Propagated infra-slow intrinsic brain activity reorganizes across wake and slow wave sleep

Propagation of slow intrinsic brain activity has been widely observed in electrophysiogical studies of slow wave sleep (SWS). However, in human resting state fMRI (rs-fMRI), intrinsic activity has been understood predominantly in terms of zero-lag temporal synchrony (functional connectivity) within systems known as resting state networks (RSNs). Prior rs-fMRI studies have found that RSNs are generally preserved across wake and sleep. Here, we use a recently developed analysis technique to study propagation of infra-slow intrinsic blood oxygen level dependent (BOLD) signals in normal adults during wake and SWS. This analysis reveals marked changes in propagation patterns in SWS vs. wake. Broadly, ordered propagation is preserved within traditionally defined RSNs but lost between RSNs. Additionally, propagation between cerebral cortex and subcortical structures reverses directions, and intra-cortical propagation becomes reorganized, especially in visual and sensorimotor cortices. These findings show that propagated rs-fMRI activity informs theoretical accounts of the neural functions of sleep

Sleep onset uncovers thalamic abnormalities in patients with idiopathic generalised epilepsy

The thalamus is crucial for sleep regulation and the pathophysiology of idiopathic generalised epilepsy (IGE), and may serve as the underlying basis for the links between the two. We investigated this using EEG-fMRI and a specific emphasis on the role and functional connectivity (FC) of the thalamus. We defined three types of thalamic FC: thalamocortical, inter-hemispheric thalamic, and intra-hemispheric thalamic. Patients and controls differed in all three measures, and during wakefulness and sleep, indicating disorder-dependent and state-dependent modification of thalamic FC. Inter-hemispheric thalamic FC differed between patients and controls in somatosensory regions during wakefulness, and occipital regions during sleep. Intra-hemispheric thalamic FC was significantly higher in patients than controls following sleep onset, and disorder-dependent alterations to FC were seen in several thalamic regions always involving somatomotor and occipital regions. As interactions between thalamic sub-regions are indirect and mediated by the inhibitory thalamic reticular nucleus (TRN), the results suggest abnormal TRN function in patients with IGE, with a regional distribution which could suggest a link with the thalamocortical networks involved in the generation of alpha rhythms. Intra-thalamic FC could be a more widely applicable marker beyond patients with IGE. Keywords: Functional connectivity, Generalised epilepsy, Sleep, Thalamic reticular nucleus thalamu

Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm-/- mice.

Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia

THE THALAMIC RETICULAR NUCLEUS: A MULTIFACETED GUARDIAN

Interactions between the cortex and the thalamus are essential for major brain functions such as sensory information processing and integration, sleep and wake regulation and cognitive processes. The thalamic reticular nucleus (TRN) is strategically positioned within the thalamocortical circuit and has a strong inhibitory control over the thalamus. It can act on a global scale, such as suppressing the flow of sensory information from the thalamus to the cortex during sleep. The TRN also acts locally on the activity of single cells or small cell groups. To reconcile both of these global and local aspects of TRN functions, we studied the cellular, synaptic and functional heterogeneity of the TRN, with a focus on the comparison between the classical sensory TRN and the less well-described limbic TRN. In study 1, using anatomical tracing and cellular electrophysiology, we identified the dorsal presubiculum (dPreS), the retrosplenial cortex (RSC) and the anterior thalamic nuclei (ATN) as part of a novel thalamo-cortical circuit involving the limbic TRN in mice. The dPreS, RSC and ATN are three key structures for spatial navigation. dPreS/RSC excitatory glutamatergic synapses formed on TRN and ATN are part of a feedforward circuit through which TRN-mediated inhibition generates large burst-mediated inhibitory synaptic currents. The PreS/RSC afferents to the TRN showed driver-like characteristics, which is unprecedented for corticoreticular synapses and expands the scope of the TRN heterogeneity to the nature of its synaptic afferents. We further investigated the role of the limbic TRN in the control of head-direction neurons that were previously described to be located in the anterodorsal thalamus. The width of the tuning curve of head-direction neurons in the thalamus was broadened upon chemogenetic silencing of the TRN, revealing a novel form of internal sensory gating by the TRN. About half of the head-direction neurons showed action potential discharge patterns consistent with feedforward inhibitory responses upon light activation of dPreS/RSC. These data suggest that the limbic TRN sharpens the tuning of thalamic head-direction neurons under dPreS/RSC control. Finally, we investigated the potential function of the limbic TRN in the hidden version of the Morris watermaze. We discovered that chemogenetic silencing of the limbic TRN biased the search patterns towards allocentric strategies and generated perseverance to previously learned escape positions, suggesting an impairment of the egocentric system in which the head-direction system plays a critical role. In study 2, we combined opto-tagging of TRN sectors with in vitro electrophysiological recordings and discovered that the limbic TRN neurons produced less repetitive burst firing than their sensory counterpart. The burst discharge of sensory TRN neurons is known to generate sleep spindles that propagate to the cortex, that are a marker of sleep quality and that correlate with memory consolidation. Consistently, local field potential recordings in the prefrontal cortex that is related to the less bursty limbic TRN revealed smaller amplitude and slower sleep spindles compared to sensory ones, making the heterogeneity of the TRN a critical player in local sleep rhythms. This thesis summarizes elements supporting the heterogeneity of the TRN, in particular between the sensory and the limbic TRN. It also provides a novel function for the limbic TRN in the spatial navigation system

Pre- and post-task resting-state differs in clinical populations

Resting-state functional connectivity has generated great hopes as a potential brain biomarker for improving prevention, diagnosis, and treatment in psychiatry. This neuroimaging protocol can routinely be performed by patients and does not depend on the specificities of a task. Thus, it seems ideal for big data approaches that require aggregating data across multiple studies and sites. However, technical variability, diverging data analysis approaches, and differences in data acquisition protocols introduce heterogeneity to the aggregated data. Besides these technical aspects, a prior task that changes the psychological state of participants might also contribute to heterogeneity. In healthy participants, studies have shown that behavioral tasks can influence resting-state measures, but such effects have not yet been reported in clinical populations. Here, we fill this knowledge gap by comparing resting-state functional connectivity before and after clinically relevant tasks in two clinical conditions, namely substance use disorders and phobias. The tasks consisted of viewing craving-inducing and spider anxiety provoking pictures that are frequently used in cue-reactivity studies and exposure therapy. We found distinct pre- vs post-task resting-state connectivity differences in each group, as well as decreased thalamo-cortical and increased intra-thalamic connectivity which might be associated with decreased vigilance in both groups. Our results confirm that resting-state measures can be strongly influenced by prior emotion-inducing tasks that need to be taken into account when pooling resting-state scans for clinical biomarker detection. This demands that resting-state datasets should include a complete description of the experimental design, especially when a task preceded data collection

Chapter Sleep Spindles – As a Biomarker of Brain Function and Plasticity

Alternative & renewable energy sources & technolog

Sleep Spindles – As a Biomarker of Brain Function and Plasticity

Alternative & renewable energy sources & technolog

Computational models of the thalamocortical circuit: sleep oscillations and receptive fields.

The thalamus is a subcortical structure, which consists of a collection of functionally and morphologically defined nuclei. A subset of these, the sensory nuclei, receive information from the periphery and relay it to the related primary cortical area. Hence the thalamus was traditionaUy assumed to passively relay afferent information. However, the fact that thalamic relay cells receive a large proportion of their sjoiaptic inputs from the cortical cells to which they project, has led to the consensus that there is a more significant thalamic contribution to sensory processing. This thesis investigates the role of the thalamocortical feedback loop using population-level computational models. In particular two states of thalamocortical activity are investigated: early sleep, and active visual processing. During early sleep, the network displays 7-14Hz spindle oscillations. These osciUations have been previously modelled using conductance-based paradigms, but here the activity is investigated through the nonhnear dynamics of the circuitry. It is shown that the circuit has an intrinsic resonant frequency in the spindles range. During visual processing, the role of the lateral geniculate nucleus (the primary visual thalamic nucleus) was previously overlooked, as thalamic receptive fields are spatially identical to those in the retina. Temporally however, thalamic and retinal responses differ in magnitude, and the second model in this thesis shows how cortical feedback can have a role in augmenting thalamic temporal responses. This model was reduced in order to find the minimal thalamic circuitry that can produce such responses, and this final model can also exhibit steady state oscillatory behaviour. The transition from transient visual activity to sustained oscillatory activity in this model, required a switch in the relative cortical feedback weights to the thalamocortical and the reticular populations. Together, these results indicate that the contribution of the thalamus to neural activity can no longer be ignored

Manipulating sleep spindles - expanding views on sleep, memory, and disease.

Sleep spindles are distinctive electroencephalographic (EEG) oscillations emerging during non-rapid-eye-movement sleep (NREMS) that have been implicated in multiple brain functions, including sleep quality, sensory gating, learning, and memory. Despite considerable knowledge about the mechanisms underlying these neuronal rhythms, their function remains poorly understood and current views are largely based on correlational evidence. Here, we review recent studies in humans and rodents that have begun to broaden our understanding of the role of spindles in the normal and disordered brain. We show that newly identified molecular substrates of spindle oscillations, in combination with evolving technological progress, offer novel targets and tools to selectively manipulate spindles and dissect their role in sleep-dependent processes