In humans, the pineal hormone melatonin can phase shift a number of circadian rhythms (e.g., "fatigue," endogenous melatonin, core body temperature) together with the timing of prolactin secretion. It is uncertain, however, whether melatonin can fully entrain all human circadian rhythms. In this study, the authors investigated the effects of daily melatonin administration on sighted individuals kept in continuous very dim light. A total of 10 normal, healthy males were maintained in two separate groups in partial temporal isolation under constant dim light (
Corbett RW, Middleton B, Arendt J (2012) An hour of bright white light in the early morning improves performance and advances sleep and circadian phase during the Antarctic winter, Neuroscience Letters
Previous work has demonstrated that exposure to an hour of bright light in the morning and the evening during the Polar winter has beneficial effects on circadian phase. This study investigated the effect of a single hour of bright white morning light on circadian phase, sleep, alertness and cognitive performance. Nine individuals (eight male, one female, median age 30 years), wintering at Halley Research Station (75°S), Antarctica from 7th May until 6th August 2007, were exposed to bright white light for a fortnight from 08:30 to 09:30 h, with two fortnight control periods on either side. This sequence was performed twice, before and following Midwinter. Light exposure, sleep and alertness were assessed daily by actigraphy, sleep diaries and subjective visual analogue scales. Circadian phase (assessed by urinary 6-sulphatoxymelatonin rhythm) and cognitive performance were evaluated at the end of each fortnight. During light exposure circadian phase was advanced from 4.97 ± 0.96 decimal hours (dh) (mean ± SD) to 4.08 ± 0.68 dh (p = 0.003). Wake-up time was shifted by a similar margin from 8.45 ± 1.83 dh to 7.59 ± 0.78 dh (p
This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean ± SD: 23 ± 5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERB±) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.
Wulff K, Joyce EM, Middleton B, Foster RG, Dijk DJ (2007) Sleep and circadian activity/rest disturbances in schizophrenia patients in comparison to unemployed healthy controls, EUROPEAN NEUROPSYCHOPHARMACOLOGY 17 pp. S415-S416 ELSEVIER SCIENCE BV
Benloucif S, Burgess HJ, Klerman EB, Lewy AJ, Middleton B, Murphy PJ, Parry BL, Revell VL (2008) Measuring melatonin in humans, Journal of Clinical Sleep Medicine 4 (1) pp. 66-69
Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, Cui N, Middleton B, Ackermann K, Kayser M, Thumser AE, Raynaud FI, Skene DJ (2014) Effect of sleep deprivation on the human metabolome., Proc Natl Acad Sci U S A 111 (29) pp. 10761-10766
Sleep restriction and circadian clock disruption are associated with metabolic disorders such as obesity, insulin resistance, and diabetes. The metabolic pathways involved in human sleep, however, have yet to be investigated with the use of a metabolomics approach. Here we have used untargeted and targeted liquid chromatography (LC)/MS metabolomics to examine the effect of acute sleep deprivation on plasma metabolite rhythms. Twelve healthy young male subjects remained in controlled laboratory conditions with respect to environmental light, sleep, meals, and posture during a 24-h wake/sleep cycle, followed by 24 h of wakefulness. Two-hourly plasma samples collected over the 48 h period were analyzed by LC/MS. Principal component analysis revealed a clear time of day variation with a significant cosine fit during the wake/sleep cycle and during 24 h of wakefulness in untargeted and targeted analysis. Of 171 metabolites quantified, daily rhythms were observed in the majority (n = 109), with 78 of these maintaining their rhythmicity during 24 h of wakefulness, most with reduced amplitude (n = 66). During sleep deprivation, 27 metabolites (tryptophan, serotonin, taurine, 8 acylcarnitines, 13 glycerophospholipids, and 3 sphingolipids) exhibited significantly increased levels compared with during sleep. The increased levels of serotonin, tryptophan, and taurine may explain the antidepressive effect of acute sleep deprivation and deserve further study. This report, to our knowledge the first of metabolic profiling during sleep and sleep deprivation and characterization of 24 h rhythms under these conditions, offers a novel view of human sleep/wake regulation.
Gogenur I, Middleton B, Burgdorf S, Rasmussen LS, Skene DJ, Rosenberg J (2007) Impact of sleep and circadian disturbances in urinary 6-sulphatoxymelatonin levels, on cognitive function after major surgery, JOURNAL OF PINEAL RESEARCH 43 (2) pp. 179-184 BLACKWELL PUBLISHING
Montagnese S, Middleton B, Skene DJ, Morgan MY (2008) Sleep-wake disturbances in patients with cirrhosis: relations to neuropsychiatric performance and health-related quality of life, JOURNAL OF SLEEP RESEARCH 17 pp. 76-76 WILEY-BLACKWELL PUBLISHING, INC
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2009) Sleep and circadian abnormalities in patients with cirrhosis: features of delayed sleep phase syndrome?, METABOLIC BRAIN DISEASE 24 (3) pp. 427-439 SPRINGER/PLENUM PUBLISHERS
Skene DJ, Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson R, Cui N, Middleton B, Ackermann K, Kayser M, Thumser AE, Raynaud FI (2014) Effect of sleep deprivation on human plasma metabolome rhythms, JOURNAL OF SLEEP RESEARCH 23 pp. 36-37 WILEY-BLACKWELL
The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive hormones in humans. Eight healthy men took part in this double-blind, crossover study. Surge/sustained release melatonin (1.5 mg) or placebo was administered for 8 d at the beginning of a 16-h sleep opportunity (1600 h to 0800 h) in dim light. Compared with placebo, melatonin administration advanced the timing of endogenous melatonin and cortisol rhythms. Activity was reduced in the first half and increased in the second half of the sleep opportunity with melatonin; however, total activity during the sleep opportunities and wake episodes was not affected. Melatonin treatment did not affect the endogenous melatonin profile duration, pituitary/gonadal hormone levels (24-h), or sleepiness and mood levels on the subsequent day. In the short term, suitably timed sustained-release melatonin phase-shifts circadian rhythms and redistributes activity during a 16-h sleep opportunity, with no evidence of changes in the duration of endogenous melatonin secretion or pituitary/gonadal hormones.
Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S (1997) Efficacy of melatonin treatment in jet lag, shift work, and blindness., Journal of Biological Rhythms 12 (6) pp. 604-617 Sage
Melatonin has chronobiotic properties in humans. It is able to phase shift strongly endogenous rhythms, such as core temperature and its own endogenous rhythm, together with the sleep-wake cycle. Its ability to synchronize free-running rhythms has not been fully investigated in humans. There is evidence for synchronization of the sleep-wake cycle, but the available data suggest that it is less effective with regard to endogenous melatonin and core temperature rhythms. When suitably timed, most studies indicate that fast release preparations are able to hasten adaptation to phase shift in both field and simulation studies of jet lag and shift work. Both subjective and objective measures support this statement. However, not all studies have been successful. Careful evaluation of the effects on work-related performance is required. When used to alleviate the non-24-h sleep-wake disorder in blind subjects, again most studies report a successful outcome using behavioral measures, albeit in a small number of individuals. The pres suggest, however, that although leep-wake can be stabilized to 24 h, entrainment of other rhythms is exceptionally rare.
Sletten TL, Revell VL, Middleton B, Lederle KA, Skene DJ (2009) Age-Related Changes in Acute and Phase-Advancing Responses to Monochromatic Light, JOURNAL OF BIOLOGICAL RHYTHMS 24 (1) pp. 73-84 SAGE PUBLICATIONS INC
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2008) EVIDENCE OF CENTRAL CIRCADIAN DISRUPTION IN PATIENTS WITH CIRRHOSIS, HEPATOLOGY 48 (4) pp. 1063A-1063A JOHN WILEY & SONS INC
Montagnese S, Middleton B, Skene DJ, Morgan MY (2009) Night-time sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis, LIVER INTERNATIONAL 29 (9) pp. 1372-1382 WILEY-BLACKWELL PUBLISHING, INC
Isherwood C, Otway DT, Maentele S, Middleton B, Wright J, Robertson MD, Skene DJ, Gibbs M, Johnston JD (2015) Daily rhythms in hormonal markers of diabetes and obesity: effect of weight and Type 2 diabetes, PROCEEDINGS OF THE NUTRITION SOCIETY 74 (OCE1) pp. E37-E37 CAMBRIDGE UNIV PRESS
Lewis PD, Middleton BA, Gous RM (2005) Supplementary radio noise advances sexual maturity in domestic pullets exposed to 7-h photoperiods, SOUTH AFRICAN JOURNAL OF ANIMAL SCIENCE 35 (3) pp. 180-185 SOUTH AFRICAN JOURNAL OF ANIMAL SCIENCES
Middleton BA, Arendt J, Stone B (1996) Human circadian rhythms in constant dim light (8 lux) with knowledge of clock time, Journal of Sleep Research 5 (2) pp. 69-76 Wiley
The light/dark (L/D) cycle is a major synchronizer of human circadian rhythms. In the absence of a strong L/D cycle, synchrony with 24 hours can nevertheless be maintained in a socially structured environment, as shown in Polar regions (Broadway et al. 1987) and by some blind subjects (Czeisler et al. 1995a). The relative contribution of other time cues to entrainment in dim light has not been fully explored. The present study investigated the behaviour of melatonin (assessed as 6-sulphatoxymelatonin); rectal temperature; activity and sleep (actigraphy and logs) in constant dim light (L/L) with access to a digital clock. 6 normal healthy males were maintained as a group in partial temporal isolation with attenuated sound and ambient temperature for 21 days. All 6 subjects showed free-running periodicity for 6-sulphatoxymelatonin and 5/6 subjects for temperature, activity and sleep offset. The average period (tau) was 24.26±0.049, substantially shorter than in previous experiments with a self selected L/D cycle but similar to a recent study conducted in very dim light. One subject maintained a rigid sleep/wake cycle throughout whilst his 6-sulphatoxymelatonin rhythm free-ran. Total sleep time, from actigraph data, did not change but sleep efficiency decreased during the experiment. The subjects did not show group synchronization. These results confirm previous data indicating the importance of the L/D cycle in human entrainment and underline the lesser role of social cues and knowledge of clock time. This particular approach will permit the administration of timed medication to sighted humans under free-running conditions.
Merchant NM, Azzopardi DV, Hawwa AF, McElnay JC, Middleton B, Arendt J, Arichi T, Gressens P, Edwards AD (2013) Pharmacokinetics of melatonin in preterm infants, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 76 (5) pp. 725-733 WILEY-BLACKWELL
Muto V, Jaspar M, Meyer C, LeBourdiec AS, Kussee C, Chellappa SL, Vandewalle G, Degueldre C, Luxen A, Collette F, Phillips C, Middleton B, Archer SN, Dijk D-J, Maquet P (2014) Neural correlates of sustained attention under sleep deprivation during a constant routine: circadian and homeostatic interaction, JOURNAL OF SLEEP RESEARCH 23 pp. 61-61 WILEY-BLACKWELL
Wulff K, Joyce EM, Middleton B, Foster RG, Dijk D (2008) Sleep and rest/activity cycle disturbances in schizophrenia patients in comparison to unemployed healthy controls, JOURNAL OF SLEEP RESEARCH 17 pp. 76-77 WILEY-BLACKWELL PUBLISHING, INC
Muto V, Jaspar M, Meyer C, Kusse C, Chellappa SL, Degueldre C, Balteau E, Shaffii-Le Bourdiec A, Luxen A, Middleton B, Archer SN, Phillips C, Collette F, Vandewalle G, Dijk D-J, Maquet P (2016) Local modulation of human brain responses by circadian rhythmicity and sleep debt, SCIENCE 353 (6300) pp. 687-690
AMER ASSOC ADVANCEMENT SCIENCE
Lewis PD, Middleton BA, Gous RM (2006) Exogenous melatonin modifies rate of sexual maturation in domestic pullets, POULTRY SCIENCE 85 (1) pp. 117-122 POULTRY SCIENCE ASSOC INC
Howatson G, Bell PG, Tallent J, Middleton B, McHugh MP, Ellis J (2012) Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality, European Journal of Nutrition 51 (8) pp. 909-916 Springer Verlag
Gringras P, Middleton B, Skene DJ, Revell VL (2015) Bigger, Brighter, Bluer-Better? Current Light-Emitting Devices - Adverse Sleep Properties and Preventative Strategies., Frontiers in public health 3
In an effort to enhance the efficiency, brightness, and contrast of light-emitting (LE) devices during the day, displays often generate substantial short-wavelength (blue-enriched) light emissions that can adversely affect sleep. We set out to verify the extent of such short-wavelength emissions, produced by a tablet (iPad Air), e-reader (Kindle Paperwhite 1st generation), and smartphone (iPhone 5s) and to determine the impact of strategies designed to reduce these light emissions.University of Surrey dedicated chronobiology facility.First, the spectral power of all the LE devices was assessed when displaying identical text. Second, we compared the text output with that of "Angry Birds" - a popular top 100 "App Store" game. Finally, we measured the impact of two strategies that attempt to reduce the output of short-wavelength light emissions. The first strategy employed an inexpensive commercially available pair of orange-tinted "blue-blocking" glasses. The second strategy tested an app designed to be "sleep-aware" whose designers deliberately attempted to reduce short-wavelength light emissions.All the LE devices shared very similar enhanced short-wavelength peaks when displaying text. This included the output from the backlit Kindle Paperwhite device. The spectra when comparing text to the Angry Birds game were also very similar, although the text emissions were higher intensity. Both the orange-tinted glasses and the "sleep-aware" app significantly reduced short-wavelength emissions.The LE devices tested were all bright and characterized by short-wavelength enriched emissions. Since this type of light is likely to cause the most disruption to sleep as it most effectively suppresses melatonin and increases alertness, there needs to be the recognition that at night-time "brighter and bluer" is not synonymous with "better." Ideally future software design could be better optimized when night-time use is anticipated, and hardware should allow an automatic "bedtime mode" that shifts blue and green light emissions to yellow and red as well as reduce backlight/light intensity.
Gribble L, Korimbocus A, Middleton B, Gouni R, Kerr D, Coppini D, Boyle J (2008) Sleep in painful diabetic peripheral neuropathy: Subjective measures and actigraphy analysis, SLEEP 31 pp. A299-A299 AMER ACAD SLEEP MEDICINE
MIDDLETON BA, MORGAN LM, AHERNE GW, MARKS V (1988) THE EFFECT OF STORAGE-TEMPERATURE AND PHYSICAL STATE ON THE PERFORMANCE OF ANTISERA IN RADIOIMMUNOASSAY AFTER LONG-TERM STORAGE, ANNALS OF CLINICAL BIOCHEMISTRY 25 pp. 89-95 ROYAL SOC MEDICINE SERVICES LTD
Skene DJ, Timbers SE, Middleton B, English J, Kopp C, Tobler I, Ioannides C (2006) Mice convert melatonin to 6-sulphatoxymelatonin, GENERAL AND COMPARATIVE ENDOCRINOLOGY 147 (3) pp. 371-376 ACADEMIC PRESS INC ELSEVIER SCIENCE
Ackermann K, Lao O, Revell VL, Plomp R, Middleton B, Skene DJ, Kayser M (2012) Effect of total sleep deprivation on clock gene expression and melatonin rhythms in human peripheral blood cells, JOURNAL OF SLEEP RESEARCH 21 pp. 39-39 WILEY-BLACKWELL
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2010) Melatonin Rhythms in Patients With Cirrhosis, AMERICAN JOURNAL OF GASTROENTEROLOGY 105 (1) pp. 220-222 NATURE PUBLISHING GROUP
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2009) PLASMA CORTISOL PROFILES IN PATIENTS WITH CIRRHOSIS: BEWARE THE TIME OF SAMPLING, GUT 58 pp. A76-A76 B M J PUBLISHING GROUP
Lockley SW, Skene DJ, Thapan K, English J, Ribeiro D, Haimov I, Hampton S, Middleton B, von Schantz M, Arendt J (1998) Extraocular light exposure does not suppress plasma melatonin in humans., The Journal of Clinical Endocrinology & Metabolism 83 (9) pp. 3369-3372
Light affects the circadian axis in at least two ways. It can cause the acute suppression of pineal melatonin synthesis, and/or a phase-shift of the circadian oscillator. As recent evidence has suggested that extraocular light exposure may cause phase-shifts of the circadian clock, we have investigated whether suppression of melatonin can be induced by the same type of light exposure. In the first study subjects? eyes were exposed to white light (2250 lux for 30 min) via a fibre optic cable. As expected, suppression of nighttime plasma melatonin levels (61 ± 6%) was observed. In the second study, light of the same quality but higher intensity (14,000 or 67,500 lux for 180 mins) was delivered in the same manner to the popliteal region behind the subjects? knees, whilst shielding their eyes. No suppression of plasma melatonin levels (4 ± 7%) was detected in any of the subjects. Thus, extraocular photoreception, if it exists in mammals, does not affect the suprachiasmatic nuclei-pineal pathway.
Montagnese S, Middleton B, Mani AR, Skene DJ, Morgan MY (2011) Changes in the 24-h plasma cortisol rhythm in patients with cirrhosis, J HEPATOL 54 (3) pp. 588-590 ELSEVIER SCIENCE BV
Skene DJ, Sletten TL, Ackermann K, Herljevic M, Lederle KA, Middleton B, Archer SN, Revell VL (2009) LIGHT AND THE HUMAN CIRCADIAN TIMING SYSTEM: AGE-RELATED CHANGES, JOURNAL OF PHYSIOLOGICAL SCIENCES 59 pp. 37-37 SPRINGER TOKYO
Morgan PL, Hampton S, Karatziotou A, Zaslona J, Middleton B (2012) Validation of two new activity monitors: motionwatch 8 and pro-diary motion, JOURNAL OF SLEEP RESEARCH 21 pp. 217-218 WILEY-BLACKWELL
Sletten TL, Revell VL, Middleton B, Lederle KA, Skene DJ (2008) Short wavelength light exposure in the elderly: acute and phase shifting effects, JOURNAL OF SLEEP RESEARCH 17 pp. 79-79 WILEY-BLACKWELL PUBLISHING, INC
Meyer C, Jaspar M, Muto V, Kusse C, Chellappa SL, Degueldre C, Balteau E, Luxen A, Collette F, Middleton B, Phillips C, Archer SN, Dijk D-J, Vandewalle G, Maquet P (2014) Seasonal variation in human executive brain responses, JOURNAL OF SLEEP RESEARCH 23 pp. 171-171 WILEY-BLACKWELL
Bonmati-Carrion MA, Middleton B, Revell VL, Skene DJ, Rol MA, Madrid JA (2015) Validation of an innovative method, based on tilt sensing, for the assessment of activity and body position., Chronobiol Int 32 (5) pp. 701-710
Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep-wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects (N = 13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep-wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA (R = 0.607, p = 0.028; R = 0.582, p = 0.037; R = 0.620, p = 0.031, respectively), while for WA, only acrophase did (R = 0.621, p = 0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95 ± 0.01 versus 0.86 ± 0.02), while the agreement rate and sensitivity were higher for AA (0.76 ± 0.02 versus 0.66 ± 0.02 and 0.71 ± 0.03 versus 0.53 ± 0.03, respectively). Cohen's kappa coefficient also present
Circadian rhythmicity and non-visual sensitivity to light can be assessed, in healthy subjects, by measuring the rhythm of the urinary melatonin metabolite 6-sulphatoxymelatonin (aMT6s) and by determining the response of plasma melatonin to nocturnal retinal light exposure, respectively. However, the validity of these techniques has not been assessed in disease states in which disruption of the circadian rhythm is known or suspected to occur. Thus, the aims of this study were as follows: (i) to assess the reliability of circadian aMT6s profile estimates derived from 36 h versus 56 h urine collections and (ii) to test different models for calculating melatonin suppression in response to light in healthy volunteers and patients with cirrhosis. Twenty patients with biopsy-proven cirrhosis and 10 matched healthy volunteers undertook: (i) separate 36 - and 56-h urine collections, under controlled conditions, for cosinor analysis of the urinary aMT6s profile; (ii) a melatonin suppression test, comprising of a baseline night, during which subjects were woken and asked to sit in front of a switched off light sphere, and an experimental night, identically executed, except that the light sphere was switched on and the subjects were exposed to white light (4.1 × 10(14) photons/cm(2)/s) for 30 min. Alternative approaches to the calculation of melatonin suppression were taken, with/without inclusion of the baseline night. Eighteen patients and eight healthy volunteers had matched analysable 36 - and 56-h urinary samples. Cosinor analysis showed a significant fit in 88% of the remaining 56 h collections, and 48% of the remaining 36-h collections. Thus, eight patients and five healthy volunteers had matched analysable samples for cosinor analysis. In the healthy volunteers, aMT6s profile indices obtained using the 36 - and the 56-h collections did not differ significantly. In contrast, considerably more variability was observed in patients [i.e. the difference in the aMT6s peak time was 0.5 ± 1.7 h (limits of agreement: -3.9; +2.9 h)]. No difficulties were encountered in obtaining suppression estimates by use of the experimental night only. In contrast, suppression estimates obtained by use of both nights were considered inaccurate in one (11%) healthy volunteer and in 5 (28%) patients, primarily because: (i) melatonin concentrations at the beginning of light administration were significantly different on baseline and experimental night; (ii) the rise in melatonin was in
Montagnese S, Middleton B, Skene DJ, Morgan MY (2008) Sleep disturbances are not a feature of hepatic encephalopathy, JOURNAL OF HEPATOLOGY 48 pp. S40-S40 ELSEVIER SCIENCE BV
Gogenur I, Middleton B, Kristiansen VB, Skene DJ, Rosenberg J (2007) Disturbances in melatonin and core body temperature circadian rhythms after minimal invasive surgery, ACTA ANAESTHESIOLOGICA SCANDINAVICA 51 (8) pp. 1099-1106 BLACKWELL PUBLISHING
Arendt J, Middleton B, Williams P, Francis G, Luke C (2006) Sleep and circadian phase in a ships crew, JOURNAL OF BIOLOGICAL RHYTHMS 21 (3) pp. 214-221 SAGE PUBLICATIONS INC
Arendt J, Middleton B, Stone B, Skene D (1999) Complex effects of melatonin: evidence for photoperiodic responses in humans?, Sleep 22 (5) pp. 625-635 American Academy of Sleep Medicine
The primary function of melatonin in mammals is to convey information about the changing length of the night in the course of the year. This information is used by photoperiodic species to ensure the correct timing of seasonally variable functions such as reproduction, coat growth, and probably the duration and organization of sleep. Melatonin appears not to be essential for circadian organization but reinforces functions associated with darkness. In diurnal humans this of course includes sleep and lowered body temperature. It may act as an adjunct to light for the maintenance of synchrony with the solar day. Exogenous melatonin can both advance and delay the timing of sleep and other circadian functions and appears to stabilize sleep to a 24 h period taken daily at an appropriate time in free running conditions. However, there is as yet little evidence that it can consistently synchronize free running strongly endogenous variables such as core temperature. Its effects on sleep in free run are complex, depend on circadian time of administration, and can in part be interpreted on a photoperiodic basis.
Mäntele S, Otway D, Middleton BA, Bretschneider S, Wright J, Robertson MD, Skene DJ, Johnston JD (2012) Daily Rhythms of Plasma Melatonin, but Not Plasma Leptin or Leptin mRNA, Vary between Lean, Obese and Type 2 Diabetic Men., PLoS One 7 (5)
Public Library of Science
Melatonin and leptin exhibit daily rhythms that may contribute towards changes in metabolic physiology. It remains unclear, however, whether this rhythmicity is altered in obesity or type 2 diabetes (T2DM). We tested the hypothesis that 24-hour profiles of melatonin, leptin and leptin mRNA are altered by metabolic status in laboratory conditions. Men between 45-65 years old were recruited into lean, obese-non-diabetic or obese-T2DM groups. Volunteers followed strict sleep-wake and dietary regimes for 1 week before the laboratory study. They were then maintained in controlled light-dark conditions, semi-recumbent posture and fed hourly iso-energetic drinks during wake periods. Hourly blood samples were collected for hormone analysis. Subcutaneous adipose biopsies were collected 6-hourly for gene expression analysis. Although there was no effect of subject group on the timing of dim light melatonin onset (DLMO), nocturnal plasma melatonin concentration was significantly higher in obese-non-diabetic subjects compared to weight-matched T2DM subjects (p
Ly J, Gaggioni G, Chellappa S, Papachilleos S, Brzozowski A, Borsu C, Rosanova M, Sarasso S, Middleton BA, Luxen A, Archer S, Phillips C, Dijk D, Maquet P, Massimini M, Vandewalle G (2016) Circadian regulation of human cortical excitability, Nature Communications 11828
Nature Publishing Group
Prolonged wakefulness alters cortical excitability, which is essential for proper brain function and cognition. However, besides prior wakefulness, brain function and cognition are also affected by circadian rhythmicity. Whether the regulation of cognition involves a circadian impact on cortical excitability is unknown. Here, we assessed cortical excitability from scalp EEG-responses to transcranial magnetic stimulation in 22 participants during 29-h of wakefulness under constant conditions. Data reveal robust circadian dynamics of cortical excitability that were strongest in those individuals with highest endocrine markers of circadian amplitude. In addition, the time course of cortical excitability correlated with changes in EEG synchronization and cognitive performance. These results demonstrate that the crucial factor for cortical excitability, and basic brain function in general, is the balance between circadian rhythmicity and sleep need, rather than sleep homeostasis alone. These findings have implications for clinical applications such as noninvasive brain stimulation in neurorehabilitation.
Negative impacts of night work on employees are well documented, but little is known about immediate consequences for family members. This study examines how night work within a rotating shift pattern affects the sleep, mood and cortisol levels of female nurses, their husbands and children. Participants included twenty nurses (42.7 ± 6.5 years), their husbands and children (n=34, 8-18 years) who completed sleep diaries, rated their sleep quality, alertness and mood daily, and collected saliva samples each morning and evening for 14 days. Comparisons were made between night work and other shifts (Wilcoxon Signed Ranks test); and between periods preceding, during and following night shifts (repeated measures ANOVA with Tukey posthoc tests). Nurses? sleep after the final night shift was significantly shorter (3h 58 mins ± 46 mins) and ended significantly earlier (13:28 ± 0:48h) than after the first night shift (sleep duration 5h 17 mins ± 1h 36 mins; wake time 14:58 ± 1:41h) (p
The pronounced cachexia (unexplained wasting) seen in Huntington?s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients.
Circadian rhythms, metabolism and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hour delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hour intervals, beginning either 0.5 (early) or 5.5 (late) hours after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants' circadian rhythms were measured in a 37-hour constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hours (p
Objective: Environmental (little outdoor light; low indoor lighting) and age-related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes.
Methods: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 ± 8 yrs (mean ± SD), participated (MMSE 19 ± 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue-enriched white lighting (17000 K E 900 lux) were compared with four weeks of control white lighting (4000 K E 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p
Conclusion: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people.
Conflicting evidence exists as to whether there are differences between males and females in circadian timing. The aim of the current study was to assess whether sex differences are present in the circadian regulation of melatonin and cortisol in plasma and urine matrices during a constant routine protocol. Thirty-two healthy individuals (16 females taking the oral contraceptive pill (OCP)), aged 23.8 ± 3.7 (mean ± SD) years, participated. Blood (hourly) and urine (4-hourly) samples were collected for measurement of plasma melatonin and cortisol, and urinary 6-sulfatoxymelatonin (aMT6s) and cortisol, respectively. Data from 28 individuals (14 females) showed no significant differences in the timing of plasma and urinary circadian phase markers between sexes. Females, however, exhibited significantly greater levels of plasma melatonin and cortisol than males (AUC melatonin: 937 ± 104 (mean ± SEM) vs. 642 ± 47 pg/ml.h; AUC cortisol: 13581 ± 1313 vs. 7340 ± 368 mmol/L.h). Females also exhibited a significantly higher amplitude rhythm in both hormones (melatonin: 43.8 ± 5.8 vs. 29.9 ± 2.3 pg/ml; cortisol: 241.7 ± 23.1 vs. 161.8 ± 15.9 mmol/L). Males excreted significantly more urinary cortisol than females during the CR (519.5 ± 63.8 vs. 349.2 ± 39.3 mol) but aMT6s levels did not differ between sexes. It was not possible to distinguish whether the elevated plasma melatonin and cortisol levels observed in females resulted from innate sex differences or the OCP affecting the synthetic and metabolic pathways of these hormones. The fact that the sex differences observed in total plasma concentrations for melatonin and cortisol were not reproduced in the urinary markers challenges their use as a proxy for plasma levels in circadian research, especially in OCP users.
One of the possible causes of disturbed circadian rhythms and sleep in the elderly may be impaired photic input to the circadian clock. Age-related changes in lens density are known to reduce the transmission of short wavelength light, which has been shown to be most effective in suppressing nocturnal melatonin. The aim of the study therefore was to investigate age-related changes in melatonin suppression in response to short and medium wavelength light. Young premenopausal (n=13) and postmenopausal (n=21) women were exposed to 30 min of monochromatic light at two different wavelengths and irradiances (»max 456 nm: 3.8 and 9.8 ¼W/cm2; »max 548 nm: 28 and 62 ¼W/cm2). Melatonin suppression was compared across light treatments and between age groups. Significantly reduced melatonin suppression was noted in the elderly subjects following exposure to short wavelength (456 nm) light compared to the young subjects. These results are likely to reflect age-related changes in lens density.
Chellappa S, Gaggioni G, Ly J, Papachilleos S, Borsu C, Brzozowski A, Rosanova M, Sarasso S, Luxen A, Middleton BA, Archer S, Dijk D, Massimini M, Maquet P, Phillips C, Moran R, Vandewalle G (2016) Circadian dynamics in measures of cortical excitation and inhibition balance, Scientific Reports 6 33661
Nature Publishing Group
Several neuropsychiatric and neurological disorders have recently been characterized as dysfunctions arising from a ?final common pathway? of imbalanced excitation to inhibition within cortical networks. How the regulation of a cortical E/I ratio is affected by sleep and the circadian rhythm however, remains to be established. Here we addressed this issue through the analyses of TMS-evoked responses recorded over a 29h sleep deprivation protocol conducted in young and healthy volunteers. Spectral analyses of TMS-evoked responses in frontal cortex revealed non-linear changes in gamma band evoked oscillations, compatible with an influence of circadian timing on inhibitory interneuron activity. In silico inferences of cell-to-cell excitatory and inhibitory connectivity and GABA/Glutamate receptor time constant based on neural mass modeling within the Dynamic causal modeling framework, further suggested excitation/inhibition balance was under a strong circadian influence. These results indicate that circadian changes in EEG spectral properties, in measure of excitatory/inhibitory connectivity and in GABA/glutamate receptor function could support the maintenance of cognitive performance during a normal waking day, but also during overnight wakefulness. More generally, these findings demonstrate a slow daily regulation of cortical excitation/inhibition balance, which depends on circadian-timing and prior sleep-wake history.
Turco M, Biscontin A, Corrias M, Caccin L, Bano M, Chiaromanni F, Salamanca M, Mattei D, Salvoro C, Mazzotta G, De Pittà C, Middleton Benita, Skene Debra, Montagnese S, Costa R (2017) Diurnal preference, mood and the response to morning light in
relation to polymorphisms in the human clock gene PER3, Scientific Reports 7 (6967) pp. 1-10
Nature Publishing Group
PER3 gene polymorphisms have been associated with differences in human sleep-wake phenotypes,
and sensitivity to light. The aims of this study were to assess: i) the frequency of allelic variants at
two PER3 polymorphic sites (rs57875989 length polymorphism: PER34, PER35; rs228697 SNP: PER3C,
PER3G) in relation to sleep-wake timing; ii) the effect of morning light on behavioural/circadian
variables in PER34/PER34 and PER35/PER35 homozygotes. 786 Caucasian subjects living in Northern
Italy donated buccal DNA and completed diurnal preference, sleep quality/timing and sleepiness/
mood questionnaires. 19 PER34/PER34 and 11 PER35/PER35 homozygotes underwent morning light
administration, whilst monitoring sleep-wake patterns and the urinary 6-sulphatoxymelatonin
(aMT6s) rhythm. No significant relationship was observed between the length polymorphism and
diurnal preference. By contrast, a significant association was observed between the PER3G variant and
morningness (OR = 2.10), and between the PER3G-PER34 haplotype and morningness (OR = 2.19), for
which a mechanistic hypothesis is suggested. No significant differences were observed in sleep timing/
aMT6s rhythms between PER35/PER35 and PER34/PER34 subjects at baseline. After light administration,
PER34/PER34 subjects advanced their aMT6s acrophase (p
sleep-wake timing. In conclusion, significant associations were observed between PER3 polymorphic
variants/their combinations and both diurnal preference and the response to light.
Marini S, Santangeli O, Saarelainen P, Middleton Benita, Chowdhury Namrata Roy, Skene Debra, Costa R, Porkka-Heiskanen T, Montagnese S (2017) Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia, Frontiers in Physiology 8 636
Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking EEG. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 hours of sleep deprivation. Adenosine and metabolite levels were measured by HPLC and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.
Light at night (LAN) is a major factor in disruption of SCN function, including melatonin suppression. Melatonin has been linked to a variety of biological processes such as lipid and glucose metabolism, vascular parameters, appetite, and behaviour. However, few human studies have investigated the effect of LAN and suppressed melatonin prior to and after an evening meal.
The current thesis aims to investigate the impact of light at night and/or mela- tonin on hormones, metabolites, appetite, vascular function, and behaviour prior to and after an evening test meal in healthy participants.
The first study investigated the effect of dim or bright light conditions on hor- mones, metabolites, appetite, vascular function and behavioural responses. Glucose tolerance and insulin sensitivity were reduced, lipid profiles altered and salivary melatonin suppressed under bright light compared to dim light conditions. Subjec- tive mood was improved and appetite scores increased in bright light. No differences were seen in vascular parameters. Although clear differences were apparent it could not be determined whether the effects were due to the light at night, the absence of melatonin or a combination of the two.
The second study involved three conditions with the administration of exogenous melatonin 90 mins before the evening test meal under bright and dim light conditions compared to bright light alone with the consequent melatonin suppression. Glucose tolerance and insulin sensitivity were reduced and lipid profile altered in bright light when melatonin was suppressed compared to the two conditions with exogenous melatonin. Mood was improved and appetite increased with lower leptin levels and elevated wrist temperature with bright light and suppressed melatonin. Statistical
analysis showed that the major effects were due to melatonin.
These studies demonstrate a possible role for melatonin in glucose tolerance,
insulin sensitivity and lipid metabolism when eating late at night which may have implications for shift-workers.
Many animal studies have reported an association between melatonin suppression and the disturbance of metabolic responses; yet, few human studies have investigated bright light effects on metabolic and hormonal responses at night. This study investigated the impact of light on plasma hormones and metabolites prior to, and after, an evening meal in healthy participants. Seventeen healthy participants, 8 females (22.2 ± 2.59 years, mean ± s.d.) and 9 males (22.8 ± 3.5 years) were randomised to a two-way cross-over design protocol; dim light (DL) (500 lux) sessions, separated by at least seven days. Saliva and plasma samples were collected prior to and after a standard evening meal at specific intervals. Plasma non-esterified fatty acid (NEFA) levels were significantly higher pre-meal in DL compared to BL (P
Background. Subjective reports of insomnia and hypersomnia are common in bipolar disorder (BD). It is unclear to what extent these relate to underlying circadian rhythm disturbance (CRD). In this study we aimed to objectively assess sleep and circadian rhythm in a cohort of patients with BD compared to matched controls. Method. Forty-six patients with BD and 42 controls had comprehensive sleep/circadian rhythm assessment with respiratory sleep studies, prolonged accelerometry over 3 weeks, sleep questionnaires and diaries, melatonin levels, alongside mood, psychosocial functioning and quality of life (QoL) questionnaires. Results. Twenty-three (50%) patients with BD had abnormal sleep, of whom 12 (52%) had CRD and 29% had obstructive sleep apnoea. Patients with abnormal sleep had lower 24-h melatonin secretion compared to controls and patients with normal sleep. Abnormal sleep/CRD in BD was associated with impaired functioning and worse QoL. Conclusions. BD is associated with high rates of abnormal sleep and CRD. The association between these disorders, mood and functioning, and the direction of causality, warrants further investigation.
Misalignment between internal circadian rhythmicity and externally
imposed behavioral schedules, such as occurs in shift workers, has
been implicated in elevated risk of metabolic disorders. To determine
underlying mechanisms, it is esse
ntial to assess whether and how
peripheral clocks are disturbed during shift work and to what extent
this is linked to the central suprachiasmatic nuclei (SCN) pacemaker
and/or misaligned behavioral time cues. Investigating rhythms in
circulating metabolites as biomarkers of peripheral clock distur-
bances may offer new insight
s. We evaluated the impact of
misaligned sleep/wake and feeding/fasting cycles on circulating
metabolites using a targeted metabolomics approach. Sequential
plasma samples obtained during a 24-h constant routine that
followed a 3-d simulated night-s
hift schedule, compared with a
simulated day-shift schedule, we
re analyzed for 132 circulating
metabolites. Nearly half of these metabolites showed a 24-h rhyth-
micity under constant routine following either or both simulated shift
schedules. However, while tradition
al markers of the circadian clock
in the SCN
melatonin, cortisol, and
stable phase alignment after both schedules, only a few metabo-
lites did the same. Many showed reversed rhythms, lost their
rhythms, or showed rhythmicity only under constant routine fol-
lowing the night-shift schedule. Here, 95% of the metabolites with
a 24-h rhythmicity showed rhythms that were driven by behavior-
al time cues externally imposed during the preceding simulated
shift schedule rather than being driven by the central SCN circa-
dian clock. Characterization of these metabolite rhythms will pro-
vide insight into the underlying mechanisms linking shift work and
Diessler Shanaz, Jan Maxime, Emmenegger Yann, Guex Nicolas, Middleton Benita, Skene Debra J., Ibberson Mark, Burdet Frederic, Götz Lou, Pagni Marco, Sankar Martial, Liechti Robin, Hor Charlotte N., Xenarios Ioannis, Franken Paul (2018) A systems genetics resource and analysis of sleep regulation in the mouse, PLOS Biology 16 (8) e2005750 pp. 1-39
Public Library of Science
Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep "sleep-wake" phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%?78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply ±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.
Lech Karolina, Liu Fan, Davies Sarah K., Ackermann Katrin, Ang Joo Ern, Middleton Benita, Revell Victoria L., Raynaud Florence I., Hoveijn Igor, Hut Roelof A., Skene Debra J., Kayser Manfred (2017) investigation of metabolites for estimating blood deposition time, International Journal of Legal Medicine 132 (1) pp. 25-32
Trace deposition timing reflects a novel concept in forensic molecular biology involving the use of rhythmic biomarkers for estimating the time within a 24-h day/night cycle a human biological sample was left at the crime scene, which in principle allows verifying a sample donor?s alibi. Previously, we introduced two circadian hormones for trace deposition timing and recently demonstrated that messenger RNA (mRNA) biomarkers significantly improve time prediction accuracy. Here, we investigate the suitability of metabolites measured using a targeted metabolomics approach, for trace deposition timing. Analysis of 171 plasma metabolites collected around the clock at 2-h intervals for 36 h from 12 male participants under controlled laboratory conditions identified 56 metabolites showing statistically significant oscillations, with peak times falling into three day/night time categories: morning/noon, afternoon/evening and night/early morning. Time prediction modelling identified 10 independently contributing metabolite biomarkers, which together achieved prediction accuracies expressed as AUC of 0.81, 0.86 and 0.90 for these three time categories respectively. Combining metabolites with previously established hormone and mRNA biomarkers in time prediction modelling resulted in an improved prediction accuracy reaching AUCs of 0.85, 0.89 and 0.96 respectively. The additional impact of metabolite biomarkers, however, was rather minor as the previously established model with melatonin, cortisol and three mRNA biomarkers achieved AUC values of 0.88, 0.88 and 0.95 for the same three time categories respectively. Nevertheless, the selected metabolites could become practically useful in scenarios where RNA marker information is unavailable such as due to RNA degradation. This is the first metabolomics study investigating circulating metabolites for trace deposition timing, and more work is needed to fully establish their usefulness for this forensic purpose.
Turco Matteo, Cazzagon Nora, Franceschet Irene, Formentin Chiara, Frighetto Giovanni, Giordani Francesca, Cellini Nicola, Mazzotta Gabriella, Costa Rodolfo, Middleton Benita, Skene Debra, Floreani Annarosa, Montagnese Sara (2018) Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study, Frontiers in Physiology 9 1530
Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits,
disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is
reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning
light treatment. The aim of the present pilot study was to test the effect of morning light
treatment in a group of 13 well-characterized patients with PBC [all females; (mean ± SD)
53 ± 10 years]. Six healthy individuals (4 females, 57 ± 14 years) and 7 patients
with cirrhosis (1 female, 57 ± 12 years) served as controls and diseased controls,
respectively. At baseline, all participants underwent an assessment of quality of life,
diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness,
and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day
course of morning bright light treatment, immediately after getting up (light box, 10,000
lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline,
both patients with PBC and patients with cirrhosis had significantly worse subjective
sleep quality compared to controls. In patients with PBC, light treatment resulted in
an improvement in subjective sleep quality and a reduction in daytime sleepiness. In
addition, both their sleep onset and get-up time were significantly advanced. Finally,
the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after
light administration but post-hoc comparisons were not significant in any of the groups.
In conclusion, a brief course of morning bright light treatment had positive effects on
subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This
unobtrusive, side-effect free, non-pharmacological treatment is worthy of further study.
Robertson Nicola J., Martinello Kathryn, Lingam Ingran, Avdic-Belltheus Adnan, Meehan Christopher, Alonso-Alconada Daniel, Ragab Sara, Bainbridge Alan, Sokolska Magdalena, Tachrount Mohamed, Middleton Benita, Price David, Hristova Mariya, Golay Xavier, Soliani Raschini Annamaria, Aquino Giancarlo, Pelizzi Nicola, Facchinetti Fabrizio (2018) Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study., Neurobiology of Disease 121 pp. 240-251
Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15/mg/kg/24/h melatonin (proprietary formulation) administered at 2/h and 26/h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5/°C, 2?26/h) and vehicle (HT/+/V;n/=/13); b) HT and 5/mg/kg melatonin over 6/h at 2/h and 26/h after HI (HT/+/Mel-5;n/=/4); c) HT and 15/mg/kg melatonin over 6/h at 2/h and 26/h after HI (HT/+/Mel-15;n/=/13). Intensive care was maintained for 48/h; brain MRS was acquired and cell death (TUNEL) evaluated at 48/h. Comparing HT/+/V with HT/+/Mel-5 and HT/+/Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24/h and 48/h was similar, ATP/phosphate pool was higher for HT/+/Mel-15 versus HT/+/V at 24/h (p/=/0.038) but not 48/h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15/mg/kg melatonin group (HT/+/Mel-15 versus HT/+/V; p/0.003) but not in the 5/mg/kg melatonin group (HT/+/Mel-5 versus HT/+/V; p/=/0.808). Putative therapeutic melatonin levels were reached 8/h after HI (104 increase from baseline; ~15?30/mg/l). Mean/±/SD peak plasma melatonin levels after the first infusion were 0.0014/±/0.0012/mg/l in the HT/+/V group, 3.97/±/1.53/mg/l in the HT/+/Mel-5 group and 16.8/±/8.3/mg/l in the HT/+/Mel-15 group. Protection was dose dependent; 15/mg/kg melatonin started 2/h after HI, given over 6/h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.
Gaggioni Giulia, Ly Julien Q.M., Chellappa Sarah L., Coppieters ?t Wallant Dorothée, Rosanova Mario, Sarasso Simone, Luxen André, Salmon Eric, Middleton Benita, Massimini Marcello, Schmidt Christina, Casali Adenauer, Phillips Christophe, Vandewalle Gilles (2018) Human fronto-parietal response scattering subserves vigilance at night., NeuroImage 175 pp. 354-364
Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18?30/yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29/h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well-rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies.
Wild Jennifer, El-Salahi Shama, Tyson Gabriella, Lorenz Hjördis, Pariante Carmine M, Danese Andrea, Tsiachristas Apostolos, Watkins Edward, Middleton Benita, Blaber Amanda, Ehlers Anke (2018) Preventing PTSD, depression and associated health problems in student paramedics: protocol for PREVENT-PTSD, a randomised controlled trial of supported online cognitive training for resilience versus alternative online training and standard practice, BMJ Open 8 (12) e022292 pp. 1-10
BMJ Publishing Group
Introduction Emergency workers dedicate their lives to promoting public health and safety, yet suffer higher rates of post-traumatic stress disorder (PTSD) and major depression (MD) compared with the general population. They also suffer an associated increased risk for physical health problems, which may be linked to specific immunological and endocrine markers or changes in relevant markers. Poor physical and mental health is costly to organisations, the National Health Service and society. Existing interventions aimed at reducing risk of mental ill health in this population are not very successful. More effective preventative interventions are urgently needed. We first conducted a large-scale prospective study of newly recruited student paramedics, identifying two cognitive factors (rumination and resilience appraisals) that predicted episodes of PTSD and MD over a 2-year period. We then developed internet-delivered cognitive training for resilience (iCT-R), a supported online intervention, to modify cognitive predictors. This protocol is for a randomised controlled trial to evaluate the efficacy of the resilience intervention.
Methods and analysis 570 student paramedics will be recruited from participating universities. They will be randomly allocated to iCT-R or to supported online training of an alternative, widely available intervention or to training-as-usual. Follow-up will occur after the intervention/standard practice period and at 6, 12 and 24 months. Primary outcomes include rates of PTSD and MD and subsydnromal PTSD and MD, measured by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fifth edition, the Patient-Health Questionnaire-9 and the Post-traumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Secondary outcomes include measures of resilience, rumination, anxiety, psychological distress, well-being, salivary cortisol, plasma levels of C-reactive protein, smoking and alcohol use, weight gain, sleep problems, health-related quality of life, health resource utilisation and productivity.
Ethics and dissemination The Medical Sciences Inter-Divisional Research Ethics Committee at the University of Oxford granted approval, reference: R44116/RE001. The results will be published in a peer-reviewed journal. Access to raw data and participant information will be available only to members of the research team.
Functional connectivity (FC) of the human brain?s intrinsically connected networks underpins cognitive functioning and disruptions of FC are associated with sleep and neurological disorders. However, there is limited research on the impact of circadian phenotype and time of day on FC.
The aim of this study was to investigate resting state FC of the default mode network (DMN) in Early and Late circadian phenotypes over a socially constrained day.
38 healthy individuals (14 male, 22.7 ± 4.2 years) categorised as Early (n =16) or Late (n = 22) using the Munich ChronoType Questionnaire took part. Following a two week baseline of actigraphy coupled with saliva samples for melatonin and cortisol rhythms, participants underwent testing at 14.00 h, 20.00 h and 08.00 h the following morning. Testing consisted of resting state functional MRI, a structural T1 scan, attentional cognitive performance tasks and self-reported daytime sleepiness. Seed based FC analysis from the medial prefrontal and posterior cingulate cortices of the DMN was performed, compared between groups and linked with behavioural data.
Fundamental differences in the DMN were observed between Early and Late circadian phenotypes. Resting state FC of the DMN predicted individual differences in attention and subjective ratings of sleepiness.
Differences in FC of the DMN may underlie the compromised attentional performance and increased sleepiness commonly associated with Late types when they conform to a societally constrained day that does not match their intrinsic circadian phenotype.
There is a lack of research into 25-hydroxyvitamin D (25(OH)D) status, light exposure and sleep patterns in South Asian populations. In addition, results of research studies are conflicting as to whether there is an association between 25(OH)D status and sleep quality.
We investigated 25(OH)D status, self-reported and actigraphic sleep quality in n = 35 UK dwelling postmenopausal women (n = 13 South Asians, n = 22 Caucasians), who kept daily sleep diaries and wore wrist-worn actiwatch (AWL-L) devices for 14 days. A subset of n = 27 women (n = 11 South Asian and n = 16 Caucasian) also wore a neck-worn AWL-L device to measure their light exposure.
For 25(OH)D concentration, South Asians had a median ± IQR of 43.8 ± 28.2 nmol/L, which was significantly lower than Caucasians (68.7 ± 37.4 nmol/L)(P = 0.001). Similarly, there was a higher sleep fragmentation in the South Asians (mean ± SD 36.9 ± 8.9) compared with the Caucasians (24.7 ± 7.1)(P = 0.002). Non-parametric circadian rhythm analysis of rest/activity patterns showed a higher night-time activity (L5) (22.6 ± 14.0 vs. 10.5 ± 4.4; P = 0.0008) and lower relative amplitude (0.85 ± 0.07 vs. 0.94 ± 0.02; P Â 0.0001) in the South Asian compared with the Caucasian women. More South Asians (50%) met the criteria for sleep disorders (PSQI score Ã5) than did Caucasians (27%) (P = 0.001, Fishers Exact Test). However, there was no association between 25(OH)D concentration and any sleep parameter measured (P Ã 0.05) in either ethnic group. South Asians spent significantly less time in illuminance levels over 200 lx (P = 0.009) than did Caucasians.
Overall, our results show that postmenopausal South Asian women have lower 25(OH)D concentration than Caucasian women. They also have higher sleep fragmentation, as well as a lower light exposure across the day. This may have detrimental implications for their general health and further research into sleep quality and light exposure in the South Asian ethnic group is warranted.
Fagotti Juliane, Targa Adriano D. S., Rodrigues Lais S., Noseda Ana Carolina D., Dorieux Flávia W. C., Scarante Franciele F., Ilkiw Jessica L., Louzada Fernando M., Chowdhury Namrata, Van Der Veen Daan, Middleton Benita, Pennings Jeroen L. A., Swann Jonathan R., Skene Debra, Lima Marcelo M. S. (2019) Chronic sleep restriction in the rotenone Parkinson?s disease model in rats reveals peripheral early-phase biomarkers, Scientific Reports 9 (1) 1898
Springer Nature Publishing
Parkinson?s disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep
disturbances and cognitive decline, which are key non-motor features of the disease. Increasing
evidence of a possible association between sleep disruption and the neurodegenerative process
suggests that sleep impairment could produce a detectable metabolic signature on the disease. In
order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted
metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days)
condition. We found that SR combined with PD altered several behavioural (reversal of locomotor
activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters
(branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to
mitochondrial impairment). If combined, our results bring a plethora of parameters that represents
reliable early-phase PD biomarkers which can easily be measured and could be translated to human
Disruption to sleep and circadian rhythms can impact on metabolism. The study aimed to investigate the effect of acute sleep deprivation on plasma melatonin, cortisol and metabolites, to increase understanding of the metabolic pathways involved in sleep/wake regulation processes. Twelve healthy young female subjects remained in controlled laboratory conditions for ~92 h with respect to posture, meals and environment light (18:00?23:00 h and 07:00?09:00 h
There is conflict between living according to our endogenous biological rhythms and our
external environment, with disruptions resulting in negative consequences to health and performance.
This is often documented in shift work and jet lag, but ?societal norms? (eg, typical working hours) can
create profound issues for ?night owls?, people whose internal biological timing predisposes them to
follow an unusually late sleep-wake cycle. Night owls have also been associated with health issues, mood
disturbances, poorer performance and increased mortality rates.
This study used a randomized control trial design aimed to shift the late timing of night owls to
an earlier time (phase advance), using non-pharmacological, practical interventions in a real-world
setting. These interventions targeted light exposure (through earlier wake up/sleep times), fixed meals
times, caffeine intake and exercise.
Overall, participants demonstrated a significant advance of ~2 h in sleep/wake timings as
measured by actigraphy and circadian phase markers (dim light melatonin onset and peak time of the
cortisol awakening response), whilst having no adverse effect on sleep duration. Notably, the phase
advance was accompanied by significant improvements to self-reported depression and stress, as well as
improved cognitive (reaction time) and physical (grip strength) performance measures during the typical
'suboptimal morning hours.
Our findings propose a novel strategy for shifting clock timing towards a pattern that is
more aligned to societal demands that could significantly improve elements of performance, mental
health and sleep timing in the real world.