D.F. Swaab, M.A. Hofman, M. Mirmiran, R. Ravid and F.W. van Leeuwen (Eds.) Progress in Brain Research, Vol. 93 0 1992 Elsevier Science Publishers B.V. All rights reserved.

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CHAPTER 11

Circadian rhythms and the suprachiasmatic nucleus in perinatal development, aging and Alzheimer’s disease M. Mirmiran, D.F. Swaab, J.H. Kok’, M.A. Hofman, W. Witting and W.A. Van Goo12 Netherlands Institute for Brain Research, 1105 A 2 Amsterdam, The Netherlands; and Departments of I Neonatology and Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

’

Introduction

Many physiological phenomena, such as rest-activity, sleep-wakefulness, body temperature, plasma levels of different hormones and activity of different neurotransmitters in the brain, exhibit an endogenous “circadian rhythmicity”, i.e., they have a free-running period of about 24 h (Pittendrigh, 1974; Aschoff, 1981; Moore-Ede et al., 1982). Different biological rhythms have a strict phase relation to the environmental (e.g., light/dark) cycles and they are temporally interrelated. These phase relations and internal synchronization are aspects of the circadian rhythm-generating system which appear to be important for the optimal functioning of the organism (Van Goo1 and Mirmiran, 1986). Although different areas of the brain and/or body may be able to generate circadian rhythms, a “bidogical clock” in the anterior hypothalamus, i.e., the suprachiasmatic nucleus (SCN), harmonizes these rhythms to induce a single circadian oscillation in mammals (Rusak and Zucker, 1979; Moore, 1983; Turek, 1985; Rosenwasser and Adler, 1986; Meijer andRietveld, 1989; Rusak, 1989; Ralphet al., 1990; Moore, this volume). Light conveyed to the SCN via the retinohypothalamic pathways is the main factor in the daily entrainment of the endogenous activity of the biological clock to 24-h time cues.

Several studies made an important contribution to explainipg the role of the human hypothalamus in the generation of circadian rhythms. First of all, in addition to the conventional staining methods, the use of immunocytochemical and autoradiographic staining techniques enabled the visualization of the human SCN (Dierickx and Vandersande, 1977; Lydicet al., 1980; Sadunetal., 1984; Stopaet al., 1984; Swaab et al., 1985; Reppert et al., 1988; Moore, 1989; Friedmanetal., 1991; Maiet al., 1991; seealso Moore, this volume); secondly, recently two cases were reported which suggested that, also in the human, a lesion in the suprachiasmatic region of the anterior hypothalamus indeed results in disturbed circadian rhythms (Schwartz et al., 1986; Cohen and Albers, 1991). Moreover, contrary to the conventional belief that the human circadian rhythm system is irresponsive to light, Czeisler et al. (1989, 1990) convincingly showed in a series of experiments that in humans, as in animals, light can reset the endogenous circadian oscillator, which is most probably the SCN of the human hypothalamus (see also Wever, 1989). In the present review we describe human circadian rhythms during early development, in aging and’in Alzheimer’s disease (AD) with particular attention to its relation with the changes that occur in the SCN.

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Circadian rhythms in early human development Earlier studies in which the circadian rhythms of newborn infants were investigated did not give any indication of rhythmicity of rest-activity or sleepwake until at 3 months of age (Kleitman, 1963; Parmalee et al., 1964; Hellbrugge, 1974; Mills, 1975; Davis, 1981; Minors and Waterhouse, 1981; Coons and Guilleminault, 1982; Navelet et al., 1982; Alley and Rogers, 1986). However, these studies were hampered by the fact that: (1) the short-term (i,e., 24 h maximally) recordings were carried out in a highly masked irregular environment; and (2) the data from different individuals were pooled and cross-sectionally studied for age effects. It is of course clear that if any endogenous rhythmicity was present in each individual infant, this would not have been notified in such data analysis. Interestingly, in two cases in which the environmental masking effects were minimized and the infants were fed on demand and recorded longitudinally it became apparent that these infants showed an endogenous free-running rhythm of the sleep-wake cycle until around 15 - 16 weeks of age when the rhythm was entrained to the light-dark cycle (Kleitman and Engelman, 1953; Paupousek and Papousek, 1984; Reppert, this volume). These results indicate perinatal emergence of endogenous circadian rhythms most probably induced in the hypothalamus, which only develops its entrainment to the environmental light-dark cycle post-natally. However, recent studies have indicated a much earlier emergence of diurnal rhythms, i.e. in “newborn” infants, than was originally assumed (Spangler, 1991). Many overt rhythms that are driven by the biological clock in the hypothalamus in adulthood have also been shown to be present during human prenatal life. Rest-activity, breathing movements, heart rate and urine production show a circadian rhythm in the fetus (Patrick et al., 1982;Visser et al., 1982; De Vries et al., 1987; Honnebier et al., 1989; Mirmiranet al., 1989;Rabinowitzet al., 1989;Tuffnell et al., 1990). Circadian rhythms of fetal heart rate variability could be recorded as early as at 22

weeks of gestation (De Vries et al., 1987). To establish the time of circadian rhythm emergence it is important to know whether the fetal rhythms recorded during gestation simply reflect the influence of a maternal circadian system or whether the fetus independently generates a certain amount of circadian rhythmicity by virtue of its own endogenous biological clock activity (Mirmiran et al., 1990). It is for obvious reasons impossible to record fetal circadian rhythms in the absence of maternal influences. We have therefore taken advantage of the unique opportunitiy to explore the possibility of the existence of circadian rhythms in very early human development by recording them in pre-term infants under fairly constant environmental conditions, i.e., in a nursery unit. The rectal or skin QUT 29 WEEKS CONCEPTIONAL 200

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Fig. 1. Circadian rhythms of different physiological variables recorded simultaneously from a pre-term infant at 29 weeks of conceptional age. (From Mirmiran and Kok, 1991, with permission.)

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temperature, heart rate and rest-activity cycles were recorded in a group of low-risk pre-term infants (29 - 35 weeks of conceptional age). Throughout the recordings the lights were continuously on, the feeding was done intragastrically every 2 h and the incubator temperature was constant. Under these conditions circadian rhythms (with a periodicity ranging between 24 and 27 h) were found in the body temperature and heart rate of about 50% of the infants (Mirmiran et al., 1990; Mirmiran and Kok, 1991; Fig. 1). For comparison, the circadian rhythm of body temperature of another pre-term infant with a conceptional age of 33 weeks and that of a womam in her 33rd week of pregnancy are shown in Fig. 2. These findings are the first evidence in support of the existence of an endogenous circadian rhythm (possibly generated by the SCN in the fetal hypothalamus) in early human development. However, in contrast to adult rhythms, these early emerging circadian rhythms are more variable and they are not synchronized with the time of day (see also Fig.

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2). FLrthermore, whether the individual differences among pre-term infants (see also Abe and Fukui, 1979) with respect to the presence or absence of circadian rhythms are related to differences in the stage of development of the biological clock in the hypothalamus or pre-natal maternal entrainment requires further study. As far as the entrainment of circadian rhythms to the environmental light-dark cycle is concerned, a recent study has shown that an approximately 4week exposure of infants to the cyclic home environment is, sufficient for the entrainment to develop (McMillen et al., 1991). Pre-term infants as young as 34 weeks of age responded to the cyclic environment and developed fully entrained circadian rhythms of sleep and wakefulness as early as at 45 weeks of conceptional age. The emergence of entrainment in human infants requires that the afferent and efferent neural pathways to and from the hypothalamic circadian pacemaker are functional. The study of McMillen et al. (1991) suggests that 100

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Fig. 2. Circadian rhythm of body temperature of a woman in the 33rd week of pregnancy (top) and that of a pre-term infant with a conceptional age of 33 weeks. Chi-square periodogram analysis showed a significant circadian rhythm with a maximum period length of 24 h in both subjects. However, note that despite the significant periodicity the rhythm is more variable from day to day in the pre-term baby than in the mother. The latter could partly be the result of constantly being in the incubator under continuous illumination in the neonatal intensive care unit.

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these components of the circadian rhythm generating system are present as early as 35 weeks after conception and that the rate-limiting factor in the emergence of an entrained biological rhythm after this age is the length of exposure to cyclic zeitgebers. McMillen et al. also reported one term infant that never developed an entrained sleep-wake cycle throughout the study. This infant was the only one that was fed at night in full light. Sander et al. (1972) reported that the ability of the infant to differentiate between day and night with regard to the sleep-wake rhythm was already evident by the 4th day of life, if it received individual care from birth onwards. However, such recognition of day and night was not present in infants having multiple care givers. Factors such as the intensity of light (which is higher in the neonatal intensive care than at home both day and night), presence or absence of a light-dark zeitgeber, single vs. multiple care givers and feeding on demand vs. continuous feeding (or at fixed intervals of 2 h) are among those that might influence the developing biological clock of the human infant hypothalamus as early as by 30 - 35 weeks of conceptional age. The early appearance of a functional biological clock in human infants is for instance of particular importance for pre-term infants that are kept in the neonatal intensive care units for several weeks. Early exposure to a cyclical light-dark environment would result in earlier synchronization of the infant’s behavioral and hormonal rhythms with the external environment and subsequently an improvement of their development. Two recent intervention studies in pre-term infants were in accordance with this proposition (Mann et al., 1986; Fajardo, 1990).

metabolic changes are present in the fetal SCN region of the rat and squirrel monkey (Reppert and Schwartz, 1984a,b; Reppert, this volume). It is difficult to convincingly visualize the human SCN by means of conventional histological staining techniques (cf., Swaab et al., 1990). However, immunocytochemical staining of the SCN with antibodies against arginine-vasopressin (AVP) seems to be a good marker of this nucleus in the human brain, enabling morphological and morphometric investigations of the human SCN (Dierickx and Vandersande, 1977; Stopa et al., 1984; Swaab et al., 1985; Hofman et al., 1988; Mai et al., 1991). Positive immunocytochemical staining for AVP of parvocellular neurons and the lack of staining for oxytocin in the suprachiasmatic region of the anterior hypothalamus near the third ventricle differentiate the human SCN from the neurons of, e.g., the supraoptic and paraventricular region that stain for both AVP and oxytocin. In 11 fetal brains (27 - 42 weeks of conceptional age) positive staining for AVP was only found from 31 weeks onwards. Fig. 3 summarizes the development of the human SCN. Although both the number of AVP cells and the total cell number at term (i.e., between 38-42 weeks; n = 7) were respectively 13% and 21% of that found in adulthood, it is interesting to note that there was overlap between the

Human SCN changes during early development The observation that, although generally speaking human newborns lack circadian rhythms, some rhythms might be present in pre-term infants under well-controlled environmental conditions, makes the question when exactly the human SCN becomes functional a particularly interesting one. This point was reinforced by the observation that diurnal

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Fig. 3. Development of vasopressin (VP) cell number in the human suprachiasmatic nucleus (SCN) of the hypothalamus. Log-log scale. The period at term (38 - 42 weeks of gestation) is indicsted by the vertical bar. (From Swaab et al., 1990, with perm,ssio.i .)

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fetal and adult AVP cell numbers (Fig. 3). Other evidence in favor of hypothalamic control of circadian rhythms during early human development comes from a study of Reppert et al. (1988). These investigators showed that using specific melatonin receptor ligand enables the visualization of the fetal human SCN region as early as at the gestational age of 7 months. Animal studies have shown that SCN neurons seem to be able to express circadian rhythmicity well before this nucleus is capable of coordinating overt rhythms; in an altricial mammal such as the rat the rhythm of SCN 2-deoxyglucose uptake appears on embryonic day 19 (Reppert and Schwartz, 1983), a prominent dayhight rhythm of AVP mRNA is evident in the SCN on day 21 of gestation (Reppert and Uhl, 1987) and the spontaneous firing rate of SCN neurons shows a diurnal rhythm, at least on the last day of gestation, i.e., day 22 (Shibata and Moore, 1987). Using 2-deoxyglucose uptake as a measure of the level of neuronal activity within the SCN, Reppert and Schwartz (1983) convincingly showed that non-human primates have a clear rhythm in the activity of their fetal biological clock during gestation that was entrained to a light-dark cycle by the mother. These observations support the hypothesis that SCN neurons express their pacemaker circadian activity long before they are able to communicate this rhythm to the rest of the brain. Still, as was suggested by Moore and Bernstein (1989), it is possible that from the moment they originate SCN neurons are able to generate endogenous circadian activity, an activity genetically coded in these pacemakers cells; furthermore, these cells might be able to induce circadian rhythmicity in certain physiological variables (such as body temperature), but not in others (such as rest-activity). However, these rhythms are not internally synchronized and not entrained to the environmental light-dark cycle in the absence of maternal influences either. It should be noted that at present the data on the development of the human SCN obtained so far are based upon the expression of AVP in the SCN, according to animal studies, whereas VIP expression might appear earlier (Roberts et al., 1987; Hares andFoster, 1988;

Laemle, 1988; Moore and Bernstein, 1989; Davis et al., 1990). Our observation on the early development of body temperature in pre-term infants as young as 29 weeks of conceptional age might thus be related to a development of the SCN neurons in the human hypothalamus which is earlier than that of the AVP neurons. Labeling of the fetal human SCN, using new carbocyanine dye (DiI) tracer in combination with immunocytochemical staining (e.g., for GABA, somatostatin as well as glia cells), is required before one can relate the structural and functional development of the human SCN. Circadian rhythms change in aging and in AD Sleep disturbances are common among elderly people and especially among AD patients (Dement et al., 1985; Prinz et al., 1987, 1990). More than 40% of the hypnotics in the United States are prescribed to elderly people, including patients with AD (Morgan, 1983; Prinzet al., 1990). And about 2 - 10% of the American population over the age of 65 suffers from dementia (Mortimer and Hutton, 1985). AD accounts for more than 50% of these cases (Terry and Katzman, 1983). Sleep-wake rhythm disturbances, insomnia and nocturnal wandering are often important factors in a family’s decision to institutionalize their demented relatives (Sanford, 1975; Prinz et al., 1990). The ineffectiveness of hypnotic therapy draws the attention to the underlying mechanism of such complaints. Furthermore, the residual effects of these drugs may worsen the daytime cognitive performance of the individuals. It has been suggested that circadian rhythms play an important role in sleep regulation (Czeisler et al., 1980; Daan et al., 1984; Strogatz et al., 1986). In fact, disorders of the circadian timing system during aging may first be manifested as sleep-wake pathologies (for a review, see Moore-Ede et al., 1983; Brock, 1985; Dement et al., 1985; Van Goo1 and Mirmiran, 1986; Czeisler et al., 1987; Monk, 1989; Stone, 1989; Van Cauter, 1989; Richardson, 1990). Weitzman et al. (1982), who studied young and elderly subjects under conditions of temporal isolation, reported a reduction in the amplitude and

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period length of the body temperature rhythm because of aging. Reduced amplitude of the body temperature rhythm of elderly subjects was also shown in other studies (Richardson et al., 1982). This reduction seems to exist under home and laboratory conditions. However, the age effect diminishes when the environmental masking effect on the circadian timing system is removed (Monk, 1989). In temporal isolation experiments in which the endogenous activity of the biological clock was studied two interesting observations were done concerning aging (Monk, 1989). One is that there seems to be a negative relationship between the period of the clock (measured by monitoring rectal body temperature) and the age of the individual. Secondly, approximately 80% of the subjects in the 50 - 80 year range showed a spontaneous internal desynchronization, whereas for those in the 20 - 30 year age group the rate was 20%. It has been postulated that desynchronization among internal rhythms could affect not only the sleep pattern, but other aspects of biological aging as well (Czeisler et a1., 1980,1987). In a study on elderly oil-refinery operators, Reinberg and colleagues found that a low amplitude of the circadian temperature rhythm was associated with a poor tolerance of shift-work (Reinberg et al., 1980, 1984). A similar reduction in the amplitude of the rest-activity cycles was found in long-term activity records of healthy elderly vs. young men (Renfrew et al., 1987). This difference was even present during weekends. It seems that the reduction in the amplitude of circadian rhythms, early evening sleep onset, early morning awakening and daytime napping are the result of shortening endogenous circadian rhythms probably due to the loss of SCN neurons (cf, Swaab et al., 1985, 1987). These effects are minimized when the elderly subjects are not forced to follow the strict 24-h entrainment scheme of daily life, but rather sleep or wake on the basis of their own endogenous clock time (Monk and Moline, 1988; Monk, 1989). One of the characteristics of sleep changes in clinically well-defined AD patients is an increase in nocturnal wakefulness after sleep onset indicated by an increased number of awakenings at night (i.e.,

sleep fragmentation) (Prinz et al., 1982, 1987, 1990; Mirmiran et al., 1991). Although spontaneous daytime naps increase in aged individuals, the AD group spent significantly more time napping than the agematched controls. Moreover, it seems that there is a positive relationship between the degree of dementia and that of sleep disturbance (Prinz et al., 1987). There are reasons to suggest that circadian rhythms are disturbed in AD. Continuous 24-h sleep-wake records have shown that AD patients

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Fig. 4. Left panel: raw data of subjects’ rest-activity recorded over several days are double-plotted. Right panel: the x2 periodogram statistical analysis of the data is presented; the straight line indicates the level of statistical significance below which a signal is considered to be random. Top and middle data are from a 41-year-old (D.F.S.) and a 78-year-old (L.I.S.) healthy control; data from an Alzheimer patient (aged 79) are illustrated in the two bottom panels. Note the peak of rest-activity rhythm at 24 h for control subjects, a much smaller nonsignificant peak with a shorter periodicity for the Alzheimer patient. (From Mirmiran et al., 1988, with permission.)

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Fig. 5 . Circadian rhythm of rest-activityrecorded over 1week in a young and an old healthy subject (top, two records) and two Alzheimer patients. Increased variability of rest-activity within a day and between successive days is noticeable in both patients compared with controls.

sleep more during day and wake up more often at night compared to age-matched non-demented or young-adult controls (Prinz et al., 1982). Most of the sleep-wake studies are, however, only carried out for a relatively short period, whereas circadian rhythm studies require several days of continuous recording. Longer sleep-wakefulness studies are not convenient, since the attachment of electrodes and the need to carry the ambulatory EEG recorder interfere considerably with regular daily activities. We have recently completed a series of studies in which the circadian rhythms of rest-activity were recorded in AD patients and controls for a period of 1 week using a small activity monitor (Mirmiran et al., 1988; Witting et al., 1990; see also Figs. 4 and 5 ) . Fourteen patients with clinically well-defined AD, 13 age-matched controls and six young healthy controls were studied. An increased nighttime activity was found both in the elderly and the AD group. The AD group showed a significant reduction of rhythm stability on successive days as well as an increased variability of the rhythm on each individual day

(Fig. 6 ) . This led to a significant reduction in the amplitude of the rest-activity of this group. Furthermore, there was a trend towards positive correlation between circadian rhythm disturbances and the degree of dementia in AD. Prinz et al. (1984) recorded the rectal body temperature of elderly and AD patients for 48 h following one night of adaptation to 1.0

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Fig. 6. Mean interdaily stability and intradaily variability of the different groups. Pvalues of I-test below 0.20 are indicated. No differences were observed between young (Y)and old (0)controls. Both variables showed significant negative effects for Alzheimer patients (AD), which is most pronounced in the subgroup of sedative users (SU) as compared with non-users (NU). (Modified from Witting et al., 1990, with permission.)

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the clinical research center, but found no effect of AD on the circadian rhythm of body temperature. However, they reported an increased intradaily variability of the rhythm of the AD group. In support of our findings it is interesting to refer to the studies of Campbell et al. (1986, 1988a,b), who recorded AD and elderly controls in their home environment and found both phase advance and reduced amplitude of their body temperature (more so in men than in women). Nevertheless, it should be indicated that there are individual differences in elderly and AD patients with regard to circadian rhythm disturbances. Whether individuals with disturbed circadian rhythms are among those showing loss of SCN neurons (or secondary functional changes in the activity of these neurons via reduced light input; Hinton et al., 1986; Campbell et al., 1988a,b) should be clarified by further research (see also Stone, 1989).

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Direct evidence of biological clock dysfunctioning during aging and in AD was demonstrated by Swaab and colleagues (Swaab et al., 1985,1987; Hofman et al., 1988). Compared to younger age groups, a marked decrease in SCN volume, AVP cell number and total number of SCN cells was found in 80100-year-old patients (Fig. 7). Corresponding SCN changes in AD patients were even more pronounced than those observed during normal aging. Neither AVP cell density nor total cell density, as determined by thionin staining, showed any significant changes. In rats using deoxyglucose uptake as a measure of neuronal activity in the SCN, a substantial decrease of SCN activity is shown in aged rats (Wise et al., 1987, 1988). Immunocytochemical staining of arginine vasopressin or vasoactive intestinal polypeptide has also shown loss of these neurons in old rats (Roozendaal et al., 1987; Chee et al., 1988). Partial lesion studies in the animal SCN (including that of non-human primates) made it clear that the size of the SCN is crucial for the expression of its pacemaker properties (Albers et al., 1984; Davis and Gorski, 1984; Rusak, 1989; Woll-

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Fig. 7. Total cell number of the SCN in different age groups and in Alzheimer's disease. The mean age of the Alzheimer group was 78 & 5 years. The total cell number in the Alzheimer group is significantly lower than in the oldest control group. (Modified from Swaab et al., 1987, with permission.)

nick and Turek, 1989; Gerkema et al., 1990; Mirmiran and Bos, 1990). The observed decrease in SCN volume and cell number, particularly in AD, might well be the underlying factor for the circadian rhythm disturbances found in these patients. Summary and conclusions Circadian rhythms are already present in the fetus. At a certain stage of pre-natal hypothalamic development (around 30 weeks of gestation) the fetus becomes responsive to maternal circadian signals. Moreover, recent studies showed that the fetal biological clock is able to generate circadian rhythms, as exemplified by the rhythms of body temperature and heart rate of pre-term babies in the absence of maternal or environmental entrainment factors. Pre-term babies that are deprived of mater-

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nal entrainment and kept under constant environmental conditions (e.g., continuous light) in the neonatal intensive care unit run the risk of developing a biological clock dysfunctioning. However, the fact should be acknowledged that at least in mice the development of the circadian pacemaker (i.e., SCN) does not depend on environmental influences (Davis and Menaker, 1981), although other data suggest that severe disruption of the maternal circadian rhythm indeed abolishes the circadian rhythm of the fetal SCN (Shibata and Moore, 1988). During aging and in particular in AD circadian rhythms are disturbed. These disturbances include phase advance and reduced period and amplitude, as well as an increased intradaily variability and a decreased interdaily stability of the rhythm. Among the factors underlying these changes the loss of SCN neurons seems to play a central role. Other contributory factors may be reduced amount of light, degenerative changes in the visual system and the level of activity and decreased melatonin.

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Discussion R. Ravid: What is the change in rest-activity rhythm in demented patients who are staying at home instead of a nursing home? M. Mirmiran: In our own studies we have compared recordings of the Alzheimer (AD) group monitored in the hospital with elderlypeople recorded at home (Witting et al., 1990). This factor hampers to some extent the conclusion of the study, viz. disturbed circadian rhythmicity in AD. However, we believe that if there is any effect of staying in a hospital on our recordings this would be in favor of the AD group, since environmental zeitgeber effects are stronger in the hospital than at home. Nevertheless, future home recordings of elderly and AD groups - using our newly developed very small ambulatory activity monitor (Van Someren et al., 1992) - are required before definitive conclusions on disturbed circadian rhythms in AD can be drawn. It is important to indicate that in a study by Campbell et al. (1986, 1988b) a significant reduction of both amplitude and period of circadian rhythms was found in AD patients recorded at home. Yet, Prinz et al. (1984) did not find significant differences in the recordingsof bothelderlyand ADpatientsexcept for anincreased intradaily variability in the AD group. S.M. Reppert: Are the rhythms you monitored in pre-term infants diurnal or circadian? M. Mirmiran: Statistical analysis of our data using x2 periodogram showed significant periodicity with a maximum peak in the power spectrum between 24 and 27 h (Mirmiran and Kok, 1991). However, even in those babies in which “mean” period lengths were 24 h, the rhythm was not diurnal since there were daily changes in the period length (including phase jumps). Although variations in body temperature and heart rate with a periodicity “around 24 h” were present in successive days of recording, no indication of any relationship between these variations and the time of the day were found in pre-term infants, M.L. Summar: What effect would you expect from the pre-natal administration of steroids, which are used to induce pulmonary maturation, in the circadian rhythm of premature infants?

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M. Mirmiran: There is one study in rats in which perinatal exposure to corticosteroids induced significant reduction in the amplitude of circadian rhythms post-natally (Krieger, 1972). Though often used in humans, there are no reports on the effect of corticosteroids on circadian rhythms. The fact that total adrenalectomy or blocking fetal-maternal adrenal activity in pregnant women eliminate circadian rhythm in fetal heart rates, suggests that corticosteroids are important prenatal zeitgebers for circacian rhythms (Arduini et al., 1986a,b, 1987). In future studies it is essential to examine “timed” and daily administration of corticosteroids (or melatonin, see Davis and Mannion, 1988; Cassone, 1990; Yuan et al., 1991) and their effect on the development of human circadian rhythms. W.A. Scherbaum: I was interested in the observation in which you refer to the lack of fetal rhythmicity in the adrenalectomized mother. It has been shown that after experimental adrenalectomy colocalized CRF within AVP cells in the PVN is considerably upregulated so that one might speculate that there is either input from the PVN to the SCN or that AVP cells within the SCN respond directly to cortisol. Do you have data on the cellular expression of CRF in the SCN after experimental adrenolectomy? M. Mirmiran: I do not know of any data on CRF changes in the SCN following adrenalectomy. However, CRF as a maternal signal influencing fetal circadian rhythms is an intriguing hypothesis. There are also indications from the literature that show high levels of corticosteroid receptors in the rat SCN, particularly in early (fetal) development (De Kloet et al., 1988). Certainly it is interesting to hypothesize that CRF directly influences the SCN or indirectly via the PVN. It is also known from rat studies that both hyper- and hypocorticism changes the time course of development of both VIP and somatostatin cells in the SCN (Nobou et al., 1985).

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