Introduction
Higher order brain functions rely on distributed networks involving the cortex and subcortical regions. The thalamus plays a crucial role in the proper functioning of these networks: thalamo-cortical loops are associated with sensory processing, memory formation, executive functions, many of which are tightly related with sleep state-dependent neural oscillations (Fama and Sullivan 2015; Wolff et al. 2021). The thalamus also plays an important role in the coordinated connection between the cortex and hippocampus (Latchoumane et al. 2017). The human anterior thalamic nucleus (ANT) is a higher-order thalamic nucleus which is interconnected with the hippocampus (Aggleton et al. 2010). It has reciprocal connections with the anterior cingulate cortex, retrosplenial cortex, and subiculum, and selective inactivation of the ANT leads to impaired memory formation similarly to hippocampal lesions. Furthermore, the ANT plays an important role in the propagation of epileptic seizures and therefore became an important target for deep brain stimulation (DBS) which serves as a treatment for medically refractory epilepsy (Salanova 2018). Another important higher-order nucleus in the human thalamus is the mediodorsal nucleus (MD) which is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions, and therefore it is assumed to interact with the cortex and hippocampus in declarative memory formation during non-REM (NREM) sleep (Mitchell and Chakraborty 2013). Reduced MD volume was associated with decreased sleep spindle density in frontal brain regions which suggest that the MD is involved in sleep spindle generation and/or propagation (Buchmann et al. 2014).
Sleep spindles are NREM sleep state-specific oscillations characterized by waxing/waning 10–16 Hz waveforms that are generated by the reticular nucleus of the thalamus and are propagated to other brain regions by thalamo-cortical circuits (Huguenard and McCormick 2007; Steriade 2005). Animal studies confirmed that dynamic reticular thalamic-thalamo-cortical interactions are responsible for the generation of sleep spindles (Steriade, 2005; Steriade et al., 1987), which were associated with cognitive functions such as learning and memory consolidation (Cairney et al. 2018; Saletin, Goldstein, and Walker 2011), and intellectual ability (Fogel and Smith 2011; Ujma 2018; Ujma, Bódizs, and Dresler 2020). Sleep spindles tend to co-occur with and coordinate the faster oscillations, called hippocampal ripples (~100–200 Hz), providing efficient off-line plasticity windows for memory consolidation and reorganization (Girardeau and Zugaro 2011; Wilson and McNaughton 1994). Besides neural plasticity sleep spindles were associated with pathological off-line plasticity in epileptic models and human epilepsy patients (Gelinas et al. 2016). Findings regarding the strong relationship between NREM sleep oscillations, neuroplasticity and epilepsy indicate that sleep-associated interictal epileptic discharges (IEDs) harm cognitive functions, inducing a significant cognitive loss (Halász et al. 2019).
The aim of the current study was to assess the function of ANT and MD in sleep-related neural oscillations measured by the association between thalamic sleep spindles and thalamic ripples during NREM sleep. It was proposed that sleep-related epileptic transformation of normal neurological networks, involving the hippocampus, thalamus and cortex, interfere with sleep-related synaptic homeostasis, neural plasticity, and cognitive functioning (for a recent review, see Halász and Szűcs 2020). In this pathway, the role of the human ANT and MD is not clear. Although, different aspects of sleep spindle-related dynamic thalamocortical interactions were revealed (Mak-Mccully et al. 2017; Tsai et al. 2010), relationships between sleep spindles and ripples in the thalamus remained questionable. A recent report (Rektor et al. 2016) indicated the occurrence of high frequency oscillations, such as ripples in the human thalamus, however results confirming the involvement of ripples in the thalamus is remarkably sparse. Furthermore, IEDs in the human thalamus, such as in the ANT LFP records were observed and suggested the involvement of ANT in the propagation of epileptic activity and to contribute to the epileptic network (Hodaie et al. 2002; Sweeney-Reed et al. 2016). Here we investigated the association between thalamic sleep spindles and ripples within two higher-order thalamic nuclei in human subjects, the ANT and the MD. We hypothesized that sleep spindles and ripples in these thalamic nuclei are not pathological expressions of epilepsy, but physiological oscillatory patterns. Sleep spindles, and especially fast sleep spindles measured on the scalp have a close connection with cognitive performance and intelligence (Bestmann et al. 2019; Bódizs et al. 2005; Chatburn et al. 2013; Ujma 2018). The ANT has tight anatomical and functional connections with the hippocampus, as well as different parts of the prefrontal cortex, and might act as an interface between them. In order to test the hypothesis that sleep spindles and ripples are physiological oscillations in the ANT, we assessed the association between sleep spindles and ripples with general intelligence and clinical epilepsy characteristics.