Elisabet Ortiz-Tudela

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.

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. (Author correspondence: angerol@um.es)

Cancer Chronotherapeutics: Experimental, Theoretical, and Clinical Aspects

The circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single-agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.

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

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.

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 patients 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 Alzheimers 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.

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.