Hippocampal and Reticulo-Thalamic Parvalbumin Interneurons and Synaptic Re-Organization during Sleep Disorders in the Rat Models of Parkinson's Disease Neuropathology.

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.

Migraine and Sleep-An Unexplained Association?

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.

Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep.

Sleep is an essential component of physical and emotional well-being, and lack, or disruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control. Currently available evidence suggests that herbal extracts may exert some of their hypnotic and anxiolytic activity through interacting with GABA receptors and modulating GABAergic signaling in the brain, but their mechanism of action in the treatment of insomnia is not completely understood.

5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology.

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.

Vitamin D and sleep duration: Is there a bidirectional relationship?

Vitamin D contributes to numerous physiological processes within the body but primarily calcium and bone homeostasis. Emerging evidence highlights a novel role for vitamin D in maintaining and regulating optimal sleep. Sleep is a known regulator of bone health, highlighting the interconnectedness between vitamin D concentrations, sleep duration and bone metabolism. It is possible that the relationship between sleep length and vitamin D is bidirectional, with vitamin D playing a role in sleep health and conversely, sleep affecting vitamin D levels. Nevertheless, limited information on the direction of the interaction is available, and much remains to be learned concerning the complex relationship between insufficient sleep duration and vitamin D deficiency. Given the potential to implement interventions to improve sleep and vitamin D supplementation, understanding this relationship further could represent a novel way to support and improve health.

Uncovering the pharmacological mechanism of the effects of the Banxia-Xiakucao Chinese Herb Pair on sleep disorder by a systems pharmacology approach.

Sleep disorder (SD) has a high incidence and seriously affects quality of life, mental health and even the manifestation of physical diseases. The combination of Pinellia ternata (Chinese name: banxia) and Prunella vulgaris (Chinese name: xiakucao), known as the Banxia-Xiakucao Chinese herb pair (BXHP), is a proven Chinese herbal medicine that has been used to treat SD for thousands of years due to its significant clinical effects. However, its active pharmacological components and sedative-hypnotic mechanisms have not been fully elucidated. Thus, the present study used a systematic pharmacological approach to develop pharmacokinetic screens and target predictions via construction of a protein-protein interaction network and annotation database for SD-related and putative BXHP-related targets. Visualization, screening and integrated discovery enrichment analyses were conducted. The BXHP chemical database contains 166 compounds between the two herbal ingredients, and of these, 22 potential active molecules were screened by pharmacokinetic evaluation. The targets of 114 of the active molecules were predicted, and 34 were selected for further analysis. Finally, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses suggested that BXHP can reduce inflammatory responses. and mediate immune-related and central nervous system neurotransmitters via regulation of multiple targets and pathways. The use of a systematic pharmacology-based approach in the present study further elucidated the mechanisms of action underlying BXHP for the treatment of SD from a holistic perspective and sheds light on the systemic mechanisms of action of Chinese herbal medicines in general.

The Effects of Dietary Nutrition on Sleep and Sleep Disorders.

Sleep disorder significantly affects the life quality of a large number of people but is still an underrecognized disease. Dietary nutrition is believed to play a significant impact on sleeping wellness. Many nutritional supplements have been used trying to benefit sleep wellness. However, the relationship between nutritional components and sleep is complicated. Nutritional factors vary dramatically with different diet patterns and depend significantly on the digestive and metabiotic functions of each individual. Moreover, nutrition can profoundly affect the hormones and inflammation status which directly or indirectly contribute to insomnia. In this review, we summarized the role of major nutritional factors, carbohydrates, lipids, amino acids, and vitamins on sleep and sleep disorders and discussed the potential mechanisms.

Management of Sleep Disturbances Associated with Smith-Magenis Syndrome.

Smith-Magenis syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 (RAI1) gene that maps on the short arm of chromosome 17p11.2 or a pathogenic mutation of RAI1. Smith-Magenis syndrome affects patients through numerous congenital anomalies, intellectual disabilities, behavioral challenges, and sleep disturbances. The sleep abnormalities associated with Smith-Magenis syndrome can include frequent nocturnal arousals, early morning awakenings, and sleep attacks during the day. The sleep problems associated with Smith-Magenis syndrome are attributed to haploinsufficiency of the RAI1 gene. One consequence of reduced function of RAI1, and characteristic of Smith-Magenis syndrome, is an inversion of melatonin secretion resulting in a diurnal rather than nocturnal pattern. Treatment of sleep problems in people with Smith-Magenis syndrome generally involves a combination of sleep hygiene techniques, supplemental melatonin, and/or other medications, such as melatonin receptor agonists, ß1-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. Improvement in sleep has been shown to improve behavioral outcomes, which in turn improves the quality of life for both patients and their caregivers.

Hypothalamic orexin and mechanistic target of rapamycin activation mediate sleep dysfunction in a mouse model of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1GFAPCKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1GFAPCKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1GFAPCKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1GFAPCKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC.

Influence of Dietary Sources of Melatonin on Sleep Quality: A Review.

Sleep is an essential biological phenomenon, being a physiological and behavioral process necessary for quality of life. Melatonin is a circadian hormone produced at night by the pineal gland, regulated by the light/dark cycle, under the control of the suprachiasmatic nucleus. Melatonin is an indoleamine, synthesized from the essential amino acid tryptophan via serotonin. Melatonin is also found in plants, where it helps fight oxidative stress. To present a systematic review on the ability of food sources of melatonin to promote healthy sleep. A literature search was performed on the PubMed, Scopus, and ScienceDirect databases, including only randomized, placebo-controlled trials published in English between 2005 and 2019. The methodological quality of the trials was assessed by the Jadad scale. Of the 25 eligible articles, eight met the inclusion criteria. They addressed the intake of milk or cherry juice in children, adults, and elderly subjects and evaluated sleep quality by questionnaires, sleep diary, actigraphy, or polysomnography. The analysis of the studies presented limitations, including lack of homogeneity of treatment dosage and duration. Nonetheless, the results indicated that the consumption of milk and sour cherries, sources of melatonin, may improve sleep quality in humans. These results pointed out to the potential suitability of food sources of melatonin as adjuvants in the prevention and treatment of sleep disorders. Further studies are necessary to better ascertain the aspects relevant to their use.

ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment.

The distribution of the voltage-gated Kv1 K+ channels at the axon initial segment (AIS) influences neuronal intrinsic excitability. The Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) subunits are associated with cell adhesion molecules (CAMs), including Caspr2 (also known as CNTNAP2) and LGI1, which are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). Here, by using rat hippocampal neurons in culture, we showed that LGI1 is recruited to the AIS where it colocalizes with ADAM22 and Kv1 channels. Strikingly, the missense mutations S473L and R474Q of LGI1 identified in ADLTE prevent its association with ADAM22 and enrichment at the AIS. Moreover, we observed that ADAM22 and ADAM23 modulate the trafficking of LGI1, and promote its ER export and expression at the overall neuronal cell surface. Live-cell imaging indicated that LGI1 is co-transported in axonal vesicles with ADAM22 and ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 (also known as CNTN2) to be selectively targeted to different axonal sub-regions. Hence, the combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in physiological and epileptogenic contexts.

Association between abnormal thalamic metabolites and sleep disturbance in patients with end-stage renal disease.

Sleep disturbances are common in end-stage renal disease (ESRD) patients. However, the underlying neuropathological mechanisms are largely unclear. Previous studies have revealed the important role of the thalamus in the potential mechanisms of sleep disorders. We hypothesized that the sleep disturbances in ESRD patients may correspond to metabolic changes of thalamus and the uremic factors may have a vital contribution on these changes. We performed multi-voxel 1H-MRS of bilateral thalami in 27 ESRD patients who currently receiving hemodialysis treatment and 21 age-matched healthy volunteers. ESRD patients underwent Pittsburgh Sleep Quality Index (PSQI) scale and restless legs syndrome (RLS) rating scale assessment. Laboratory blood tests including serum creatinine, serum urea, cystatin-C, serum parathyroid hormone (PTH), calcium and phosphorus levels, hemoglobin and hematocrit were performed in all ESRD patients close to the time of the MR examination. We found correlations among elevated PTH, higher PSQI score and RLS rating score in ESRD patients. ESRD patients displayed decreased N-acetylaspartate and creatine ratio (NAA/Cr) of thalami compared with controls. There were significantly negative correlation between NAA/Cr and serum PTH level or PSQI score. The metabolic changes of thalami played an important role in the neuropathological mechanisms of lower sleep quality in ESRD patients. Secondary hyperparathyroidism as one of the main uremia-related factors was closely related to abnormal metabolites of the thalamus in patients with ESRD, revealing the crosstalk procedure between renal impairment and brain function.

Chronopathophysiological implications of orexin in sleep disturbances and lifestyle-related disorders.

Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus. Central levels of orexin oscillate with the daily rhythm and peak at the awake phase. Orexin plays a major role in stabilizing the wakefulness state. Orexin deficiency causes sleep/wake-state instability, resulting in narcolepsy. Hyper-activation of the orexin system also causes sleep disturbances, such as insomnia, and hence, suvorexant, an orexin receptor antagonist, has been clinically used to treat insomnia. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating the central-autonomic nervous systems and endocrine systems. These multiple actions of orexin maintain survival. However, it remains unknown whether chronopharmacological interventions targeting the orexin system ameliorate sleep-related disorders as well as sleep in humans. To understand the significance of adequate orexin action for prevention of these disorders, this review summarizes the physiological functions of daily orexin action and pathological implications of its mistimed or reduced action in sleep disturbances and sleep-related disorders (lifestyle-related physical and neurological disorders in particular). Timed administration of drugs targeting the orexin system may prevent lifestyle-related diseases by improving the quality of life in patients with sleep disturbances.

Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [11C]PBR28 PET study.

Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.

Frontal Cortex Myo-Inositol Is Associated with Sleep and Depression in Adolescents: A Proton Magnetic Resonance Spectroscopy Study.

AIM: This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. METHODS: Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent 1H MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. RESULTS: Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. CONCLUSION: Lower frontal cortex mI may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression.

A review of sleep disorders and melatonin.

Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short- or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects.

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders.

We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

Dexamethasone Chemotherapy Does Not Disrupt Orexin Signaling.

BACKGROUND: Steroid-induced sleep disturbance is a common and highly distressing morbidity for children receiving steroid chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL). Sleep disturbance can negatively impact overall quality of life, neurodevelopment, memory consolidation, and wound healing. Hypothalamic orexin neurons are influential wake-promoting neurons, and disturbances in orexin signaling leads to abnormal sleep behavior. A new class of drug, the orexin receptor antagonists, could be an intriguing option for sleep disorders caused by increased orexinergic output. Our aim was to examine the impact of ALL treatment doses of corticosteroids on the orexin system in rodents and in children undergoing treatment for childhood ALL. METHODS: We administered repeated injections of dexamethasone to rodents and measured responsive orexin neural activity compared to controls. In children with newly diagnosed standard risk B-cell ALL receiving dexamethasone therapy per Children's Oncology Group (COG) induction therapy from 2014-2016, we collected pre- and during-steroids matched CSF samples and measured the impact of steroids on CSF orexin concentration. RESULTS: In both rodents, all markers orexin signaling, including orexin neural output and orexin receptor expression, were preserved in the setting of dexamethasone. Additionally, we did not detect a difference in pre- and during-dexamethasone CSF orexin concentrations in children receiving dexamethasone. CONCLUSIONS: Our results demonstrate that rodent and human orexin physiology is largely preserved in the setting of high dose dexamethasone. The data obtained in our experimental model fail to demonstrate a causative role for disruption of the orexin pathway in steroid-induced sleep disturbance.

A Novel Developmental Role for Dopaminergic Signaling to Specify Hypothalamic Neurotransmitter Identity.

Hypothalamic neurons expressing histamine and orexin/hypocretin (hcrt) are necessary for normal regulation of wakefulness. In Parkinson's disease, the loss of dopaminergic neurons is associated with elevated histamine levels and disrupted sleep/wake cycles, but the mechanism is not understood. To characterize the role of dopamine in the development of histamine neurons, we inhibited the translation of the two non-allelic forms of tyrosine hydroxylase (th1 and th2) in zebrafish larvae. We found that dopamine levels were reduced in both th1 and th2 knockdown, but the serotonin level and number of serotonin neurons remained unchanged. Further, we demonstrated that th2 knockdown increased histamine neuron number and histamine levels, whereas increased dopaminergic signaling using the dopamine precursor l-DOPA (l-3,4-dihydroxyphenylalanine) or dopamine receptor agonists reduced the number of histaminergic neurons. Increases in the number of histaminergic neurons were paralleled by matching increases in the numbers of hcrt neurons, supporting observations that histamine regulates hcrt neuron development. Finally, we show that histaminergic neurons surround th2-expressing neurons in the hypothalamus, and we suggest that dopamine regulates the terminal differentiation of histamine neurons via paracrine actions or direct synaptic neurotransmission. These results reveal a role for dopaminergic signaling in the regulation of neurotransmitter identity and a potential mechanism contributing to sleep disturbances in Parkinson's disease.

Melatonin rhythms in renal transplant recipients with sleep-wake disturbances.

We assessed salivary melatonin levels in renal transplant (RTx) recipients who participated in a randomised, multicentre wait-list controlled trial on the effect of bright light therapy on their sleep and circadian rhythms. A large proportion of RTx recipients in our cohort had unexpectedly low melatonin values, which precluded calculation of the dim-light melatonin onset (DLMO) as a circadian marker. Thus, the aim of this post hoc analysis was to describe the melatonin profile of home-dwelling RTx recipients diagnosed with sleep-wake disturbances (SWDs). The participants were characterised by means of sleep questionnaires, validated psychometric instruments [Pittsburgh sleep quality Index (PSQI), Epworth sleepiness scale (ESS), Morningness-Eveningness Questionnaire (MEQ) and Depression, Anxiety and Stress Scale (DASS)] in addition to melatonin assay in saliva. Data were analysed with descriptive statistics and group comparisons made with appropriate post hoc tests. RTx recipients [n = 29 (aged 54.83 ± 13.73, transplanted 10.62 ± 6.84 years ago)] were retrospectively grouped into two groups: RTx recipients whose dim light melatonin onset (DLMO) could be calculated (n = 11) and those whose DLMO could not be calculated (n = 18). RTx recipients having a measurable DLMO had a number of differences from those without DLMO: they were younger [46.4 ± 14.9 compared to 60.0 ± 10.3 (p = .007)], had higher haemoglobin values [135.36 ± 12.01 versus 122.82 ± 11.56 (p = .01)], less anxiety [4 (0;8) versus 12 (6.5;14) (p = .021)] and a better overall sense of coherence [SOC Score: 71.09 ± 12.78 versus 56.28 ± 15.48 (p = 0.013)]. These results suggest that RTx recipients whose DLMO could be calculated have less health impairments, underlying the relevance of a stable circadian system.