Frontiers in Systems Neuroscience (Apr 2015)
Bistability breaks-off deterministic responses to intracortical stimulation during non-REM sleep
Abstract
INTRODUCTION During non-rapid eye movement (NREM) sleep (stage N3), when consciousness fades, cortico-cortical interactions are impaired while neurons are still active and reactive(Tononi and Massimini, 2008). Why is this? We hypothesized that the same neuronal mechanism that underlies sleep slow waves, that is bistability, between depolarized upstates and hyperpolarized downstate in cortical neurons (Steriade et al., 1993), may substantially impair information transmission within cortical networks. Specifically, we postulated that the inescapable occurrence of a silent, down-state after an initial activation couldbreak-off cortico-cortical causal interactions, thus impairing the ability of thalamocortical circuits to sustain long-range, deterministic patterns of activation, a theoretical requisite for consciousness(Tononi, 2008).Intracranial single-pulse electrical stimulation (SPES) and simultaneous stereotactic EEG (SEEG) recordings offer a unique opportunity to test this hypothesis. First, intracranial recordings allow a reliable detection of cortical down-states as a significant suppression of high frequency power above 20 Hz(Cash et al., 2009). Second, intracranial perturbations with SPES allow assessing cortico-cortical interactions from a causal perspective by calculating the phase locking factor (PLF)(Palva et al., 2005). METHODS We employedSPES and simultaneous stereotactic electroencephalography to compare cortico-cortical evoked potentials (CCEPs) recorded during wakefulness and NREM sleepin 8 epileptic patients undergoing intra-cerebral stimulations and recordings for clinical evaluation. The number of implanted electrodes (Figure 1) varied based on surgical requirements (max: 15 electrodes, 168 contacts). Stimulation trains (30 pulses, 0.2-1 Hz, 5mA) were delivered through one couple of adjacent contacts, while recordings of LFP were obtained from all other contacts (Figure 1). Preprocessing consisted in a median filtering to remove the artifact due to stimulation, abandpass filtering (0.5-300 Hz, Butterworth, 3rd order) and splitting of trials based on a digital trigger. Contacts showing spontaneous or evoked epileptic activity were removed from further analysis. Data analysis, consisting in time-frequency analysis (Wavelet, 3 cycles) and PLF, were performed using customized MATLAB scripts. RESULTS We observed that, while during wakefulness SPES triggers a widespread pattern of sustained causal effects (phase-locked activity), during NREM sleep the same initial activation induces a cortical downstate in its cortical targets – as reflected by a clear-cut suppression of high frequency (>20Hz) oscillations – that is followed by a break-off of PLF (~200 ms), in spite of restored levels of neuronal activity (Figure 2).These results were reproducible across contacts, significant across contacts at the single subject level (Wilcoxon ranksum test, p<0.05) and consistent at the population level (Wilcoxon ranksum test, p<0.05). Finally, significant correlations in each single subject showed (i) that, during NREM sleep, larger evoked slow waves corresponded to more pronounced suppressions of high frequencies and (ii) that earlier suppressions corresponded to an earlier dampening of PLF. CONCLUSIONS These results point to bistability as the underlying critical mechanism that prevents the emergence of complex interactions in human thalamocortical networks during NREM sleep. Besides sleep, the same basic neurophysiological dynamics may play a role in pathological conditions(Casali et al., 2013; Rosanova et al., 2012) where cortico-cortical communication and consciousness are impaired in spite of preserved neuronal activity.
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