Efficacy of early warning signals and spectral periodicity for predicting transitions in bipolar patients: An actigraphy study.

Early-warning signals (EWS) have been successfully employed to predict transitions in research fields such as biology, ecology, and psychiatry. The predictive properties of EWS might aid in foreseeing transitions in mood episodes (i.e. recurrent episodes of mania and depression) in bipolar disorder (BD) patients. We analyzed actigraphy data assessed during normal daily life to investigate the feasibility of using EWS to predict mood transitions in bipolar patients. Actigraphy data of 15 patients diagnosed with BD Type I collected continuously for 180 days were used. Our final sample included eight patients that experienced a mood episode, three manic episodes and five depressed episodes. Actigraphy data derived generic EWS (variance and kurtosis) and context-driven EWS (autocorrelation at lag-720) were used to determine if these were associated to upcoming bipolar episodes. Spectral analysis was used to predict changes in the periodicity of the sleep/wake cycle. The study procedures were pre-registered. Results indicated that in seven out of eight patients at least one of the EWS did show a significant change-up till four weeks before episode onset. For the generic EWS the direction of change was always in the expected direction, whereas for the context-driven EWS the observed effect was often in the direction opposite of what was expected. The actigraphy data derived EWS and spectral analysis showed promise for the prediction of upcoming transitions in mood episodes in bipolar patients. Further studies into false positive rates are suggested to improve effectiveness for EWS to identify upcoming bipolar episode onsets.

Fractal biomarker of activity in patients with bipolar disorder.

BACKGROUND: The output of many healthy physiological systems displays fractal fluctuations with self-similar temporal structures. Altered fractal patterns are associated with pathological conditions. There is evidence that patients with bipolar disorder have altered daily behaviors. METHODS: To test whether fractal patterns in motor activity are altered in patients with bipolar disorder, we analyzed 2-week actigraphy data collected from 106 patients with bipolar disorder type I in a euthymic state, 73 unaffected siblings of patients, and 76 controls. To examine the link between fractal patterns and symptoms, we analyzed 180-day actigraphy and mood symptom data that were simultaneously collected from 14 patients. RESULTS: Compared to controls, patients showed excessive regularity in motor activity fluctuations at small time scales (<1.5 h) as quantified by a larger scaling exponent (α1 > 1), indicating a more rigid motor control system. α1 values of siblings were between those of patients and controls. Further examinations revealed that the group differences in α1 were only significant in females. Sex also affected the group differences in fractal patterns at larger time scales (>2 h) as quantified by scaling exponent α2. Specifically, female patients and siblings had a smaller α2 compared to female controls, indicating more random activity fluctuations; while male patients had a larger α2 compared to male controls. Interestingly, a higher weekly depression score was associated with a lower α1 in the subsequent week. CONCLUSIONS: Our results show sex- and scale-dependent alterations in fractal activity regulation in patients with bipolar disorder. The mechanisms underlying the alterations are yet to be determined.

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology.

AIMS: To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. METHODS: PRISMA-based systematic review of the literature. RESULTS: The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. CONCLUSIONS: The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

The characteristics of psychotic features in bipolar disorder.

BACKGROUND: In a large and comprehensively assessed sample of patients with bipolar disorder type I (BDI), we investigated the prevalence of psychotic features and their relationship with life course, demographic, clinical, and cognitive characteristics. We hypothesized that groups of psychotic symptoms (Schneiderian, mood incongruent, thought disorder, delusions, and hallucinations) have distinct relations to risk factors. METHODS: In a cross-sectional study of 1342 BDI patients, comprehensive demographical and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV (SCID-I) interview. In addition, levels of childhood maltreatment and intelligence quotient (IQ) were assessed. The relationships between these characteristics and psychotic symptoms were analyzed using multiple general linear models. RESULTS: A lifetime history of psychotic symptoms was present in 73.8% of BDI patients and included delusions in 68.9% of patients and hallucinations in 42.6%. Patients with psychotic symptoms showed a significant younger age of disease onset (ß = -0.09, t = -3.38, p = 0.001) and a higher number of hospitalizations for manic episodes (F11 338 = 56.53, p < 0.001). Total IQ was comparable between groups. Patients with hallucinations had significant higher levels of childhood maltreatment (ß = 0.09, t = 3.04, p = 0.002). CONCLUSIONS: In this large cohort of BDI patients, the vast majority of patients had experienced psychotic symptoms. Psychotic symptoms in BDI were associated with an earlier disease onset and more frequent hospitalizations particularly for manic episodes. The study emphasizes the strength of the relation between childhood maltreatment and hallucinations but did not identify distinct subgroups based on psychotic features and instead reported of a large heterogeneity of psychotic symptoms in BD.

Social jetlag and depression status: Results obtained from the Netherlands Study of Depression and Anxiety.

Social jetlag, the misalignment between the internal clock and the socially required timing of activities, is highly prevalent, especially in people with an evening chronotype and is hypothesized to be related to the link between the evening chronotype and major depressive disorder. Although social jetlag has been linked to depressive symptoms in non-clinical samples, it has never been studied in patients with major depressive disorder (MDD). This study is aimed to study social jetlag in patients with major depressive disorder and healthy controls, and to further examine the link between social jetlag and depressive symptomatology. Patients with a diagnosis of MDD (n = 1084) and healthy controls (n = 385), assessed in a clinical interview, were selected from the Netherlands Study of Depression and Anxiety. Social jetlag was derived from the Munich Chronotype Questionnaire, by calculating the absolute difference between the midsleep on free days and midsleep on work days. Depression severity was measured with the Inventory of Depressive Symptomatology. It was found that patients with MDD did not show more social jetlag compared to healthy controls, neither in a model without medication use (ß = 0.06, 95% CI: -0.03-0.15, p = 0.17) nor in a model where medication use is accounted for. There was no direct association between the amount of social jetlag and depressive symptoms, neither in the full sample, nor in the patient group or the healthy control group. This first study on social jetlag in a clinical sample showed no differences in social jetlag between patients with MDD and healthy controls.

The dysregulated brain: consequences of spatial and temporal brain complexity for bipolar disorder pathophysiology and diagnosis.

Increasingly, evidence has been accumulating emphasizing the importance of looking at bipolar disorder (BD) from a neurodevelopmental and transdimensional perspective to better understand its origins and its course. In this overview article, the problems facing pathophysiological psychiatric research in BD are addressed and interpreted in the light of brain complexity. Brain complexity can be split into spatial complexity, which constitutes the physiological levels of the central nervous system (i.e., the genetic, molecular, cellular, neuronal circuit and phenomenological levels), and temporal complexity, that is, neurodevelopment. The consequences of this consideration are discussed and suggestions for clinical practice and pathophysiological psychiatric research are made.

Coping with a life event in bipolar disorder: ambulatory measurement, signalling and early treatment.

Disruption of the biological rhythm in patients with bipolar disorder is a known risk factor for a switch in mood. This case study describes how modern techniques using ambulatory assessment of sleep parameters can help in signalling a mood switch and start early treatment. We studied a 40-year-old woman with bipolar disorder experiencing a life event while wearing an actigraph to measure sleep-wake parameters. The night after the life event the woman had sleep later and shorter sleep duration. Adequate response of both the woman and the treating psychiatrist resulted in two normal nights with the use of 1 mg lorazepam, possibly preventing further mood disturbances. Ambulatory assessment of the biological rhythm can function as an add-on to regular signalling plans for prevention of episodes in patients with bipolar disorder. More research should be conducted to validate clinical applicability, proper protocols and to understand underlying mechanisms.

Does CRP predict outcome in bipolar disorder in regular outpatient care?

BACKGROUND: The association between inflammation and the course of mood disorders is receiving increased attention. This study aims to investigate whether a sub-group of patients with BD can be identified for which a higher CRP (C-reactive protein) level at baseline is associated with an unfavorable prognosis. METHODS: This is a historic cohort study using CRP at baseline, with 15-month follow-up of mood status and medication. Cross-sectional analyses include boxplots, one-way ANOVA, receiver operating characteristics (ROC) curve and Chi square test, and the longitudinal analysis using multivariate Cox-regression. RESULTS: Eighty-four bipolar disorder patients were included in the analyses. Cross-sectionally, no statistically significant difference was found in CRP distribution across mood states (p = 0.372) or rapid cycling state (p = 0.656). Also, no CRP cut-off level was distinguished between euthymic and non-euthymic patients according to the ROC curve (p = 0.449, AUC = 0.452, 95 % CI 0.327, 0.576), and a literature-derived cut-off value (3 mg/L) again demonstrated no difference (p = 0.530). Longitudinally, no association was found between CRP and prognosis of disease neither in euthymic [-2 log likelihood = 120.460; CRP: p = 0.866, B = -0.011, OR = 0.989 (95 % CI 0.874-1.120)] nor non-euthymic patients [(-2 log likelihood = 275.028; CRP: p = 0.802, B = 0.010, OR = 1.010 (95 % CI 0.937-1.088)]. Medication use did not affect these associations. CONCLUSIONS: We found no statistically significant association between CRP and a more unfavorable BD prognosis, suggesting that the application of CRP as a practical biomarker to predict outcome in a naturalistic outpatient care setting is not as straightforward as it may seem.

Diffusion tensor imaging in euthymic bipolar disorder - A tract-based spatial statistics study.

BACKGROUND: In the current DTI study we compared euthymic bipolar I disorder (BD-I) patients and healthy controls (HC). We subsequently divided the total patient group into lithium-users and non-lithium-users and estimated differences across the three groups. METHODS: Twenty-one euthymic BD-I patients and twenty-two HC participants were included in psychiatric interviews and MRI image acquisition (diffusion-weighted (DW) and T1-weighted scans). Fractional anisotropy (FA), radial, mean and axial diffusivity (RD, MD, AD) were estimated from the DW data, using DTI. These measures were then compared between groups using FSL Tract Based Spatial Statistics (TBSS). Correlations with age at onset, number of episodes and depression score were analyzed. RESULTS: A difference in FA, MD, RD and AD between the whole sample of euthymic BD-I patients and healthy controls could not be detected. Amongst others, lithium-using patients demonstrated a higher FA and lower RD when compared to non-lithium-using BD-I patients in the corpus callosum and left anterior corona radiata. Widespread clusters demonstrated negative FA associations and positive RD and MD associations with minor depressive symptoms. LIMITATIONS: Patients were naturalistically treated. Although the sample size is comparable to several other DTI studies, a larger sample size would have been benificial. TBSS and DTI have their own limitations. CONCLUSION: Our findings support the theory that previously described DTI-based microstructural differences between HC and BD patients could be less pronounced in euthymic BD patients. Differences in FA between patients using and not using lithium suggest a counteracting effect of lithium on white matter microstructural disturbances.

Progression of Dementia Assessed by Temporal Correlations of Physical Activity: Results From a 3.5-Year, Longitudinal Randomized Controlled Trial.

Cross-sectional studies show that activity fluctuations in healthy young adults possess robust temporal correlations that become altered with aging, and in dementia and depression. This study was designed to test whether or not within-subject changes of activity correlations (i) track the clinical progression of dementia, (ii) reflect the alterations of depression symptoms in patients with dementia, and (iii) can be manipulated by clinical interventions aimed at stabilizing circadian rhythmicity and improving sleep in dementia, namely timed bright light therapy and melatonin supplementation. We examined 144 patients with dementia (70-96 years old) who were assigned to daily treatment with bright light, bedtime melatonin, both or placebos only in a 3.5-year double-blinded randomized clinical trial. We found that activity correlations at temporal scales <~2 hours significantly decreased over time and that light treatment attenuated the decrease by ~73%. Moreover, the decrease of temporal activity correlations positively correlated with the degrees of cognitive decline and worsening of mood though the associations were relatively weak. These results suggest a mechanistic link between multiscale activity regulation and circadian/sleep function in dementia patients. Whether temporal activity patterns allow unobtrusive, long-term monitoring of dementia progression and mood changes is worth further investigation.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder - A combined magnetic resonance imaging and positron emission tomography study.

BACKGROUND: The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. MATERIALS AND METHODS: Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [(11)C]-(R)-PK11195 neuroinflammation positron emission tomography scan. RESULTS: In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. CONCLUSION: Compared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

Feature-expression heat maps--a new visual method to explore complex associations between two variable sets.

INTRODUCTION: Existing methods such as correlation plots and cluster heat maps are insufficient in the visual exploration of multiple associations between genetics and phenotype, which is of importance to achieve a better understanding of the pathophysiology of psychiatric and other illnesses. The implementation of a combined presentation of effect size and statistical significance in a graphical method, added to the ordering of the variables based on the effect-ordered data display principle was deemed useful by the authors to facilitate in the process of recognizing meaningful patterns in these associations. MATERIALS AND METHODS: The requirements, analyses and graphical presentation of the feature-expression heat map are described. The graphs display associations of two sets of ordered variables where a one-way direction is assumed. The associations are depicted as circles representing a combination of effect size (color) and statistical significance (radius). RESULTS: An example dataset is presented and relation to other methods, limitations, areas of application and possible future enhancements are discussed. CONCLUSION: The feature-expression heat map is a useful graphical instrument to explore associations in complex biological systems where one-way direction is assumed, such as genotype-phenotype pathophysiological models.

Neuroinflammation in bipolar disorder - A [(11)C]-(R)-PK11195 positron emission tomography study.

BACKGROUND: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [(11)C]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [(11)C]-(R)-PK11195 binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls. MATERIAL AND METHODS: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [(11)C]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a two-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input. RESULTS: A significantly increased [(11)C]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45-1.91) versus 1.33 (CI 1.16-1.53); p=0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant. CONCLUSION: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder.

Relationship between clinical features and inflammation-related monocyte gene expression in bipolar disorder - towards a better understanding of psychoimmunological interactions.

OBJECTIVES: Existing and previously published datasets were examined for associations between illness and treatment characteristics and monocyte pro-inflammatory gene expression in patients with bipolar disorder (BD). We hypothesized a priori that increased monocyte pro-inflammatory gene expression would be found more frequently in patients with a lifetime history of psychotic symptoms. METHODS: Monocyte quantitative polymerase chain reaction and symptom data from 64 patients with BD were collected from three Dutch studies. Regression analyses were performed to analyze the various associations between pro-inflammatory gene expression and clinical features, from which feature-expression heat maps were drawn. RESULTS: No associations were found between pro-inflammatory gene expression and lifetime psychotic symptoms, whereas a positive association was identified between subcluster 2 genes and manic symptoms. For several subcluster 1a genes, a negative association was found with age at onset. For most subcluster 2 genes, a positive association was found with the duration of illness. Current use of antidepressants and of anti-epileptic agents was associated with subcluster 2 gene expression, and current use of lithium and antipsychotic agents with subcluster 1a gene expression. CONCLUSIONS: Our hypothesis that lifetime psychotic features would be associated with pro-inflammatory monocyte gene expression was not confirmed. In an explorative analysis we found: (i) a possible relationship between pro-inflammatory gene expression and manic symptomatology; (ii) a differential immune activation related to age at onset and duration of illness; and (iii) support for the concept of an immune suppressive action of some of the mood-regulating medications.

Can variation in hypothalamic-pituitary-adrenal (HPA)-axis activity explain the relationship between depression and cognition in bipolar patients?

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to be associated with more mood symptoms and worse cognitive functioning. This study examined whether variation in HPA axis activity underlies the association between mood symptoms and cognitive functioning. METHODOLOGY/PRINCIPAL FINDINGS: In 65 bipolar patients cognitive functioning was measured in domains of psychomotor speed, speed of information processing, attentional switching, verbal memory, visual memory, executive functioning and an overall mean score. Severity of depression was assessed by the Inventory of Depressive Symptomatology-self rating version. Saliva cortisol measurements were performed to calculate HPA axis indicators: cortisol awakening response, diurnal slope, the evening cortisol level and the cortisol suppression on the dexamethasone suppression test. Regression analyses of depressive symptoms and cognitive functioning on each HPA axis indicator were performed. In addition we calculated percentages explanation of the association between depressive symptoms and cognition by HPA axis indicators. Depressive symptoms were associated with dysfunction in psychomotor speed, attentional switching and the mean score, as well as with attenuation in diurnal slope value. No association was found between HPA axis activity and cognitive functioning and HPA axis activity did not explain the associations between depressive symptoms and cognition. CONCLUSIONS/SIGNIFICANCE: As our study is the first one in this field specific for bipolar patients and changes in HPA-axis activity did not seem to explain the association between severity of depressive symptoms and cognitive functioning in bipolar patients, future studies are needed to evaluate other factors that might explain this relationship.

Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial.

CONTEXT: Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms. OBJECTIVE: To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin. DESIGN, SETTING, AND PARTICIPANTS: A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia. INTERVENTIONS: Random assignment by facility to long-term daily treatment with whole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years). MAIN OUTCOME MEASURES: Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months. RESULTS: Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect). CONCLUSIONS: Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light. TRIAL REGISTRATION: controlled-trials.com/isrctn Identifier: ISRCTN93133646.

Live to the rhythm, slave to the rhythm.

Circadian rhythms in health and disease have most often been described in terms of their phases and amplitudes, and how these respond to a single exposure to stimuli denoted as zeitgebers. The present paper argues that it is also important to consider the 24-h regularity in the repeated occurrence of the zeitgebers. The effect of the regularity of stimulation by light, melatonin, physical activity, body temperature, corticosteroids and feeding on synchronization within and between the central circadian clock and peripheral oscillators is discussed. In contrast to the phase shifts that can be recorded acutely after a single zeitgeber pulse, the effects of irregularly versus regularly timed zeitgeber can be studied only in long-term protocols and may develop slowly, which is a possible reason why they have received relatively little attention. Several observations indicate a reciprocal relation between the robustness of the endogenous circadian timing system and its dependency on regularly timed zeitgebers. Especially at old age and in disease, proper functioning of the circadian timing system may become more dependent on regularly timed exposure to zeitgeber stimuli. in such conditions, regularly timed exposure to zeitgeber appears to be highly important for health. After a concise introduction on inputs to the central and peripheral oscillators of the circadian timing system, the paper discusses the responses of the circadian timing system and health to (1) a chronic lack of zeitgeber stimuli; (2) fragmented or quasi-ultradian stimuli and (3) repeated phase shifts in stimuli. Subsequently, the specific relevance to aging is discussed, followed by an overview of the effects of experimentally imposed regularly timed stimuli. Finally, a possible mechanism for the gradually evolving effects of repeated regularly timed stimuli on the circadian timing system is proposed.

Strong association of the rest-activity rhythm with well-being in demented elderly women.

OBJECTIVE: The objective of this study is to investigate the association between actigraphic estimates of the sleep-wake rhythm and a range of functional domains that contribute to well-being in demented elderly patients. METHOD: Eighty-seven women aged 85.5 +/- 5.9 years (mean +/- standard deviation) wore an actigraph for two weeks. Activity profiles were analyzed using nonparametric variables, including dichotomy indices, interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA). The associations between these variables and cognitive, functional, behavioral, and emotional states (obtained from standardized neuropsychologic assessments and questionnaires administered to caregivers) were investigated by partial correlations and stepwise regressions. RESULTS: Cognitive, functional, behavioral, and emotional states showed medium to strong correlations with multiple rhythm variables. Partial correlations indicated that this could not be attributed to a uniform worsening with advancing cognitive decline. Stepwise regressions indicated three most distinctive rhythm variables: 1) the interdaily stability of the 24-hour rhythm was most strongly, negatively, related to cognitive decline and depression; 2) the median level of daytime activity was most strongly, negatively, related to impairments of function, of activities of daily living, and of social interaction; and 3) nocturnal restlessness was secondarily, positively, related to impairments of function and social interaction. CONCLUSION: Especially the interdaily stability and median daytime activity level, and secondarily nocturnal restlessness, showed a strong relationship with the functional status and well-being of demented elderly. This raises the possibility that treatments that enhance daytime activity and the stability of the rest-activity rhythm may improve well-being.