Accessible Requires Authentication Published by De Gruyter September 14, 2019

Seizure initiation in infantile spasms vs. focal seizures: proposed common cellular mechanisms

Roger D. Traub, Friederike Moeller, Richard Rosch, Torsten Baldeweg, Miles A. Whittington and Stephen P. Hall

Abstract

Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more – the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesis – emphasizing the importance of brain pH – to explain the commonalities and differences of EEG signals in IS versus focal seizures.

Acknowledgments

This study was funded by IBM Corp. and NINDS/NIH NS044133 (R.D.T.; from the National Institute of Neurological Diseases and Stroke/National Institutes of Health); Wellcome Trust Funder Id: http://dx.doi.org/10.13039/100004440, 209164/Z/17/Z (M.A.W. and S.P.H.); with infrastructure support through the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children, NHS Foundation Trust and University College London (R.R.); and Great Ormond Street Hospital Children’s Charity (T.B.). We acknowledge the helpful discussions with Drs. Yoshio Okada, Sufi Zafar, Sam Berkovic, David Grayden, and Mark Cook. We thank Drs. Joefon Jann and Robert Walkup (IBM Corp.) for the invaluable computing support.

Appendix: Methods

Clinical intracranial SEEG recordings

Intracranial EEG data recorded here were routine clinical recordings performed as part of the comprehensive pediatric epilepsy surgery program at Great Ormond Street Hospital (London, UK) and were conducted entirely based on clinical need. SEEG was recorded via depth electrodes placed in the brain parenchyma through burr holes placed to record electrical activity from the epileptogenic network during telemetry in hospital stay. Recordings were performed at sampling frequencies of 1 kHz and displayed in bipolar reference for visualization purposes. The use of anonymized SEEG data for research purposes was reviewed and approved by the UK National Health Regulatory Authority and the local hospital research and development office.

In vitro methods

Coronal slices (450 μm thick) containing secondary somatosensory/parietal area S2/Par2 were prepared from adult male Wistar rats (~150 g) and maintained at 34°C at the interface between humidified 95% O2/5% CO2 and ACSF containing 126 mm NaCl, 3 mm KCl, 1.25 mm NaH2PO4, 1 mm MgSO4, 1.2 mm CaCl2, 24 mm NaHCO3 and 10 mm glucose. All surgical procedures were in accordance with the regulations of the UK Animals (Scientific Procedures) Act of 1986. Persistent, spontaneous delta rhythms were induced by perfusion of the cholinergic agonist carbachol (2 μm) and the D1 dopamine receptor antagonist SCH23390 (10 μm) according to the methods of Carracedo et al. (2013). Delta-based epileptiform activity was generated by bath application of TMA (1 mm) to alkalinize neuronal cytosol and dTC (10 μm) to selectively reduce superficial layer inhibition (Hall et al., 2015). Extracellular field potential recordings were taken with micropipettes (2–5 MΩ) filled with ACSF. Intracellular recordings used pipettes with 2 M potassium acetate (50–100 MΩ). Extracellular data were bandpass filtered at 0.1 Hz to 0.5 kHz, with intracellular DC recordings low-passed filtered at 2.5 kHz.

Model structure

The simulation program used was called plateauVFO.f, written in Fortran to run on 10 processors in the mpi parallel environment, Linux operating system. The processors resided in a Power8 chip in the Cognitive Computing Cluster at the IBM Thomas J. Watson Research Center. The structure of the program was similar to that of spikewaveS.f used by Hall et al. (2018), with these modifications:

  1. Deep-layer low-threshold spiking (LTS) interneurons were removed; instead, there were VIP interneurons (see Hall et al., 2018), which produce GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs) in various interneuron types, and small GABAA and GABAB receptor-mediated IPSPs in pyramidal cell dendrites in the superficial cortical layers.

  2. The numbers of neurons of different types were adjusted so that the program would run on 10 processors for computational efficiency. The neurons are superficial interneurons (100 basket, 100 axoaxonic, 100 LTS, 100 VIP, and 100 neurogliaform), deep interneurons (200 basket, 100 axoaxonic, and 200 neurogliaform), spiny stellate (500), nontufted deep pyramids (500), RS tufted deep pyramids (500), IB deep pyramids (500), and superficial RS pyramids (1000). As before, neurogliaform interneurons produce GABAA and GABAB receptor-mediated IPSPs.

  3. The code was added to allow for time-dependent alterations in membrane conductance densities (intrinsic and/or synaptic) of IB pyramidal cells; this was done to explore the conditions that result in plateau potentials. For the details of the alterations used here, see Figures 10 and 11.

The source code can be obtained from (and will be deposited in ModelDB.

References

Aggarwal, M., Kondeti, B., and McKenna, R. (2013). Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review. Expert Opin. Ther. Pat. 23, 717–724. Search in Google Scholar

Akiyama, T., Otsubo, H., Ochi, A., Ishiguro, T., Kadokura, G., Nair, R.R., Weiss, S.K., Rutka, J.T., and Snead 3rd, O.C. (2005). Focal cortical high-frequency oscillations trigger epileptic spasms: confirmation by digital video subdural EEG. Clin. Neurophysiol. 116, 2819–2825. Search in Google Scholar

Amzica, F. and Steriade, M. (1995). Short- and long-range neuronal synchronization of the slow (<1 Hz) cortical oscillation. J. Neurophysiol. 73, 20–38. Search in Google Scholar

André, V.M., Flores-Hernández, J., Cepeda, C., Starling, A.J., Nguyen, S., Lobo, M.K., Vinters, H.V., Levine, M.S., and Mathern, G.W. (2004). NMDA receptor alterations in neurons from pediatric cortical dysplasia tissue. Cereb. Cortex 14, 634–646. Search in Google Scholar

Apostolides, P.F., Milstein, A.D., Grienberger, C., Bittner, K.C., and Magee, J.C. (2016). Axonal filtering allows reliable output during dendritic plateau-driven complex spiking in CA1 neurons. Neuron 89, 770–783. Search in Google Scholar

Arroyo, S., Lesser, R.P., Fisher, R.S., Vining, E.P., Krauss, G.L., Bandeen-Roche, K., Hart, J., Gordon, B., Uematsu, S., and Webber, R. (1994). Clinical and electroencephalographic evidence for sites of origin of seizures with diffuse electrodecremental pattern. Epilepsia 35, 974–987. Search in Google Scholar

Backx, L., Ceulemans, B., Vermeesch, J.R., Devriendt, K., and Van Esch, H. (2009). Early myoclonic encephalopathy caused by a disruption of the neuregulin-1 receptor ErbB4. Eur. J. Hum. Genet. 17, 378–382. Search in Google Scholar

Bannai, H., Niwa, F., Sherwood, M.W., Shrivastava, A.N., Arizono, M., Miyamoto, A., Sugiura, K., Lévi, S., Triller, A., and Mikoshiba, K. (2015). Bidirectional control of synaptic GABAAR clustering by glutamate and calcium. Cell Rep. 13, 2768–2780. Search in Google Scholar

Bink, H., Sedigh-Sarvestani, M., Fernandez-Lamo, I., Kini, L., Ung, H., Kuzum, D., Vitale, F., Litt, B., and Contreras, D. (2018). Spatiotemporal evolution of focal epileptiform activity from surface and laminar field recordings in cat neocortex. J. Neurophysiol. 119, 2068–2081. Search in Google Scholar

Bonaiuto, J., Rossiter, H.E., Meyer, S.S., Adams, N., Little, S., Callaghan, M.F., Dick, F., Bestmann, S., and Barnes, G.R. (2018). Non-invasive laminar inference with MEG: comparison of methods and source inversion algorithms. Neuroimage 167, 372–383. Search in Google Scholar

Bonnet, U., Bingmann, D., Speckmann, E.J., and Wiemann, M. (2018). Aging is associated with a mild acidification in neocortical human neurons in vitro. J. Neural Transm. 125, 1495–1501. Search in Google Scholar

Boto, E., Holmes, N., Leggett, J., Roberts, G., Shah, V., Meyer, S.S., Muñoz, L.D., Mullinger, K.J., Tierney, T.M., Bestmann, S., et al. (2018). Moving magnetoencephalography towards real-world applications with a wearable system. Nature 555, 657–661. Search in Google Scholar

Buhl, D.L., Harris, K.D., Hormuzdi, S.G., Monyer, H., and Buzsáki, G. (2003). Selective impairment of hippocampal gamma oscillations in connexin-36 knock-out mouse in vivo. J. Neurosci. 23, 1013–1018. Search in Google Scholar

Caraballo, R.H., Reyes, G., Falsaperta, R., Ramos, B., Ruiz, A.C., Fernandez, C.A., Peretti, G., and Beltran, L. (2016). Epileptic spasms in clusters with focal EEG paroxysms: a study of 12 patients. Seizure 35, 88–92. Search in Google Scholar

Carracedo, L.M., Kjeldsen, H., Cunnington, L., Jenkins, A., Schofield, I., Cunningham, M.O., Traub, R.D., and Whittington, M.A. (2013). A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms. J. Neurosci. 33, 10750–10761. Search in Google Scholar

Cembrowski, M.S., Wang, L., Sugino, K., Shields, B.C., and Spruston, N. (2016). Hipposeq: a comprehensive RNA-seq database of gene expression in hippocampal principal neurons. eLife 5, e14997. Search in Google Scholar

Cepeda, C., André, V.M., Levine, M.S., Salamon, N., Miyata, H., Vinters, H.V., and Mathern, G.W. (2006). Epileptogenesis in pediatric cortical dysplasia: the dysmature cerebral developmental hypothesis. Epilepsy Behav. 9, 219–235. Search in Google Scholar

Cepeda, C., André, V.M., Wu, N., Yamazaki, I., Uzqil, B., Vinters, H.V., Levine, M.S., and Mathern, G.W. (2007). Immature neurons and GABA networks may contribute to epileptogenesis in pediatric cortical dysplasia. Epilepsia 48, 79–85. Search in Google Scholar

Chalifoux, J.R. and Carter, A.G. (2011). GABAB receptor modulation of voltage-sensitive calcium channels in spines and dendrites. J. Neurosci. 31, 4221–4232. Search in Google Scholar

Chiofalo, N., Fuentes, A., and Gálvez, S. (1980). Serial EEG findings in 27 cases of Creutzfeldt-Jakob disease. Arch. Neurol. 37, 143–145. Search in Google Scholar

Church, J. and Baimbridge, K.G. (1991). Exposure to high-pH medium increases the incidence and extent of dye coupling between rat hippocampal CA1 pyramidal neurons in vitro. J. Neurosci. 11, 3289–3295. Search in Google Scholar

Church, J., Baxter, K.A., and McLarnon, J.G. (1998). pH modulation of Ca2+ responses and a Ca2+-dependent K+ channel in cultured rat hippocampal neurones. J. Physiol. 511, 119–132. Search in Google Scholar

Clarke, M., Gill, J., Noronha, M., and McKinlay, I. (1987). Early infantile epileptic encephalopathy with suppression burst: Ohtahara syndrome. Dev. Med. Child Neurol. 29, 520–528. Search in Google Scholar

Colquhoun, D., Jonas, P., and Sakmann, B. (1992). Action of brief pulses of glutamate on AMPA/kainate receptors in patches from different neurons of rat hippocampal slices. J. Physiol. 458, 261–287. Search in Google Scholar

Costa, C., Leone, G., Saulle, E., Pisani, F., Bernardi, G., and Calabresi, P. (2004). Coactivation of GABAA and GABAB receptor results in neuroprotection during in vitro ischemia. Stroke 35, 596–600. Search in Google Scholar

Crino, P.B. (2015). mTOR signalling in epilepsy: insights from malformations of cortical development. Cold Spring Harb. Perspect. Med. 5, a022442. Search in Google Scholar

Cunningham, M.O., Whittington, M.A., Bibbig, A., Roopun, A., LeBeau, F.E.N., Vogt, A., Monyer, H., Buhl, E.H., and Traub, R.D. (2004). A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro. Proc. Natl. Acad. Sci. U.S.A. 101, 7152–7157. Search in Google Scholar

Cunningham, M.O., Roopun, A.K., Schofield, I.S., Whittaker, R.G., Duncan, R., Russell, A., Jenkins, A., Nicholson, C., Whittington, M.A., and Traub, R.D. (2012). Glissandi: transient fast electrocorticographic oscillation of steadily increasing frequency, explained by temporally increasing gap junction conductance. Epilepsia 53, 1205–1214. Search in Google Scholar

Curatolo, P., Seri, S., Verdecchia, M., and Bombardieri, R. (2001). Infantile spasms in tuberous sclerosis complex. Brain Dev. 23, 502–507. Search in Google Scholar

Daniels, D., Knupp, K., Benke, T., Wolter-Warmerdam, K., Moran, M., and Hickey, F. (2019). Infantile spasms in children with Down syndrome: identification and treatment response. Glob. Pediatr. Health 6, 2333794X18821939. Search in Google Scholar

Davidson, J.S., Baumgarten, I.M., and Harley, E.H. (1986). Reversible inhibition of intercellular junctional communication by glycyrrhetinic acid. Biochem. Biophys. Res. Commun. 134, 29–36. Search in Google Scholar

Degro, C.E., Kulik, A., Booker, S.A., and Vida, I. (2015). Compartmental distribution of GABAB receptor-mediated currents along the somatodendritic axis of hippocampal pyramidal cells. Front. Synaptic Neurosci. 7, 6. Search in Google Scholar

Dichter, M. and Spencer, W.A. (1969). Penicillin-induced interictal discharges from the cat hippocampus. II. Mechanisms underlying origin and restriction. J. Neurophysiol. 32, 663–687. Search in Google Scholar

Draguhn, A., Traub, R.D., Schmitz, D., and Jefferys, J.G.R. (1998). Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro. Nature 394, 189–192. Search in Google Scholar

French, R.J. and Shoukimas, J.J. (1981). Blockage of squid axon potassium conductance by internal tetra-N-alkylammonium ions of various sizes. Biophys. J. 34, 271–291. Search in Google Scholar

Fu, C., Cawthon, B., Clinkscales, W., Bruce, A., Winzenburger, P., and Ess, K.C. (2012). GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb. Cortex 22, 2111–2119. Search in Google Scholar

Fujiwara, H., Leach, J.L., Greiner, H.M., Holland-Bouley, K.D., Rose, D.F., Arthur, T., and Mangano, F.T. (2016). Resection of ictal high frequency oscillations is associated with favourable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex. Epilepsy Res. 126, 90–97. Search in Google Scholar

Gerber, U. and Gähwiler, B.H. (1994). GABAB and adenosine receptors mediate enhancement of the K+ current, IAHP, by reducing adenylyl cyclase activity in rat CA3 hippocampal neurons. J. Neurophysiol. 72, 2360–2367. Search in Google Scholar

González-Nieto, D., Gómez-Hernández, J.M., Larrosa, B., Gutiérrez, C., Muñoz, M.D., Fasciani, I., O’Brien, J.O., Zappalà, A., Cicirata, F., and Barrio, L.C. (2008). Regulation of neuronal connexin-36 channels by pH. Proc. Natl. Acad. Sci. U.S.A. 105, 17169–17174. Search in Google Scholar

Grenier, F., Timofeev, I., and Steriade, M. (2003). Neocortical very fast oscillations (ripples, 80-200 Hz) during seizures: intracellular correlates. J. Neurophysiol. 89, 841–852. Search in Google Scholar

Grinenko, O., Li, J., Mosher, J.C., Wang, I.Z., Bulacio, J.C., Gonzalez-Martinez, J., Nair, D., Najm, I., Leahy, R.M., and Chauvel, P. (2018). A fingerprint of the epileptogenic zone in human epilepsies. Brain 141, 117–131. Search in Google Scholar

Hall, S., Hunt, M., Simon, A., Cunnington, L.G., Schofield, I.S., Traub, R.D., and Whittington, M.A. (2015). Unbalanced peptidergic inhibition in superficial neocortex generates sleep-associated seizure activity. J. Neurosci. 35, 9302–9314. Search in Google Scholar

Hall, S., Traub, R.D., Adams, N.E., Cunningham, M.O., Schofield, I., Jenkins, A., and Whittington, M.S. (2018). Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike and wave-like electrographic events in vitro. J. Neurophysiol. 119, 49–61. Search in Google Scholar

Hamed, S.A. (2017). The effect of antiepileptic drugs on the kidney function and structure. Expert Rev. Clin. Pharmacol. 10, 993–1006. Search in Google Scholar

Herbst, S.M., Proepper, C.R., Geis, T., Borggraefe, I., Hahn, A., Debus, O., Haeussler, M., von Gersdorff, G., Kurlemann, G., Ensslen, M., et al. (2016). LIS1-associated classic lissencephaly: a retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs. Brain Dev. 38, 399–406. Search in Google Scholar

Hicks, R.G. and Poole, J.L. (1981). Electroencephalographic changes with hypothermia and cardiopulmonary bypass in children. J. Thorac. Cardiovasc. Surg. 81, 781–786. Search in Google Scholar

Higley, M.J. (2014). Localized GABAergic inhibition of dendritic Ca2+ signaling. Nat. Rev. Neurosci. 15, 567–572. Search in Google Scholar

Hollrigel, G.S., Chen, K., Baram, T.Z., and Soltesz, I. (1998). The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. Neuroscience 84, 71–79. Search in Google Scholar

Hrachovy, R.A. and Frost Jr., J.D. (2003). Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/West syndrome). J. Clin. Neurophysiol. 20, 408–425. Search in Google Scholar

Hrachovy, R.A. and Frost Jr., J.D. (2013). Infantile spasms. Handb. Clin. Neurol. 111, 611–618. Search in Google Scholar

Im, W.B. and Quandt, F.N. (1992). Mechanism of asymmetric block of K channels by tetraalkylammonium ions in mouse neuroblastoma cells. J. Membr. Biol. 130, 115–124. Search in Google Scholar

Inoue, T., Kobayashi, K., Oka, M., Yoshinaga, H., and Ohtsuka, Y. (2008). Spectral characteristics of EEG gamma rhythms associated with epileptic spasms. Brain Dev. 30, 321–328. Search in Google Scholar

Inoue, T., Shimizu, M., Hamano, S., Murakami, N., Nagai, T., and Sakuta, R. (2014). Epilepsy and West syndrome in neonates with hypoxic-ischemic encephalopathy. Pediatr. Int. 56, 369–372. Search in Google Scholar

Jdila, M.B., Issa, A.B., Khabou, B., Rhouma, B.B., Kamoun, F., Ammar-Keskes, L., Triki, C., and Fakhfakh, F. (2017). Novel mutations in the CKDL5 gene in complex genotypes associated with West syndrome with variable phenotype: first description of somatic mosaic state. Clin. Chim. Acta 473, 51–59. Search in Google Scholar

Kannan, L., Vogrin, S., Bailey, C., Maxiner, W., and Harvey, A.S. (2016). Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. Brain 139, 2653–2667. Search in Google Scholar

Kass, J.I. and Mintz, I.M. (2006). Silent plateau potentials, rhythmic bursts, and pacemaker firing: three patterns of activity that coexist in quadristable subthalamic neurons. Proc. Natl. Acad. Sci. U.S.A. 103, 183–188. Search in Google Scholar

Kiehn, O. (1991). Plateau potentials and active integration in the ‘final common pathway’ for motor behavior. Trends Neurosci. 14, 68–73. Search in Google Scholar

Kihara, A.H., Mantovani de Castro, L., Belmonte, M.A., Moriscot, A.S., and Hamassaki, D.E. (2006). Expression of connexins 36, 43, and 45 during postnatal development of the mouse retina. J. Neurobiol. 66, 1397–1410. Search in Google Scholar

Kim, M.-J., Yum, M.-S., Yeh, H.-R., and Ko, T.-S. (2018). Fast oscillation dynamics during hypsarrhythmia as a localization biomarker. J. Neurophys. 119, 679–687. Search in Google Scholar

Klemic, K.G., Shieh, C.C., Kirsch, G.E., and Jones, S.W. (1998). Inactivation of Kv2.1 potassium channels. Biophys. J. 74, 1779–1789. Search in Google Scholar

Kobayashi, K., Oka, M., Akiyama, T., Inoue, T., Abiru, K., Ogino, T., Yoshinaga, H., Ohtsuka, Y., and Oka, E. (2004). Very fast rhythmic activity on scalp EEG associated with epileptic spasms. Epilepsia 45, 488–496. Search in Google Scholar

Kobayashi, K., Akiyama, T., Oka, M., Endoh, F., and Yoshinaga, H. (2015). A storm of fast (40-150 Hz) oscillations during hypsarrhythmia in West syndrome. Ann. Neurol. 77, 58–67. Search in Google Scholar

Korff, C.M., Vulliemoz, S., Picard, F., and Fluss, J. (2012). Ohtahara syndrome or early-onset West syndrome? A case with overlapping features and favorable response to vigabatrin. Eur. J. Paed. Neurol. 16, 753–757. Search in Google Scholar

Kossoff, E.H. (2010). Infantile spasms. Neurologist 16, 69–75. Search in Google Scholar

Kramer, U., Sue, W.C., and Mikati, M.A. (1997). Hypsarrhythmia: frequency of variant patterns and correlation with etiology and outcome. Neurology 48, 197–203. Search in Google Scholar

Kroeger, D., Florea, B., and Amzica, F. (2013). Human brain activity patterns beyond the isoelectric line of extreme deep coma. PLoS One 8, e75257. Search in Google Scholar

Laxer, K.D., Hubesch, B., Sappey-Marinier, D., and Weiner, M.W. (1992). Increased pH and inorganic phosphate in temporal seizure foci demonstrated by [31P]MRS. Epilepsia 33, 618–623. Search in Google Scholar

Lemke, J.R., Hendrickx, R., Geider, K., Laube, B., Schwake, M., Harvey, R.J., James, V.M., Pepler, A., Steiner, I., Hörtnagel, K., et al. (2014). GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol. 75, 147–154. Search in Google Scholar

Lewis, L.D., Ching, S., Weiner, V.S., Peterfreund, R.A., Eskandar, E.N., Cash, S.S., Brown, E.N., and Purdon, P.L. (2013). Local cortical dynamics of burst suppression in the anaesthetized brain. Brain 136, 2727–2737. Search in Google Scholar

Li, T., Cheng, M., Wang, J., Hong, S., Li, M., Liao, S., Xie, L., and Jiang, L. (2018). De novo mutations of STXBP1 in Chinese children with early onset epileptic encephalopathy. Genes Brain Behav. 17, e12492. Search in Google Scholar

Ling, D.S. and Benardo, L.S. (1994). Properties of isolated GABAB-mediated inhibitory postsynaptic currents in hippocampal pyramidal cells. Neuroscience 63, 937–944. Search in Google Scholar

Madhusudanan, P., Reade, S., and Shankarappa, S.A. (2017). Neuroglia as targets for drug delivery systems: a review. Nanomedicine 13, 667–679. Search in Google Scholar

Magnotta, V.A., Heo, H.-Y., Dlouhy, B.J., Dahdaleh, N.S., Follmer, R.L., Thedens, D.R., Welsh, M.J., and Wemmie, J.A. (2012). Detecting activity-evoked pH changes in human brain. Proc. Natl. Acad. Sci. U.S.A. 109, 8270–8273. Search in Google Scholar

Major, P., Rakowski, S., Simon, M.V., Cheng, M.L., Eskandar, E., Baron, J., Leeman, B.A., Frosch, M.P., and Thiele, E.A. (2009). Are cortical tubers epileptogenic? Evidence from electrocorticography. Epilepsia 50, 147–154. Search in Google Scholar

Makani, S. and Chesler, M. (2007). Endogenous alkaline transients boost postsynaptic NMDA receptor responses in hippocampal CA1 pyramidal neurons. J. Neurosci. 27, 7438–7446. Search in Google Scholar

Makani, S. and Chesler, M. (2010). Rapid rise of extracellular pH evoked by neural activity is generated by the plasma membrane calcium ATPase. J. Neurophysiol. 103, 667–676. Search in Google Scholar

Marcotte, L., Aronica, E., Baybis, M., and Crino, P.B. (2012). Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex. Acta Neuropathol. 123, 685–693. Search in Google Scholar

McVicar, N., Li, A.X., Gonçalves, D.F., Bellyou, M., Meakin, S.O., Prado, M.A., and Bartha, R. (2014). Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. J. Cereb. Blood Flow Metab. 34, 690–698. Search in Google Scholar

Mercer, A., Bannister, A.P., and Thomson, A.M. (2006). Electrical coupling between pyramidal cells in adult cortical regions. Brain Cell Biol. 35, 13–27. Search in Google Scholar

Miles, R. and Wong, R.K.S. (1987). Inhibitory control of local excitatory circuits in the guinea-pig hippocampus. J. Physiol. 388, 611–629. Search in Google Scholar

Mohamed, A.R., Bailey, C.A., Freeman, J.L., Maixner, W., Jackson, G.D., and Harvey, A.S. (2012). Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology 79, 2249–2257. Search in Google Scholar

Mohapatra, D.P., Misonou, H., Pan, S.J., Held, J.E., Surmeier, D.J., and Trimmer, J.S. (2009). Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the KV2.1 potassium channel. Channels 3, 46–56. Search in Google Scholar

Obara, M., Szeliga, M., and Albrecht, J. (2008). Regulation of pH in the mammalian central nervous system under normal and pathological conditions: facts and hypotheses. Neurochem. Int. 52, 905–919. Search in Google Scholar

Ogawa, T., Sugiyama, A., Ishiwa, S., Suzuki, M., Ishihara, T., and Sato, K. (1984). Ontogenetic development of autoregressive component waves of waking EEG in normal infants and children. Brain Dev. 6, 289–303. Search in Google Scholar

Ohtahara, S. and Yamatogi, Y. (2003). Epileptic encephalopathies in early infancy with suppression-burst. J. Clin. Neurophysiol. 20, 398–407. Search in Google Scholar

Oka, M., Kobayashi, K., Akiyama, T., Ogino, T., and Oka, E. (2004). A study of spike-density on EEG in West syndrome. Brain Dev. 26, 105–112. Search in Google Scholar

Olbrich, E., Rusterholz, T., LeBourgeois, M.K., and Achermann, P. (2017). Developmental changes in sleep oscillations during early childhood. Neural Plast. 6160959. Search in Google Scholar

Paalasmaa, P., Taira, T., Voipio, J., and Kaila, K. (1994). Extracellular alkaline transients mediated by glutamate receptors in the rat hippocampal slice are not due to a proton conductance. J. Neurophysiol. 72, 2031–2013. Search in Google Scholar

Palacios-Prado, N., Briggs, S.W., Skeberdis, V.A., Pranevicius, M., Bennett, M.V., and Bukauskas, F.F. (2010). pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions. Proc. Natl. Acad. Sci. U.S.A. 107, 9897–9902. Search in Google Scholar

Pavlov, I., Kaila, K., Kullmann, D.M., and Miles, R. (2013). Cortical inhibition, pH and cell excitability in epilepsy: what are optimal targets for antiepileptic interventions? J. Physiol. 591, 765–774. Search in Google Scholar

Pérez-Garci, E., Larkum, M.E., and Nevian, T. (2013). Inhibition of dendritic Ca2+ spikes by GABAB receptors in cortical pyramidal neurons is mediated by a direct Gi/o-βγ-subunit interaction with Cav1 channels. J. Physiol. 591, 1599–1612. Search in Google Scholar

Perez-Velazquez, J.L., Valiante, T.A., and Carlen, P.L. (1994). Modulation of gap junctional mechanisms during calcium-free induced field burst activity: a possible role for electrotonic coupling in epileptogenesis. J. Neurosci. 14, 4308–4317. Search in Google Scholar

Perucca, P., Dubeau, F., and Gotman, J. (2014). Intracranial electroencephalographic seizure-onset patterns: effect of underlying pathology. Brain 137, 183–196. Search in Google Scholar

Petroff, O.A. and Rothman, D.L. (1998). Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin. Mol. Neurobiol. 16, 97–121. Search in Google Scholar

Prince, D.A. and Wilder, B.J. (1967). Control mechanisms in cortical epileptogenic foci. ‘Surround’ inhibition. Arch. Neurol. 16, 194–202. Search in Google Scholar

Ramachandrannair, R., Ochi, A., Imai, K., Benifla, M., Akiyama, T., Holowka, S., Rutka, J.T., Snead 3rd, O.C., and Otsubo, H. (2008). Epileptic spasms in older pediatric patients: MEG and ictal high-frequency oscillations suggest focal-onset seizures in a subset of epileptic spasms. Epilepsy Res. 78, 216–224. Search in Google Scholar

Reis, G.M. and Duarte, I.D. (2006). Baclofen, an agonist at peripheral GABAB receptors, induces antinociception via activation of TEA-sensitive potassium channels. Br. J. Pharmacol. 149, 733–739. Search in Google Scholar

Riikonen, R. (2014). Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs 28, 279–290. Search in Google Scholar

Roopun, A.K., Simonotto, J.D., Pierce, M.L., Jenkins, A., Nicholson, C., Schofield, I.S., Whittaker, R.G., Kaiser, M., Whittington, M.A., Traub, R.D., et al. (2010). A non-synaptic mechanism underlying interictal discharges in human epileptic neocortex. Proc. Natl. Acad. Sci. U.S.A. 107, 338–343. Search in Google Scholar

Ruffin, V.A., Salameh, A.I., Boron, W.F., and Parker, M.D. (2014). Intracellular pH regulation by acid-base transporters in mammalian neurons. Front. Physiol. 5, 43. Search in Google Scholar

Ruusuvuori, E. and Kaila, K. (2014). Carbonic anyhdrases and brain pH in the control of neuronal excitability. Subcell. Biochem. 75, 271–290. Search in Google Scholar

Saxena, A. and Sampson, J.R. (2015). Epilepsy in tuberous sclerosis: phenotypes, mechanisms, and treatments. Semin. Neurol. 35, 269–276. Search in Google Scholar

Schmitz, D., Schuchmann, S., Fisahn, A., Draguhn, A., Buhl, E.H., Petrasch-Parwez, R.E., Dermietzel, R., Heinemann, U., and Traub, R.D. (2001). Axo-axonal coupling: a novel mechanism for ultrafast neuronal communication. Neuron 31, 831–840. Search in Google Scholar

Schwindt, P. and Crill, W. (1999). Mechanisms underlying burst and regular spiking evoked by dendritic depolarization in layer 5 cortical pyramidal neurons. J. Neurophysiol. 81, 1341–1354. Search in Google Scholar

Siesjö, B.K. (1989). Calcium and cell death. Magnesium 8, 223–237. Search in Google Scholar

Simon, A., Traub, R.D., Vladimirov, N., Jenkins, A., Nicholson, C., Whittaker, R., Schofield, I., Clowry, G.J., Cunningham, M.O., and Whittington, M.A. (2014). Gap junction networks can generate both ripple-like and fast-ripple-like oscillations. Eur. J. Neurosci. 39, 46–60. Search in Google Scholar

Smith, J.B., Westmoreland, B.F., Reagan, T.J., and Sandok, B.A. (1975). A distinctive clinical EEG profile in herpes simplex encephalitis. Mayo Clin. Proc. 50, 469–474. Search in Google Scholar

Sohn, J.W., Lee, D., Cho, H., Lim, W., Shin, H.S., Lee, S.H., and Ho, W.K. (2007). Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus. J. Physiol. 580, 411–422. Search in Google Scholar

Song, J.M., Hahn, J., Kim, S.H., and Chang, M.J. (2017). Efficacy of treatments for infantile spasms: a systematic review. Clin. Neuropharmacol. 40, 63–84. Search in Google Scholar

Sotero de Menezes, M.A. and Rho, J.M. (2002). Clinical and electrographic features of epileptic spasms persisting beyond the second year of life. Epilepsia 43, 623–630. Search in Google Scholar

Staley, K.J., Longacher, M., Bains, J.S., and Yee, A. (1998). Presynaptic modulation of CA3 network activity. Nat. Neurosci. 1, 201–209. Search in Google Scholar

Steriade, M., Nuñez, A., and Amzica, F. (1993). A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: depolarizing and hyperpolarizing components. J. Neurosci. 13, 3252–3265. Search in Google Scholar

Steriade, M., Amzica, F., and Contreras, D. (1994). Cortical and thalamic cellular correlates of electroencephalographic burst-suppression. Electroencephalogr. Clin. Neurophysiol. 90, 1–16. Search in Google Scholar

Sun, L., Zhang, K., Li, J., Liu, D., Lu, Y., and Zhang, Z. (2012). An impairment of cortical GABAergic neurons is involved in alkalosis-induced brain dysfunctions. Biochem. Biophys. Res. Commun. 419, 627–631. Search in Google Scholar

Tippens, A.L., Pare, J.F., Langwieser, N., Moosmang, S., Milner, T.A., Smith, Y., and Lee, A. (2008). Ultrastructural evidence for pre- and postsynaptic localization of Cav1.2 L-type Ca2+ channels in the rat hippocampus. J. Comp. Neurol. 506, 569–583. Search in Google Scholar

Tombaugh, G.C. and Somjen, G.G. (1996). Effects of extracellular pH on voltage-gated Na+, K+ and Ca2+ currents in isolated rat CA1 neurons. J. Physiol. 493, 719–732. Search in Google Scholar

Tombaugh, G.C. and Somjen, G.G. (1997). Differential sensitivity to intracellular pH among high- and low-threshold Ca2+ currents in isolated rat CA1 neurons. J. Neurophysiol. 77, 639–653. Search in Google Scholar

Tovar, K.R., Maher, B.J., and Westbrook, G.L. (2009). Direct actions of carbenoxolone on synaptic transmission and neuronal membrane properties. J. Neurophysiol. 102, 974–978. Search in Google Scholar

Traub, R.D. and Whittington, MA. (2010). Cortical Oscillations in Health and Disease (New York, USA: Oxford University Press). Search in Google Scholar

Traub, R.D., Schmitz, D., Jefferys, J.G.R., and Draguhn, A. (1999). High-frequency population oscillations are predicted to occur in hippocampal pyramidal neuronal networks interconnected by axonal gap junctions. Neuroscience 92, 407–426. Search in Google Scholar

Traub, R.D., Whittington, M.A., Buhl, E.H., LeBeau, F.E.N., Bibbig, A., Boyd, S., Cross, H., and Baldeweg, T. (2001). A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures. Epilepsia 42, 153–170. Search in Google Scholar

Traub, R.D., Draguhn, A., Whittington, M.A., Baldeweg, T., Bibbig, A., Buhl, E.H., and Schmitz, D. (2002). Axonal gap junctions between principal neurons: A novel source of network oscillations, and perhaps epileptogenesis. Rev. Neurosci. 13, 1–30. Search in Google Scholar

Traub, R.D., Contreras, D., Cunningham, M.O., Murray, H., LeBeau, F.E.N., Roopun, A., Bibbig, A., Wilent, W.B., Higley, M.J., and Whittington, M.A. (2005). Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles and epileptogenic bursts. J. Neurophysiol. 93, 2194–2232. Search in Google Scholar

Traub, R.D., Duncan, R., Russell, A.J.C., Baldeweg, T., Tu, Y., Cunningham, M.O., and Whittington, M.A. (2010). Spatiotemporal patterns of electrocorticographic very fast oscillations (>80 Hz) consistent with a network model based on electrical coupling between principal neurons. Epilepsia 51, 1587–1597. Search in Google Scholar

Traub, R.D., Whittington, M.A., Gutiérrez, R., and Draguhn, A. (2018). Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions. Cell Tissue Res. 373, 671–691. Search in Google Scholar

Wang, S.J. (2005). Activation of neuropeptide Y Y1 receptors inhibits glutamate release through reduction of voltage-dependent Ca2+ entry in the rat cerebral cortex nerve terminals: suppression of this inhibitory effect by the protein kinase C-dependent facilitatory pathway. Neuroscience 134, 987–1000. Search in Google Scholar

Wang, Y., Barakat, A., and Zhou, H. (2010). Electrotonic coupling between pyramidal neurons in the neocortex. PLoS One 5, e10253. Search in Google Scholar

Westmoreland, B.F., Blume, W.T., and Gomez, M.R. (1976). Generalized sharp and slow wave and electrodecremental seizure pattern in subacute sclerosing panencephalitis. Mayo Clin. Proc. 51, 107–111. Search in Google Scholar

Whittington, M.A., Stanford, I.M., Colling, S.B., Jefferys, J.G.R., and Traub, R.D. (1997). Spatiotemporal patterns of γ frequency oscillations tetanically induced in the rat hippocampal slice. J. Physiol. 502, 591–607. Search in Google Scholar

Williams, S.R. and Stuart, G.J. (1999). Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons. J. Physiol. 521, 467–482. Search in Google Scholar

Yamatogi, Y. and Ohtahara, S. (1981). Age-dependent epileptic encephalopathy: a longitudinal study. Folia Psychiatr. Neurol. Jpn. 35, 321–332. Search in Google Scholar

Yashiro, K. and Philpot, B.D. (2008). Regulation of NMDA receptor subunit expression and its implications for LTD, LTP, and metaplasticity. Neuropharmacology 55, 1081–1094. Search in Google Scholar

Zhang, F., Lin, Y.A., Kannan, S., and Kannan, R.M. (2016).Targeting specific cells in the brain with nanomedicines for CNS therapies. J. Control Release 240, 212–226. Search in Google Scholar

Received: 2019-03-05
Accepted: 2019-06-01
Published Online: 2019-09-14
Published in Print: 2020-01-28

©2020 Walter de Gruyter GmbH, Berlin/Boston