PLoS Comput Biol. 2014 Sep 25;10(9):e1003855. doi: 10.1371/journal.pcbi.1003855. eCollection 2014 Sep.

Synchronization of isolated downstates (K-complexes) may be caused by cortically-induced disruption of thalamic spindling.

Mak-McCully RA¹, Deiss SR², Rosen BQ³, Jung KY⁴, Sejnowski TJ⁵, Bastuji H⁶, Rey M⁷, Cash SS⁸, Bazhenov M⁹, Halgren E¹⁰.

Author information

1: Department of Neurosciences, University of California, San Diego, San Diego, California, United States of America.
2: Computer Science and Engineering Department, University of California, San Diego, San Diego, California, United States of America.
3: Department of Radiology, University of California, San Diego, San Diego, California, United States of America.
4: Department of Neurology, Seoul National University College of Medicine, Seoul, Korea.
5: Division of Biological Sciences, University of California, San Diego, San Diego, California, United States of America; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California, United States of America.
6: Central Integration of Pain, Lyon Neuroscience Research Center, INSERM, U1028; CNRS, UMR5292; Université Claude Bernard, Lyon, Bron, France; Unité d'Hypnologie, Service de Neurologie Fonctionnelle et d'Épileptologie, Hôpital Neurologique, Hospices Civils de Lyon, Bron, France.
7: Clinical Neurophysiology Sleep Unit, APHM, Timone Hospital, Aix Marseille Université, Marseille, France.
8: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts, United States of America.
9: Department of Cell Biology and Neuroscience, University of California, Riverside, Riverside, California, United States of America.
10: Department of Neurosciences, University of California, San Diego, San Diego, California, United States of America; Department of Radiology, University of California, San Diego, San Diego, California, United States of America; Department of Psychiatry, University of California, San Diego, San Diego, California, United States of America.

Abstract

Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise.

PMID:: 25255217
PMCID:: PMC4177663
DOI:: 10.1371/journal.pcbi.1003855

[Indexed for MEDLINE]

Free PMC Article

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Figure 1

Quasi-synchrony and topography of spontaneous and evoked KCs in EEG and ECOG.

A, An individual spontaneous KC shows quasi-synchrony over frontal, central, and occipital scalp EEG channels. Overlaid channels participating in the KC are color-coded by scalp position: frontal channels in green, central in pink, and occipital in purple. There is no evidence of a systematic propagation of green frontal to purple posterior channels. The vertical black line is plotted at the time point where there is a 0 ms delay in the timing of the most negative peak of the KC in channels across the anterior to posterior axis: Fp1, Fpz, F1, Fc2, C4, Po3, and Po8. B, Almost all ECOG channels show a quasi-synchronous surface negative potential at the time of a single spontaneous KC detected at the scalp. The left plot depicts the color coded local field potentials while the right plot depicts the waveforms of this KC. Regions listed are: temporal pole (TempPole), lateral occipital (LatOc), anterior orbitofrontal (antOrbF), anterior prefrontal (antPreF), and ventral occipital (VenOc). C, Both spontaneous (black) and evoked (red) KCs in ECOG are characterized by a quasi-synchronous and widespread surface negativity. KCs were averaged over trials on the most negative peak of the KC as detected at the pictured scalp EEG electrode, C4. Waveforms are the average of 86 spontaneous (black) and 42 evoked (red) KCs. Patient is the same as in B. D, Traces of KC averages from all channels pictured in C are superimposed to demonstrate the regularity of the waveforms across sites. E, On both an average and single trial basis, spontaneous and evoked KCs show similar topographical profiles that are quasi-synchronous across the cortex. The scalp EEG electrode and ECOG channels from across the cortex (selected to be maximally far apart) are pictured for the averaged spontaneous or evoked KC, as depicted in C & D, as well as a single trial. The vertical black line indicates time zero of the most negative peak of the scalp KC on the average (left) and the single trial (right). Channel location regions listed are the same as in B.

Synchronization of Isolated Downstates (K-Complexes) May Be Caused by Cortically-Induced Disruption of Thalamic Spindling

PLoS Comput Biol. 2014 Sep;10(9):e1003855.

Figure 8

Parametric analysis of evoking KCs by directly versus indirectly depolarizing RE.

The effect of increasing levels of RE depolarization or PY stimulation was inspected at individual time points. The schematic to the left outlines the connectivity and the order of effects on: 1) RE neurons, 2) TC neurons, and 3) PY neurons, based on RE depolarization (A) or PY stimulation (B). Five simulations with different random seeds were run for each value plotted, as well as a no stimulation baseline run. Baseline correction was performed for membrane potential (Vm) and high gamma power. Percent change was calculated for spindling power and firing. The average of five runs at a particular stimulation value and time point is plotted ± SEM. A, As the level of applied RE depolarization increases, so does the RE membrane potential (purple asterisk); however, RE firing does not increase until high levels of depolarization are reached (red box and orange asterisk). The green box highlights a level of RE depolarization that is subthreshold for evoking KCs. At 114.4pA (purple box), PY firing and high gamma power drop (blue and black asterisks, respectively), indicating a KC. Spindling also decreases in all three cell populations (red asterisk). The red box outlines a level of stimulation where RE firing increases, leading to the production of a KC. B, When stimulating 6 PY neurons projecting to all RE neurons, the spindling in all three populations drops 100 ms after stimulation is applied at a level of 20pA or higher (red asterisk). At 20pA (purple box), the firing in all cell populations (blue asterisk) and high gamma power in PY neurons (black asterisk) drop 300 ms after stimulation, indicating a KC. The green box highlights a subthreshold level of PY stimulation. At 80pA of PY stimulation (grey box), there is a drop in spindling but no KC, presumably because the direct cortical excitation is sufficient to counteract the removal of thalamic input (green asterisks).

Synchronization of Isolated Downstates (K-Complexes) May Be Caused by Cortically-Induced Disruption of Thalamic Spindling

PLoS Comput Biol. 2014 Sep;10(9):e1003855.