Non-invasive electroencephalography-based technique for rapid diagnostics of absence epilepsy in rats
Electroencephalography (EEG) is a crucial tool for diagnosing absence epilepsy, a type of generalized epilepsy characterized by brief lapses of consciousness. Here, we used a Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat genetic model of absence epilepsy, in which spike-wave discharges (SWDs) manifested spontaneously and were linked to absence-like behavior. Conventionally, invasive electrocorticography (ECoG) with surgically implanted chronic electrodes has been used to confirm the absence epilepsy by the presence of SWDs in rats. However, this restricts the utilization of the same rat subject in multiple experiments. Therefore, there is a need for non-invasive EEG-based diagnostic tools in rats. This study introduces a novel, non-invasive EEG-based technique designed specifically for the rapid diagnosis of absence epilepsy. This approach is based on the sedative effect of xylazine and its unique capacity to induce SWDs. This approach was evaluated in a well-accepted genetic WAG/Rij rat model of absence epilepsy, including adult subjects of both sexes. Non-invasive EEG recording lasted 6 – 9 min. During the 6-min post-injection period, xylazine-induced SWDs closely resembled spontaneous SWDs in terms of the spike-wave morphology and frequency. The proposed non-invasive EEG-based technique is rapid, safe, inexpensive, and yields consistent results. Importantly, it can be repeated throughout a rat’s lifespan to assess the age-related progression of absence epilepsy.
- Bilo L, Pappatà S, De Simone R, Meo R. The syndrome of absence status epilepsy: Review of the literature. Epilepsy Res Treat. 2014;2014:624309. doi: 10.1155/2014/624309
- Hirsch E, French J, Scheffer IE, Bogacz A, Alsaadi T, Sperling MR, et al. ILAE definition of the Idiopathic generalized epilepsy syndromes: Position statement by the ILAE task force on nosology and definitions. Epilepsia. 2022;63(6):1475-1499. doi: 10.1111/epi.17236
- Panayiotopoulos CP. The new ILAE report on terminology and concepts for the organization of epilepsies: Critical review and contribution. Epilepsia. 2012;53(3):399-404. doi: 10.1111/J.1528-1167.2011.03381.X
- Koutroumanidis M, Tsiptsios D, Kokkinos V, Kostopoulos GK. Focal and generalized EEG paroxysms in childhood absence epilepsy: Topographic associations and distinctive behaviors during the first cycle of non-REM sleep. Epilepsia. 2012;53(5):840-849. doi: 10.1111/j.1528-1167.2012.03424.x
- Sadleir LG, Scheffer IE, Smith S, Carstensen B, Farrell K, Connolly MB. EEG features of absence seizures in idiopathic generalized epilepsy: Impact of syndrome, age, and state. Epilepsia. 2009;50(6):1572-1578. doi: 10.1111/J.1528-1167.2008.02001.X
- Jafarian M, Esmaeil Alipour M, Karimzadeh F. Experimental models of absence epilepsy. Basic Clin Neurosci J. 2020;11(6):715-726. doi: 10.32598/bcn.11.6.731.1
- Cortez MA, Kostopoulos GK, Snead OC. Acute and chronic pharmacological models of generalized absence seizures. J Neurosci Methods. 2016;260:175-184. doi: 10.1016/j.jneumeth.2015.08.034
- Coenen AML, Van Luijtelaar ELJM. The WAG/Rij rat model for absence epilepsy: Age and sex factors. Epilepsy Res. 1987;1(5):297-301. doi: 10.1016/0920-1211(87)90005-2
- Coenen AML, Van Luijtelaar ELJM. Genetic animal models for absence epilepsy: A review of the WAG/Rij strain of rats. Behav Genet. 2003;33(6):635-655. doi: 10.1023/a:1026179013847
- Van Luijtelaar G, Sitnikova E. Global and focal aspects of absence epilepsy: The contribution of genetic models. Neurosci Biobehav Rev. 2006;30(7):983-1003. doi: 10.1016/j.neubiorev.2006.03.002
- Van Luijtelaar G, Van Oijen G. Establishing drug effects on electrocorticographic activity in a genetic absence epilepsy model: Advances and pitfalls. Front Pharmacol. 2020;11:395. doi: 10.3389/fphar.2020.00395
- Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C. Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol. 1998;55(1): 27-57. doi: 10.1016/S0301-0082(97)00091-9
- Marescaux C, Vergnes M. Genetic absence epilepsy in rats from strasbourg (GAERS). Ital J Neurol Sci. 1995;16(1- 2):113-118. doi: 10.1007/BF02229083
- Depaulis A, Van Luijtelaar G. Genetic models of absence epilepsy in the rat. In: Models of Seizures and Epilepsy. Netherlands: Elsevier; 2006. p. 233-248. doi: 10.1016/B978-012088554-1/50020-7
- Depaulis A, David O, Charpier S. The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies. J Neurosci Methods. 2016;260:159-174. doi: 10.1016/j.jneumeth.2015.05.022
- Pearce PS, Friedman D, LaFrancois JJ, et al. Spike-wave discharges in adult Sprague-Dawley rats and their implications for animal models of temporal lobe epilepsy. Epilepsy Behav. 2014;32:121-131. doi: 10.1016/j.yebeh.2014.01.004
- Shaw FZ. Is spontaneous high-voltage rhythmic spike discharge in long evans rats an absence-like seizure activity? J Neurophysiol. 2004;91(1):63-77. doi: 10.1152/jn.00487.2003
- Sitnikova E, Van Luijtelaar G. Electroencephalographic precursors of spike-wave discharges in a genetic rat model of absence epilepsy: Power spectrum and coherence EEG analyses. Epilepsy Res. 2009;84(2-3):159-171.
- Vergnes M, Marescaux C, Micheletti G, et al. Spontaneous paroxysmal electroclinical patterns in rat: A model of generalized non-convulsive epilepsy. Neurosci Lett. 1982;33(1):97-101. doi: 10.1016/0304-3940(82)90136-7
- Vergnes M, Marescaux C, Depaulis A. Mapping of spontaneous spike and wave discharges in Wistar rats with genetic generalized non-convulsive epilepsy. Brain Res. 1990;523(1):87-91. doi: 10.1016/0006-8993(90)91638-W
- Moon H, Kwon J, Eun J, et al. Electrocorticogram (ECoG): Engineering approaches and clinical challenges for translational medicine. Adv Mater Technol. 2024;9(12):2301692. doi: 10.1002/admt.202301692
- Sitnikova E. Behavioral and cognitive comorbidities in genetic rat models of absence epilepsy (focusing on GAERS and WAG/Rij rats). Biomedicines. 2024;12(1):122. doi: 10.3390/biomedicines12010122
- Leo A, De Caro C, Nesci V, et al. WAG/Rij rat model: A resource for the pharmacology of epileptogenesis and related neurological/psychiatric comorbidities. Neurosci Res Notes. 2019;1(3):18-34. doi: 10.31117/neuroscirn.v1i3.22
- Marks WN, Cavanagh ME, Greba Q, Cain SM, Snutch TP, Howland JG. The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans. Eur J Neurosci. 2016;43(1):25-40. doi: 10.1111/ejn.13110
- Sitnikova E, Pupikina M, Rutskova E. Alpha2 adrenergic modulation of spike-wave epilepsy: Experimental study of pro-epileptic and sedative effects of dexmedetomidine. Int J Mol Sci. 2023;24(11):9445. doi: 10.3390/ijms24119445
- Sitnikova E. Adrenergic mechanisms of absence status epilepticus. Front Neurol. 2023;14:1298310. doi: 10.3389/fneur.2023.1298310
- Buzsáki G, Kennedy B, Solt VB, Ziegler M. Noradrenergic control of thalamic oscillation: The role of alpha-2 receptors. Eur J Neurosci. 1991;3(3):222-229. doi: 10.1111/j.1460-9568.1991.tb00083.x
- Kandel A, Buzsáki G. Cellular-synaptic generation of sleep spindles, spike-and-wave discharges, and evoked thalamocortical responses in the neocortex of the rat. J Neurosci. 1997;17(17):6783-6797. doi: 10.1523/JNEUROSCI.17-17-06783.1997
- Van Luijtelaar ELJM, Coenen AML. Two types of electrocortical paroxysms in an inbred strain of rats. Neurosci Lett. 1986;70(3):393-397. doi: 10.1016/0304-3940(86)90586-0
- Russo E, Citraro R, Constanti A, et al. Upholding WAG/ Rij rats as a model of absence epileptogenesis: Hidden mechanisms and a new theory on seizure development. Neurosci Biobehav Rev. 2016;71:388-408. doi: 10.1016/j.neubiorev.2016.09.017
- Van Luijtelaar G, Onat FY, Gallagher MJ. Animal models of absence epilepsies: What do they model and do sex and sex hormones matter? Neurobiol Dis. 2014;72(PB):167-179. doi: 10.1016/j.nbd.2014.08.014
- Sitnikova E, Hramov AE, Grubov V, Koronovsky AA. Age-dependent increase of absence seizures and intrinsic frequency dynamics of sleep spindles in rats. Neurosci J. 2014;2014:370764. doi: 10.1155/2014/370764
- Sitnikova E, Van Luijtelaar G. Electroencephalographic characterization of spike-wave discharges in cortex and thalamus in WAG/Rij rats. Epilepsia. 2007;48(12): 2296-2311. doi: 10.1111/j.1528-1167.2007.01250.x
- Lazarini-Lopes W, Campos-Rodriguez C, Palmer D, N’Gouemo P, Garcia-Cairasco N, Forcelli PA. Absence epilepsy in male and female WAG/Rij rats: A longitudinal EEG analysis of seizure expression. Epilepsy Res. 2021;176:106693. doi: 10.1016/j.eplepsyres.2021.106693
- Sitnikova E. Xylazine Induces Continuous Spike-wave Discharges in Rat Electrocorticogram Encyclopedia MDPI. Encyclopedia; 2024. Available from: https://encyclopedia. pub/video/video_detail/1305 [Last accessed on 2024 Jul 22].
- Ngoupaye GT, Adassi MB, Foutsop AF, Yassi FB, Ngo Bum E. Pentylenetetrazole kindling-induced epilepsy rat models: Insight on the severity state, a comparative study. IBRO Neurosci Rep. 2022;13:164-176. doi: 10.1016/j.ibneur.2022.08.003
- Van Erum J, Van Dam D, De Deyn PP. PTZ-induced seizures in mice require a revised Racine scale. Epilepsy Behav. 2019;95:51-55. doi: 10.1016/j.yebeh.2019.02.029
- Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr Protoc Neurosci. 2012;58(1). doi: 10.1002/0471142301.ns0937s58
- Singh T, Mishra A, Goel RK. PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: Relevance and reliability. Metab Brain Dis. 2021;36(7):1573-1590. doi: 10.1007/S11011-021-00823-3/TABLES/5
- Onat FY, Van Luijtelaar G, Nehlig A, Snead OC. The involvement of limbic structures in typical and atypical absence epilepsy. Epilepsy Res. 2013;103(2-3):111-123. doi: 10.1016/j.eplepsyres.2012.08.008
- Van Luijtelaar G, Bikbaev A. Midfrequency cortico-thalamic oscillations and the sleep cycle: Genetic, time of day and age effects. Epilepsy Res. 2007;73(3):259-265. doi: 10.1016/j.eplepsyres.2006.11.002
- Crunelli V, Lőrincz ML, McCafferty C, et al. Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures. Brain. 2020;143(8):2341-2368. doi: 10.1093/brain/awaa072
- Guilhoto LM. Absence epilepsy: Continuum of the clinical presentation and epigenetics? Seizure Eur J Epilepsy. 2017;44:53-57. doi: 10.1016/j.seizure.2016.11.031