Subjective Positive and Negative Sleep Variables Differentially Affect Cellular Immune Activity in a Breast Cancer Survivor: A Time-series Analysis Approach

Abstract

This study on a breast cancer survivor suffering from cancer-related fatigue (CaRF) and depression investigated the bidirectional relationship between cellular immune activity and subjective sleep. The 49-year-old patient (breast cancer diagnosis 5 years before the study, currently in remission) collected her full urine output for 28 days in 12-h intervals (8:00 p.m. to 8:00 a.m. and 8:00 a.m. to 8:00 p.m.). These urine samples were used to determine urinary neopterin (cellular immune activation marker) and creatinine concentrations via high-pressure liquid chromatography (HPLC). Each morning, the patient answered questions on five sleep variables: sleep quality (SQ), sleep recreational value (SRV), total sleep time (TST), total wake time (TWT), and awakenings during sleep period (ADS). For the purpose of this study, the time series of the nighttime urinary neopterin levels and the five sleep variables were determined. Using centered moving average (CMA) smoothing and cross-correlational analysis, this study showed that increases in the positive sleep variables SQ and SRV were followed by urinary neopterin concentration decreases after 96–120 h (SQ, lag 4: r = −0.411; p = 0.044; SRV: lag 4: r = −0.472; p = 0.021) and 120–144 h (SRV, lag 5: r = −0.464; p = 0.026). Increases in the negative sleep variable TWT, by contrast, were followed by increases in urinary neopterin concentrations 72–96 h later (lag 3: r = 0.522; p = 0.009). No systematic effects in the other direction, i.e., from urinary neopterin levels to sleep, were observed in this study. Although preliminary, the findings of this study highlight the benefit of carefully investigating temporal delays and directions of effects when studying the dynamic relationship between sleep and immune variables in the natural context of everyday life.

Bidirectional Cause–Effect Relationship Between Urinary Interleukin-6 and Mood, Irritation, and Mental Activity in a Breast Cancer Survivor

“…In conclusion, this integrative single-case study on a breast cancer survivor suffering from depression and fatigue showed that positive emotional states such as elevated mood can be both positively and negatively correlated with IL-6 – in both directions of effect, with different temporal delays and intertwined with feedback circuits. Such findings confirm recent data from our working group on the complexity of emotion–immune interplay under conditions of “life as it is lived” ( Schubert et al, 2003 , 2006 , 2012 , 2015 ; Haberkorn et al, 2013 ; Singer et al, 2018 ). The results of this study again raise the possibility that data inconsistency in current PNI research may result from not taking the complex functional aspects of life-science data into account.…”

“…This study is part of a wider project using the “integrative single case study” design ( Schubert et al, 1999 , 2012 ) to investigate the impact of emotionally meaningful daily incidents on stress system activity in breast cancer survivors suffering from cancer-related fatigue. Results from this study have already been published ( Haberkorn et al, 2013 ; Singer et al, 2018 ).…”

“…In the patient of this study, we found that increases in urinary neopterin concentrations preceded increases in fatigue intensity with a temporal delay of 60–72 h, whereas elevations of the patient’s mood were followed by a cyclic response pattern of urinary neopterin levels with an ultimate decrease in neopterin after 132–144 h ( Haberkorn et al, 2013 ). In addition, increases in the patient’s positive sleep variables (i.e., sleep quality, sleep recreational value) were followed by urinary neopterin concentration decreases after 96–120 h and 120–144 h. Conversely, increases in total wake time, a negative sleep variable, were followed by increases in urinary neopterin levels 72–96 h later ( Singer et al, 2018 ). These findings from previous evaluations show that not only the patient’s urinary IL-6 but also her urinary neopterin concentrations were dynamically interrelated with various emotional and behavioral variables.…”

“…We approach these methodological demands on PNI research by applying the “integrative single-case study” design ( Schubert et al, 1999 , 2012 ; Singer et al, 2018 ). Over a period of 55 12-h intervals (28 days), we investigated in the current study the correlations between urinary IL-6 levels and mood, irritation, and mental activity in a patient with prior breast cancer under conditions of “life as it is lived.” As anti-inflammatory medication ( Zhang et al, 2017 ) and physical activity ( Meneses-Echávez et al, 2016 ) are two examples of potential confounders of the IL-6 relations investigated in this study, we included theses variables in the analyses.…”

Case Report: Dynamic Interdependencies Between Complementary and Alternative Medicine (CAM) Practice, Urinary Interleukin-6 Levels, and Fatigue in a Breast Cancer Survivor

“…This integrative single-case study is part of a larger project on breast cancer survivors that examines the effects of emotionally meaningful incidents on stress system activity. Various results dealing with this patient have already been published (22,23,35,36).…”