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BMJ Open May 2024Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a...
INTRODUCTION
Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series.
METHODS AND ANALYSIS
SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion.
ETHICS AND DISSEMINATION
The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial.
TRIAL REGISTRATION NUMBER
NCT04680910.
Topics: Humans; Propofol; Cognitive Dysfunction; Aged; Sleep, Slow-Wave; Electroencephalography; Male; Anesthetics, Intravenous; Depressive Disorder, Treatment-Resistant; Female; Middle Aged; Clinical Trials, Phase I as Topic
PubMed: 38816055
DOI: 10.1136/bmjopen-2024-087516 -
Clinical and Translational Science May 2024Sleep deprivation is a prevalent problem in critically ill patients, which leads to delayed recovery and delirium. Slow-wave sleep (SWS) is essential to energy... (Randomized Controlled Trial)
Randomized Controlled Trial
Sleep deprivation is a prevalent problem in critically ill patients, which leads to delayed recovery and delirium. Slow-wave sleep (SWS) is essential to energy restoration, tissue repair, and immune system strengthening. This study aimed to investigate the effects of gabapentin on SWS in critically ill patients. We performed a prospective open-label randomized controlled study to compare SWS and the clinical outcomes of gabapentin versus a control intervention in critically ill adult patients admitted to the intensive care unit (ICU) within 24 h. The patients' characteristics and sleep-related outcomes were recorded. The sleep-related outcomes, namely, bispectral analysis (BIS), the Richards-Campbell Sleep Questionnaire (RCSQ), and insulin-like growth factor-1 (IGF-1) levels, were evaluated. Furthermore, clinical outcomes and safety were assessed. Sixty patients from 348 cases were eligible for randomization. On day 3 of the study, patients in the gabapentin group had significantly increased SWS (66.79 vs. 0.00 min; p < 0.001), total sleep time (TST) (331.39 vs. 46.16 min; p = 0.001), RCSQ score (55.05 ± 20.18 vs. 32.80 ± 15.31; p < 0.001), and IGF-1 concentrations (84.33 ± 12.40 vs. 44.00 ± 10.20 ng/mL, p < 0.001) compared with the control group. Improvements in clinical outcomes, such as delirium, ICU-free days, and mechanical ventilator-free days, were observed; however, these differences did not reach statistically significant. Gabapentin at bedtime increased SWS, TST, and IGF-1 concentrations in critically ill patients. This regimen might be beneficial to critically ill patients for improving their sleep quality.
Topics: Humans; Gabapentin; Critical Illness; Male; Female; Middle Aged; Aged; Prospective Studies; Sleep, Slow-Wave; Adult; Intensive Care Units; Insulin-Like Growth Factor I; Sleep Deprivation; Treatment Outcome
PubMed: 38803031
DOI: 10.1111/cts.13815 -
ENeuro May 2024Sleep's contribution to affective regulation is insufficiently understood. Previous human research has focused on memorizing or rating affective pictures and less on...
Sleep's contribution to affective regulation is insufficiently understood. Previous human research has focused on memorizing or rating affective pictures and less on physiological affective responsivity. This may result in overlapping definitions of affective and declarative memories, and inconsistent deductions for how rapid eye movement sleep (REMS) and slow-wave sleep (SWS) are involved. Literature associates REMS theta (4-8Hz) activity with emotional memory processing, but its contribution to social stress habituation is unknown.Applying selective sleep stage suppression and oscillatory analyses, we investigated how sleep modulated affective adaptation towards social stress and retention of neutral declarative memories. Native Finnish participants (N=29, age M=25.8y) were allocated to REMS or SWS suppression conditions. We measured physiological (skin conductance response, SCR) and subjective stress response and declarative memory retrieval three times: before laboratory night, the next morning, and after three days. Linear mixed models were applied to test the effects of condition and sleep parameters on emotional responsivity and memory retrieval.Greater overnight increase in SCR towards the social stressor emerged after suppressed SWS (intact REMS) relative to suppressed REMS (20.1% vs. 6.1%, p=.016). The overnight SCR increase was positively associated with accumulated REMS theta energy irrespective of the condition (r=.601, p=.002). Subjectively rated affective response and declarative memory recall were comparable between the conditions.The contributions of REMS and SWS to habituation of social stress are distinct. REMS theta activity proposedly facilitates the consolidation of autonomic affective responses. Declarative memory consolidation may not have greater dependence on intact SWS relative to intact REMS. Disrupted sleep is a common problem with negative effects on affective regulation. While research indicates that rapid eye movement sleep has a central role in off-line affective processing, the mechanisms are not well defined. We used selective sleep stage suppression to investigate how disrupted sleep and stage-specific neural activity modulated the affective responsivity towards a self-conscious stressor inducing shame. We show that theta band oscillatory activity during rapid eye movement sleep is especially important for preserving the physiological stress response overnight. Understanding sleep-driven affective regulation facilitates development of applications aiming at improving mental wellbeing.
PubMed: 38802242
DOI: 10.1523/ENEURO.0453-23.2024 -
Brain Sciences May 2024The duration of slow-wave sleep (SWS) is related to the reported sleep quality and to the important variables of mental and physical health. The internal cues to end an...
The duration of slow-wave sleep (SWS) is related to the reported sleep quality and to the important variables of mental and physical health. The internal cues to end an episode of SWS are poorly understood. One such internal cue is the initiation of a body movement, which is detectable as electromyographic (EMG) activity in sleep-electroencephalography (EEG). In the present study, we characterized the termination of SWS episodes by movement to explore its potential as a biomarker. To this end, we characterized the relation between the occurrence of SWS termination by movement and individual characteristics (age, sex), SWS duration and spectral content, chronotype, depression, medication, overnight memory performance, and, as a potential neurological application, epilepsy. We analyzed 94 full-night EEG-EMG recordings (75/94 had confirmed epilepsy) in the video-EEG monitoring unit of the EpiCARE Centre Salzburg, Austria. Segments of SWS were counted and rated for their termination by movement or not through the visual inspection of continuous EEG and EMG recordings. Multiple linear regression was used to predict the number of SWS episodes that ended with movement by depression, chronotype, type of epilepsy (focal, generalized, no epilepsy, unclear), medication, gender, total duration of SWS, occurrence of seizures during the night, occurrence of tonic-clonic seizures during the night, and SWS frequency spectra. Furthermore, we assessed whether SWS movement termination was related to overnight memory retention. According to multiple linear regression, patients with overall longer SWS experienced more SWS episodes that ended with movement (t = 5.64; = 0.001). No other variable was related to the proportion of SWS that ended with movement, including no epilepsy-related variable. A small sample (n = 4) of patients taking Sertraline experienced no SWS that ended with movement, which was significant compared to all other patients (t = 8.00; < 0.001) and to n = 35 patients who did not take any medication (t = 4.22; < 0.001). While this result was based on a small subsample and must be interpreted with caution, it warrants replication in a larger sample with and without seizures to further elucidate the role of the movement termination of SWS and its potential to serve as a biomarker for sleep continuity and for medication effects on sleep.
PubMed: 38790471
DOI: 10.3390/brainsci14050493 -
Sleep Medicine May 2024During preadolescence the sleep electroencephalography undergoes massive qualitative and quantitative modifications. Despite these relevant age-related peculiarities,...
BACKGROUND
During preadolescence the sleep electroencephalography undergoes massive qualitative and quantitative modifications. Despite these relevant age-related peculiarities, the specific EEG pattern of the wake-sleep transition in preadolescence has not been exhaustively described.
METHODS
The aim of the present study is to characterize regional and temporal electrophysiological features of the sleep onset (SO) process in a group of 23 preadolescents (9-14 years) and to compare the topographical pattern of slow wave activity and delta/beta ratio of preadolescents with the EEG pattern of young adults.
RESULTS
Results showed in preadolescence the same dynamics known for adults, but with peculiarities in the delta and beta activity, likely associated with developmental cerebral modifications: the delta power showed a widespread increase during the SO with central maxima, and the lower bins of the beta activity showed a power increase after SO. Compared to adults, preadolescents during the SO exhibited higher delta power only in the slowest bins of the band: before SO slow delta activity was higher in prefrontal, frontal and occipital areas in preadolescents, and, after SO the younger group had higher slow delta activity in occipital areas. In preadolescents delta/beta ratio was higher in more posterior areas both before and after the wake-sleep transition and, after SO, preadolescents showed also a lower delta/beta ratio in frontal areas, compared to adults.
CONCLUSION
Results point to a general higher homeostatic drive for the developing areas, consistently with plastic-related maturational modifications, that physiologically occur during preadolescence.
PubMed: 38781667
DOI: 10.1016/j.sleep.2024.05.037 -
Scientific Reports May 20245-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is...
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent classical psychedelic known to induce changes in locomotion, behaviour, and sleep in rodents. However, there is limited knowledge regarding its acute neurophysiological effects. Local field potentials (LFPs) are commonly used as a proxy for neural activity, but previous studies investigating psychedelics have been hindered by confounding effects of behavioural changes and anaesthesia, which alter these signals. To address this gap, we investigated acute LFP changes in the hippocampus (HP) and medial prefrontal cortex (mPFC) of freely behaving rats, following 5-MeO-DMT administration. 5-MeO-DMT led to an increase of delta power and a decrease of theta power in the HP LFPs, which could not be accounted for by changes in locomotion. Furthermore, we observed a dose-dependent reduction in slow (20-50 Hz) and mid (50-100 Hz) gamma power, as well as in theta phase modulation, even after controlling for the effects of speed and theta power. State map analysis of the spectral profile of waking behaviour induced by 5-MeO-DMT revealed similarities to electrophysiological states observed during slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep. Our findings suggest that the psychoactive effects of classical psychedelics are associated with the integration of waking behaviours with sleep-like spectral patterns in LFPs.
Topics: Animals; Prefrontal Cortex; Rats; Hippocampus; Wakefulness; Male; Sleep; Electroencephalography; Theta Rhythm; Hallucinogens
PubMed: 38760450
DOI: 10.1038/s41598-024-61474-9 -
BioRxiv : the Preprint Server For... May 2024Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and...
Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2R neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2R →PBN circuit or the postsynaptic PROKR2 neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2 neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.
PubMed: 38746393
DOI: 10.1101/2024.04.30.591948 -
GeroScience May 2024Sleep is a potential early, modifiable risk factor for cognitive decline and dementia. Impaired slow wave sleep (SWS) is pronounced in individuals with cognitive...
Sleep is a potential early, modifiable risk factor for cognitive decline and dementia. Impaired slow wave sleep (SWS) is pronounced in individuals with cognitive impairment (CI). Cognitive decline and impairments of SWS are bi-directionally linked in a vicious cycle. SWS can be enhanced non-invasively using phase-locked acoustic stimulation (PLAS), potentially breaking this vicious cycle. Eighteen healthy older adults (HC, age, 68.3 ± 5.1) and 16 older adults (age, 71.9 ± 3.9) with CI (Montreal Cognitive Assessment ≤ 25) underwent one baseline (sham-PLAS) night and three consecutive stimulation nights (real-PLAS). EEG responses and blood-plasma amyloid beta Aβ42/Aβ40 ratio were measured pre- and post-intervention, as was episodic memory. The latter was again evaluated 1 week and 3 months after the intervention. In both groups, PLAS induced a significant electrophysiological response in both voltage- and time-frequency analyses, and memory performance improved in association with the magnitude of this response. In the CI group, both electrophysiological and associated memory effects were delayed compared to the healthy group. After 3 intervention nights, electrophysiological response to PLAS was no longer different between CI and HC groups. Only in the CI sample, stronger electrophysiological responses were significantly associated with improving post-intervention Aβ42/Aβ40 ratios. PLAS seems to improve SWS electrophysiology, memory, and amyloid dynamics in older adults with CI. However, effects on memory require more time to unfold compared to healthy older adults. This indicates that PLAS may become a potential tool to ameliorate cognitive decline, but longer interventions are necessary to compensate for declining brain integrity. This study was pre-registered (clinicaltrials.gov: NCT04277104).
PubMed: 38744792
DOI: 10.1007/s11357-024-01195-z -
Journal of Clinical Medicine Apr 2024Epileptic encephalopathies (EE) are characterized by severe drug-resistant seizures, early onset, and unfavorable developmental outcomes. This article discusses the use...
Epileptic encephalopathies (EE) are characterized by severe drug-resistant seizures, early onset, and unfavorable developmental outcomes. This article discusses the use of intravenous methylprednisolone (IVMP) pulse therapy in pediatric patients with EE to evaluate its efficacy and tolerability. This is a retrospective study from 2020 to 2023. Inclusion criteria were ≤18 years at the time of IVMP pulse therapy and at least 6 months of follow-up. Efficacy and outcome, defined as seizure reduction > 50% (responder rate), were evaluated at 6 and 9 months of therapy, and 6 months after therapy suspension; quality of life (QoL) was also assessed. Variables predicting positive post-IVMP outcomes were identified using statistical analysis. The study included 21 patients, with a responder rate of 85.7% at 6 and 9 months of therapy, and 80.9% at 6 months after therapy suspension. Variables significantly predicting favorable outcome were etiology ( = 0.0475) and epilepsy type ( = 0.0475), with the best outcome achieved in patients with genetic epilepsy and those with encephalopathy related to electrical status epilepticus during slow-wave sleep (ESES). All patients evidenced improvements in QoL at the last follow-up, with no relevant adverse events reported. : Our study confirmed the efficacy and high tolerability of IVMP pulse therapy in pediatric patients with EE. Genetic epilepsy and ESES were positive predictors of a favorable clinical outcome. QOL, EEG tracing, and postural-motor development showed an improving trend as well. IVMP pulse therapy should be considered earlier in patients with EE.
PubMed: 38731025
DOI: 10.3390/jcm13092497 -
Frontiers in Pharmacology 2024Slow wave sleep (SWS) is highly relevant for verbal and non-verbal/spatial memory in healthy individuals, but also in people with epilepsy. However, contradictory...
Slow wave sleep (SWS) is highly relevant for verbal and non-verbal/spatial memory in healthy individuals, but also in people with epilepsy. However, contradictory findings exist regarding the effect of seizures on overnight memory retention, particularly relating to procedural and non-verbal memory, and thorough examination of episodic memory retention with ecologically valid tests is missing. This research explores the interaction of SWS duration with epilepsy-relevant factors, as well as the relation of spectral characteristics of SWS on overnight retention of procedural, verbal, and episodic memory. In an epilepsy monitoring unit, epilepsy patients (N = 40) underwent learning, immediate and 12 h delayed testing of memory retention for a fingertapping task (procedural memory), a word-pair task (verbal memory), and an innovative virtual reality task (episodic memory). We used multiple linear regression to examine the impact of SWS duration, spectral characteristics of SWS, seizure occurrence, medication, depression, seizure type, gender, and epilepsy duration on overnight memory retention. Results indicated that none of the candidate variables significantly predicted overnight changes for procedural memory performance. For verbal memory, the occurrence of tonic-clonic seizures negatively impacted memory retention and higher psychoactive medication load showed a tendency for lower verbal memory retention. Episodic memory was significantly impacted by epilepsy duration, displaying a potential nonlinear impact with a longer duration than 10 years negatively affecting memory performance. Higher drug load of anti-seizure medication was by tendency related to better overnight retention of episodic memory. Contrary to expectations longer SWS duration showed a trend towards decreased episodic memory performance. Analyses on associations between memory types and EEG band power during SWS revealed lower alpha-band power in the frontal right region as significant predictor for better episodic memory retention. In conclusion, this research reveals that memory modalities are not equally affected by important epilepsy factors such as duration of epilepsy and medication, as well as SWS spectral characteristics.
PubMed: 38725659
DOI: 10.3389/fphar.2024.1374760