Treating insomnia symptoms with medicinal cannabis: a randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo.

STUDY OBJECTIVES: This randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the safety and efficacy of 2 weeks of nightly sublingual cannabinoid extract (ZTL-101) in treating chronic insomnia (symptoms ≥3 months). METHODS: Co-primary study endpoints were safety of the medication based on adverse event reporting and global insomnia symptoms (Insomnia Severity Index [ISI]). Secondary endpoints included: self-reported (sleep diary), actigraphy-derived, and polysomnography measurements of sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), sleep efficiency (SE); and self-reported assessments of sleep quality (sSQ) and feeling rested upon waking. Adjusted mean differences between placebo and ZTL-101 were calculated. RESULTS: Twenty-three of 24 randomized participants (n = 20 female, mean age 53 ± 9 years) completed the protocol. No serious adverse events were reported. Forty mild, nonserious, adverse events were reported (36 during ZTL-101) with all but one resolving overnight or soon after waking. Compared to placebo, ZTL-101 decreased ISI (-5.07 units [95% CI: -7.28 to -2.86]; p = 0.0001) and self-reported SOL (-8.45 min [95% CI: -16.33 to -0.57]; p = 0.04) and increased self-reported TST (64.6 min [95% CI: 41.70 to 87.46]; p < 0.0001), sSQ (0.74 units [95% CI: 0.51 to 0.97]; p < 0.0001), and feeling of being rested on waking (0.51 units [95% CI: 0.24 to 0.78]; p = 0.0007). ZTL-101 also decreased actigraphy-derived WASO (-10.2 min [95% CI: -16.2 to -4.2]; p = 0.002), and increased actigraphy-derived TST (33.4 min [95% CI: 23.07 to 43.76]; p < 0.001) and SE (2.9% [95% CI: 2.0 to 3.8]; p = 0.005). CONCLUSIONS: Two weeks of nightly sublingual administration of a cannabinoid extract (ZTL-101) is well tolerated and improves insomnia symptoms and sleep quality in individuals with chronic insomnia symptoms. CLINICAL TRIAL: ANZCTR; anzctr.org.au; ACTRN12618000078257.

Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington's disease: A nine-month pilot study.

BACKGROUND: Hypothalamic pathology is a well-documented feature of Huntington's disease (HD) and is believed to contribute to circadian rhythm and habitual sleep disturbances. Currently, no therapies exist to combat hypothalamic changes, nor circadian rhythm and habitual sleep disturbances in HD. OBJECTIVE: To evaluate the effects of multidisciplinary rehabilitation on hypothalamic volume, brain-derived neurotrophic factor (BDNF), circadian rhythm and habitual sleep in individuals with preclinical HD. METHODS: Eighteen individuals with HD (ten premanifest and eight prodromal) undertook a nine-month multidisciplinary rehabilitation intervention (intervention group), which included exercise, cognitive and dual task training and social events, and were compared to a community sample of eleven individuals with premanifest HD receiving no intervention (control group). Hypothalamic volume, serum BDNF, salivary cortisol and melatonin concentrations, subjective sleep quality, daytime somnolence, habitual sleep-wake patterns, stress and anxiety and depression symptomatology were evaluated. RESULTS: Hypothalamus grey matter volume loss was significantly attenuated in the intervention group compared to the control group after controlling for age, gender, Unified Huntington's Disease Rating Scale-Total Motor Score and number of cytosine-adenine-guanine repeats. Serum BDNF levels were maintained in the intervention group, but decreased in the control group following the study period. Both groups exhibited decreases in cortisol and melatonin concentrations. No changes were observed in sleep or mood outcomes. CONCLUSIONS: This exploratory study provides evidence that multidisciplinary rehabilitation can reduce hypothalamic volume loss and maintain peripheral BDNF levels in individuals with preclinical HD but may not impact on circadian rhythm. Larger, randomised controlled trials are required to confirm these findings.

The Effects of the Removal of Electronic Devices for 48 Hours on Sleep in Elite Judo Athletes.

This study examined the effects of evening use of electronic devices (i.e., smartphones, etc.) on sleep quality and next-day athletic and cognitive performance in elite judo athletes. Over 6 consecutive days and nights, 23 elite Australian judo athletes were monitored while attending a camp at the Australian Institute of Sport (AIS). In 14 athletes, all electronic devices were removed on days 3 and 4 (i.e., for 48 hours: the "device-restricted group"), whereas 9 were permitted to use their devices throughout the camp (the "control group"). All athletes wore an activity monitor (Readiband) continuously to provide measures of sleep quantity and quality. Other self-reported (diary) measures included time in bed, electronic device use, and rate of perceived exertion during training periods. Cognitive performance (Cogstate) and physical performance (single leg triple hop test) were also measured. When considering night 2 as a "baseline" for each group, removal of electronic devices on nights 3 and 4 (device-restricted group) resulted in no significant differences in any sleep-related measure between the groups. When comparing actigraphy-based measures of sleep to subjective measures, all athletes significantly overestimated sleep duration by 58 ± 85 minutes (p = 0.001) per night and underestimated time of sleep onset by 37 ± 72 minutes (p = 0.001) per night. No differences in physical or cognitive function were observed between the groups. CONCLUSION: This study has shown that the removal of electronic devices for a period of two nights (48 hours) during a judo camp does not affect sleep quality or quantity or influence athletic or cognitive performance.

Neuroendocrine and neurotrophic signaling in Huntington's disease: Implications for pathogenic mechanisms and treatment strategies.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways.

Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea.

RATIONALE: Hypoglossal nerve stimulation (HGNS) recruits lingual muscles, reduces pharyngeal collapsibility, and treats sleep apnea. OBJECTIVES: We hypothesized that graded increases in HGNS relieve pharyngeal obstruction progressively during sleep. METHODS: Responses were examined in 30 patients with sleep apnea who were implanted with an HGNS system. Current (milliampere) was increased stepwise during non-REM sleep. Frequency and pulse width were fixed. At each current level, stimulation was applied on alternating breaths, and responses in maximal inspiratory airflow (V(I)max) and inspiratory airflow limitation (IFL) were assessed. Pharyngeal responses to HGNS were characterized by the current levels at which V(I)max first increased and peaked (flow capture and peak flow thresholds), and by the V(I)max increase from flow capture to peak (ΔV(I)max). MEASUREMENTS AND MAIN RESULTS: HGNS produced linear increases in V(I)max from unstimulated levels at flow capture to peak flow thresholds (215 ± 21 to 509 ± 37 ml/s; mean ± SE; P < 0.001) with increasing current from 1.05 ± 0.09 to 1.46 ± 0.11 mA. V(I)max increased in all patients and IFL was abolished in 57% of patients (non-IFL subgroup). In the non-IFL compared with IFL subgroup, the flow response slope was greater (1241 ± 199 vs. 674 ± 166 ml/s/mA; P < 0.05) and the stimulation amplitude at peak flow was lower (1.23 ± 0.10 vs. 1.80 ± 0.20 mA; P < 0.05) without differences in peak flow. CONCLUSIONS: HGNS produced marked dose-related increases in airflow without arousing patients from sleep. Increases in airflow were of sufficient magnitude to eliminate IFL in most patients and IFL and non-IFL subgroups achieved normal or near-normal levels of flow, suggesting potential HGNS efficacy across a broad range of sleep apnea severity.

Treating obstructive sleep apnea with hypoglossal nerve stimulation.

BACKGROUND: Reduced upper airway muscle activity during sleep is fundamental to obstructive sleep apnea (OSA) pathogenesis. Hypoglossal nerve stimulation (HGNS) counteracts this problem, with potential to reduce OSA severity. STUDY OBJECTIVES: To examine safety and efficacy of a novel HGNS system (HGNS, Apnex Medical, Inc.) in treating OSA. PARTICIPANTS: Twenty-one patients, 67% male, age (mean ± SD) 53.6 ± 9.2 years, with moderate to severe OSA and unable to tolerate continuous positive airway pressure (CPAP). DESIGN: Each participant underwent surgical implantation of the HGNS system in a prospective single-arm interventional trial. OSA severity was defined by apnea-hypopnea index (AHI) during in-laboratory polysomnography (PSG) at baseline and 3 and 6 months post-implant. Therapy compliance was assessed by nightly hours of use. Symptoms were assessed using the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Index (SAQLI), and the Beck Depression Inventory (BDI). RESULTS: HGNS was used on 89% ± 15% of nights (n = 21). On these nights, it was used for 5.8 ± 1.6 h per night. Nineteen of 21 participants had baseline and 6-month PSGs. There was a significant improvement (all P < 0.05) from baseline to 6 months in: AHI (43.1 ± 17.5 to 19.5 ± 16.7), ESS (12.1 ± 4.7 to 8.1 ± 4.4), FOSQ (14.4 ± 2.0 to 16.7 ± 2.2), SAQLI (3.2 ± 1.0 to 4.9 ± 1.3), and BDI (15.8 ± 9.0 to 9.7 ± 7.6). Two serious device-related adverse events occurred: an infection requiring device removal and a stimulation lead cuff dislodgement requiring replacement. CONCLUSIONS: HGNS demonstrated favorable safety, efficacy, and compliance. Participants experienced a significant decrease in OSA severity and OSA-associated symptoms. CLINICAL TRIAL INFORMATION: NAME: Australian Clinical Study of the Apnex Medical HGNS System to Treat Obstructive Sleep Apnea. REGISTRATION NUMBER: NCT01186926. URL: http://clinicaltrials.gov/ct2/show/NCT01186926.

Inspiratory muscle training for patients with chronic obstructive pulmonary disease: a practical guide for clinicians.

Reduced inspiratory muscle strength is common in people with chronic obstructive pulmonary disease (COPD) and is associated with dyspnea and decreased exercise capacity. Most studies of inspiratory muscle training (IMT) in COPD have demonstrated increased inspiratory muscle strength. Many have also shown improvements in dyspnea and exercise capacity. However, a persisting challenge when translating and applying the findings of these studies in clinical practice is the disparity in training loads, modalities, and outcomes measures used in the different studies. This commentary summarizes our clinical and research experience with a threshold IMT device with the aim of providing clinicians interested in prescribing IMT in this population with practical recommendations regarding patient selection, assessment, and implementation of training. We propose using an interval-based high-intensity threshold IMT program for people who are unable to participate fully in whole-body exercise training because of comorbidities such as severe musculoskeletal problems. Initial training loads equivalent to at least 30% of a person's maximum inspiratory pressure (PImax) are required for all people undertaking IMT. Supervision, which includes monitoring of oxygen saturation throughout the first training session, is recommended, and patients are warned to expect transient delayed-onset muscle soreness, a consequence of muscle adaptation to an unaccustomed activity. We recommend training be undertaken 3 times a week for 8 weeks, with loads progressively increased as symptoms permit. It is prudent to exclude people at risk of pneumothorax or spontaneous rib fracture. Evaluation of IMT should include measures of PImax, dyspnea, health-related quality of life, and exercise capacity.

Anaerobic metabolism of inspiratory muscles in COPD.

OBJECTIVE: The purpose of this study was to determine if the respiratory muscles of patients with COPD could be made to function anaerobically, as evidenced by an increase in arterial blood lactate concentration ([lactate](a)) during specific loading of the inspiratory muscles and, if so, the effect of a programme of high-intensity inspiratory muscle training on this function. METHODS: In seven patients with COPD (FEV(1) = 33 +/- 14% of predicted), measurements of [lactate](a) were made each minute during progressive inspiratory threshold loading to voluntary exhaustion. These tests were performed before and after an 8-week programme of specific high-intensity inspiratory muscle training, combined with general whole-body exercise training. RESULTS: During inspiratory muscle loading small increases in [lactate](a) (0.83 +/- 0.32 mM) were observed in two subjects before training, and in five subjects after training (0.69 +/- 0.57 mM). [Lactate](a) only increased when the inspiratory work rate exceeded 6.9 cm H(2)O L/min per kilogram of body weight, and when baseline maximum inspiratory pressure exceeded 65 cm H(2)O. CONCLUSIONS: The results of this study demonstrated that it is possible for COPD patients to increase inspiratory muscle work rate to a level requiring a major energy contribution from anaerobic glycolytic metabolism. This was only seen when inspiratory muscle strength and endurance were sufficient to allow it. Some patients who failed to demonstrate an increase in [lactate](a) at baseline did so after a programme of high-intensity inspiratory muscle training.

Dyspnoea in COPD: can inspiratory muscle training help?

Chronic obstructive pulmonary disease (COPD) is a progressive, common and costly condition. Dyspnoea frequently limits activity and reduces health-related quality of life. In addition to impaired lung function, peripheral muscle deconditioning and respiratory muscle dysfunction also contribute to dyspnoea and reduced exercise capacity. Pulmonary rehabilitation using whole body exercise training improves peripheral muscle function and reduces dyspnoea but does not improve respiratory muscle function. Providing that adequate training intensities are utilised, specific loading of the inspiratory muscles with commercially available hand-held devices can improve inspiratory muscle strength and endurance. Several studies have investigated the effects of inspiratory muscle training on dyspnoea in COPD subjects. Results of these studies are conflicting, most likely reflecting methodological shortcomings including insufficient training load, insensitive outcome measures, and inadequate statistical power. This paper describes the origin of dyspnoea in COPD, with particular attention given to the role of inspiratory muscle dysfunction in its genesis and its possible amelioration through inspiratory muscle training.