Insomnia: A Current Review.

Insomnia is a prevalent sleep disorder with pervasive effects on quality of life. The deleterious effects of insomnia are largely preventable with appropriate therapeutic interventions. Pharmacotherapy should be initiated in patients with inadequate response to CBT-I and tailored to comorbidities. Referral to a sleep medicine specialist should be considered in patients with a suboptimal response.

Ischemic Stroke Disrupts Sleep Homeostasis in Middle-Aged Mice.

Sleep disturbances, including insomnia and excessive daytime sleepiness, are highly prevalent in patients with ischemic stroke (IS), which severely impacts recovery and rehabilitation efforts. However, how IS induces sleep disturbances is unclear. Three experiments were performed on middle-aged C57BL/6J mice, instrumented with sleep recording electrodes and/or subjected to 1 h of middle cerebral artery (MCAO; Stroke group) or sham (Sham group) occlusion to induce IS. After 48 h of reperfusion (a) experiment 1 verified sensorimotor deficit (using Garcia scale) and infarction (using TTC staining) in this mouse model; (b) experiment 2 examined the effects of IS on the quality (sleep latency and NREM delta power) and quantity (duration) of sleep; and (c) experiment 3 determined the effects of IS on sleep homeostasis using sleep deprivation (SD) and recovery sleep (RS) paradigm. Stroke mice display (a) a significant correlation between sensorimotor deficit and cerebral infarction; (b) insomnia-like symptoms (increased sleep latency, reduced NREM duration and delta power) during the light (inactive) period and daytime sleepiness-like symptoms during the dark (active) period mimicking sleep in IS patients; and (c) impairments in the markers of sleep pressure (during SD) and sleep dissipation (during RS). Our results suggest that IS disrupts sleep homeostasis to cause sleep disturbances.

Sleep, sleep homeostasis and arousal disturbances in alcoholism.

The effects of alcohol on human sleep were first described almost 70 years ago. Since then, accumulating evidences suggest that alcohol intake at bed time immediately induces sleep [reduces the time to fall asleep (sleep onset latency), and consolidates and enhances the quality (delta power) and the quantity of sleep]. Such potent sleep promoting activity makes alcohol as one of the most commonly used "over the counter" sleep aid. However, the somnogenic effects, after alcohol intake, slowly wane off and often followed by sleep disruptions during the rest of the night. Repeated use of alcohol leads to the development of rapid tolerance resulting into an alcohol abuse. Moreover, chronic and excessive alcohol intake leads to the development of alcohol use disorder (AUD). Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceed $18 billion. Thus, although alcohol associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, a conceptual framework and clinical research focused on understanding the relationship between alcohol and sleep is first described. In the next section, our new and exciting preclinical studies, to understand the cellular and molecular mechanism of how acute and chronic alcohol affects sleep, are described. In the end, based on observations from our recent findings and related literature, opportunities for the development of innovative strategies to prevent and treat AUD are proposed.

Activation of dopamine D2 receptors in the medial shell region of the nucleus accumbens increases Per1 expression to enhance alcohol consumption.

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption.

Setting Up a Teleneurology Clinic during COVID-19 Pandemic: Experience from an Academic Practice.

The declaration of the COVID-19 pandemic necessitated rapid implementation of telehealth across all neurological subspecialties. Transitioning to telehealth technology can be challenging for physicians and health care facilities with no prior experience. Here, we describe our experience at the Neurology and Sleep Disorders Clinic at the University of Missouri-Columbia of successful transition of all in-person clinic visits to telehealth visits within a span of 2 weeks with a collaborative effort of clinic staff and the leadership. Within a month of launch, 18 clinic providers with no prior telehealth experience conducted 1451 telehealth visits, which was the 2nd highest number of telehealth visits conducted by any department at the University of Missouri-Columbia Health Care system. Lack of connectivity, poor video/audio quality, and unavailability of smart devices among rural populations were the important shortcomings identified during our telehealth experience. Our study highlighted the need for expansion of high-speed internet access across rural Missouri. We hope our experience will help other health care facilities to learn and incorporate telehealth technology at their facilities, overcome the associated challenges, and serve patient needs while limiting the spread of the COVID-19.

Antisense-induced downregulation of major circadian genes modulates the expression of histone deacetylase-2 (HDAC-2) and CREB-binding protein (CBP) in the medial shell region of nucleus accumbens of mice exposed to chronic excessive alcohol consumption.

Circadian genes in the medial accumbal shell (mNAcSh) region regulate binge alcohol consumption. Here, we investigated if antisense-induced knockdown of major circadian genes (Per1, Per2, and NPAS2) in the mNAcSh of mice exposed to intermittent access two-bottle choice (IA2BC) paradigm modulates the expression of histone deacetylase-2 (HDAC-2) and CREB-binding protein (CBP), key epigenetic modifiers associated with withdrawal-associated behaviors such as anxiety. Adult male C57BL/6J mice (N = 28), surgically implanted with bilateral guide cannulas above the mNAcSh, were chronically (4 weeks) exposed to alcohol (20% v/v) or saccharin (0.03%) via IA2BC paradigm. In the fourth week, a mixture of antisense (AS-ODNs; N = 14/group) or nonsense (NS-ODNs; N = 14/group) oligodeoxynucleotides against circadian genes were bilaterally infused into the mNAcSh. Subsequently, alcohol/saccharin consumption and preference were measured followed by euthanization of animals and verification of microinjection sites by visual inspection and the expression of HDAC-2 and CBP by using RT-PCR along with the verification of antisense-induced downregulation of circadian genes in the mNAcSh. As compared with NS-ODNs, AS-ODNs infusion significantly attenuated the alcohol-induced increase in HDAC-2 and reduction in CBP expression in the mNAcSh along with a significant reduction in alcohol consumption and preference. No significant effect was observed on either saccharin consumption or preference. Our results suggest that circadian genes in the mNAcSh may have a causal to play in mediating epigenetic changes observed after chronic alcohol consumption.

COVID-19 Exposure During Neurology Practice: Results of American Academy of Neurology Survey.

BACKGROUND: To determine the exposure risk for coronavirus 2019 (COVID-19) during neurology practice. Neurological manifestations of COVID-19 are increasingly being recognized mandating high level of participation by neurologists. METHODS: An American Academy of Neurology survey inquiring about various aspects of COVID-19 exposure was sent to a random sample of 800 active American Academy of Neurology members who work in the United States. Use of second tier protection (1 or more including sterile gloves, surgical gown, protective goggles/face shield but not N95 mask) or maximum protection (N95 mask in addition to second tier protection) during clinical encounter with suspected/confirmed COVID-19 patients was inquired. RESULTS: Of the 81 respondents, 38% indicated exposure to COVID-19 at work, 1% at home, and none outside of work/home. Of the 28 respondents who did experience at least 1 symptom of COVID-19, tiredness (32%) or diarrhea (8%) were reported. One respondent tested positive out of 12 (17%) of respondents who were tested for COVID-19 within the last 2 weeks. One respondent received health care at an emergency department/urgent care or was hospitalized related to COVID-19. When seeing patients, maximum protection personal protective equipment was used either always or most of the times by 16% of respondents in outpatient setting and 56% of respondents in inpatient settings, respectively. CONCLUSIONS: The data could enhance our knowledge of the factors that contribute to COVID-19 exposure during neurology practice in United States, and inform education and advocacy efforts to neurology providers, trainees, and patients in this unprecedented pandemic.

Antisense-induced knockdown of cAMP response element-binding protein downregulates Per1 gene expression in the shell region of nucleus accumbens resulting in reduced alcohol consumption in mice.

INTRODUCTION: We recently showed that circadian genes expressed in the shell region of nucleus accumbens (NAcSh) play a key role in alcohol consumption, though, the molecular mechanism of those effects is unclear. Because CREB-binding protein (CBP) promotes Per1 gene expression, we hypothesized that alcohol consumption would increase CBP expression in the NAcSh and antisense-induced knockdown of CBP would reduce Per1 expression and result in a reduction in alcohol consumption. METHODS: To test our hypothesis, we performed two experiments. The Drinking-in-the-dark (DID) paradigm was used to evaluate alcohol consumption in male C57BL/6J mice. In Experiment 1 we examined the effects of alcohol consumption on CBP gene expression in the NAcSh. Control animals were exposed to, sucrose [10% (w/v) taste and calorie] and water (consummatory behavior). In Experiment 2 examined the effects of CBP gene silencing on the expression of the Per1 gene in the NAcSh and alcohol consumption in mice exposed to alcohol using the DID paradigm. CBP gene silencing was achieved by local infusion of two doses of either CBP antisense oligodeoxynucleotides (AS-ODNs; Antisense group) or nonsense ODNs (NS-ODNs; Nonsense group) bilaterally microinjected into the NAcSh within 24 h before alcohol consumption on Day 4 of the DID paradigm. The microinfusion sites were verified by cresyl violet staining. RESULTS: Compared to sucrose, alcohol consumption, under the DID paradigm, significantly increased the expression of CBP in the NAcSh. Compared to Controls, bilateral infusion of CBP AS-ODNs significantly reduced the expression of Per1 in the NAcSh and alcohol consumption without affecting the amount of sucrose consumed. CONCLUSIONS: Our results suggest that CBP is an upstream regulator of Per1 expression in the NAcSh and may act via Per1 to modulate alcohol consumption.

Sleep Fragmentation and Atherosclerosis: is There a Relationship?

Sleep fragmentation refers to the disruption of sleep architecture with poor quality of sleep despite optimal duration of sleep. Sleep fragmentation has been shown to have multiple effects on different body systems. This article reviews the effect of sleep fragmentation on the rate of atherosclerosis which has been linked to comorbidities like myocardial infarction, stroke, and coronary artery disease with an aim to educate patients regarding the importance of sleep hygiene and to incorporate a good amount and quality of sleep as life style modification along with diet and exercise.

Insomnia treatment effects among young adult drinkers: Secondary outcomes of a randomized pilot trial.

BACKGROUND: Cognitive behavioral therapy for insomnia (CBT-I) has moderate-to-large effects on insomnia among young adult drinkers, with preliminary data indicating that improvements in insomnia may have downstream effects on alcohol-related consequences. However, the mechanism(s) by which insomnia treatment may facilitate reductions in alcohol-related problems is unclear. Secondary outcome data from a randomized pilot trial were used to examine CBT-I effects on four proposed mediators of the insomnia/alcohol link: alcohol craving, delay discounting, negative affect, and difficulties with emotion regulation. METHODS: Young adults (ages 18 to 30 years) with insomnia who reported 1+ binge drinking episode (4/5+ drinks for women/men) in the past month were randomized to receive CBT-I (n = 28) or to a sleep hygiene control (n = 28). Outcomes were assessed at baseline, after 5 weeks of treatment, and at 1-month posttreatment. RESULTS: Relative to those in sleep hygiene, CBT-I participants reported greater decreases in alcohol craving (d = 0.33) at the end of treatment and greater 1-month posttreatment decreases in delay discounting of large rewards (d = 0.42). CBT-I did not have a significant effect on delay discounting of smaller rewards or momentary negative affect. There was also no significant treatment effect on difficulties with emotion regulation, although findings were confounded by a significant group difference at baseline in difficulties with emotion regulation. CONCLUSIONS: Treatment of insomnia may lead to improvements in alcohol craving and delay discounting of large rewards among young adult drinkers with insomnia. Additional research examining whether improvement in insomnia is a mechanism for improvement in addiction domains is warranted.

Antisense-Induced Downregulation of Clock Genes in the Shell Region of the Nucleus Accumbens Reduces Binge Drinking in Mice.

INTRODUCTIONS: Binge drinking is a deadly pattern of alcohol consumption. Evidence suggests that genetic variation in clock genes is strongly associated with alcohol misuse; however, the neuroanatomical basis for such a relationship is unknown. The shell region of the nucleus accumbens (NAcSh) is well known to play a role in binge drinking. Hence, we examined whether clock genes in the NAcSh regulate binge drinking. METHODS: To address this question, 2 experiments were performed on male C57BL/6J mice. In the first experiment, mice exposed to alcohol or sucrose under the 4-day drinking-in-the-dark (DID) paradigm were euthanized at 2 different time points on day 4 [7 hours after light (pre-binge drinking) or dark (post-binge drinking) onset]. The brains were processed for RT-PCR to examine the expression of circadian clock genes (Clock, Per1, and Per2) in the NAcSh and suprachiasmatic nucleus (SCN). In the second experiment, mice were exposed to alcohol, sucrose, or water as described above. On day 4, 1 hour prior to the onset of alcohol exposure, mice were bilaterally infused with either a mixture of circadian clock gene antisense oligodeoxynucleotides (AS-ODNs; antisense group) or nonsense/random ODNs (R-ODNs; control group) through surgically implanted cannulas above the NAcSh. Alcohol/sucrose/water consumption was measured for 4 hours. Blood alcohol concentration was measured to confirm binge drinking. Microinfusion sites were histologically verified using cresyl violet staining. RESULTS: As compared to sucrose, mice euthanized post-binge drinking (not pre-binge drinking) on day 4 displayed a greater expression of circadian genes in the NAcSh but not in the SCN. Knockdown of clock genes in the NAcSh caused a significantly lower volume of alcohol to be consumed on day 4 than in the control treatment. No differences were found in sucrose or water consumption. CONCLUSIONS: Our results suggest that clock genes in the NAcSh play a crucial role in binge drinking.

Telehealth cognitive behavioral therapy for insomnia in children with autism spectrum disorder: A pilot examining feasibility, satisfaction, and preliminary findings.

LAY ABSTRACT: Insomnia is common in children with autism. Cognitive behavioral treatment for childhood insomnia (CBT-CI) may improve sleep and functioning in children with autism and their parents, but typical delivery involving multiple office visits can make it difficult for some children to get this treatment. This pilot study tested telehealth delivery of CBT-CI using computers, which allowed children and their parents to get the treatment at home. This pilot shows therapists that parents and children were able to use telehealth CBT-CI to improve child and parent sleep, child behavior and arousal, and parent fatigue. Parents found telehealth CBT-CI helpful, age-appropriate, and autism-friendly. Telehealth CBT-CI holds promise for treating insomnia in school-aged children with autism and deserves further testing.

Cognitive behavioral therapy for insomnia among young adults who are actively drinking: a randomized pilot trial.

STUDY OBJECTIVES: More than half of young adults at risk for alcohol-related harm report symptoms of insomnia. Insomnia symptoms, in turn, have been associated with alcohol-related problems. Yet one of the first-line treatments for insomnia (Cognitive Behavioral Therapy for Insomnia or CBT-I) has not been tested among individuals who are actively drinking. This study tested (1) the feasibility and short-term efficacy of CBT-I among binge-drinking young adults with insomnia and (2) improvement in insomnia as a predictor of improvement in alcohol use outcomes. METHODS: Young adults (ages 18-30 years, 75% female, 73% college students) who met criteria for Insomnia Disorder and reported 1+ binge drinking episode (4/5+ drinks for women/men) in the past month were randomly assigned to 5 weekly sessions of CBT-I (n = 28) or single-session sleep hygiene (SH, n = 28). All participants wore wrist actigraphy and completed daily sleep surveys for 7+ days at baseline, posttreatment, and 1-month follow-up. RESULTS: Of those randomized, 43 (77%) completed posttreatment (19 CBT-I, 24 SH) and 48 (86%) completed 1-month follow-up (23 CBT-I, 25 SH). CBT-I participants reported greater posttreatment decreases in insomnia severity than those in SH (56% vs. 32% reduction in symptoms). CBT-I did not have a direct effect on alcohol use outcomes; however, mediation models indicated that CBT-I influenced change in alcohol-related consequences indirectly through its influence on posttreatment insomnia severity. CONCLUSIONS: CBT-I is a viable intervention among individuals who are actively drinking. Research examining improvement in insomnia as a mechanism for improvement in alcohol-related consequences is warranted. TRIAL REGISTRATION: U.S. National Library of Medicine, https://clinicaltrials.gov/ct2/show/NCT03627832, registration #NCT03627832.

Short-term sleep deprivation immediately after contextual conditioning inhibits BDNF signaling and disrupts memory consolidation in predator odor trauma mice model of PTSD.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric illness affecting > 7 million people every year in the US. Recently, we have shown that the mouse model of predator odor trauma (POT) displayed contextual conditioning and core features of PTSD including sleep disturbances (hyperarousal) and retrieval of traumatic memories following exposure to objective reminders (re-experiencing). PTSD is a disorder of memory function. Since memory consolidation requires the expression of BDNF along with an activation of MAPK/pERK signaling pathway in limbic brain structures (hippocampus and amygdala) and sleep favors memory consolidation, we hypothesized that short-term sleep deprivation (SD, 3 h), immediately after contextual conditioning will attenuate molecular correlates of memory consolidation, sleep disturbances, and memory consolidation. We performed two experiments in adult male C57BL/6J mice to test our hypothesis. Experiment 1 determined the effects of SD on contextual conditioning and changes in sleep wakefulness. Experiment 2 determined the effects of SD on contextual conditioning-induced changes in the expression of BDNF and pERK in hippocampus and amygdala. SD immediately after contextual conditioning (POT + SD group) significantly attenuated sleep disturbances, memory retrieval, and expression of pERK and BDNF in the hippocampus and amygdala as compared to POT-SD group (no SD after contextual conditioning). No significant differences were observed between POT + SD, NOC-SD (no contextual conditioning + no SD), and NOC + SD (no contextual conditioning + SD) groups. Memory consolidation requires sleep and the expression of pERK and BDNF in hippocampus and amygdala immediately after contextual conditioning in POT model of PTSD in mice.

Rats exposed to chronic alcohol display protracted insomnia and daytime sleepiness-like behavior during alcohol withdrawal✰.

INTRODUCTION: Alcohol use disorder (AUD), a chronic brain disorder, is characterized by a multitude of symptoms, including insomnia, during withdrawal. Previously, we have shown that rats exposed to chronic alcohol displayed insomnia-like symptoms during acute withdrawal. Since insomnia lasts for several years and is a major risk factor of relapse to alcoholism, the present study is designed to investigate the long-term effects of alcohol withdrawal on sleep-wakefulness. METHODS: Adult male Sprague-Dawley rats, instrumented with sleep recording electrodes, were divided into two groups: Alcohol and Control. Rats were either administered alcohol (35% v/v), mixed with infant formula (Alcohol group) or control mixture containing water and infant formula (Controls; 10 mL/kg) every 8 h for 4 days using Majchrowicz's chronic binge drinking protocol. Electrographic recordings of sleep-wakefulness were performed until withdrawal day 7, however, the data was analyzed for withdrawal days 3, 5 and 7 in both Control and Alcohol groups. RESULTS: As compared to the controls, alcohol-exposed rats displayed insomnia-like symptoms as revealed by a) significant reduction in the quantity and quality of sleep during the light (inactive) period and b) a significant increase in NREM sleep with a concomitant reduction in the amount of time spent in the wakefulness during the dark (active) period of alcohol withdrawal. CONCLUSION: Our results suggest that the chronic binge model of alcohol dependence mimics clinical symptoms of AUD especially protracted insomnia and is suitable for understanding the mechanisms associated with alcohol withdrawal-induced behaviors.

Orexin gene expression is downregulated in alcohol dependent rats during acute alcohol withdrawal.

Alcohol use disorders (AUD) are chronic relapsing brain disorder characterized by compulsive and heavy alcohol consumption. During acute withdrawal, patients with AUD display excessive daytime sleepiness, a condition linked to serious life-threatening complications, however, the mechanism is not known. Orexin and melanin-concentrating hormone (MCH) are the two hypothalamic neuropeptides that regulate many behaviors including sleep-wakefulness, and alcohol consumption, reinforcement, and reinstatement. Importantly, loss of orexin neurons causes narcolepsy, a severe sleep disorder with excessive daytime sleepiness. Does acute alcohol withdrawal reduce orexin gene expression? To investigate this, male Sprague-Dawley rats were divided in two groups: Rats were either administered with alcohol, mixed with infant formula (alcohol group) or control mixture containing water and infant formula (Controls) by gastric intubation every 8 h for 4 days using Majchrowicz's chronic binge drinking protocol. The doses of alcohol were adjusted depending on degree of intoxication, exhibited by animals, prior to each dose. The animals were euthanized after 12 h of last alcohol/water administration. During withdrawal, the hypothalamus was rapidly dissected out, and the expressions of orexin and MCH genes were examined by Real-time PCR. There was a significant reduction in orexin gene expression in rats subjected to alcohol withdrawal as compared to controls. No such change was observed in the MCH gene expression. These results suggest that downregulation of orexin gene expression may be a possible mechanism responsible for excessive daytime sleepiness associated with alcohol withdrawal in patients with AUD.

Protocol for the impact of CBT for insomnia on pain symptoms and central sensitisation in fibromyalgia: a randomised controlled trial.

INTRODUCTION: Approximately 50% of individuals with fibromyalgia (a chronic widespread pain condition) have comorbid insomnia. Treatment for these comorbid cases typically target pain, but growing research supports direct interventions for insomnia (eg, cognitive behavioural treatment for insomnia (CBT-I)) in these patients. Previous research suggests sustained hyperarousal mediated by a neural central sensitisation mechanism may underlie insomnia and chronic pain symptoms in fibromyalgia. We hypothesise CBT-I will improve insomnia symptoms, improve clinical pain and reduce central sensitisation. The trial will be the first to evaluate the short-term and long-term neural mechanisms underlying insomnia and pain improvements in fibromyalgia. Knowledge obtained from this trial might allow us to develop new or modify current treatments to better target pain mechanisms, perhaps reversing chronic pain or preventing it. METHODS AND ANALYSIS: Female participants (n=130) 18 years of age and older with comorbid fibromyalgia (with pain severity of at least 50/100) and insomnia will be recruited from the University of Missouri in Columbia, Missouri, and surrounding areas. Participants will be randomised to 8 weeks (plus 4 bimonthly booster sessions) of CBT-I or a sleep hygiene control group (SH). Participants will be assessed at baseline, post-treatment, 6 and 12 months follow-ups. The following assessments will be completed: 2 weeks of daily diaries measuring sleep and pain, daily actigraphy, insomnia severity index, pain-related disability, single night of polysomnography recording, arousal (heart rate variability, cognitive affective arousal), structural and functional MRI to examine pain-related neural activity and plasticity and mood (depression, anxiety). ETHICS AND DISSEMINATION: Ethics approval was obtained in July 2018 from the University of Missouri. All data are expected to be collected by 2022. Full trial results are planned to be published by 2024. Secondary analyses of baseline data will be subsequently published. TRIAL REGISTRATION NUMBER: NCT03744156.

Chronic alcohol exposure reduces acetylated histones in the sleep-wake regulatory brain regions to cause insomnia during withdrawal.

BACKGROUND: Alcohol use disorder (AUD) develops after chronic and heavy use of alcohol. Insomnia, a hallmark of AUD, plays a crucial role in the development of AUD. However, the causal mechanisms are unknown. Since chronic alcohol reduces acetylated histones and disrupts the epigenome, we hypothesized that chronic alcohol exposure will reduce acetylated histones in wake-promoting regions of the brain to cause insomnia during alcohol withdrawal. METHODS: Adult male C57BL/6J mice, surgically instrumented for electrophysiological monitoring of sleep-wakefulness, were exposed to chronic alcohol (6.8%) consumption using Lieber-DeCarli liquid diet. Three experiments were performed. First, the effect of chronic alcohol consumption was examined on sleep-wakefulness during 7 days of withdrawal. Second, the expression of acetylated histones, H3 lysine 14 (AcH3K14), was examined in two major sleep-wake regulatory brain regions: basal forebrain (BF) and lateral hypothalamus (LH) of the brain by using western blotting. Next, blockade of histone deacetylase, via systemic administration of TSA was examined on alcohol-induced changes in sleep-wakefulness. RESULTS: Alcoholic mice displayed a significant reduction in the quality and quantity of NREM sleep coupled with a significant increase in wakefulness that lasted for several days during alcohol withdrawal. In addition, alcoholic mice displayed a significant reduction in the expression of AcH3K14 in both BF and LH. Systemic administration of TSA significantly attenuated insomnia and improved the quality and quantity of sleep during alcohol withdrawal. CONCLUSIONS: Based on our results, we suggest that a causal relationship exists between reduced histone acetylation and insomnia during alcohol withdrawal.

Sleep Loss Immediately After Fear Memory Reactivation Attenuates Fear Memory Reconsolidation.

Permanently stored memories become labile through a process called reactivation. Once reactivated, these memories need reconsolidation to become permanent. Sleep is critical for memory consolidation. Is sleep necessary for memory reconsolidation? We hypothesized that sleep loss immediately after fear reactivation (FR) will prevent memory reconsolidation. To test our hypothesis, two experiments were performed in adult male C57BL/6J mice exposed to contextual fear conditioning paradigm with inescapable foot shock as unconditional stimulus (US) and contextual cage as conditional stimulus (CS). Sleep loss was achieved either by 5 h of sleep deprivation (SD; Experiment 1) or by systemic infusion of modafinil (200 mg/Kg, ip), an FDA approved wake-promoting agent (Experiment 2). One hour after light-onset, fear memory acquisition (FMA) was performed on Day 1. Mice were allowed to explore CS for 5 min followed by presentation of US (7 foot-shocks; 0.5 mA, 2.0 s duration) at pseudorandom intervals. Controls were exposed to similar CS but no shocks were delivered. On Day 2, mice were exposed to CS for 2 min (without US; for FR) followed by either sleep loss or no sleep loss. On Day 3, fear memory recall (FMR) was performed by exposing mice to CS (without US) for 12 min. Percent time spent in freezing was monitored during FC, FR and FMR. Our results suggested that as compared to sleeping controls, mice with sleep loss immediately after FR displayed a significant reduction in percent time freezing during FMR. These results suggest that sleep loss may prevent memory reconsolidation.

Cognitive behavioral treatment of insomnia in school-aged children with autism spectrum disorder: A pilot feasibility study.

Insomnia is common in autism and associated with challenging behavior and worse parent sleep. Cognitive behavioral treatment for childhood insomnia (CBT-CI) is efficacious in typically developing children, but not yet tested in school-aged children with autism. This single arm pilot tested 8-session CBT-CI in 17 children with autism and insomnia (M age = 8.76 years, SD = 1.99) and their parent(s) (M age = 39.50 years, SD = 4.83). Treatment integrity was assessed for each session [delivery (by therapist), receipt (participant understanding), and enactment (home practice)]. Children and parents wore actigraphs and completed electronic diaries for 2-weeks to obtain objective and subjective sleep onset latency (SOL), total sleep/wake times (TST/TWT), and sleep efficiency (SE) at pre/post/1-month follow-up. Parents also completed the Aberrant Behavior Checklist [irritability, lethargy, stereotypy, hyperactivity, inappropriate speech (e.g., excessive/repetitive, loud self-talk)] at pre/post/1-month. Fifteen children completed all sessions. Average integrity scores were high [90%-delivery/receipt, 87.5%-enactment]. Parents found CBT-CI helpful, age-appropriate, and autism-friendly. Paired samples t-tests (family-wise error controlled) found CBT-CI improved child sleep (objective SOL-18 min, TWT- 34 min, SE-5%; subjective SOL-29 min, TST-63 min, TWT-45 min, SE-8%), and decreased irritability, lethargy, stereotypy, and hyperactivity. At 1-month, objective TST improved, inappropriate speech decreased, but hyperactivity was no longer decreased. Other gains were maintained. Parent sleep (objective SOL-12 min, TST-35 min, TWT-21 min, SE-4%; subjective SOL-11 min, TWT- 31min, SE-11%) and fatigue also improved. At 1-month, gains were maintained. This pilot shows CBT-CI is a feasible treatment that holds promise for improving child and parent sleep and functioning and suggests a randomized controlled trial in school-aged children with autism is worth conducting. Autism Res 2020, 13: 167-176. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Insomnia is common in autism and associated with challenging behaviors and poor parent sleep and stress. Cognitive behavioral treatment for childhood insomnia (CBT-CI) has not been tested in school-aged children with autism. This pilot study shows therapists, parents, and children were able to use CBT-CI to improve child and parent sleep, child behavior, and parent fatigue. Parents found CBT-CI helpful, age-appropriate, and autism-friendly. CBT-CI holds promise for treating insomnia in school-aged children with autism and deserves further testing.