nature of SWDs (e.g. Kaplan, 1985; Wiest and Nicolelis, 2003). None of us have studied absence seizures or SWDs, except recently (Rodgers et al., 2015). The research history and publication record of Blumenfeld et al., however, could incline them toward an imbalanced interpretation of our results. We do not understand what specifically were the “overstatements” and inappropriate “assumptions” in Taylor et al. that Blumenfeld et al. claimed in the beginning of their eLetter. We urge readers to re-read our Significance Statement in the context of the eLetter by Blumenfeld et al.: “Our evidence that inbred and outbred rats learn to control the duration of spike–wave discharges (SWDs) suggests a voluntary behavior with maintenance of consciousness. If SWDs model mild absence seizures and/or complex partial seizures in humans, then an opportunity may exist for operant control complementing or in some cases replacing medication. Their equal occurrence in outbred rats also implies a major potential confound for behavioral neuroscience experiments, at least in adult rats where SWDs are prevalent. Alternatively, the presence and voluntary control of SWDs in healthy outbred rats could indicate that these phenomena do not always model heritable absence epilepsy or post-traumatic epilepsy in humans, and may instead reflect typical rodent behavior.”

While writing and revising this manuscript in response to successive peer reviews, we responded to the points of Blumenfeld et al. and tried to objectively incorporate reviewers’ suggestions and avoid misinterpretations of our data. We are disappointed that our efforts were either largely ignored or misrepresented in the eLetter, since this unnecessarily complicates an already controversial subject and detracts from what we believe is the importance of this work.

References

Engle, J, Jr. (2013) Seizures and Epilepsy, 2nd ed. New York ; London: Oxford University Press. Kaplan BJ (1985) The epileptic nature of rodent electrocortical polyspiking is still unproven. Exp Neurol 88:425–436. Loiseau, P, Panayiotopoulos, CP (2000) Childhood absence epilepsy. In: Neurobase. San Diego: Arbor. Rodgers KM, Dudek FE, Barth DS (2015) Progressive, seizure-Like, spike-Wave discharges are common in both Injured and uninjured Sprague-Dawley rats: Implications for the fluid percussion injury model of post-traumatic epilepsy. J Neurosci 35:9194–9204. Wiest MC, Nicolelis MAL (2003) Behavioral detection of tactile stimuli during 7-12 Hz cortical oscillations in awake rats. Nat Neurosci 6:913–914.