The University of Birmingham Mechanisms of physiological and epileptic HFO

High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and networks, investigated in a variety of experimental in vitro and in vivo models. Diverse mechanisms are described, from intrinsic membrane oscillations to network processes involving different types of synaptic interactions, gap junctions and ephaptic coupling. HFOs with similar frequency ranges can differ considerably in their physiological mechanisms. The fact that in most cases the combination of intrinsic neuronal membrane oscillations and synaptic circuits are necessary to sustain network oscillations is emphasized. Evidence for pathological HFOs, particularly fast ripples, in experimental models of epilepsy and in human epileptic patients is scrutinized. The underlying mechanisms of fast ripples are examined both in the light of animal observations, in vivo and in vitro, and in epileptic patients, with emphasis on single cell dynamics. Experimental observations and computational modeling have led to hypotheses for these mechanisms, several of which are considered here, namely the role of out-of-phase firing in neuronal clusters, the importance of strong excitatory AMPA-synaptic currents and recurrent inhibitory connectivity in combination with the fast time scales of IPSPs, ephaptic coupling and the contribution of interneuronal coupling through gap junctions. The statistical behaviour of fast ripple events can provide useful information on the underlying mechanism and can help to further improve classification of the diverse forms of HFOs. 2012 Published by Elsevier Ltd. Abbreviations: a, alpha (rhythm or oscillation); AMPA, 2-amino-3-(5-methyl-3-oxo-1,2oxazol-4-yl)propanoic acid, a subtype of ionotropic glutamate receptors; AP, action potential; b, beta (oscillation); CA, cellular automata; ECoG, electrocorticogram; EEG, electroencephalogram; GABA, gamma amino butyric acid; GABAA, ionotropic gamma amino butyric acid receptor; g, gamma (oscillation); HFO, High Frequency Oscillation; Hz, Hertz (cycles per second); Ih, the h-current, a depolarizing, cationic current activated by hyperpolarization; IPSC, inhibitory postsynaptic current; IPSP, inhibitory postsynaptic potential; KA, kainic acid; LFP, local field potential; MEG, magnetoencephalogram; mGluR, metabotropic glutamate receptor; m, mu (oscillation); NMDA, N-methyl D-aspartate, a subtype of ionotropic glutamate receptor; pHFO, pathological high frequency oscillation; SPWR, sharp-wave ripples; TLE, temporal lobe epilepsy. * Corresponding author. Tel.: +44 121 414 7525; fax: +44 121 414 7625. E-mail address: [email protected] (John G.R. Jefferys).