Healthier rhythm, healthier brain? Integrity of circadian melatonin and temperature rhythms relates to the clinical state of brain‐injured patients

Abstract

Background Healthy circadian rhythmicity has been suggested to relate to a better state of brain‐injured patients and to support the emergence of consciousness in patient groups characterized by a relative instability thereof such as patients with disorders of consciousness (DOC). Methods Going beyond earlier studies, a systems‐level perspective was adopted and, using multilevel modelling, the joint predictive value of three indices of circadian rhythm integrity derived from skin temperature variations, melatoninsulfate secretion, and physical activity (wrist actigraphy) patterns was evaluated for the behaviourally assessed state [Coma Recovery Scale ‐ Revised (CRS‐R) score] of DOC patients [13 unresponsive wakefulness syndrome; seven minimally conscious (exit) state]. Additionally, it was assessed in a subset of 16 patients whether patients’ behavioural repertoire (CRS‐R score) varied (i) with time of day or (ii) offset from the body temperature maximum (BTmax), i.e. when cognitive performance is expected to peak. Results The results reveal that better integrity of circadian melatoninsulfate and temperature rhythms relate to a richer behavioural repertoire. Moreover, higher CRS‐R scores are, by trend, related to assessments taking place at a later daytime or deviating less from the pre‐specified time of occurrence of BTmax. Conclusions In conclusion, the results suggest that therapeutic approaches aimed at improving circadian rhythms in brain‐injured patients are promising and should be implemented in hospitals or nursing homes. Beyond this, it might be helpful to schedule diagnostic procedures and therapies around the (pre‐assessed) BTmax (≈4 pm in healthy individuals) as this is when patients should be most responsive.

Actigraphy in brain-injured patients – A valid measurement for assessing circadian rhythms?

“…345 Besides this, the general usefulness of actigraphy data in severely brain-injured 346 individuals especially for diagnostic and prognostic purposes seems questionable as the 347 validity of motor data is severely limited by several factors such as motor impairments, 348 spasticity and the usage of muscle relaxants in these patients. In a previous study of our lab, 349 we did not find any relation between the IS of the patients' physical activity levels and the 350 CRS-R scores 5 . In the current study, IS correlated positively only with the motor subscale 351 score, but not with the other subscale scores.…”

“…This indicates more preserved 337 circadian rhythms in MCS/EMCS patients and is well in line with previous studies that 338 investigated circadian rhythms in DOC patients. Specifically, these studies showed that a 339 higher integrity of circadian temperature and melatonin rhythms predict a richer behavioral 340 repertoire, which is directly related to results of CRS-R assessments 5,12 . Also on a brain level, 341 day-night changes of EEG signal complexity are more pronounced in MCS than in UWS 342 patients (with significantly higher signal complexity during day than during night 25 ), and 343 periods of "daytime wakefulness" and "night-time sleep" are better distinguishable in MCS 344 than in UWS patients 26 .…”

“…As consolidated periods of wakefulness and 30 sleep resulting from well-entrained circadian rhythms, seem crucial for adequate arousal 31 levels and thus (conscious) wakefulness, circadian rhythms have been the focus of recent 32 research in DOC patients. Research from our group 5,12 suggests that a better integrity of 33 patients' circadian melatonin(-sulfate) and temperature rhythms is indeed related to a richer 34 behavioral repertoire (as measured with the CRS-R). Knowing a patient's circadian rhythm in 35 turn has been suggested to help finding the optimal time for behavioral assessments and 36 therapies as cognitive functions also vary with the time of day [12][13][14] .…”

“…Recently, actigraphy was also used for the investigation of 5 day/night patterns as well as circadian rhythms (i.e. rhythms with a period length of 6 approximately 24 h) in patients following severe brain injury [2][3][4][5] . As those patients often need 7 full-time care, actigraphy measures are probably highly influenced by external movements in 8 this patient population, wherefore in this study we sought to systematically control for 9 external movements.…”

Development of a Phytomelatonin-Rich Extract from Cultured Plants with Excellent Biochemical and Functional Properties as an Alternative to Synthetic Melatonin

“…The first related action of melatonin was that it enlightens skin color changes in fish, frogs, and tadpoles as a consequence of the aggregation of the melanophores present in melanocytes, which is why the substance was called melatonin [1,4]. Today, melatonin is related with a broad spectrum of functions, among which the actions influencing circadian rhythms, mood, sleep, body temperature and activity, food intake, endocrine rhythms, sexual behavior, and neuronal and immunomodulatory activity have been the most studied [5][6][7][8][9][10][11][12][13]. More recently, interesting studies on the role of melatonin regulating metabolic pathways have been published [14][15][16].…”