Functional connectivity between medial pulvinar and cortical networks as a predictor of arousal to noxious stimuli during sleep.

The interruption of sleep by a nociceptive stimulus is favoured by an increase in the pre-stimulus functional connectivity between sensory and higher level cortical areas. In addition, stimuli inducing arousal also trigger a widespread electroencephalographic (EEG) response reflecting the coordinated activation of a large cortical network. Because functional connectivity between distant cortical areas is thought to be underpinned by trans-thalamic connections involving associative thalamic nuclei, we investigated the possible involvement of one principal associative thalamic nucleus, the medial pulvinar (PuM), in the sleeper's responsiveness to nociceptive stimuli. Intra-cortical and intra-thalamic signals were analysed in 440 intracranial electroencephalographic (iEEG) segments during nocturnal sleep in eight epileptic patients receiving laser nociceptive stimuli. The spectral coherence between the PuM and 10 cortical regions grouped in networks was computed during 5 s before and 1 s after the nociceptive stimulus and contrasted according to the presence or absence of an arousal EEG response. Pre- and post-stimulus phase coherence between the PuM and all cortical networks was significantly increased in instances of arousal, both during N2 and paradoxical (rapid eye movement [REM]) sleep. Thalamo-cortical enhancement in coherence involved both sensory and higher level cortical networks and predominated in the pre-stimulus period. The association between pre-stimulus widespread increase in thalamo-cortical coherence and subsequent arousal suggests that the probability of sleep interruption by a noxious stimulus increases when it occurs during phases of enhanced trans-thalamic transfer of information between cortical areas.

Telehealth-delivered CBT-I programme enhanced by acceptance and commitment therapy for insomnia and hypnotic dependence: A pilot randomized controlled trial.

Cognitive behavioural therapy for insomnia is the recommended treatment for chronic insomnia. However, up to a quarter of patients dropout from cognitive behavioural therapy for insomnia programmes. Acceptance, mindfulness and values-based actions may constitute complementary therapeutic tools to cognitive behavioural therapy for insomnia. The current study sought to evaluate the efficacy of a remotely delivered programme combining the main components of cognitive behavioural therapy for insomnia (sleep restriction and stimulus control) with the third-wave cognitive behavioural therapy acceptance and commitment therapy in adults with chronic insomnia and hypnotic dependence on insomnia symptoms and quality of life. Thirty-two participants were enrolled in a pilot randomized controlled trial: half of them were assigned to a 3-month waiting list before receiving the four "acceptance and commitment therapy-enhanced cognitive behavioural therapy for insomnia" treatment sessions using videoconference. The primary outcome was sleep quality as measured by the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. All participants also filled out questionnaires about quality of life, use of hypnotics, depression and anxiety, acceptance, mindfulness, thought suppression, as well as a sleep diary at baseline, post-treatment and 6-month follow-up. A large effect size was found for Insomnia Severity Index and Pittsburgh Sleep Quality Index, but also daytime improvements, with increased quality of life and acceptance at post-treatment endpoint in acceptance and commitment therapy-enhanced cognitive behavioural therapy for insomnia participants. Improvement in Insomnia Severity Index and Pittsburgh Sleep Quality Index was maintained at the 6-month follow-up. Wait-list participants increased their use of hypnotics, whereas acceptance and commitment therapy-enhanced cognitive behavioural therapy for insomnia participants evidenced reduced use of them. This pilot study suggests that web-based cognitive behavioural therapy for insomnia incorporating acceptance and commitment therapy processes may be an efficient option to treat chronic insomnia and hypnotic dependence.

Local sleep spindles in the human thalamus.

KEY POINTS: Sleep spindles have recently been shown to occur not only across multiple neocortical regions but also locally in restricted cortical areas. Here we show that local spindles are indeed present in the human posterior thalamus. Thalamic local spindles had lower spectral power than non-local ones. While non-local thalamic spindles had equal local and non-local cortical counterparts, local thalamic spindles had significantly more local cortical counterparts (i.e. occurring in a single cortical site). The preferential association of local thalamic and cortical spindles supports the notion of thalamocortical loops functioning in a modular way. ABSTRACT: Sleep spindles are believed to subserve many sleep-related functions, from memory consolidation to cortical development. Recent data using intracerebral recordings in humans have shown that they occur across multiple neocortical regions but may also be spatially restricted to specific brain areas (local spindles). The aim of this study was to characterize spindles at the level of the human posterior thalamus, with the hypothesis that, besides the global thalamic spindling activity usually observed, local spindles could also be present in the thalamus. Using intracranial, time-frequency EEG recordings in 17 epileptic patients, we assessed the distribution of thalamic spindles during natural sleep stages N2 and N3 in six thalamic nuclei. Local spindles (i.e. spindles present in a single pair of recording contacts) were observed in all the thalamic regions explored, and compared with non-local spindles in terms of intrinsic properties and cortical counterparts. Thalamic local and non-local spindles did not differ in density, frequency or duration, but local spindles had lower spectral power than non-local ones. Each thalamic spindle had a cortical counterpart. While non-local thalamic spindles had equal cortical local and non-local counterparts, local thalamic spindles had significantly more local cortical counterparts (i.e. occurring in a single cortical site). The preferential association of local thalamic and cortical spindles supports the notion of thalamocortical loops functioning in a modular way.

Cortical modulation of nociception by galvanic vestibular stimulation: A potential clinical tool?

OBJECTIVE: Vestibular afferents converge with nociceptive ones within the posterior insula, and can therefore modulate nociception. Consistent with this hypothesis, caloric vestibular stimulation (CVS) has been shown to reduce experimental and clinical pain. Since CVS can induce undesirable effects in a proportion of patients, here we explored an alternative means to activate non-invasively the vestibular pathways using innocuous bi-mastoid galvanic stimulation (GVS), and assessed its effects on experimental pain. METHODS: Sixteen healthy volunteers participated in this study. Experimental pain was induced by noxious laser-heat stimuli to the left hand while recording pain ratings and related brain potentials (LEPs). We evaluated changes of these indices during left- or right-anodal GVS (cathode on contralateral mastoid), and contrasted them with those during sham GVS, optokinetic vestibular stimulation (OKS) using virtual reality, and attentional distraction to ascertain the vestibular-specific analgesic effects of GVS. RESULTS: GVS elicited brief sensations of head/trunk deviation, inoffensive to all participants. Both active GVS conditions showed analgesic effects, greater for the right anodal stimulation. OKS was helpful to attain significant LEP reductions during the left-anodal stimulation. Neither sham-GVS nor the distraction task were able to modulate significantly pain ratings or LEPs. CONCLUSIONS: GVS appeared as a well-tolerated and powerful procedure for the relief of experimental pain, probably through physiological interaction within insular nociceptive networks. Either isolated or in combination with other types of vestibular activation (e.g., optokinetic stimuli), GVS deserves being tested in clinical settings.

The generation and propagation of the human alpha rhythm.

The alpha rhythm is the longest-studied brain oscillation and has been theorized to play a key role in cognition. Still, its physiology is poorly understood. In this study, we used microelectrodes and macroelectrodes in surgical epilepsy patients to measure the intracortical and thalamic generators of the alpha rhythm during quiet wakefulness. We first found that alpha in both visual and somatosensory cortex propagates from higher-order to lower-order areas. In posterior cortex, alpha propagates from higher-order anterosuperior areas toward the occipital pole, whereas alpha in somatosensory cortex propagates from associative regions toward primary cortex. Several analyses suggest that this cortical alpha leads pulvinar alpha, complicating prevailing theories of a thalamic pacemaker. Finally, alpha is dominated by currents and firing in supragranular cortical layers. Together, these results suggest that the alpha rhythm likely reflects short-range supragranular feedback, which propagates from higher- to lower-order cortex and cortex to thalamus. These physiological insights suggest how alpha could mediate feedback throughout the thalamocortical system.

Theta Bursts Precede, and Spindles Follow, Cortical and Thalamic Downstates in Human NREM Sleep.

Since their discovery, slow oscillations have been observed to group spindles during non-REM sleep. Previous studies assert that the slow-oscillation downstate (DS) is preceded by slow spindles (10-12 Hz) and followed by fast spindles (12-16 Hz). Here, using both direct transcortical recordings in patients with intractable epilepsy (n = 10, 8 female), as well as scalp EEG recordings from a healthy cohort (n = 3, 1 female), we find in multiple cortical areas that both slow and fast spindles follow the DS. Although discrete oscillations do precede DSs, they are theta bursts (TBs) centered at 5-8 Hz. TBs were more pronounced for DSs in NREM stage 2 (N2) sleep compared with N3. TB with similar properties occur in the thalamus, but unlike spindles they have no clear temporal relationship with cortical TB. These differences in corticothalamic dynamics, as well as differences between spindles and theta in coupling high-frequency content, are consistent with NREM theta having separate generative mechanisms from spindles. The final inhibitory cycle of the TB coincides with the DS peak, suggesting that in N2, TB may help trigger the DS. Since the transition to N1 is marked by the appearance of theta, and the transition to N2 by the appearance of DS and thus spindles, a role of TB in triggering DS could help explain the sequence of electrophysiological events characterizing sleep. Finally, the coordinated appearance of spindles and DSs are implicated in memory consolidation processes, and the current findings redefine their temporal coupling with theta during NREM sleep.SIGNIFICANCE STATEMENT Sleep is characterized by large slow waves which modulate brain activity. Prominent among these are downstates (DSs), periods of a few tenths of a second when most cells stop firing, and spindles, oscillations at ∼12 times a second lasting for ∼a second. In this study, we provide the first detailed description of another kind of sleep wave: theta bursts (TBs), a brief oscillation at ∼six cycles per second. We show, recording during natural sleep directly from the human cortex and thalamus, as well as on the scalp, that TBs precede, and spindles follow DSs. TBs may help trigger DSs in some circumstances, and could organize cortical and thalamic activity so that memories can be consolidated during sleep.

Coordination of cortical and thalamic activity during non-REM sleep in humans.

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.

Sleep spindles and human cortical nociception: a surface and intracerebral electrophysiological study.

KEY POINTS: Sleep spindle are usually considered to play a major role in inhibiting sensory inputs. Using nociceptive stimuli in humans, we tested the effect of spindles on behavioural, autonomic and cortical responses in two experiments using surface and intracerebral electroencephalographic recordings. We found that sleep spindles do not prevent arousal reactions to nociceptive stimuli and that autonomic reactivity to nociceptive inputs is not modulated by spindle activity. Moreover, neither the surface sensory, nor the insular evoked responses were modulated by the spindle, as detected at the surface or within the thalamus. The present study comprises the first investigation of the effect of spindles on nociceptive information processing and the results obtained challenge the classical inhibitory effect of spindles. ABSTRACT: Responsiveness to environmental stimuli declines during sleep, and sleep spindles are often considered to play a major role in inhibiting sensory inputs. In the present study, we tested the effect of spindles on behavioural, autonomic and cortical responses to pain, in two experiments assessing surface and intracerebral responses to thermo-nociceptive laser stimuli during the all-night N2 sleep stage. The percentage of arousals remained unchanged as a result of the presence of spindles. Neither cortical nociceptive responses, nor autonomic cardiovascular reactivity were depressed when elicited within a spindle. These results could be replicated in human intracerebral recordings, where sleep spindle activity in the posterior thalamus failed to depress the thalamocortical nociceptive transmission, as measured by sensory responses within the posterior insula. Hence, the assumed inhibitory effect of spindles on sensory inputs may not apply to the nociceptive system, possibly as a result of the specificity of spinothalamic pathways and the crucial role of nociceptive information for homeostasis. Intriguingly, a late scalp response commonly considered to reflect high-order stimulus processing (the 'P3' potential) was significantly enhanced during spindling, suggesting a possible spindle-driven facilitation, rather than attenuation, of cortical nociception.

Heterogeneity of arousals in human sleep: A stereo-electroencephalographic study.

Wakefulness, non-rapid eye movement (NREM), and rapid eye movement (REM) sleep are characterized by specific brain activities. However, recent experimental findings as well as various clinical conditions (parasomnia, sleep inertia) have revealed the presence of transitional states. Brief intrusions of wakefulness into sleep, namely, arousals, appear as relevant phenomena to characterize how brain commutes from sleep to wakefulness. Using intra-cerebral recordings in 8 drug-resistant epileptic patients, we analyzed electroencephalographic (EEG) activity during spontaneous or nociceptive-induced arousals in NREM and REM sleep. Wavelet spectral analyses were performed to compare EEG signals during arousals, sleep, and wakefulness, simultaneously in the thalamus, and primary, associative, or high-order cortical areas. We observed that 1) thalamic activity during arousals is stereotyped and its spectral composition corresponds to a state in-between wakefulness and sleep; 2) patterns of cortical activity during arousals are heterogeneous, their manifold spectral composition being related to several factors such as sleep stages, cortical areas, arousal modality ("spontaneous" vs nociceptive-induced), and homeostasis; 3) spectral compositions of EEG signals during arousal and wakefulness differ from each other. Thus, stereotyped arousals at the thalamic level seem to be associated with different patterns of cortical arousals due to various regulation factors. These results suggest that the human cortex does not shift from sleep to wake in an abrupt binary way. Arousals may be considered more as different states of the brain than as "short awakenings." This phenomenon may reflect the mechanisms involved in the negotiation between two main contradictory functional necessities, preserving the continuity of sleep, and maintaining the possibility to react.

Synchronization of isolated downstates (K-complexes) may be caused by cortically-induced disruption of thalamic spindling.

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.

Thalamic deactivation at sleep onset precedes that of the cerebral cortex in humans.

Thalamic and cortical activities are assumed to be time-locked throughout all vigilance states. Using simultaneous intracortical and intrathalamic recordings, we demonstrate here that the thalamic deactivation occurring at sleep onset most often precedes that of the cortex by several minutes, whereas reactivation of both structures during awakening is synchronized. Delays between thalamus and cortex deactivations can vary from one subject to another when a similar cortical region is considered. In addition, heterogeneity in activity levels throughout the cortical mantle is larger than previously thought during the descent into sleep. Thus, asynchronous thalamo-cortical deactivation while falling asleep probably explains the production of hypnagogic hallucinations by a still-activated cortex and the common self-overestimation of the time needed to fall asleep.

Human thalamic and cortical activities assessed by dimension of activation and spectral edge frequency during sleep wake cycles.

STUDY OBJECTIVES: Using spectral edge frequency (SEF95) and dimension of activation (DA), a new tool derived from the dimension of correlation, we assessed the activation of thalamus and cortex in the different vigilance states. PATIENTS: Results were gathered from intracerebral recordings performed in 12 drug-resistant epileptic patients during video-stereoelectroencephalographic (SEEG) monitoring. RESULTS: In the cortex, we observed a progressive decrease of DA from wake to sleep, with minimal DA values characterizing the deep slow wave sleep (dSWS) stage. During paradoxical sleep (PS), cortical level of activity returned to DA values similar to those obtained during wakefulness. In the thalamus, DA values during wakefulness were higher than the values observed during light SWS (ISWS), deep SWS (dSWS) and PS; there were no significant differences between the 3 sleep stages. Similar variations were observed with SEF95. CONCLUSION: DA analysis proved reliable for quantification of cortical activity, in agreement with data issued from classical vigilance states scoring and spectral analysis. At the thalamic level, only 2 levels of activity within a sleep wake cycle were observed, pointing to dissociated levels of activation between the thalamus and the neocortex during ISWS and PS.

Human thalamic medial pulvinar nucleus is not activated during paradoxical sleep.

Wakefulness and paradoxical sleep (PS) share a similar electrophysiological trait, namely, a more elevated level of high-frequency activities at both thalamic and cortical levels relative to slow wave sleep (SWS). The spatio-temporal binding of these high-frequency activities within thalamo-cortical networks is presumed to generate cognitive experiences during wakefulness. Similarly during PS, this phenomenon could be at the origin of the perceptual experiences forming dreams. However, contents of dreams often present some bizarre features which depart from our cognitive experiences in waking. This suggests some differences in processing and/or integration of brain activities during waking and PS. Using intracranial recordings in epileptic patients we observed, specifically during PS, the presence of unexpected delta frequency oscillations, as well as a surprisingly low amount of high-frequency activities, in a posterior region of the thalamus, the medial pulvinar nucleus (PuM). This discrepancy between activities in a thalamic nucleus and its related cortical areas may compromise the spatio-temporal binding of the high-frequency activities, resulting in altered perceptual experiences during dream periods.