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

Abstract

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.