Aus dem Institut für Medizinische Psychologie der Ludwig-Maximilians-Universität München komm. Vorstand: Prof. Dr. Till Roenneberg Sleep and Chronotype in Adolescents - a Chronobiological Field-Study - Dissertation zum Erwerb des Doktorgrades der Medizin an der medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Stephanie Böhm aus Thuine 2012 Mit Genehmigung der Medizinschen Fakultät der Universität München Berichterstatter: Prof. Dr. Till Roenneberg Mitberichterstatter: Prof. Dr. Axel Steiger Prof. Dr. Brigitte Bondy Dekan: Prof. Dr. Dr. h.c. Maximilian Reiser, FACR, FRCR Tag der mündlichen Prüfung: 08.03.2012 Dedicated to Felix Table of Contents 1 Introduction ................................................................................................... 6 1.1 Chronobiology and Biological Rhythms ....................................................... 6 1.2 Circadian Rhythms in Humans ...................................................................... 7 1.2.1 Chronotype ..................................................................................................... 8 1.2.2 The Circadian Clock in Adolescence ............................................................ 10 1.3 Sleep ................................................................................................................ 11 1.3.1 Anatomy and Physiology of Sleep ................................................................ 12 1.3.2 Sleep-EEG and Sleep Stages .......................................................................... 14 1.3.3 Sleeping into Adulthood: Characteristics of Sleep in Adolescence ............ 16 1.4 “Social Jetlag” and its Effects......................................................................... 18 1.5 Adolescents’ Sleep – a Health Care Subject ................................................. 19 1.6 Aims of this Study .........................................................................................20 2 Materials and Methods .................................................................................24 2.1 Participants ....................................................................................................24 2.1.1 Exclusion Criteria ..........................................................................................24 2.1.2 Ethical Approval ............................................................................................ 25 2.2 Materials ........................................................................................................26 2.2.1 Munich Chronotype Questionnaire (MCTQ) ..............................................26 2.2.2 Sleep Logs (SL) ..............................................................................................26 2.2.3 Zeo® – Advantages and Functions of a Simplified EEG ............................... 27 2.2.4 Software for Data Handling and Computation ........................................... 33 2.3 Methods ......................................................................................................... 33 2.3.1 Data Collection .............................................................................................. 33 2.3.2 Data Treatment ............................................................................................. 35 3 Results ........................................................................................................... 40 3.1 Description of Obtained Data ..................................................................... 40 3.1.1 List of Obtained Data ................................................................................... 40 3.1.2 Zeo®-Measurements ..................................................................................... 40 3.1.3 Further Parameters Calculated from Zeo®-Data.......................................... 41 3.1.4 REM-Phases, Sleep Cyles and Appearance of Sleep-Onset-REM ............... 41 3.2 Analysis of Obtained Data ............................................................................42 3.2.1 Analysing Variance of Sleep-Parameters between the 1st and 2nd Night ....42 3.2.2 Comparing MCTQ-Data with Sleep Log Data ............................................. 43 3.2.3 Comparing MCTQ–Database-Distributions with those of the Present Study ............................................................................................................. 46 3.2.4 Correlation of Chronotype and Social Jetlag ...............................................47 3.2.5 Relation between MSF and øSD .................................................................47 sc 3.2.6 Relations between MSF and Zeo®-Parameters ......................................... 48 sc 3.2.7 Relations among Zeo®-Parameters ...............................................................50 3.2.8 Correlation of Sleep Onset and Sleep End between MCTQ and Zeo® ....... 52 3.2.9 Post-Hoc Hypotheses: A Challenge of SOREM ........................................... 52 4 Discussion ...................................................................................................... 55 4.1 Students’ Chronotypes .................................................................................. 55 4.2 Chronotype and Social Jetlag ........................................................................56 4.3 The First Night Effect ....................................................................................56 4.4 Night Phases, Compared to other Studies ................................................... 57 4.5 Sleep Mobile Sleep Timing in Relation to Real Life Sleep Timing .............58 4.6 Sleep-Phases In Relation to Chronotype and in Relation to Each Other ...59 4.7 Correlations among Sleep Phases ................................................................ 60 4.8 Problems Measuring REM Sleep – Post Hoc Hypotheses .......................... 60 4.9 Several Reasons for the Assumption that Zeo® Overestimates REM.......... 63 4.9.1 General Considerations on Measuring REM with Automated- and Classical EEGs ................................................................................................ 63 4.9.2 Specific Evidence for Zeo’s® Overestimation of REM ..................................65 4.10 Strengths & Weaknesses of this Study .........................................................67 4.11 Follow-Up Perspectives for this Study ........................................................ 69 4.12 Conclusions .................................................................................................. 69 5 References ...................................................................................................... 71 6 Acknowledgements ...................................................................................... 80 6.1 To Colleagues, Friends and Family ............................................................. 80 6.2 To Schools and Participants ........................................................................ 80 7 Deutsche Zusammenfassung ........................................................................82 8 Abstract of the Present Thesis ..................................................................... 86 9 Appendices ................................................................................................... 89 9.1 Consent Form for Students Younger than 18 Years .................................... 89 9.2 Consent Form for Students Older than 18 Years ......................................... 91 9.3 Consent Form for the Publication of Fotos ................................................. 93 9.4 Anamnesis Sheet .......................................................................................... 94 9.5 Percentile Sheets ...........................................................................................97 9.6 WHO-5-Questionnaire ................................................................................ 99 9.7 MCTQ .......................................................................................................... 100 9.8 Students’ MCTQ .......................................................................................... 103 9.9 Sleep Log ..................................................................................................... 106 10 List of Abbreviations ................................................................................... 107 11 Curriculum Vitae ......................................................................................... 109 Boys in bed, girls in bed All now go to sleep Sleep, sweet dreams Wake to a new today tomorrow R.E.M. It’s a free world baby (1992) Introduction 1 Introduction 1.1 Chronobiology and Biological Rhythms Everything has Rhythm. Everything Dances. Maya Angelou (1928) Every living organism, from the most simple protozoan to the most complex plant or animal, including humans, has inherent clock mechanisms that reign its place and functioning in time (Roenneberg and Merrow 2003; Kuhlman, Mackey et al. 2007). Among the first to realise that living organisms arrange themselves in advantageous environmental conditions in order to be provided with the best setting for survival and reproduction was Darwin (1859 ). He found evolution to occur via selection of ran- domly appearing genetic mutations that would provide advantages over other species. Almost 100 years later Hutchinson (1957) termed the unique and advantageous circum- stance of different species’ settlement as the “ecological niche”. Modern chronobiology has enlarged the frame of this term by adding the concept of a temporal niche of or- ganisms. Every organism has its individual arrangement of activity times and rest times. In this way, advantages can be gained e.g. when being active at times that pro- vide the best frame for food intake, photosynthesis or mating, at the same time being minimally endangered by predators (Roenneberg 2010). Rather than only being divided into rest and activity times, life itself appears to be profoundly rhythmic, as in more and more physiological processes, rhythmicity is being found to play a vital role (Arendt 1998). In the human being, among the most basic of such rhythmic processes are heart rate, respiratory rate, blood pressure, the ovarian cycle, activity bursts, hor- mone secretion and sleep phases (Aschoff 1965; Zulley and Knab 2003; Moser, Fruhwirth et al. 2006). The first scientist who invented a new terminology of rhythms was Halberg (1959). These, rather than being perfectly exact are “circa-rhythms”, corresponding roughly with the earth’s rhythms of moon and sun. Chronobiology investigates about biologi- cal rhythms. These may be circannual- (rhythms of approximately one year), circalu- 6 Introduction nar- (rhythms of approximately one lunar cycle of 29.5 days), circatidal- (rhythms of approximately one ocean tide - usually 12 h and 25 min), infradian- (rhythms with a period longer than 24 h), ultradian- (rhythms with a period shorter than 24 h) or cir- cadian (rhythms of approximately one day)(Refinetti 2011). The present study will en- gage in an inquiry into several aspects of circadian sleep-wake rhythms in human ado- lescents. 1.2 Circadian Rhythms in Humans Es gibt ein großes und doch ganz alltägliches Geheimnis. Alle Menschen haben daran teil, jeder kennt es, aber die wenigsten denken je darüber nach. Die meisten Leute nehmen es einfach so hin und wundern sich kein bisschen darüber. Dieses Geheimnis ist die Zeit. Michael Ende, Momo (1973) In his novel „Momo“ (1973/2009), Ende continues, referring to “the mystery of time” as something every person carries within themselves. Science has shown that this state- ment beautifully approaches truth. Like all living creatures, the human being has an internal ability of measuring time within the body (Roenneberg 2010). According to Roenneberg, this “clock” governs not only sleeping habits, but all bodily functions, such as blood pressure, hormone levels and body temperature, to name but a few. While every cell has several clock mechanisms which are governed by numerous genes (Young and Kay 2001; Roenneberg and Merrow 2003), the master clock consists of the suprachiasmatic nuclei (SCN), located bilaterally in the anterior hypothalamus, above the optic chiasm (Fuller, Gooley et al. 2006; Moore 2007). These circadian oscil- lators contain approximately 20.000 clock neurons in their ventrolateral division, many of which are spontaneous oscillators. The period length of the SCN approximately ap- proaches a length of 24 hours, within a range from 22 to 28 hours per day (Ospeck, Coffey et al. 2009). This phenomenon was first demonstrated by Aschoff et al. (1965), who showed that participants in temporal isolation, i.e. who were completely deprived of any external “zeitgeber” (German for “time-giver”) (Golombek and Rosenstein 2010) 7 Introduction – and thus of any factor that might help to orientate within time, like sunlight, clocks, noise, or social contacts - (Roenneberg, Wirz-Justice et al. 2003) developed their own day-lengths that took sometimes up to 30 hours per day. Those experiments showed that humans have free-running periods which endure even in the absence of any ex- ternal zeitgeber. The SCN, rather than obtruding their own rhythm to the organism, serve as coordinating agents, exerting influence on numerous circadian clocks in the body, throughout several systems, down to a cellular level of circadian metabolism. On this level, several genes have been identified to be of importance for cellular control- ling mechanisms (Hastings, Maywood et al. 2008). When the SCN are lesioned, sleep- wake circadian rhythms are found to become entirely erratic (Lee, Swanson et al. 2009). Beyond coordinating numerous physiological functions, the main role of the SCN is to synchronise the individual with external time, responding to the main zeitgeber, sunlight, in alternation with darkness (Aschoff 1965; Roenneberg, Wirz-Justice et al. 2003; Reinoso-Suarez, de Andres et al. 2011). The inner retina possesses intrinsically photosensitive retinal ganglion cells (ipRGC), expressing the photopigment melanop- sin which enables them to respond to light (Berson 2003; Rollag, Berson et al. 2003). Via the retino-hypothalamic tract, the SCN receive their input (Kumar and Rani 1999; Hannibal and Fahrenkrug 2006), hence being entrained to the day/night cycle (Golombek and Rosenstein 2010; Pickard and Sollars 2010). In summary the SCN en- sure that “physiology across the entire organism is temporally integrated and thus maximally adapted” (Hastings, Maywood et al. 2008). 1.2.1 Chronotype “Chronotype refers to the point in time when an individual’s endogenous circadian clock synchronises (entrains) to the 24 hour day.” (Roenneberg, Kuehnle et al. 2004). Along with genetic factors, it depends on different environmental cues or individual characteristics, such as on age (Roenneberg, Wirz-Justice et al. 2003). In his book „Wie wir ticken “ (2010), Roenneberg states that: „different people can be entirely different chronotypes – in extreme cases the discrepancy may account up to 12 hours”. A per- 8