In addition of detecting thalamic sleep spindles in human
subjects, we revealed their association with thalamic ripples.
SP(ripple) made up around 20% of overall ANT and MD sleep spindles,
respectively. These spindles were of longer duration and characterized
by different time-frequency activity profiles than sleep spindles in the
absence of ripples: SP(ripple) were associated with an excess of
thalamic ripple and lower (5-15 Hz) frequency activity compared to
SP(pure). This 5-15 Hz activity occurred later, roughly 500 ms after
sleep spindle onset, which is assumed to reflect the elongation of
ripple-associated sleep spindles. The increased ripple-band activity was
the basis of ripples-associated sleep spindle definition; however, no
signs of power difference were observed in the same time window at scalp
derivations.
The coordinated interactions between hippocampal ripples and cortical
sleep spindles plays crucial role in memory formation (Latchoumane et
al. 2017; Siapas and Wilson 1998; Staresina et al. 2015). It was
proposed that NREM sleep-based memory formation depends on the
hierarchical nesting of slow waves, sleep spindles and hippocampal
ripples, as these oscillations are instrumental in transferring
information from the hippocampus to the neocortex (Diekelmann and Born
2010; Staresina et al. 2015). In the past few years, accumulating
evidence were found for the existence of ripples outside of the
hippocampus (for a review, see McKenzie, Nitzan, and English 2020).
Ripples were detected in several cortical areas such as somatosensory
and motor cortices (Averkin et al. 2016), olfactory cortices (Manabe et
al. 2011), parahippocampal regions (Axmacher, Elger, and Fell 2008) and
higher order associational cortices as well (Khodagholy, Gelinas, and
Buzsáki 2017). These cortical ripples were frequently coupled with
slower oscillations including sleep spindles. In the prefrontal cortex,
mesio-temporal and neocortical structures, ripples were detected both
before sleep spindles and locked to the spindle troughs (Bruder et al.
2021; Peyrache, Battaglia, and Destexhe 2011). Similar results were
observed confirming that cortical ripples were embedded into spindle
troughs during natural sleep (Averkin et al. 2016). Although it
is not entirely clear, whether ripples in the thalamus are connected
with pathological processes related to epilepsy. A close relationship
between epilepsy and high-frequency oscillations (80–600 Hz, HFOs)
occurrence is repeatedly found in animal and human studies (for a
review, see Jiruska et al. 2017). In a recent study, Rektor et al.
(2016) found HFOs during wakefulness in the human ANT up to 240 Hz
frequency, and 500 Hz frequency in one case, which was the first report
of HFOs in the human thalamus. Deutschová et al (2021) reported a
relationship between prestimulation HFO power and ANT-BDS treatment
reponse, with reduced awake resting 65–500 Hz activity forecasting
better outcome. In the current study, ripples (100–200 Hz) were
revealed in both ANT and MD nuclei during NREM sleep. Ripple events were
in part coupled with sleep spindles, but also detected outside spindles
during NREM sleep. We found a strong phase-amplitude coupling measured
by the modulation index between sleep spindle phase and ripple
amplitude. However, thalamic 100–200 Hz ripples emerging during sleep
spindles were not associated with pathological processes, rather,
SP(ripple) were shown to indicate preserved cognitive ability. Here we
found a positive correlation between the density of SP(ripple) in the
ANT and general intelligence (overall cognitive functions) of our
patients. This latter result indicates that 100–200 Hz ripples detected
in the human ANT during NREM sleep spindles may contribute to the
physiological expression of thalamocortical oscillations. Furthermore,
these results suggest that thalamic ripples could indicate physiological
forms of neural activity.
The temporal dynamics of sleep spindles in the thalamus and the scalp
show that cortical spindle preceded thalamic spindles, especially those
associated with ripples. Sleep spindles are generated by the reticular
thalamic nucleus and propagate to the cortex through thalamo-cortical
network (Steriade 2005; Steriade et al. 1987). The temporal advantage of
the scalp sleep spindles suggest that ANT and MD sleep spindles are
propagated through cortico-thalamic networks, and not directly through
thalamo-thalamic projections. It was suggested that cortico-thalamic
feedback projections from the cortical sites to the reticular thalamus
is responsible for the large-scale synchronization of sleep spindles
(Destexhe, Contreras, and Steriade 1998). The ANT has a bidirectional
connection with the anterior cingulate cortex, retrosplenial cortex, and
subiculum, whereas the MD is interconnected with the medial-prefrontal
cortex (Aggleton et al. 2010; Mitchell and Chakraborty 2013; Pergola et
al. 2018). The recent results suggest that sleep spindles propagate
through these cortical sites to the ANT and MD. Thus, the thalamus seems
to play an important interface between the propagation of these neural
oscillations in the hippocampal-prefrontal network.
Former studies suggested that the human ANT contribute to the epileptic
network, and the ANT became an important target for DBS in epilepsy
treatment (Hodaie et al. 2002; Salanova 2018; Sweeney-Reed et al. 2016).
Furthermore, interictal discharges were also detected in the MD
(Sweeney-Reed et al. 2016). Although, there is no direct anatomical
connection between the ANT and MD, this report indicates that the MD
might be involved in the epileptic circuitry as well. Our current
results further support this assumption. Besides interictal discharges,
the presence of different sleep spindle (slow vs fast) could be also
indicative for specific network dysfunctions. The density of slow
SP(pure) in the MD showed a negative correlation with the year since
epilepsy onset. In contrast to slow spindles, fast SP(pure) density
showed a positive correlation with seizure prevalence. These results
suggest that the ANT and MD are involved in different epileptogenic
circuitries. The occurrence of fast sleep spindles may indicate the
altered functioning of the MD due to network-based changes through
epilepsy propagation, whereas the occurrence of fast spindles seems
physiological in the ANT. This was also indicated by the lower
overall fast spindle density in the MD. Sleep spindles in the
mediodorsal thalamus were also indicative in schizophrenia patients,
where a negative association were found between the volume of the MD and
scalp-recorded sleep spindle density (Ferrarelli and Tononi 2017). To
our best knowledge, this is the first report where sleep spindles were
separated to fast and slow spindles, showing that the appearance of fast
sleep spindles may indicate pathological mechanisms in the mediodorsal
thalamic functions.