Rest Activity Research Articles

Rest-activity rhythms and white matter microstructure across the lifespan.

The purpose of this study was to examine how rest-activity (RA) rhythm stability may be associated with white matter microstructure across the lifespan in healthy adults free of significant cardiovascular risk. We analyzed multi-shell diffusion tensor images from 103 healthy young and older adults using tract-based spatial statistics (TBSS) to examine relationships between white matter microstructure and RA rhythm stability. RA measures were computed using both cosinor and non-parametric methods derived from 7 days of actigraphy data. Fractional anisotropy (FA) and mean diffusivity (MD) were examined in this analysis. Because prior studies have suggested that the corpus callosum (CC) is sensitive to sleep physiology and RA rhythms, we also conducted a focused region of interest analysis on the CC. Greater rest-activity rhythm stability was associated with greater FA across both young and older adults, primarily in the CC and anterior corona radiata. This effect was not moderated by age group. While RA measures were associated with sleep metrics, RA rhythm measures uniquely accounted for the variance in white matter integrity. This study strengthens existing evidence for a relationship between brain white matter structure and RA rhythm stability in the absence of health risk factors. While there are differences in RA stability between age groups, the relationship with brain white matter was present across both young and older adults. RA rhythms may be a useful biomarker of brain health across both periods of adult development.

Characteristics of circadian rhythms in rest-activity and energy expendi-ture in cancer in-patients

The objective of the current study was to assess the rest-activity (RA) and energy expenditure (EE) rhythms in cancer in-patients. Twenty chemothera-py receiving cancer in-patients (10 males and 10 females) and ten apparently healthy human subjects (5 males and 5 females) wore a non-invasive elec-tronic device – the Actical on their non dominant wrist. Data were recorded at 1-minute epoch for at least 3-4 consecutive days. Significant differences in RA and EE patterns were observed between cancer in-patients and control subjects, irrespective of gender. Control subjects showed absolute rhythm detection ratio in RA and EE, whereas, ratio was of low magnitude in cancer patients, especially with reference to EE. Statistically significant decrement in circadian amplitudes and advancement in circadian peaks of RA and EE were observed in cancer in-patients as compared to control subjects. Significant independent effects of factors, namely ‘disease’ and ‘gender’ on total activity count (TAC), average activity count (AAC), total energy expenditure (TEE) and average energy expenditure (AEE) were observed. TEE and AEE were signifi-cantly lower in cancer in-patients as compared to control subjects. Further, factors, ‘disease’ and ‘gender’ also produced significant effects on activity energy expenditure (AcEE), metabolic energy expenditure (MET) and resting energy expenditure (REE). In conclusion, the findings indicate disruption of the circadian rhythms in rest-activity and energy expenditure in cancer in-patients. This disruption is gauged from alterations in rhythm characteristics of RA and EE. However, additional studies involving more patients are re-quired for further validation of the present findings.

Daily rhythms of native Brazilians in summer and winter

Access to electricity, granting relative independence of human activity on the dark phase of the day, has been pointed out as an important cause for the absence of seasonal changes in the daily rhythms of humans living in urban areas. Featuring a population of adult Guarani natives living without access to electricity, the present naturalistic study was designed to explore possible effects of different natural photoperiods and temperature on human circadian rhythms. We compared time series of wrist temperature (WT) and motor activity in winter and summer, respectively, of 24 individuals aged 18 to 80. Twenty-four-hour rhythms of WT showed lower amplitudes and higher mean levels in summer, with no significant seasonal differences in acrophase. In contrast, rest-activity (RA) rhythms exhibited a significantly later rest on- and offset in summer, but no seasonal changes in duration, amplitude and mean level. We furthermore identified a phase advance of both the WT acrophase and rest onset with increasing age of the individuals. We concluded that in our study the effect of different seasons was reflected in the amplitude and mean level of the WT rhythm, as well the onset of nighttime rest, which was delayed in summer.

Relevance of circadian coordination for the outcome of patients with advanced gastro-intestinal (GI) cancer

15043 Background: Experimental cancer progression is controlled by the circadian timing system whose function can be assessed through non-invasive continuous rest-activity (RA) monitoring. Here, we investigated the relevance of I<O, a critical RA rhythm parameter that compares the relative amounts of activity in bed (I) and out of bed (O), for predicting tumor response, progression-free survival (PFS) and overall survival (OS) in an international cohort of 584 cancer patients (pts). Methods: RA rhythm was monitored for ≥ 48 h using a wrist-worn accelerometer (Ambulatory Monitoring Inc., Ardsley, NY, USA) before chemotherapy delivery (12 centers in 4 countries). A comprehensive database was constructed including pts history and characteristics, treatment received, its tolerability and efficacy. Main items were verified in pt charts and updated for 372 GI pts. This process is ongoing for the remaining pts. Univariate and multivariate analyses (SPSS 15.0) determined the relationship between I<O (range: 50%, no rhythm; 100%, marked rhythm) and pt characteristics, tumor response, PFS and OS. Results: Pts characteristics: 198 men, 174 women; median age, 58.4 y (range: 21–79); WHO performance status 0/1/2, 210/133/29 pts; colon/rectum/other, 260/103/9 pts; 1/2/3 metastatic sites, 164/151/55 pts; % liver involvement, none/≤25%/>25%, 68/158/141 pts; prior chemotherapy, 152 pts. Median I<O at baseline was 97.3 [25th-75th percentile, 93.7 - 99.2]. Chronotherapy was given to 280 pts. A good RA circadian rhythm (I<O above median) predicted for better response (partial + complete: 42.1 vs 30.5%, p = 0.026), median PFS (6.5 vs 4.5 months, p = 0.009) and OS (18 vs 11 months, p < 0.0001). Multivariate analyses confirmed that I<O was an independent prognostic factor (p<0.001) for treatment response jointly with gender (p=0.011) and for PFS and OS jointly with performance status (p = 0.001), number of metastatic sites (p <0.002) and prior chemotherapy (p < 0.015). Conclusions: Pts with metastatic GI cancer achieve better clinical outcome on treatment if their baseline circadian rhythm in rest-activity is maintained. Therapeutics targeted at clock genes or circadian signalling pathways deserve testing for improving the outcome of pts with circadian disruption. No significant financial relationships to disclose.

Lesions of suprachiasmatic nucleus efferents selectively affect rest-activity rhythm

The suprachiasmatic nucleus (SCN) of the hypothalamus controls circadian rhythms in behavioral, neuroendocrine and physiological functions. In this study, we test the hypothesis that caudal SCN efferents to the subparaventricular zone (SPVZ) control the rhythm in rest-activity (R-A) through projections on posterior hypothalamic area arousal systems (PHA). Small electrolytic lesions of the ventral SPVZ cause a selective loss of the circadian R-A rhythm, sparing the core body temperature rhythm. In contrast, large excitotoxic lesions of the posterior hypothalamic area (PHA) that effectively ablate populations of hypocretin and melanin concentrating hormone neurons projecting to cortex and subcortical arousal areas decrease R-A rhythm amplitude but do not disrupt circadian regulation. Since dorsomedial hypothalamic nucleus lesions have effects similar to PHA lesions (Chou, T.C., Scammell, T.E., Gooley, J.J., Gaus, S.E., Saper, C.B., Lu, J., 2003. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J. Neurosci. 23:10691–10702), these data support the view that the SPVZ is the principal relay nucleus for SCN signals to the multiple posterior hypothalamic arousal systems involved in generation of the R-A rhythm.

High serum TGFα, TNFα and IL6 correlate with abnormal circadian rhythms in patients with metastatic colorectal cancer (MCC)

9650 Background: Poor quality of life and poor survival of cancer patients were independently predicted by an alteration of the rest-activity (RA) and/or cortisol circadian rhythms. This disturbance could be mediated by high levels of tumor- or host- derived growth factors, known to modulate circadian clock function.Methods: TGFα, TNFα and IL6 levels were determined with ELISA in sera from 80 MCC patients whose rhythms in RA (wrist actimetry for 3 d) and cortisol (serum drawn at 08:00 and 16:00 ) were prospectively studied (Mormont et al. Clin Cancer Res 2000). The samples were selected from patients having rhythmic (group 1, n=40) or damped (group 2, n=40) RA pattern, as assessed with autocorrelation for a period of 24 h (r24). Groups were compared with Kruskall-Wallis test. Correlations between factor concentrations and circadian parameters were explored with Spearman ρ test.Results: Median RA r24 were 0.56 (range, 0.47 to 0.77) in group 1 and 0.22 (0.03 to 0.35) in group 2 (p < 0.0001). Median cortisol ratio (value at 08:00 / value at 16:00 ± quartile) were 1.72 [1.48 - 1.98] and 1.60 [1.14 - 1.77] respectively (p = 0.031). Median (± quartile) dichotomy index (I<O), an integrated estimate of RA pattern and sleep quality, was 98.5 % [97.0 - 99.7] in group 1 and 91.4 % [82.1 - 96.7] in group 2 (p < 0.0001). TGFα, TNFα and IL6 serum levels (pg/ml) were significantly lower in group 1 as compared to group 2 (Table) and negatively correlated with I<O (r = - 0.45, p < 0.0001; r = -0.27, p = 0.022; r = -0.37, p = 0.001, respectively). IL6 levels were also negatively correlated with cortisol rhythm estimate (r = - 0.31, p = 0.005). Conclusions: Altered circadian function was associated with increased production of cancer-derived growth factors, suggesting a mechanism through which a tumor can promote its own development via the disturbance of host physiology. Supported by: ARTBC; J W Sieg fund. No significant financial relationships to disclose.

Inhibitory effect of cyclic guanosine 3′,5′-monophosphate (cGMP) on the afferent resting activity in the cephalopod statocyst

The effects of exo- and endogenous cGMP on the resting activity (RA) of afferent crista fibers were studied in isolated preparations of the statocysts of the cuttlefish Sepia officinalis and the squid Sepioteuthis lessoniana. Bath application of the membrane-permeable cGMP analogs 8-bromo-cGMP (B-cGMP) and N 2,2′- o-dibutyryl 3′,5′-cyclic guanosine monophosphate (dB-cGMP), and of the selective inhibitor of cGMP-phosphodiesterase zaprinast (ZAP), caused an inhibition of RA. The inhibitory effects of B-cGMP and dB-cGMP remained when the preparation was pre-treated with: (i) the guanylate cyclase inhibitors 1 H-[1,2,4]oxadiazolo[4,3,- a]quinoxalin-1-one (ODQ) or cystamine (CYS); (ii) the adenylate cyclase inhibitors nicotinic acid (NIC-A), 2′,3′dideoxyadenosine (DDA), or MDL-12330A (MDL); (iii) the guanylate cyclase inhibitor methylene blue (M-BLU) and the adenylate cyclase inhibitor MDL combined; or (iv) the nitric oxide (NO) synthase inhibitors N G-nitric- l-arginine methyl ester HCl ( l-NAME) or N G-nitro- l-arginine ( l-NOARG). These data indicate that cGMP, as an intracellular messenger, has a tonic inhibitory effect on the RA of afferent crista fibers in cephalopod statocysts.

Effects of nitric oxide donors on the afferent resting activity in the cephalopod statocyst

The effects of bath applications of the nitric oxide (NO) donors sodium nitroprusside (SNP), diethylamine sodium (DEA), 3-morpholinosydnonimine (SIN-1), and S-nitroso- N-acetyl-penicillamine (SNAP) on the resting activity (RA) of afferent crista fibers were studied in isolated statocysts of the cuttlefish Sepia officinalis. The NO donors had three different effects: inhibition, excitation, and excitation followed by an inhibition. The SNAP analog N-acetyl- dl-penicillamine (xSNAP; with no NO moiety) had no effect. When the preparation was pre-treated with the NO synthase inhibitor N G -nitric- l-arginine methyl ester HCl ( l-NAME), the NO donors were still effective. When the preparation was pre-treated with the guanylate cyclase inhibitors methylene blue (M-BLU) or cystamine (CYS), NO donors had only excitatory effects, whereas their effects were inhibitory only when pre-treatment was with the adenylate cyclase inhibitors nicotinic acid (NIC-A), 2′,3′-dideoxyadenosine (DDA), or MDL-12330A. When pre-treatment was with a guanylate and an adenylate cyclase inhibitor combined, NO donors had no effect; in that situation, the RA of the afferent fibers remained and the preparation still responded to bath applications of GABA. Selective experiments with statocysts from the squid Sepioteuthis lessoniana and the octopod Octopus vulgaris gave comparable results. These data indicate that in cephalopod statocysts an inhibitory NO–cGMP and an excitatory NO–cAMP signal transduction pathway exist, that these two pathways are the key pathways for the action of NO, and that they have only modulatory effects on, and are not essential for the generation of, the RA.

Effects of l-arginine on the afferent resting activity in the cephalopod statocyst

The effects of bath application of the nitric oxide (NO) precursor l-arginine ( l-ARG) on the resting activity (RA) of afferent crista fibers were studied in isolated statocysts of the cuttlefish Sepia officinalis under various experimental conditions. l-ARG (threshold 10 −7 M) had three different effects: inhibition, excitation, and excitation followed by an inhibition; only the inhibitory effect of l-ARG was dose-dependent. d-Arginine ( d-ARG) had no effect. When the preparation was pre-treated with NO synthase inhibitors ( N G-Nitric- l-arginine methyl ester HCl ( l-NAME), N G-Nitro- l-arginine ( l-NOARG)), both the inhibitory and the excitatory effects of l-ARG significantly decreased at higher concentrations (10 −5 to −4 M), or were completely blocked at lower concentrations (10 −7 to −6 M), of l-ARG. When the preparation was pre-treated with guanylate cyclase inhibitors (1 H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), methylene blue (M-BLU), cystamine (CYS)), l-ARG had only excitatory effects, whereas its effects were only inhibitory when the preparation was pre-treated with adenylate cyclase inhibitors 2′,3′-dideoxyadenosine (DDA), MDL-12330A (MDL), nicotinic acid (NIC-A)). l-ARG had no effects when the pre-treatment was with a guanylate cyclase inhibitor and an adenylate cyclase inhibitor combined; in that situation, the RA of the afferent fibers remained. These data indicate that in cephalopod statocysts, a cGMP and a cAMP signal transduction pathway (presumably via the generation of NO) are responsible for the effects of l-ARG on the RA of crista afferent fibers. They also indicate that the l-ARG–cGMP pathway is the dominant pathway and is inhibitory, and that both pathways have only modulatory effects on, but are not essential for, the generation of the RA.

Randomized, DIM Light Controlled, Crossover test of Morning Bright Light Therapy for Rest-Activity Rhythm Disorders in Patients with Vascular Dementia and Dementia of Alzheimer's type

The authors compared the therapeutic effect of morning bright and dim light exposure on rest-activity (R-A) rhythm disorders in patients with vascular dementia (VD) and patients with dementia of Alzheimer's type (DAT). Participants in this study were 12 patients with VD (M/F = 5/7; average age = 81 years) and 10 patients with DAT (M/F = 4/6; average age = 78 years). They were exposed to 2 weeks of bright light (BL; 5000-8000 lux) and 2 weeks of dim light (DL; 300 lux) in the morning (09:00-11:00) in a randomized crossover design in which the 2-week treatment period took place between pretreatment (1 week) and posttreatment (1 week) periods. Continuous R-A monitoring was performed at 1-minute intervals throughout the study using an actigraph around the nondominant wrist. The BL exposure for 2 weeks induced a significant reduction in both nighttime activity and percentages of nighttime activity to total activity compared with the pretreatment period, as well as compared with the DL condition in the VD group, but not in the DAT group. These findings support the assumption that the therapeutic efficacies of morning BL exposure are prominent in VD patients and are mainly due to its photic effect rather than nonphotic effects such as the intensification of social interaction accompanying light therapy. (Chronobiology International, 15(6), 647-654, 1998)

Different manifestations of circadian rhythms in senile dementia of Alzheimer's type and multi-infarct dementia

Using an actigraph and a long-term body temperature (BT) monitoring system, we simultaneously monitored rest-activity (R-A) and BT rhythms in patients with senile dementia of Alzheimer's type (SDAT; n = 20) or multi-infarct dementia (MID; n = 21) for 5–7 consecutive days. The SDAT group exhibited a well-organized BT rhythm with significantly higher amplitude compared with the MID group. The SDAT group also showed significant positive correlation between the total daily activity as well as percentage of nighttime activity and the degree of dementia, while no such tendency was observed in the MID group. The different properties of the biological rhythm disorders among the SDAT and MID groups possibly underlie their sleep and behavioral disorders.