Relevance of internal time and circadian robustness for cancer patients.

BACKGROUND: Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing. METHODS: Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period. RESULTS: Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study. CONCLUSIONS: The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.

The circadian rest-activity rhythm, a potential safety pharmacology endpoint of cancer chemotherapy.

The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (I

Sleep disruption in breast cancer patients and survivors.

Sleep disruption is prevalent in patients and survivors of breast cancer. Most patients undergoing chemotherapy will experience transient sleep disruption, and nearly 60% will have chronic sleep problems. Numerous factors contribute to sleep disruption in women diagnosed with breast cancer. Sleep disruption is a consequence of several biological alterations, including circadian disruption and immune and metabolic deregulations. These systems also play significant roles in the control and progression of breast cancer. Sleep disruption is associated with many side effects and psychiatric and medical comorbidities. This article discusses the relationship between stress and posttraumatic stress disorder, depression and fatigue, and how sleep disturbance might be the cause or consequence of these disorders. Current evidence for management of sleep disturbance in breast cancer and high chronic use of hypnotic medication in this population is also discussed. Finally, the differences in management of sleep disturbance during acute cancer care and during the survivorship phase are discussed. More research is needed on accurate and timely assessment of sleep disturbance associated with breast cancer, and additional tailored approaches for the management of sleep problems in breast cancer should be developed.

A new integrated variable based on thermometry, actimetry and body position (TAP) to evaluate circadian system status in humans.

The disruption of the circadian system in humans has been associated with the development of chronic illnesses and the worsening of pre-existing pathologies. Therefore, the assessment of human circadian system function under free living conditions using non-invasive techniques needs further research. Traditionally, overt rhythms such as activity and body temperature have been analyzed separately; however, a comprehensive index could reduce individual recording artifacts. Thus, a new variable (TAP), based on the integrated analysis of three simultaneous recordings: skin wrist temperature (T), motor activity (A) and body position (P) has been developed. Furthermore, we also tested the reliability of a single numerical index, the Circadian Function Index (CFI), to determine the circadian robustness. An actimeter and a temperature sensor were placed on the arm and wrist of the non-dominant hand, respectively, of 49 healthy young volunteers for a period of one week. T, A and P values were normalized for each subject. A non-parametric analysis was applied to both TAP and the separate variables to calculate their interdaily stability, intradaily variability and relative amplitude, and these values were then used for the CFI calculation. Modeling analyses were performed in order to determine TAP and CFI reliability. Each variable (T, A, P or TAP) was independently correlated with rest-activity logs kept by the volunteers. The highest correlation (r= -0.993, p<0.0001), along with highest specificity (0.870), sensitivity (0.740) and accuracy (0.904), were obtained when rest-activity records were compared to TAP. Furthermore, the CFI proved to be very sensitive to changes in circadian robustness. Our results demonstrate that the integrated TAP variable and the CFI calculation are powerful methods to assess circadian system status, improving sensitivity, specificity and accuracy in differentiating activity from rest over the analysis of wrist temperature, body position or activity alone.

Ambulatory circadian monitoring (ACM) based on thermometry, motor activity and body position (TAP): a comparison with polysomnography.

An integrated variable based on the combination of wrist Temperature, motor Activity and body Position (TAP) was previously developed at our laboratory to evaluate the functioning of the circadian system and sleep-wake rhythm under ambulatory conditions. However, the reliability of TAP needed to be validated with polysomnography (PSG). 22 subjects suffering from sleep disorders were monitored for one night with a temperature sensor (iButton), an actimeter (HOBO) and exploratory PSG. Mean waveforms, sensitivity (SE), specificity (SP), agreement rates (AR) and comparisons between TAP and sleep stages were studied. The TAP variable was optimized for SE, SP and AR with respect to each individual variable (SE: 92%; SP: 78%; AR: 86%). These results improved upon estimates previously published for actigraphy. Furthermore, TAP values tended to decrease as sleep depth increased, reaching the lowest point at phase 3. Finally, TAP estimates for sleep latency (SL: 37±9 min), total sleep time (TST: 367±13 min), sleep efficiency (SE: 86.8±1.9%) and number of awakenings (NA>5 min: 3.3±.4) were not significantly different from those obtained with PSG (SL: 29±4 min; SE: 89.9±1.8%; NA>5 min: 2.3±.4), despite the heterogeneity of the sleep pathologies monitored. The TAP variable is a novel measurement for evaluating circadian system status and sleep-wake rhythms with a level of reliability better to that of actigraphy. Furthermore, it allows the evaluation of a patient's sleep-wake rhythm in his/her normal home environment, and at a much lower cost than PSG. Future studies in specific pathologies would verify the relevance of TAP in those conditions.

The characterization of biological rhythms in mild cognitive impairment.

INTRODUCTION: Patients with dementia, especially Alzheimer's disease, present several circadian impairments related to an accelerated perturbation of their biological clock that is caused by the illness itself and not merely age-related. Thus, the objective of this work was to elucidate whether these circadian system alterations were already present in patients with mild cognitive impairment (MCI), as compared to healthy age-matched subjects. METHODS: 40 subjects (21 patients diagnosed with MCI, 74.1 ± 1.5 y.o., and 19 healthy subjects, 71.7 ± 1.4 y.o.) were subjected to ambulatory monitoring, recording wrist skin temperature, motor activity, body position, and the integrated variable TAP (including temperature, activity, and position) for one week. Nonparametrical analyses were then applied. RESULTS: MCI patients exhibited a significant phase advance with respect to the healthy group for the following phase markers: temperature M5 (mean ± SEM: 04:20 ± 00:21 versus 02:52 ± 00:21) and L10 (14:35 ± 00:27 versus 13:24 ± 00:16) and TAP L5 (04:18 ± 00:14 versus 02:55 ± 00:30) and M10 (14:30 ± 00:18 versus 13:28 ± 00:23). CONCLUSIONS: These results suggest that significant advances in the biological clock begin to occur in MCI patients, evidenced by an accelerated aging of the circadian clock, as compared to a healthy population of the same age.

Uncovering different masking factors on wrist skin temperature rhythm in free-living subjects.

Most circadian rhythms are controlled by a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. However, these variables are susceptible to masking effects as the result of activity, body position, light exposure, environmental temperature and sleep. Recently, wrist skin temperature (WT) has been proposed as a new index for evaluating circadian system status. In light of previous evidence suggesting the important relationship between WT and core body temperature regulation, the aim of this work was to purify the WT pattern in order to obtain its endogenous rhythm with the application of multiple demasking procedures. To this end, 103 subjects (18-24 years old) were recruited and their WT, activity, body position, light exposure, environmental temperature and sleep were recorded under free-living conditions for 1 week. WT demasking by categories or intercepts was applied to simulate a "constant routine" protocol (awakening, dim light, recumbent position, low activity and warm environmental temperature). Although the overall circadian pattern of WT was similar regardless of the masking effects, its amplitude was the rhythmic parameter most affected by environmental conditions. The acrophase and mesor were determined to be the most robust parameters for characterizing this rhythm. In addition, a circadian modulation of the masking effect was found for each masking variable. WT rhythm exhibits a strong endogenous component, despite the existence of multiple external influences. This was evidenced by simultaneously eliminating the influence of activity, body position, light exposure, environmental temperature and sleep. We therefore propose that it could be considered a valuable and minimally-invasive means of recording circadian physiology in ambulatory conditions.

[Chronodisruption and ageing]. / La cronodisrupción como causa de envejecimiento.

Modern life leads to a more active nocturnal lifestyle, reduced sleep hours and sometimes abrupt shifts across time zones (such as jet lag and shift work) that generate chronodisruption (CD) which can result in premature ageing. CD is defined as a significant disturbance of the internal temporal order of biochemical, physiological and behavioural circadian rhythms. Epidemiological studies show that CD induced by shift work, chronic jet lag, social jet lag and excessive exposure of bright light at night is associated with an increased incidence of metabolic syndrome, cardiovascular disease, cognitive and affective impairment, sleep disorders, some cancers and premature ageing. CD may be the result of disturbances in different components of the circadian system (central pacemaker and peripheral oscillators, inputs to central clock, mainly due to visual deficiencies, and output signals from the pacemaker and oscillators). Exposure to different synchronizers (light, meal times, physical and social activities) with a regular pattern results in a chronoenhacement that can prevent age-related CD.

Crosstalk between environmental light and internal time in humans.

Daily exposure to environmental light is the most important zeitgeber in humans, and all studied characteristics of light pattern (timing, intensity, rate of change, duration, and spectrum) influence the circadian system. However, and due to lack of current studies on environmental light exposure and its influence on the circadian system, the aim of this work is to determine the characteristics of a naturalistic regimen of light exposure and its relationship with the functioning of the human circadian system. Eighty-eight undergraduate students (18-23 yrs) were recruited in Murcia, Spain (latitude 38°01'N) to record wrist temperature (WT), light exposure, and sleep for 1 wk under free-living conditions. Light-exposure timing, rate of change, regularity, intensity, and contrast were calculated, and their effects on the sleep pattern and WT rhythm were then analyzed. In general, higher values for interdaily stability, relative amplitude, mean morning light, and light quality index (LQI) correlated with higher interdaily stability and relative amplitude, and phase advance in sleep plus greater stability in WT and phase advance of the WT circadian rhythm. On the other hand, a higher fragmentation of the light-exposure rhythm was associated with more fragmented sleep. Naturalistic studies using 24-h ambulatory light monitoring provide essential information about the main circadian system input, necessary for maintaining healthy circadian tuning. Correcting light-exposure patterns accordingly may help prevent or even reverse health problems associated with circadian disruption.

Influencia de la exposición a la luz sobre el sistema circadiano / No disponible

Introducción: El sincronizador más importante del sistema circadiano humano es la alternancia de luzoscuridad con un periodo de 24 horas. Los estudios en laboratorio han demostrado que todas las características de la exposición a la luz estudiadas (momento de exposición, intensidad, duración y espectro) son importantes en cuanto a su influencia sobre el sistema circadiano (SC). Sin embargo, poco se conoce acerca de la influencia del ciclo luz-oscuridad sobre el SC, en general, y sobre el ritmo de sueño-vigilia, en particular, en sujetos monitorizados de forma no-invasiva y ambulatoria. Objetivos: El objetivo de este trabajo ha sido el de determinar las características del régimen de exposición a la luz y su relación con el ritmo de sueño-vigilia y el funcionamiento del SC en sujetos monitorizados ambulatoriamente. Materiales y Métodos: Para ello, 88 voluntarios de entre 18 a 23 años, todos ellos estudiantes universitarios residentes en Murcia, fueron monitorizados ambulatoriamente durante una semana registrando temperatura periférica (TP), exposición a la luz y patrón de sueño en condiciones de vida normal. Se analizaron diferentes características del patrón de iluminación y sus efectos sobre TP y sueño. Resultados: En general, un patrón de exposición a la luz fragmentado se refleja en una mayor fragmentación en el ritmo de sueño. Además, un ritmo de exposición a la luz estable, amplio, con mayor intensidad luminosa durante la mañana y un mejor índice de calidad de la luz, producen mayor estabilidad y avance de fase en los ritmos de sueño-vigilia y de temperatura periférica. Conclusiones: La monitorización ambulatoria de la exposición a la luz proporciona una información esencial sobre el principal sincronizador del SC, que puede ser utilizada para prevenir y/o corregir problemas de salud relacionados con la disrupción circadiana (AU)

Introduction: The most important zeitgeber for the human circadian system is the alternation of light and darkness in a 24 hr period. Laboratory studies showed that all light characteristics (timing, intensity, duration and spectrum) strongly influence the circadian system (CS). However, little is known about the influence of light-dark cycle on CS and sleep-wake rhythm in subjects monitored under ambulatory conditions. Objectives: The objective of this work was to determine the characteristics of a naturalistic regime of light exposure and its relationship with the sleep-wake rhythm and the functioning of the human circadian system under ambulatory conditions. Materials and Methods: With this aim, 88 undergraduate volunteer students (18-23 years old) living in Murcia were ambulatory monitored for 1 week, recording wrist temperature (WT), light exposure and sleep pattern under free-living conditions. Different light pattern characteristics and their effects on WT and sleep were analysed. Results: In general, a more fragmented light exposure pattern provokes sleep fragmentation. In addition, light exposure rhythms that are more stable, robust, with higher light intensity during the morning and a better light quality index produce more stability and phase advances in sleep and WT. Conclusions: Ambulatory monitoring of light exposure provides essential information about the main circadian system input; it may be used to prevent or reverse health problems associated with circadian disruption (AU)

La cronodisrupción como causa de envejecimiento / Chronodisruption and ageing

La sociedad actual favorece un modo de vida con mayor actividad nocturna, disminución de las horas de sueño y, en ocasiones, desplazamientos horarios (tales como jet lag o trabajo a turnos) que generan cronodisrupción (CD), la cual puede conducir a un envejecimiento prematuro. La CD se define como una alteración relevante del orden temporal interno de los ritmos circadianos bioquímicos, fisiológicos y de comportamiento. Estudios epidemiológicos muestran una relación entre la CD y el aumento en la incidencia de síndrome metabólico, enfermedades cardiovasculares, deterioro cognitivo, trastornos afectivos, alteraciones del sueño, algunos tipos de cáncer y envejecimiento acelerado. La CD puede ser el resultado de alteraciones en los distintos componentes del sistema circadiano (marcapasos central y osciladores periféricos, entradas al reloj, principalmente debidas a defectos de la visión, y salidas del marcapasos y osciladores). La exposición a diferentes sincronizadores (luz, actividad física y social, alimentación) de manera regular robustece el funcionamiento del sistema circadiano mediante la cronopotenciación, que puede atenuar la CD asociada al envejecimiento(AU)

Modern life leads to a more active nocturnal lifestyle, reduced sleep hours and sometimes abrupt shifts across time zones (such as jet lag and shift work) that generate chronodisruption (CD) which can result in premature ageing. CD is defined as a significant disturbance of the internal temporal order of biochemical, physiological and behavioural circadian rhythms. Epidemiological studies show that CD induced by shift work, chronic jet lag, social jet lag and excessive exposure of bright light at night is associated with an increased incidence of metabolic syndrome, cardiovascular disease, cognitive and affective impairment, sleep disorders, some cancers and premature ageing. CD may be the result of disturbances in different components of the circadian system (central pacemaker and peripheral oscillators, inputs to central clock, mainly due to visual deficiencies, and output signals from the pacemaker and oscillators). Exposure to different synchronizers (light, meal times, physical and social activities) with a regular pattern results in a chronoenhacement that can prevent age-related CD(AU)