High amplitude theta wave bursts: a novel electroencephalographic feature of rem sleep and cataplexy

Viviana Carmen Lo Martire, Stefano Bastianini, Chiara Berteotti, Alessandro Silvani, Giovanna Zoccoli


In 2012, high amplitude theta wave bursts (HATs) were originally described during REMS and cataplexy in ORX-deficient mice as a novel neurophysiological correlate of narcolepsy (Bastianini et al., 2012). This finding was replicated the following year by Vassalli et al. in both ORX-deficient narcoleptic mice and narcoleptic children during cataplexy episodes (Vassalli et al, 2013). The relationship between HATs and narcolepsy-cataplexy in mice and patients indicates that the lack of ORX peptides is responsible for this abnormal EEG activity, the physiological meaning of which is still unknown. This review aimed to explore different phasic EEG events previously described in the published literature in order to find analogies and differences with HATs observed in narcoleptic mice and patients. We found similarities in terms of morphology, frequency and duration between HATs and several physiological (mu and wicket rhythms, sleep spindles, saw-tooth waves) or pathological (SWDs, HVSs, bursts of polyphasic complexes EEG complexes reported in a mouse model of CJD, and BSEs) EEG events. However, each of these events also shows significant differences from HATs, and thus cannot be equaled to them. The available evidence thus suggests that HATs are a novel neurophysiological phenomenon. One possibility that has yet to be explored is whether the dysfunction of other neurotransmitter systems is involved in the genesis of the HATs, in addition to that of ORX peptides. There are some evidences suggesting an involvement of histamine signalling.

ORX neurons widely project into the brain (Peyron et al., 1998), and in particular, densely innervate the tubero-mamillary nucleus (TMN) in the hypothalamus (Chemelli et al., 1999). ORX type 2 receptor are expressed in TMN (Marcus et al., 2001). Data obtained in narcoleptic patients and mice relative to the functionality of the histamine system are still controversial. Histamine levels in the cerebrospinal fluid of narcoleptic patients are reduced or unchanged compared to normal subjects (Dauvilliers et al., 2012; Kanbayashi et al., 2009) and the number of histamine neurons is increased or unchanged in ORX-deficient narcoleptic mice and human patients (John et al., 2013; Valko et al., 2013). At present, it is not possible to conclude whether the loss of ORX peptides control determines an effect on the neuronal production of histamine and on histamine discharge. Interestingly, Anaclet et al. (2010) reported episodes of EEG hypersynchronization during wakefulness and cataplexy in double KO mice lacking both histamine and ORX peptides (Anaclet et al., 2010). Moreover, preliminary results obtained in histidine-decarboxylase KO mice, lacking histamine, reported  the occurrence of HATs during REMS (Zoccoli et al., 2014). Moreover, the same EEG figure was described in WT mice after intracerebroventricular infusion of alpha-fluoromethyl-histidine, an inhibitor of the histamine-synthetizing enzyme.

Further investigations on HATs are required in order to investigate their physiological meaning, to individuate their brain structure(s) of origin, and to clarify the neural circuits involved in their manifestation.



Full Text:



Anaclet, C., Ouk, K., Guidon, G., Buda, C., Sastre, J., Ohtsu, H., Yanagisawa, M., Franco, P., Lin, J. Complementary and Synergistic Control of Wakefulness by Orexins and Histamine, Demonstrated Using a Double Knockout Mouse Model. J Sleep Res, 19 (Suppl 2): 154, 2010.

Arain, F.M., Boyd, K.L., Gallagher, M.J. Decreased viability and absence-like epilepsy in mice lacking or deficient in the GABAA receptor alpha1 subunit. Epilepsia, 53: e161-165, 2012.

Bastianini, S., Silvani, A., Berteotti, C., Lo Martire, V., Zoccoli, G. High-amplitude theta wave bursts during REM sleep and cataplexy in hypocretin-deficient narcoleptic mice. J Sleep Res, 21: 185-188, 2012.

Buzsaki, G. Theta oscillations in the hippocampus. Neuron, 33: 325-340, 2002.

Chemelli, R.M., Willie, J.T., Sinton, C.M., Elmquist, J.K., Scammell, T., Lee, C., Richardson, J.A., Williams, S.C., Xiong, Y., Kisanuki, Y., Fitch, T.E., Nakazato, M., Hammer, R.E., Saper, C.B., Yanagisawa, M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98: 437-451, 1999.

Dauvilliers, Y., Arnulf, I., Mignot, E. Narcolepsy with cataplexy. Lancet, 369: 499-511, 2007.

Dauvilliers, Y., Delallee, N., Jaussent, I., Scholz, S., Bayard, S., Croyal, M., Schwartz, J.C., Robert, P. Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions. Sleep, 35: 1359-1366, 2012.

Dauvilliers, Y., Pennestri, MH., Petit, D, Dang-Vu, T., Lavigne, G., Montplaisir, J. Periodic leg movements during sleep and wakefulness in narcolepsy. The Journal of Sleep Research, 16: 333-339, 2007.

Dossena, S., Imeri, L., Mangieri, M., Garofoli, A., Ferrari, L., Senatore, A., Restelli, E., Balducci, C., Fiordaliso, F., Salio, M., Bianchi, S., Fioriti, L., Morbin, M., Pincherle, A., Marcon, G., Villani, F., Carli, M., Tagliavini, F., Forloni, G., Chiesa, R. Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron, 60: 598-609, 2008.

Drinkenburg, W.H., van Luijtelaar, E.L., van Schaijk, W.J., Coenen, A.M. Aberrant transients in the EEG of epileptic rats: a spectral analytical approach. Physiol Behav, 54: 779-783, 1993.

Duntley, S.P., Kim, A.H., Silbergeld, D.L., Miller, J.W. Characterization of the mu rhythm during rapid eye movement sleep. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 112: 528-531, 2001.

Gelisse, P., Kuate, C., Coubes, P., Baldy-Moulinier, M., Crespel, A. Wicket spikes during rapid eye movement sleep. J Clin Neurophysiol, 20: 345-350, 2003.

Govindaiah, G., Cox, C.L. Modulation of thalamic neuron excitability by orexins. Neuropharmacology, 51: 414-425, 2006.

Hara, J., Beuckmann, CT., Nambu, T., Willie, JT., Chemelli, RM., Sinton, CM., Sugiyama, F., Yagami, K., Goto, K., Yanagisawa, M., Sakurai, T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30: 345-354, 2001.

Jacobs, J. Hippocampal theta oscillations are slower in humans than in rodents: implications for models of spatial navigation and memory. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 369: 20130304, 2014.

John, J., Thannickal, T.C., McGregor, R., Ramanathan, L., Ohtsu, H., Nishino, S., Sakai, N., Yamanaka, A., Stone, C., Cornford, M., Siegel, J.M. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol, 74: 786-793, 2013.

Kanbayashi, T., Kodama, T., Kondo, H., Satoh, S., Inoue, Y., Chiba, S., Shimizu, T., Nishino, S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep, 32: 181-187, 2009.

Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M., Elmquist, J.K. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol, 435: 6-25, 2001.

Marini, G., Ceccarelli, P., Mancia, M. Characterization of the 7-12 Hz EEG oscillations during immobile waking and REM sleep in behaving rats. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, 119: 315-320, 2008.

Meeren, H.K., Veening, J.G., Moderscheim, T.A., Coenen, A.M., van Luijtelaar, G. Thalamic lesions in a genetic rat model of absence epilepsy: dissociation between spike-wave discharges and sleep spindles. Exp Neurol, 217: 25-37, 2009.

Muthukumaraswamy, S.D., Johnson, B.W., McNair, N.A. Mu rhythm modulation during observation of an object-directed grasp. Brain research. Cognitive brain research, 19: 195-201, 2004.

Peyron, C., Tighe, D.K., van den Pol, A.N., de Lecea, L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci, 18: 9996-10015, 1998.

Radek, R.J., Curzon, P., Decker, M.W. Characterization of high voltage spindles and spatial memory in young, mature and aged rats. Brain Res Bull, 33: 183-188, 1994.

Ryan, L.J. Characterization of cortical spindles in DBA/2 and C57BL/6 inbred mice. Brain Res Bull, 13: 549-558, 1984.

Sakurai, T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci, 8: 171-181, 2007.

Sales-Carbonell, C., Rueda-Orozco, P.E., Soria-Gomez, E., Buzsaki, G., Marsicano, G., Robbe, D. Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony. Proc Natl Acad Sci U S A, 110: 719-724, 2013.

Sato, S., McCutchen, C., Graham, B., Freeman, A., von Albertini-Carletti, I., Alling, D.W. Relationship between muscle tone changes, sawtooth waves and rapid eye movements during sleep. Electroencephalogr Clin Neurophysiol, 103: 627-632, 1997.

Scammell, T.E., Willie, JT., Guilleminault, C., Siegel, JM. A consensus definition of cataplexy in mouse models of narcolepsy. Sleep, 32: 111-116, 2009.

Scammell, T.E. The neurobiology, diagnosis, and treatment of narcolepsy. Ann. Neurol. , 53: 154-166, 2003.

Serafini, A., Crespel, A., Velizarova, R., Gelisse, P. Activation of wicket spike by REM sleep. Neurophysiol Clin, 44: 245-249, 2014.

Silber, M.H., Ancoli-Israel, S., Bonnet, M.H., Chokroverty, S., Grigg-Damberger, M.M., Hirshkowitz, M., Kapen, S., Keenan, S.A., Kryger, M.H., Penzel, T., Pressman, M.R., Iber, C. The visual scoring of sleep in adults. J Clin Sleep Med, 3: 121-131, 2007.

Silvani, A., Bastianini, S., Berteotti, C., Cenacchi, G., Leone, O., Lo Martire, V., Papa, V., Zoccoli, G. Sleep and cardiovascular phenotype in middle-aged hypocretin-deficient narcoleptic mice. J Sleep Res, 23 98-106, 2014.

Stern, J. Atlas of EEG patterns. 2013, New York: Lippincoat Williams & Wilkins.

Valko, P.O., Gavrilov, Y.V., Yamamoto, M., Reddy, H., Haybaeck, J., Mignot, E., Baumann, C.R., Scammell, T.E. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol, 74: 794-804, 2013.

van Sweden, B., Wauquier, A., Niedermeyer, E. Normal aging and transient cognitive disorders in the elderly. pp. 340-348. In: Niedermeyer E., and Lopes da Silva F. (Eds.) Electroencephalography, Basic Principles, Clinical Applications and Related Fields. Baltimore, Williams & Wilkins, 1999.

Vassalli, A., Dellepiane, J.M., Emmenegger, Y., Jimenez, S., Vandi, S., Plazzi, G., Franken, P., Tafti, M. Electroencephalogram paroxysmal theta characterizes cataplexy in mice and children. Brain, 136: 1592-1608, 2013.

Vyazovskiy, V.V., Achermann, P., Borbely, A.A., Tobler, I. The dynamics of spindles and EEG slow-wave activity in NREM sleep in mice. Arch Ital Biol, 142: 511-523, 2004.

Willie, J.T., Chemelli, R.M., Sinton, C.M. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38: 715-730, 2003.

Zoccoli, G., Bastianini, S., Berteotti, C., Lin, J.S., Lo Martire, V., Ohtsu, H., Silavni, A. Theta wave bursts during rapid-eye-movement sleep in histamine-deficient mice. J. Sleep Res, 23: 319, 2014.

DOI: https://doi.org/10.4449/aib.v153i2-3.4040


  • There are currently no refbacks.