Theta Bursts Precede, and Spindles Follow, Cortical and Thalamic Downstates in Human NREM Sleep

Abstract

Since their discovery, slow oscillations have been observed to group spindles during non-REM sleep. Previous studies assert that the slow-oscillation downstate (DS) is preceded by slow spindles (10-12 Hz) and followed by fast spindles (12-16 Hz). Here, using both direct transcortical recordings in patients with intractable epilepsy (n ϭ 10, 8 female), as well as scalp EEG recordings from a healthy cohort (n ϭ 3, 1 female), we find in multiple cortical areas that both slow and fast spindles follow the DS. Although discrete oscillations do precede DSs, they are theta bursts (TBs) centered at 5-8 Hz. TBs were more pronounced for DSs in NREM stage 2 (N2) sleep compared with N3. TB with similar properties occur in the thalamus, but unlike spindles they have no clear temporal relationship with cortical TB. These differences in corticothalamic dynamics, as well as differences between spindles and theta in coupling high-frequency content, are consistent with NREM theta having separate generative mechanisms from spindles. The final inhibitory cycle of the TB coincides with the DS peak, suggesting that in N2, TB may help trigger the DS. Since the transition to N1 is marked by the appearance of theta, and the transition to N2 by the appearance of DS and thus spindles, a role of TB in triggering DS could help explain the sequence of electrophysiological events characterizing sleep. Finally, the coordinated appearance of spindles and DSs are implicated in memory consolidation processes, and the current findings redefine their temporal coupling with theta during NREM sleep.

Heterogeneous profiles of coupled sleep oscillations in human hippocampus

“…2A), with phases of maximal coupling towards the SO trough and peak, respectively ( Fig. 2B), consistent with previous findings (25,27,40). Note that theta clusters extended into the slow spindle range without clear boundaries (see Discussion).…”

“…Scalp-level group analyses indicated well-known NREM coupling phenomena between SO phase and amplitudes of both spindle and theta activity ( Fig. 4A) (24,25,27,28,40). These effects were stronger in N3 compared to N2, consistent with the lower density of SOs in N2 (mostly constituting K-complexes) (25).…”

“…Moreover, HPC ripples often occur in conjunction with ~4 Hz sharp waves (38), which could be expressed as delta-ripple PAC (21,39). Finally, neocortical theta (~6 Hz) activity is also organized by the SO phase (40), and this coupling has been related to memory consolidation (41). Whether analogous SOtheta coupling exists in human HPC is unknown.…”

Phase-based coordination of hippocampal and neocortical oscillations during human sleep

“…Local PAC among SOs, spindles, and ripples has been well characterized for various brain structures including HPC (24,26,36,(42)(43)(44)(45)(46)(47), and is considered a fundamental building block of memory consolidation theories (48). However, local PAC exists for other frequency pairs (26), with SOs exerting particularly powerful drives not only over spindle and ripple activity, but also over delta (49), theta (50), and gamma (36,38) components. Extending the notion of local PAC to cross-regional interactions, the phase of a slower rhythm in one brain structure may modulate expression of faster activity at the other site (24,47,51), thus constituting a second potential form of HPC-NC communication.…”

mPFC Spindle Cycles Organize Sparse Thalamic Activation and Recently Active CA1 cells During non-REM Sleep

“…The up-states of the non-REM slow and delta oscillations are thought to provide discrete and relatively broad windows of hundreds of miliseconds in which hippocampal-neocortical interactions can occur 65, 66 . Hippocampal SWRs happen mainly during up-states and nested within the cycles of spindles, and spindles are themselves largest in amplitude following the transition from the down-to-up state 17,67 . Thalamic cells often showed a rebound in firing after mPFC KCs (LFP markers of the slow oscillation trough), suggesting that SWRs that occur during the down-to-up state transition overlap in time with an increase in thalamic drive.…”