Every night, the human brain produces thousands of downstates and spindles during non-REM sleep. Previous studies indicate that spindles originate thalamically and downstates cortically, loosely grouping spindle occurrence. However, the mechanisms whereby the thalamus and cortex interact in generating these sleep phenomena remain poorly understood. Using bipolar depth recordings, we report here a sequence wherein: (1) convergent cortical downstates lead thalamic downstates; (2) thalamic downstates hyperpolarize thalamic cells, thus triggering spindles; and (3) thalamic spindles are focally projected back to cortex, arriving during the down-to-upstate transition when the cortex replays memories. Thalamic intrinsic currents, therefore, may not be continuously available during non-REM sleep, permitting the cortex to control thalamic spindling by inducing downstates. This archetypical cortico-thalamo-cortical sequence could provide the global physiological context for memory consolidation during non-REM sleep.

K-complexes (KCs) are thought to play a key role in sleep homeostasis and memory consolidation; however, their generation and propagation remain unclear. The commonly held view from scalp EEG findings is that KCs are primarily generated in medial frontal cortex and propagate parietally, whereas an electrocorticography (ECOG) study suggested dorsolateral prefrontal generators and an absence of KCs in many areas. In order to resolve these differing views, we used unambiguously focal bipolar depth electrode recordings in patients with intractable epilepsy to investigate spatiotemporal relationships of human KCs. KCs were marked manually on each channel, and local generation was confirmed with decreased gamma power. In most cases (76%), KCs occurred in a single location, and rarely (1%) in all locations. However, if automatically detected KC-like phenomena were included, only 15% occurred in a single location, and 27% occurred in all recorded locations. Locally generated KCs were found in all sampled areas, including cingulate, ventral temporal, and occipital cortices. Surprisingly, KCs were smallest and occurred least frequently in anterior prefrontal channels. When KCs occur on two channels, their peak order is consistent in only 13% of cases, usually from prefrontal to lateral temporal. Overall, the anterior-posterior separation of electrode pairs explained only 2% of the variance in their latencies. KCs in stages 2 and 3 had similar characteristics. These results open a novel view where KCs overall are universal cortical phenomena, but each KC may variably involve small or large cortical regions and spread in variable directions, allowing flexible and heterogeneous contributions to sleep homeostasis and memory consolidation.

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.