Altered thalamocortical and intra-thalamic functional connectivity during light sleep compared with wake
Introduction
The thalamus receives primary afferents from peripheral sense organs and selectively filters related incoming information before relaying it to functionally-specialised cortical regions (Steriade et al., 1993, Sherman and Guillery, 2002, Saalmann, 2014). However, the majority of its inputs are modulatory, feedback connections originating in widespread structures including neighbouring thalamic nuclei and cortex (Sherman and Guillery, 1996, Sherman, 2007). As such, both intra-thalamic and thalamocortical pathways fundamentally underlie information flow within the brain (Saalmann and Kastner, 2011). Dramatic differences in integration of information across the thalamocortical network are associated with changes in the state of consciousness (Alkire et al., 2008, Coenen, 2010, Llinas, 2003, Tononi and Massimini, 2008), which can be most readily investigated in the healthy brain in relation to sleep. The thalamus plays a crucial role in diverse sleep-related physiological phenomena. These include: attenuation of occipital alpha (Iber et al., 2007), generation and maintenance of sleep spindles (Contreras et al., 1997, Steriade, 1997) and propagation of K-complexes (Jahnke et al., 2012). However, despite their fundamental involvement, the intricacies of thalamocortical and intra-thalamic interactions in the sleeping human brain are yet to be definitively established.
Simultaneous acquisition of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data has provided non-invasive insight into the functional architecture of the human brain across the sleep–wake cycle (Duyn, 2012). Typically, EEG data is used to identify individual sleep stages or the electrophysiological discharges of sleep (Schabus et al., 2007, Dang-Vu et al., 2011), whilst temporal correlation between Blood Oxygenation-Level Dependent (BOLD) fMRI timecourses provides a measure of functional connectivity (FC) in these stages. To date only a handful of studies have investigated the influence of sleep on human cortical circuits. Evidence broadly suggests that cortical FC is preserved during light sleep (Horovitz et al., 2008, Larson-Prior et al., 2009, Sämann et al., 2011, Spoormaker et al., 2011). Furthermore, Spoormaker et al. (2010) reported widespread elevations in cortico-cortical FC during early stages of sleep compared with wakefulness. By contrast, the transition into N2 and slow wave sleep (SWS) has been shown to be accompanied by an uncoupling of intra-network relationships (Larson-Prior et al., 2011, Spoormaker et al., 2010, Wilson et al., 2015), including dissociation between the anterior and posterior subdivisions of the default mode network (DMN) (Horovitz et al., 2009, Koike et al., 2011, Sämann et al., 2011).
Direct evidence of changes in human thalamocortical coupling in association with sleep is scarce. Laufs et al. (2007) investigated the FC of a thalamic seed activated by sleep spindles in a single subject, but reported no significant change in thalamocortical connectivity in relation to sleep stage. Subsequent group studies have, however, identified sleep-related decreases in thalamocortical FC (Picchioni et al., 2014, Spoormaker et al., 2010). Spoormaker et al. (2010) found bilateral thalamus was unique in displaying significantly reduced FC with extensive cortical regions in sleep compared with wake. This decrease was most pronounced during non-REM stage 1 (N1). Indeed, during N2 and SWS thalamocortical FC was seen to increase to similar levels as observed during wakefulness, with this re-synchronisation perhaps an effect of thalamically-generated discharges such as sleep spindles. Meanwhile, Picchioni et al. (2014) reported significant decreases in FC between the centromedial thalamic nucleus (CMN) and widespread heteromodal cortical areas, including the precuneus, cingulate gyrus and medial frontal gyrus, during N2 and SWS compared with wake. These studies have either considered the thalamus as a whole (Spoormaker et al., 2010) or have focused on FC measured from a single thalamic region (Laufs et al., 2007, Picchioni et al., 2014). However, the thalamus is comprised of anatomically distinct nuclei which project to specific cortical areas, forming a topographically organised thalamocortical network (Herrero et al., 2002, Mumford, 1998, Sherman and Guillery, 2013). The supplementary results of Picchioni et al. (2014), which, in contrast to their findings for the CMN, showed no differences in FC between the lateral geniculate nucleus (LGN) and calcarine cortex during SWS and wake, are suggestive of regional variation in the effect of sleep on thalamocortical FC. Clearer understanding of the role of the thalamus and thalamocortical interactions in sleep, and of the differential effects of sleep on specific parts of the thalamocortical system, therefore rests upon a more fine-grained, functionally-motivated partitioning of the thalamus.
Much of what is known about thalamic structure has been derived from work in animals (Jones, 1998, Jones, 2007, Nieuwenhuys, 1988, Webster et al., 1995) and histological studies (Morel et al., 1997). The feasibility of using waking resting-state fMRI data to non-invasively segment the human thalamus into functionally specific subdivisions has been demonstrated (Zhang et al., 2008), with similar functional parcellations being reported in subsequent fMRI studies (Fair et al., 2010, Hale et al., 2015, Kim et al., 2013, Woodward et al., 2012). Functionally-derived thalamic subdivisions also largely match those from previous tract-tracing studies as well as anatomical thalamic segmentations evaluated using diffusion tensor imaging (DTI) (Behrens et al., 2003a, Johansen-Berg et al., 2005, Unrath et al., 2008, Wiegell et al., 2003, Zhang et al., 2010).
In the current study we employed seed-based FC analysis similar to that applied previously to resting state fMRI data (Fair et al., 2010, Hale et al., 2015, Woodward et al., 2012, Zhang et al., 2008) enabling us to investigate the impact of nocturnal sleep (in non sleep deprived individuals) on specific functional thalamocortical relationships. In accordance with previous studies (Picchioni et al., 2014, Spoormaker et al., 2010) we hypothesised that thalamocortical FC would alter progressively with sleep stage, most likely showing decreased FC during early stages of sleep compared with wake. We further hypothesised that sleep-related differences in FC across the thalamocortical network would be dissociable, in the sense that they would vary according to the thalamic and cortical regions being investigated. In addition to considering FC between the thalamus and cortex, we studied intra-thalamic FC. Despite their importance in mediating the transfer of information to and between areas of cortex (Sherman and Guillery, 1996), very few electrophysiological studies have focused on intra-thalamic pathways (Crabtree, 1999, Crabtree et al., 1998). The shortage of research in this area and the proposal that intra-thalamic mechanisms underlie the production of sleep spindles (Contreras et al., 1997), motivated our study of intra-thalamic FC, which we predicted would be altered by the sleep/wake cycle.
Section snippets
Participants
21 healthy volunteers (10 male, 25 ± 3 years) (mean ± standard deviation) participated in the study. Written informed consent was obtained from all participants, and the study was approved by the Research Ethics Board of the University of Birmingham. The volunteers, who were all accustomed to the MR environment, had no personal history of neurological, psychiatric or sleep disorder. Participants' habitual sleep patterns were monitored through sleep diaries and wrist actigraphy (Actiwatch2, Philips,
Results
Sleep questionnaire, actigraphy data, sleep diary data and the total and average number of epochs for each sleep stage from the final sample of 13 participants are summarised in Table 1. Participants were found to have normal levels of daytime sleepiness and fatigue, no evidence of insomnia, and sleep quality and habitual sleep times were representative of normal sleepers. There was no significant difference between sleep duration estimated by actigraphy and sleep diary (T(12) = 2.00, p = 0.069).
Discussion
By integrating techniques for identifying functionally specific thalamocortical relationships this work provides novel insights into the effect of sleep on both thalamocortical and intra-thalamic network activity. We have demonstrated altered thalamocortical FC during light sleep (in non sleep deprived individuals) compared with wakefulness, which is in line with previous work (Picchioni et al., 2014, Spoormaker et al., 2010). Importantly, sleep was also shown to differentially influence
Conclusion
This study, the first to our knowledge to investigate FC during sleep across multiple thalamic ROIs, demonstrates significant modulations of both thalamocortical and intra-thalamic networks in sleep. In line with previous work, during wakefulness cortical ROIs were found to be functionally connected to distinct thalamic regions. Our finer-grained functional thalamic parcellation, compared with other studies, allowed us to observe differential effects of sleep across the thalamocortical network.
Acknowledgments
This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC) (grant number EP/J002909/1); EPSRC (grant number EP/I022325/1) to S.D.M. and Birmingham University Fellowship to S.D.M.
Participants did not consent to their data being made openly available. Further information about the data and conditions for access are available at the University of Birmingham Research at Birmingham website at http://rab.bham.ac.uk/.
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