Elevated pain sensitivity is associated with reduced REM sleep in females with comorbid temporomandibular disorder and insomnia.

OBJECTIVE: Patients with chronic pain disorders, including Temporomandibular Disorders (TMDs) endorse high levels of sleep disturbances, frequently reporting reduced sleep quality. Despite this, little is known about the effect that daytime pain has on the microstructure and macro-architecture of sleep. Therefore, we aimed to examine the extent to which daytime pain sensitivity, measured using quantitative sensory testing (QST), is associated with objective sleep parameters the following night, including sleep architecture and power spectral density, in women with TMD. METHODS: : 144 females with myalgia and arthralgia by examination using the Diagnostic criteria for TMD completed a comprehensive QST battery consisting of General Pain Sensitivity, Central Sensitization Index, and Masseter Pressure Pain Threshold assessments. Polysomnography (PSG) was collected the same night to measure sleep architecture and calculate relative power in delta, theta, alpha, sigma, and beta power bands. RESULTS: Central Sensitization (B= -3.069, P = 0.009), General Pain Sensitivity Indices (B= -3.069, P = 0.007), and Masseter Pain Pressure Threshold (B = 0.030, P = 0.008) were significantly associated with lower REM% both before and after controlling for covariates. Pain sensitivity measures were not significantly associated with relative power in any of the spectral bands, nor with any other sleep architectural stages. CONCLUSIONS: Our findings demonstrate that higher generalized pain sensitivity, masseter pain pressure threshold, as well as central sensitization were associated with a lower percentage of REM in participants with myofascial pain and arthralgia of the masticatory system. These findings provide an important step toward understanding the mechanistic underpinnings of how chronic pain interacts with sleep physiology.

Suvorexant alters dynamics of the sleep-electroencephalography-power spectrum and depressive-symptom trajectories during inpatient opioid withdrawal.

STUDY OBJECTIVES: Opioid withdrawal is an aversive experience that often exacerbates depressive symptoms and poor sleep. The aims of the present study were to examine the effects of suvorexant on oscillatory sleep-electroencephalography (EEG) band power during medically managed opioid withdrawal, and to examine their association with withdrawal severity and depressive symptoms. METHODS: Participants with opioid use disorder (N = 38: age-range:21-63, 87% male, 45% white) underwent an 11-day buprenorphine taper, in which they were randomly assigned to suvorexant (20 mg [n = 14] or 40 mg [n = 12]), or placebo [n = 12], while ambulatory sleep-EEG data was collected. Linear mixed-effect models were used to explore: (1) main and interactive effects of drug group, and time on sleep-EEG band power, and (2) associations between sleep-EEG band power change, depressive symptoms, and withdrawal severity. RESULTS: Oscillatory spectral power tended to be greater in the suvorexant groups. Over the course of the study, decreases in delta power were observed in all study groups (ß = -189.082, d = -0.522, p = <0.005), increases in beta power (20 mg: ß = 2.579, d = 0.413, p = 0.009 | 40 mg ß = 5.265, d = 0.847, p < 0.001) alpha power (20 mg: ß = 158.304, d = 0.397, p = 0.009 | 40 mg: ß = 250.212, d = 0.601, p = 0.001) and sigma power (20 mg: ß = 48.97, d = 0.410, p < 0.001 | 40 mg: ß = 71.54, d = 0.568, p < 0.001) were observed in the two suvorexant groups. During the four-night taper, decreases in delta power were associated with decreases in depressive symptoms (20 mg: ß = 190.90, d = 0.308, p = 0.99 | 40 mg: ß = 433.33, d = 0.889 p = <0.001), and withdrawal severity (20 mg: ß = 215.55, d = 0.034, p = 0.006 | 40 mg: ß = 192.64, d = -0.854, p = <0.001), in both suvorexant groups and increases in sigma power were associated with decreases in withdrawal severity (20 mg: ß = -357.84, d = -0.659, p = 0.004 | 40 mg: ß = -906.35, d = -1.053, p = <0.001). Post-taper decreases in delta (20 mg: ß = 740.58, d = 0.964 p = <0.001 | 40 mg: ß = 662.23, d = 0.882, p = <0.001) and sigma power (20 mg only: ß = 335.54, d = 0.560, p = 0.023) were associated with reduced depressive symptoms in the placebo group. CONCLUSIONS: Results highlight a complex and nuanced relationship between sleep-EEG power and symptoms of depression and withdrawal. Changes in delta power may represent a mechanism influencing depressive symptoms and withdrawal.

People with IBD evidence more microarousals during sleep architecture assessments.

OBJECTIVE: Poor sleep is common in inflammatory bowel disease (IBD) and may be associated with overall worse disease outcomes. While the sleep/IBD literature is growing, the data are often self-reported. Further, much of the research using objective measures of sleep architecture, or the overall pattern of sleep depth, rely on single-night assessments, which can be of questionable validity. DESIGN: Participants with IBD and healthy controls were recruited from Dartmouth-Hitchcock Medical Center as part of a two-phase clinical trial. Sleep architecture was assessed using three nights of in-home electroencephalographic monitoring and scored according to the American Academy of Sleep Medicine guidelines. RESULTS: Our sample included 15 participants with IBD and 8 healthy controls. Participants with IBD were more psychiatrically complex, with more self-reported insomnia, anxiety and depression. Participants with IBD evidenced greater microarousals than healthy controls. In participants with IBD, microarousals were associated with lower insomnia and greater depression scores. Within IBD, participants with clinically significant insomnia evidenced trend towards lower sleep efficiency, while self-reported disease activity did not significantly impact findings. CONCLUSIONS: The methodology of past research may have impacted findings, including the reliance on single-night assessments and limited generalisability. Future research that uses robust, multinight assessments of sleep architecture in large, diverse samples is clearly warranted, as is research exploring the impact of cognitive and behavioural factors on sleep architecture and arousal. TRIAL REGISTRATION NUMBER: NCT04132024.

Sleep-EEG in comorbid pain and insomnia: implications for the treatment of pain disorders.

Introduction: Patients with chronic pain experience a high prevalence of comorbid insomnia, which is associated with functional impairment. Recent advances in sleep electroencephalography (sleep-EEG) may clarify the mechanisms that link sleep and chronic pain. In this clinical update, we outline current advancements in sleep-EEG assessments for pain and provide research recommendations. Results: Promising preliminary work suggests that sleep-EEG spectral bands, particularly beta, gamma, alpha, and delta power, may create candidate neurophysiological signatures of pain, and macro-architectural parameters (e.g., total sleep time, arousals, and sleep continuity) may facilitate EEG-derived sleep phenotyping and may enable future stratification in the treatment of pain. Conclusion: Integration of measures obtained through sleep-EEG represent feasible and scalable approaches that could be adopted in the future. We provide research recommendations to progress the field towards a deeper understanding of their utility and potential future applications in clinical practice.

Brain-based correlates of antidepressant response to ketamine: a comprehensive systematic review of neuroimaging studies.

Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can provide predictive and mechanistic insights, but findings are limited by small sample sizes. This systematic review covers neuroimaging studies investigating baseline (pre-treatment) and longitudinal (post-treatment) biomarkers of responses to ketamine. All modalities were included. We performed searches of five electronic databases (from inception to April 26, 2022). 69 studies were included (with 1751 participants). There was substantial methodological heterogeneity and no well replicated biomarker. However, we found convergence across some significant results, particularly in longitudinal biomarkers. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions in electrophysiological studies, post-treatment increases in functional connectivity within the prefrontal cortex, and post-treatment increases in the functional activation of the striatum. Although a well replicated neuroimaging biomarker of ketamine response was not identified, there are biomarkers that warrant further investigation.

A randomized, placebo-controlled, double-blinded mechanistic clinical trial using endotoxin to evaluate the relationship between insomnia, inflammation, and affective disturbance on pain in older adults: A protocol for the sleep and Healthy Aging Research for pain (SHARE-P) study.

Chronic pain is prevalent in older adults. Treatment, especially with opioids, is often ineffective and poses considerable negative consequences in this population. To improve treatment, it is important to understand why older adults are at a heightened risk for developing chronic pain. Insomnia is a major modifiable risk factor for chronic pain that is ubiquitous among older adults. Insomnia can also lead to heightened systemic inflammation and affective disturbance, both of which may further exacerbate pain conditions in older adults. Endotoxin exposure can be used as an experimental model of systemic inflammation and affective disturbance. The current study aims to understand how insomnia status and endotoxin-induced changes in inflammation and affect (increased negative affect and decreased positive affect) may interact to impact pain facilitatory and inhibitory processes in older adults. Longitudinal data will also assess how pain processing, affective, and inflammatory responses to endotoxin may predict the development of pain and/or depressive symptoms. The current study is a randomized, double-blinded, placebo-controlled, mechanistic clinical trial in men and women, with and without insomnia, aged 50 years and older. Participants were randomized to either 0.8ng/kg endotoxin injection or saline placebo injection. Daily diaries were used to collect variables related to sleep, mood, and pain at two-week intervals during baseline and 3-, 6-, 9-, and 12-months post-injection. Primary outcomes during the experimental phase include conditioned pain modulation, temporal summation, and affective pain modulation ∼5.5 hours after injection. Primary outcomes for longitudinal assessments are self-reported pain intensity and depressive symptoms. The current study uses endotoxin as an experimental model for pain. In doing so, it aims to extend the current literature by: (1) including older adults, (2) investigating insomnia as a potential risk factor for chronic pain, (3) evaluating the role of endotoxin-induced affective disturbances on pain sensitivity, and (4) assessing sex differences in endotoxin-induced hyperalgesia. Clinicaltrialsgov: NCT03256760. Trial sponsor: NIH R01AG057750-01.

Nocturnal Delta Power is Associated With Lower Next-Day Pain But Not Pain Catastrophizing: Results From a Cohort of Female Participants With Temporomandibular Joint Pain.

Existing data demonstrate reduced delta power during sleep in patients with depression and chronic pain. However, there has been little examination of the relationship between delta power and pain-reports, or pain-catastrophizing. We recruited female participants (n = 111) with insomnia and temporomandibular disorder, and measured nocturnal and daytime measures of pain and pain catastrophizing, and calculated relative nocturnal delta (0.5-4 Hz) power during sleep. We fit linear regression models, and further examined the moderating effect of depressive symptom severity. Lower relative delta power across the whole night was significantly associated with greater nocturnal pain (B = -20.276, P = .025, R2 = 0.214). Lower relative delta power during the first-third of the night, was associated with greater nocturnal pain (B = -17.807, p = 0.019, R2 = 0.217), next-day pain (B = 13.876, P = .039, R2 = 0.195), and next-morning pain (B = -15.751, P = .022, R2 = 0.198). Lower relative delta power during the final-third of the night was significantly associated with greater nocturnal (B = -17.602, P = .029, R2 = 0.207) and next-morning pain (3rd: B = -14.943, P = .042, R2 = 0.187). Depressive symptom severity did not moderate these relationships. Delta power was not significantly associated with nocturnal or daytime pain catastrophizing. These findings demonstrate that greater relative delta power during sleep is associated with lower nocturnal and next-day pain in patients with temporomandibular disorder. This data may guide the use of sleep interventions in clinical pain populations, with the aim of improving pain outcomes. PERSPECTIVE: This article presents data demonstrating an association between increased nocturnal delta power and reduced next-day pain. These findings may help promote interventions which aim to increase nocturnal delta power in clinical pain populations, with the goal of improving pain outcomes.

Adverse childhood experiences and sleep links in a predominantly Black sample of overweight adults.

Adverse childhood experiences (ACEs) have been associated with worse sleep, but existing literature is limited by use of predominantly White samples, lack of objective sleep measurement, and use of non-standardized questionnaires. We investigated associations between retrospectively reported ACEs and sleep in adulthood in a sample of 43 adults 20-53 years of age, free from chronic conditions, with a Body mass index (BMI) ≥ 25 (Mean age = 33.14 [SD = 10.05], 74% female, 54% Black). Sleep efficiency (SE), total sleep time (TST), wake after sleep onset (WASO), and sleep onset latency (SOL), were measured by actigraphy and daily diary. Global sleep quality and insomnia severity were measured by questionnaires. Sleepiness, fatigue, and sleep quality were also measured by daily diary. Adjusting for demographic characteristics and BMI, ACEs were significantly associated with poorer global sleep quality and diary measures of greater daytime sleepiness, fatigue, and poorer sleep quality. There were no significant associations between ACEs and SE, TST, WASO, or SOL measured by diary or actigraphy. Findings suggest that ACEs are associated with worse sleep perception and daytime functioning in adulthood. Larger prospective studies are needed to replicate these findings, examine racial/ethnic differences, and determine temporal associations between ACEs, sleep, and health (e.g., BMI).

Astrocyte adaptation in Alzheimer's disease: a focus on astrocytic P2X7R.

Astrocytes are key homeostatic and defensive cells of the central nervous system (CNS). They undertake numerous functions during development and in adulthood to support and protect the brain through finely regulated communication with other cellular elements of the nervous tissue. In Alzheimer's disease (AD), astrocytes undergo heterogeneous morphological, molecular and functional alterations represented by reactive remodelling, asthenia and loss of function. Reactive astrocytes closely associate with amyloid ß (Aß) plaques and neurofibrillary tangles in advanced AD. The specific contribution of astrocytes to AD could potentially evolve along the disease process and includes alterations in their signalling, interactions with pathological protein aggregates, metabolic and synaptic impairments. In this review, we focus on the purinergic receptor, P2X7R, and discuss the evidence that P2X7R activation contributes to altered astrocyte functions in AD. Expression of P2X7R is increased in AD brain relative to non-demented controls, and animal studies have shown that P2X7R antagonism improves cognitive and synaptic impairments in models of amyloidosis and tauopathy. While P2X7R activation can induce inflammatory signalling pathways, particularly in microglia, we focus here specifically on the contributions of astrocytic P2X7R to synaptic changes and protein aggregate clearance in AD, highlighting cell-specific roles of this purinoceptor activation that could be targeted to slow disease progression.

The effect of sleep continuity disruption on multimodal emotion processing and regulation: a laboratory-based, randomised, controlled experiment in good sleepers.

Previous research shows that experimental sleep deprivation alters emotion processing, suggesting a potential mechanism linking sleep disruption to mental ill-health. Extending previous work, we experimentally disrupted sleep continuity in good sleepers and assessed next-day emotion processing and regulation using tasks with established sensitivity to depression. In a laboratory-based study, 51 good sleepers (37 female; mean [SD] age 24 [3.63] years), were randomised to 1 night of uninterrupted sleep (n = 24) or sleep continuity disruption (n = 27). We assessed emotion perception, attention, and memory the following day. Participants also completed an emotion regulation task and measures of self-reported affect, anxiety, sleepiness, overnight declarative memory consolidation, and psychomotor vigilance. Confirming the effects of the manipulation, sleep continuity disruption led to a marked decrease in polysomnography-defined total sleep time (229.98 versus 434.57 min), increased wake-time after sleep onset (260.66 versus 23.84 min), and increased sleepiness (d = 0.81). Sleep continuity disruption led to increased anxiety (d = 0.68), decreased positive affect (d = -0.62), reduced overnight declarative memory consolidation (d = -1.08), and reduced psychomotor vigilance (longer reaction times [d = 0.64] and more lapses [d = 0.74]), relative to control. However, contrary to our hypotheses, experimental sleep disruption had no effect on perception of, or bias for, emotional facial expressions, emotional memory for words, or emotion regulation following worry induction. In conclusion, 1 night of sleep continuity disruption had no appreciable effect on objective measures of emotion processing or emotion regulation in response to worry induction, despite clear effects on memory consolidation, vigilance, and self-reported affect and anxiety.

Preliminary Evidence for the Sequentially Mediated Effect of Racism-Related Stress on Pain Sensitivity Through Sleep Disturbance and Corticolimbic Opioid Receptor Function.

Sleep disturbance predicts worse pain outcomes. Because sleep disturbance inequitably impacts Black adults - with racism as the upstream cause - understanding how racism-related stress impacts pain through sleep might help minimize racialized pain inequities. This preliminary study examined sequential mediation of the effect of racism-related stress on experimental pain through sleep disturbance and corticolimbic µOR function in pain-free non-Hispanic Black (NHB) and White (NHW) adults. Participants completed questionnaires, actigraphy, positron emission tomography, and sensory testing. We reproduced findings showing greater sleep disturbance and pain sensitivity among NHB participants; greater sleep disturbance (r = .35) and lower pain tolerance (r=-.37) were significantly associated with greater racism-related stress. In a sequential mediation model, the total effect of racism-related stress on pain tolerance (ß=-.38, P = .005) weakened after adding sleep disturbance and ventromedial prefrontal cortex (vmPFC) µOR binding potential (BPND) as mediators (ß = -.18, P = .16). The indirect effect was statistically significant [point estimate = -.003, (-.007, -.0003). Findings showed a potential sequentially mediated effect of racism-related stress on pain sensitivity through sleep disturbance and vmPFC µOR BPND. As policy efforts are enacted to eliminate the upstream cause of systemic racism, these results cautiously suggest that sleep interventions within racism-based trauma informed therapy might help prevent downstream effects on pain. PERSPECTIVE: This preliminary study identified the effect of racism-related stress on pain through sleep disturbance and mu-opioid receptor binding potential in the ventromedial prefrontal cortex. Findings cautiously support the application of sleep interventions within racism-based trauma-informed therapy to prevent pain inequities as policy changes function to eliminate all levels of racism.

Cell line specific alterations in genes associated with dopamine metabolism and signaling in midbrain dopaminergic neurons derived from 22q11.2 deletion carriers with elevated dopamine synthesis capacity.

Microdeletions at the 22q11.2 locus are associated with increased risk for schizophrenia. Recent work has demonstrated that antipsychotic naïve 22q11.2 carriers display elevated levels of dopamine synthesis capacity (DSC) as assessed by 18F-DOPA PET imaging. While this is consistent with a role for abnormal dopamine function in schizophrenia, it is unclear what molecular changes may be associated with this neuro-imaging endophenotype, and moreover, if these alterations occur independently of clinical presentation. We therefore conducted a pilot study in which we generated human induced pluripotent stem cells (hiPSCs) from two 22q11.2 deletion carriers with elevated DSC in vivo, but distinct clinical presentations. From these and neurotypical control lines we were able to robustly generate midbrain dopaminergic neurons (mDA-neurons). We then assessed whether genes associated with dopamine synthesis, metabolism or signaling show altered expression between genotypes and further between the 22q11.2 deletion lines. Our data showed alterations in expression of genes associated with dopamine metabolism and signaling that differed between the two 22q11.2 hiPSC lines with distinct clinical presentations. This reinforces the importance of considering clinical, genetic and molecular information, when possible, when choosing which donors to generate hiPSCs from, to carry out mechanistic studies.

Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD.

Since the discovery of the C9orf72 repeat expansion mutation as causative for chromosome 9-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2011, a multitude of cellular pathways have been implicated. However, evidence has also been accumulating for a key mechanism of cellular compartmentalization-phase separation. Liquid-liquid phase separation (LLPS) is fundamental for the formation of membraneless organelles including stress granules, the nucleolus, Cajal bodies, nuclear speckles and the central channel of the nuclear pore. Evidence has now accumulated showing that the formation and function of these membraneless organelles is impaired by both the toxic arginine rich dipeptide repeat proteins (DPRs), translated from the C9orf72 repeat RNA transcript, and the repeat RNA itself. Both the arginine rich DPRs and repeat RNA themselves undergo phase separation and disrupt the physiological phase separation of proteins involved in the formation of these liquid-like organelles. Hence abnormal phase separation may explain a number of pathological cellular phenomena associated with C9orf72-ALS/FTD. In this review article, we will discuss the principles of phase separation, phase separation of the DPRs and repeat RNA themselves and how they perturb LLPS associated with membraneless organelles and the functional consequences of this. We will then discuss how phase separation may impact the major pathological feature of C9orf72-ALS/FTD, TDP-43 proteinopathy, and how LLPS may be targeted therapeutically in disease.

Astrocytes in Tauopathies.

Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differential association with astrocytes, depending on the disease. Astrocytes, the most abundant neural cells in the brain, play a major role in synapse and neuronal function, and are a key component of the glymphatic system and blood brain barrier. However, their contribution to tauopathy progression is not fully understood. Here we present a brief overview of the association of tau with astrocytes in tauopathies. We discuss findings that support a role for astrocytes in the uptake and spread of pathological tau, and we describe how alterations to astrocyte phenotype in tauopathies may cause functional alterations that impedes their ability to support neurons and/or cause neurotoxicity. The research reviewed here further highlights the importance of considering non-neuronal cells in neurodegeneration and suggests that astrocyte-directed targets that may have utility for therapeutic intervention in tauopathies.

Interferon-γ signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes.

Maternal immune activation increases the risk of neurodevelopmental disorders. Elevated cytokines, such as interferon-γ (IFN-γ), in offspring's brains play a central role. IFN-γ activates an antiviral cellular state, limiting viral entry and replication. Moreover, IFN-γ is implicated in brain development. We tested the hypothesis that IFN-γ signaling contributes to molecular and cellular phenotypes associated with neurodevelopmental disorders. Transient IFN-γ treatment of neural progenitors derived from human induced pluripotent stem cells increased neurite outgrowth. RNA sequencing analysis revealed that major histocompatibility complex class I (MHCI) genes were persistently up-regulated through neuronal differentiation-an effect that was mediated by IFN-γ-induced promyelocytic leukemia protein (PML) nuclear bodies. Critically, IFN-γ-induced neurite outgrowth required both PML and MHCI. We also found evidence that IFN-γ disproportionately altered the expression of genes associated with schizophrenia and autism, suggesting convergence between genetic and environmental risk factors. Together, these data implicate IFN-γ signaling in neurodevelopmental disorder etiology.

Clusterin Is Required for ß-Amyloid Toxicity in Human iPSC-Derived Neurons.

Our understanding of the molecular processes underlying Alzheimer's disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating ß-amyloid (Aß) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in Aß processing. Here we investigate how CLU mediates Aß-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate Aß-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to Aß using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with Aß25-35 peptides and Aß1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following Aß treatment. However, in CLU knockout neurons Aß exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to Aß in neurons with the CLU deletion. Four of the five genes previously identified as downstream to Aß and Dickkopf-1 (DKK1) proteins in an Aß-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in Aß treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to Aß compared to the wild type neurons supports the role of clusterin in Aß-mediated AD pathogenesis.