AJP - Regu AJP: Lung Cellular and Molecular Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 289: R209-R216, 2005. First published March 24, 2005; doi:10.1152/ajpregu.00754.2004
0363-6119/05 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/1/R209    most recent
00754.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goel, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goel, N.

SLEEP AND TEMPERATURE REGULATION

Late-night presentation of an auditory stimulus phase delays human circadian rhythms

Namni Goel

Department of Psychology, Wesleyan University, Middletown, Connecticutt

Submitted 4 November 2004 ; accepted in final form 17 March 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Although light is considered the primary entrainer of circadian rhythms in humans, nonphotic stimuli, including exercise and melatonin also phase shift the biological clock. Furthermore, in birds and nonhuman mammals, auditory stimuli are effective zeitgebers. This study investigated whether a nonphotic auditory stimulus phase shifts human circadian rhythms. Ten subjects (5 men and 5 women, ages 18–72, mean age ± SD, 44.7 ± 21.4 yr) completed two 4-day laboratory sessions in constant dim light (<20 lux). They received two consecutive presentations of either a 2-h auditory or control stimulus from 0100 to 0300 on the second and third nights (presentation order of the stimulus and control was counterbalanced). Core body temperature (CBT) was collected and stored in 2-min bins throughout the study and salivary melatonin was obtained every 30 min from 1900 to 2330 on the baseline and poststimulus/postcontrol nights. Circadian phase of dim light melatonin onset (DLMO) and of CBT minimum, before and after auditory or control presentation was assessed. The auditory stimulus produced significantly larger phase delays of the circadian melatonin (mean ± SD, –0.89 ± 0.40 h vs. –0.27 ± 0.16 h) and CBT (–1.16 ± 0.69 h vs. –0.44 ± 0.27 h) rhythms than the control. Phase changes for the two circadian rhythms also positively correlated, indicating direct effects on the biological clock. In addition, the auditory stimulus significantly decreased fatigue compared with the control. This study is the first demonstration of an auditory stimulus phase-shifting circadian rhythms in humans, with shifts similar in size and direction to those of other nonphotic stimuli presented during the early subjective night. This novel stimulus may be a useful countermeasure to facilitate circadian adaptation after transmeridian travel or shift work.

nonphotic; melatonin; core body temperature; phase shifts; sensory stimuli

LIGHT IS CONSIDERED THE PRIMARY entrainer of circadian rhythms in mammals, including humans. Nonphotic stimuli, however, including various kinds of locomotor activity, dark pulses, and triazolam also phase shift and entrain circadian rhythms in rodents (reviewed in Refs. 55 and 59). Furthermore, in nonhuman mammals and birds, social communication signals, including olfactory and auditory sensory information, phase shift circadian rhythms (reviewed in Refs. 20 and 55).

Specifically, several studies in birds and primates indicate the biological clock is sensitive to auditory stimuli. For example, daily playback of conspecific vocalizations at fixed times of day in siskins, serins, and house sparrows (32, 52, 61), crowing from conspecific species in domestic fowl (64) and 12-h cycles of playback of conspecific vocalizations in chickens (14) all entrain circadian rhythms. Notably, nonconspecific auditory stimuli, such as buzzer noises or cage rattling, also entrain circadian activity rhythms in finches and sparrows (50, 61). Furthermore, continuous exposure to conspecific auditory cues entrains circadian rhythms in the diurnal marmoset (24), as do ambient white noise-quiet cycles in squirrel monkeys (26). Whether the human biological clock shows such sensitivity to auditory stimuli is presently unknown.

In humans, the most investigated nonphotic stimulus, timed exercise, produces phase shifts in circadian CBT, melatonin, and thyrotropin rhythms (e.g., 3, 6, 10, 12, 22, 56, 74). Beyond exercise, exogenous melatonin (40, 46, 48, 53, 68, 81), the duration and/or timing of sleep episodes (11, 19, 29, 30, 72), triazolam administration (9), and food intake (42) also phase shift circadian rhythms. Social stimuli—which in some cases have included repeated exposure to acoustically transmitted gong signals—also may entrain human circadian rhythms (2, 34, 37, 39, 76). However, these studies remain inconclusive because of methodological issues. For example, Aschoff et al. (2) and Wever (76) demonstrated that members of a group maintained in isolation produced a common free-running period. However, the subjects controlled their own lighting schedule, and thus the effects may have been due to one person controlling the lights, thereby entraining the rest of the group. In addition, Klein and Wegmann (37) found that the reentrainment rate of circadian rhythms following transmeridian travel was twice as fast when subjects left their hotel rooms (and engaged in social contact) every second day compared with remaining in isolation. However, faster reentrainment may have been due to higher light intensity in the outdoor vs. indoor environment rather than to social cues. More recently, Klerman et al. (39) reported that social cues maintain entrainment to a 24-h day in a totally blind subject, but the salient stimulus may have been the imposed rest-activity cycle.

The nonphotic phase response curve (PRC) for timed exercise in humans describes phase delays when stimuli are presented before temperature minimum in the early subjective night (3, 6, 10, 12, 22, 74). Moreover, two nonphotic PRCs—one derived from nonconspecific auditory disturbances and the other from combined conspecific auditory and visual cues—have been described in diurnal house sparrows and marmosets, respectively (61, 75). Both PRCs indicate phase delays in the early subjective night during times of normal inactivity.

This experiment determined whether an auditory stimulus could phase shift human circadian rhythms when presented before CBT minimum, in the early subjective night. To measure putative phase shifts, the circadian phase of DLMO and of CBT minimum before and after auditory or control presentation was assessed. On the basis of the aforementioned nonphotic data, it was hypothesized that the human circadian system, like that of birds and nonhuman mammals, would respond to a nonphotic auditory stimulus. Specifically, it was predicted that an auditory stimulus would elicit phase delays in circadian melatonin and temperature rhythms, based on the human exercise PRC and on evidence that sensory stimuli induce phase delays when presented during the inactive phase in other diurnal species.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Subjects

Ten subjects, 5 men and 5 women, ages 18–72 (mean age ± SD, 44.7 ± 21.4 yr) participated in this study. Subjects initially were screened by telephone and in-person interviews. Subjects with a history of psychiatric, endocrine, metabolic, or neurologic disorders, extreme morningness or eveningness (assessed by the Morningness-Eveningness Questionnaire; 35) or hearing impairments were excluded. Other exclusionary criteria included the following: use of central nervous system medications, history of smoking, irregular sleep/wake cycles, or shift work or travel across time zones for 2 months before study entry. In addition, women using oral contraceptives or with irregular menstrual cycles were excluded.

Subjects maintained a habitual, individualized wake-up time and bedtime of ~8 h for at least 1 wk before each session, verified by sleep logs and daily call-ins at bedtime and upon awakening to an answering machine with time stamp. The prestudy stimulus and control session bedtimes (stimulus: 0010 ± 01.34 h; control: 0026 ± 01.21 h) and wake times (stimulus: 0741 ± 01.12 h; control: 0747 h ± 1.01 h) were similar. Wesleyan University's Institutional Review Board approved the study protocol, and all procedures conformed to the Declaration of Helsinki. Subjects received monetary compensation for participation and signed informed consent before study entry.

Procedure

Subjects completed two 4-day laboratory sessions in constant dim light conditions, maintained throughout all waking periods following study entry, including during exposure to the auditory and control stimulus. Ordinary fluorescent lights in the laboratory did not exceed 16 lux measured at eye level and in the direction of gaze at any position as determined by a digital light meter. For both conditions, including during stimulus presentation, lighting exposure factors such as orientation toward the light source and intensity were identical. Furthermore, subjects could not control the lighting conditions at any point during the study.

The sessions consisted of one baseline night (night 1), two stimulus/control nights (nights 2 and 3) and one post-stimulus/post-control night (night 4; Fig. 1). The sessions were separated by 3–4 wks. Night 1 began at 1600. Subjects slept in darkness (0 lux) from 2400 to 1200 on nights 1 and 4 and from 0300 to 1200 on nights 2 and 3. They remained in bed in 0 lux if they awakened before 1200.



View larger version (7K):
[in this window]
[in a new window]
  		Fig. 1. Schematic representation of the study protocol. Stimulus and control session order was counterbalanced. Solid bars represent sleep time (0 lux) and open bars represent wake time in dim light (<20 lux). The shaded bars represent melatonin sampling (sampling occurred in 30-min intervals). The arrows indicate administration time of the auditory stimulus or control.

 
On nights 2 and 3, subjects received two consecutive presentations of either the stimulus or control, with session order counterbalanced. During the stimulus session, subjects received a 2-h auditory stimulus (described below) from 0100 to 0300. This time was chosen on the basis of studies in humans that found exercise produced phase delays when presented during the early subjective night (3, 10, 12, 74, 80). During presentation, subjects remained awake, with their eyes open, and remained seated in a chair. No other competing stimuli or activities were allowed during exposure. Infrared closed-circuit cameras and technicians monitored compliance. The control session was identical to the stimulus session except that subjects were informed they were receiving an auditory stimulus above the human hearing range (e.g., ultrasonic, frequency above 15 kHz); however, a blank compact disc was played instead. This procedure ensured subjects were equally attentive to the stimuli in both conditions and controlled for the possibility that phase shifts in the auditory condition could be caused by various protocol factors. To assess transient effects of the auditory stimulus and control, subjects completed the Profile of Mood States (described below) at 0050, 0150, and 0250 on nights 2 and 3. During the protocol, subjects refrained from naps, exercise, alcohol, and caffeine, and spent most of the time engaged in recreational activities (e.g., reading, playing cards, watching TV). Subjects completed the protocol throughout the year.

Auditory Stimulus

The auditory stimulus was a compact disc of bird song melodies, enhanced with a classical music background (Unison Music, Nashville, TN). Using a standard player, the compact disc was played continuously for 2 h at 60 dB, intensity equivalent to normal conversation (33). At 60 dB, subjects have rated this particular stimulus as mildly weak to neutral in intensity and more pleasant than bright light using Likert scales (25).

Data Analyses: Circadian Measures

Salivary melatonin. Subjects provided 10 saliva samples at 30-min intervals, with timing of samples enforced by technicians, under dim light conditions (described above) from 1900 to 2330 on nights 1 and 4 (Fig. 1). Dinner was completed at least 30 min before sampling began. During sampling, no food was permitted, and water was permitted only within 5 min after each sample. Saliva (1.0 to 3.0 ml) was deposited into Salivette tubes (Sarstedt, Nümbrecht, Germany) using absorbent polyester swabs placed in the mouth for 5 min. Salivettes were immediately placed in, and remained stored at, –20° C pending laboratory assay.

The dim light melatonin onset (DLMO), a reliable marker of circadian rhythm phase (47), was defined as the first interpolated point (derived from between two points) at 3.0 pg/ml on the rising curve of melatonin concentration. Concentration levels remained above this threshold thereafter. A double-antibody radioimmunoassay was used (Bühlmann Laboratories AG, Allschwil, Switzerland). Samples of 200 µl were run in duplicate. The intra- and interassay coefficients of variation were <5% and <9%, at quality control levels of 1.6 pg/ml and 16 pg/ml, respectively. Absolute recovery was >95% with a lowest detectable quantity of 0.5 pg/ml.

Core body temperature. Core body temperature (CBT) was collected and stored in 2-min intervals throughout the study using disposable rectal thermistors (YSI Precision 400 Series, Yellow Springs Instruments, Yellow Springs, OH) attached to Mini-loggers (Mini-Mitter, Sunriver, OR). The thermistors were inserted at a 10-cm depth and secured with tape. A complex cosine fit, with a 12-h harmonic determined the phase of CBT minimum on nights 1 and 4. An r2 value of ≥0.90 was used as a goodness-of-fit criterion (variance accounted for). The data were not mathematically demasked, since CBT minimum always occurred during each subject's sleep cycle and thus was not obscured by waking activity (3, 4).

Mood measures

Profile of Mood States Questionnaire. The Profile of Mood States Questionnaire (POMS; 51) is a 65-item self-report scale that assesses transient affective states in response to various stimuli, including auditory cues (69, 71). The POMS has been validated in repeated-measures designs (see review, Ref. 66). Each item is rated on a scale from 0 (not at all) to 4 (extremely), on one of six factors: depression-dejection (Depression), tension-anxiety (Tension), anger-hostility (Anger), confusion-bewilderment (Confusion), vigor-activity (Vigor), fatigue-inertia (Fatigue). The total score for each factor is calculated by adding together the respective set of adjectives corresponding to that factor. The total mood disturbance score (TMD), a global estimate of affective state, derives from summing the factors together, with vigor-activity weighted negatively.

Statistical Analyses

Baseline circadian phase and phase shift data did not show normal distributions; therefore, the Wilcoxon nonparametric test (z) assessed DLMO and CBT minimum phase shifts at baseline (night 1) and after exposure (night 4) between the auditory stimulus and control sessions and determined baseline differences in phase markers between sessions. Repeated-measures ANOVA examined differences in POMS scores for nights 2 and 3 between sessions. Pearson product-moment correlation coefficient analyses (r) quantified the various relationships between DLMO and CBT minimum phases for the stimulus and control nights. The magnitude of session differences in phase shifts and POMS scores was expressed as effect size, d, the standardized difference between means (d = 0.3, small; 0.5, medium; 0.8, large; 16). Data are presented as means ± SD; P ≤ 0.05 was considered significant for all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Circadian Rhythm Phase Shifts

Prestimulus. On night 1, the stimulus and control session DLMOs (2119 ± 0.80 h vs. 2132 ± 0.86 h; Z = –0.97, P = 0.33; r = 0.78, P < 0.009, n = 10) and CBT minimums (0427 ± 1.26 h vs. 0444 ± 1.08 h; Z = –0.87, P = 0.39; r = 0.71, P < 0.05, n = 10) did not differ significantly and were significantly related. The timing of the auditory and control stimuli did not differ significantly in relation to hours after baseline DLMO (4.68 ± 0.80 h vs. 4.46 h ± 0.86 h; Z = –0.97, P = 0.33) or hours before baseline CBT minimum (2.45 ± 1.26 h vs. 2.73 ± 1.08 h; Z = –0.87, P = 0.39). Moreover, in all cases, stimulus presentation occurred after DLMO and before CBT minimum.

Poststimulus. The auditory stimulus produced significantly larger phase delays than the control in DLMO (Z = –2.56, P = 0.009; d = 2.04; Fig. 2A) and CBT minimum (Z = –2.36, P = 0.02; d = 1.37; Fig. 2B). Individual CBT and DLMO phase changes in response to the auditory stimulus and control are plotted in relation to CBT minimum and DLMO in Figs. 3 and 4, respectively. The timing of CBT minimum or DLMO and the magnitude of phase shifts were not significantly related in either session (control: CBT: r = –0.10, P = 0.79, n = 10; DLMO: r = –0.07, P = 0.85, n = 10; stimulus: CBT: r = –0.44, P = 0.21, n = 10; DLMO: r = –0.02, P = 0.96, n = 10; Figs. 3 and 4). Overall, the auditory stimulus produced phase delays in CBT minimum and DLMO in nine subjects. Similarly, the control stimulus produced phase delays in CBT minimum and DLMO in 9 and 10 subjects, respectively (Fig. 5).



View larger version (9K):
[in this window]
[in a new window]
  		Fig. 2. (A) salivary dim light melatonin onset (DLMO) and (B) core body temperature (CBT) minimum phase delays for the auditory stimulus and control conditions. Values are presented as means ± SD. *Significantly greater than the control condition, P = 0.009 and P = 0.02, respectively.

 


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 3. Response of the endogenous circadian pacemaker as measured by (A) CBT minimum and (B) DLMO to two consecutive days of a 2-h presentation of an auditory stimulus or control. Individual data points represent the observed phase shift (as per convention, advances are designated by positive numbers, delays by negative numbers on the ordinate) in response to the auditory stimulus or control presented at a given time relative to baseline CBT minimum. The abscissa displays the interval between the midpoint of the control or auditory stimulus presentation and CBT minimum (indicated by 0); negative numbers indicate that presentation occurred before CBT minimum for all subjects.

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 4. Response of the endogenous circadian pacemaker as measured by (A) CBT minimum and (B) DLMO to two consecutive days of a 2-h presentation of an auditory stimulus or control. Individual data points represent the observed phase shift (as per convention, advances are designated by positive numbers, delays by negative numbers on the ordinate) in response to the auditory stimulus or control presented at a given time relative to baseline DLMO. The abscissa displays the interval between the midpoint of the control or auditory stimulus presentation and DLMO; positive numbers indicate that presentation occurred after DLMO for all subjects.

 


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 5. Phase shifts as measured by (A) CBT minimum and (B) DLMO to two consecutive days of a 2-h presentation of an auditory stimulus or control. Data points connected by lines represent the observed phase shift for individual subjects (numbered 1–10) in response to the auditory stimulus or control. As per convention, advances are designated by positive numbers and delays by negative numbers on the ordinate.

 
Pre- and Poststimulus relationships. Within each session, night 1 and 4 DLMOs (control: r = 0.98, P < 0.001, n = 10; stimulus: r = 0.90, P < 0.001, n = 10) and CBT minimums (control: r = 0.97, P < 0.001, n = 10; stimulus: r = 0.84, P < 0.003, n = 10) were significantly related.

Relationships between circadian phase markers. The stimulus and control sessions showed similar mean timing differences between DLMO and CBT minimum on night 1, ranging on average from 7.13 to 7.19 h. Moreover, phase shifts of these markers correlated significantly (control: r = 0.76, P < 0.05, n = 10; stimulus: r = 0.74, P < 0.05, n = 10). These measures also related positively and significantly on nights 1 and 4 for both the control (night 1: r = 0.89, P < 0.002, n = 10; night 4: r = 0.87, P < 0.002, n = 10) and auditory stimulus sessions (night 1: r = 0.71, P < 0.05, n = 10; night 4: r = 0.69, P < 0.05, n = 10).

Mood Measures

Fatigue scores showed a significant session effect on night 3, whereby the auditory stimulus decreased fatigue compared with the control (7.03 ± 5.39 vs. 10.60 ± 8.07; F(1,10) = 4.70, P = 0.05, d = 0.52). There were no other significant differences in POMS measures.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
An auditory stimulus produced significantly larger phase delays than the control in both DLMO and CBT minimum, representing the first demonstration of such phase shifts in humans. Furthermore, these results indicate that humans, like other species, show circadian sensitivity to sensory stimuli, and as such, they add to the growing database of nonphotic stimuli that phase-shift human circadian rhythms. Auditory stimuli may be beneficial in situations requiring circadian adaptation, which result from altered timing and changes in the light-dark cycle, such as transmeridian travel or shift work.

This study's results extend findings obtained in birds and nonhuman mammals that demonstrate phase-shifting effects of various conspecific and nonconspecific auditory stimuli on circadian rhythms (14, 24, 26, 32, 50, 52, 61, 64). Furthermore, the observed phase delays in response to auditory presentation in the early subjective night are comparable in direction and/or relative size to those produced by other nonphotic stimuli in humans, including exercise (3, 6, 10, 12, 74) and triazolam administration (9).

In addition to exercise, the phase delays are consistent in direction with those produced by light. In humans, phase shifts to light occur according to a well-described PRC: light presented before core body temperature minimum induces phase delays, while light presented after core body temperature minimum induces phase advances (36, 54, 73). However, despite an average phase shift of 1.16 h for temperature and 0.89 h for melatonin—and maximum shifts of 1.3–2.0 h—the magnitude of phase delays produced by the auditory stimulus was, on average, smaller than those produced by a single light pulse (31, 36, 54, 73). Direct comparisons between these two stimuli, however, must be qualified since the aforementioned studies used constant routines or free-running protocols, as well as longer light pulse durations and/or more frequent presentations. Such factors, as well as lighting intensity and wavelength, affect the magnitude of photic phase shifts (see Ref. 49). Indeed, when auditory phase shifts are compared with photic phase shifts obtained using protocols under similarly entrained conditions, circadian phase delays are of similar magnitude (e.g., 44, 62, 63, 78). Furthermore, auditory stimulus presentation at other circadian times may produce larger phase delays than those observed in this study.

Despite significant phase delays, there was no relationship between the timing of CBT minimum or DLMO and the size of phase shifts. Such a lack of a relationship presumably is due to the small range of time points (3.5–4.0 h) during which the stimulus was presented (i.e., limited to early subjective night) and has been found in other studies using photic and nonphotic stimuli (3, 31). At present, it remains unknown whether an auditory PRC will include an advance region and/or dead zone when the stimulus is presented in the morning after CBT minimum or in the afternoon and early evening, before DLMO. Thus, despite its similarity to both light and exercise in the early subjective night, whether a complete auditory PRC will resemble light or exercise or neither stimulus awaits further investigation.

The mean phase delays of the circadian temperature and melatonin rhythms produced by the auditory stimulus showed large effect sizes compared with the control. Smaller mean phase changes were observed for DLMO compared with CBT minimum, as has been noted in numerous other studies using nonphotic and photic stimuli (19, 31, 42, 68, 80). DLMO is less susceptible than CBT minimum to masking effects, and it is therefore considered a more sensitive marker (38, 47, 48). Such decreased susceptibility is evidenced in this study by the smaller variation in DLMO phase changes, particularly in the auditory condition; other studies also have shown smaller variations in DLMO (3, 31, 38).

Both CBT minimum and DLMO were closely related at baseline in the control and stimulus sessions and also were closely related to each other, demonstrating internal stability for each phase marker and a consistent temporal relationship between markers within individuals (3, 10, 40, 67, 73, 80). Furthermore, the direction and magnitude of DLMO and CBT minimum phase shifts were positively related to each other, indicating a direct effect on the intrinsic circadian timing system, in concordance with other studies (e.g., 7, 18, 19, 23, 31, 40, 67). At baseline and postexposure, DLMO occurred between 7.13 h and 7.19 h before CBT minimum, with the two markers showing a positive relationship similar to previous reports from other laboratories (e.g., 8, 13, 23).

The dim light control protocol induced small phase delays (0.27–0.44 h) in the circadian melatonin and temperature rhythms, respectively. Various other laboratories using dim light conditions have reported phase delays of approximately similar size (a 0.2 h delay per day; 3, 6, 7, 10, 12, 19, 31, 67, 73). These delays are likely due to the slightly longer than 24 h endogenous human pacemaker period length (e.g., 18, 36, 79) and to the fact that subjects were required to remain in darkness until 12 noon, thereby missing the normal phase advance to morning light.

The auditory stimulus used in this study has several potential advantages over other nonphotic stimuli such as exercise. Exercise increases body temperature (10) and affects melatonin concentration (3, 10, 12, 15, 58); although unknown, it is unlikely that the auditory stimulus directly affects either of these physiological variables. Moreover, some subjects may find exercise strenuous or inconvenient and thus not feasible; by contrast, the auditory stimulus is easily administered. The auditory stimulus also may be beneficial for a heterogeneous population, since both young and older subjects showed phase delays; similarly, older individuals have shown phase-shifting responses to exercise (3). Further research using larger sample sizes is needed to determine whether the circadian phase-shifting effects of auditory stimuli differ by age; if no such differences exist, this auditory stimulus may be a viable, easily administered nonpharmacologic alternative to exercise or bright light in the elderly.

The results from this study suggest that environmental sounds may phase-shift light-dark and sleep-wake schedules in humans. However, it is unknown which particular component of the stimulus produces circadian phase shifts. In other species, auditory stimuli without ecological content phase shift circadian rhythms (50, 61); therefore, any sound component of the stimulus, and not necessarily the bird song melody, may be the salient cue. Thus sound may have confounded other circadian studies in which the timing of lights on and off, and therefore wake time and bedtime, was announced acoustically (see Ref. 77). Interestingly, auditory deprivation also affects circadian rhythms. For example, hearing-impaired children show a higher incidence of circadian rhythm disorders compared with nonimpaired children (60). In golden hamsters, cochlear lesions decrease locomotor rhythm amplitude and delay phase angles but do not alter the reentrainment rate to an 8-h phase advance or alter tau (17). Finally, the circadian respiratory rhythm amplitude (as measured by carbon dioxide emission) is higher in deaf compared with nondeaf mice (70).

The auditory stimulus decreased fatigue scores compared with the control stimulus on night 3, indicating that this particular stimulus may be arousing. An alerting auditory stimulus could significantly increase cutaneous sympathetic nerve activity and produce vasoconstriction, which could lead to reduced heat loss and phase delays of the circadian body temperature rhythm (see Refs. 5 and 41). Of interest, other nonphotic stimuli produce acute states of elevated activity/arousal that relate to circadian phase shifts (reviewed in Refs. 55 and 59). It should be noted, however, that in a previous study, this particular auditory stimulus lowered POMS anger scores within 15 min of exposure (25) and was rated as mildly sedative (3.47 ± 0.18 on a 7-point Likert scale ranging from "very sedative" to "very stimulating"; N. Goel and G. Etwaroo, unpublished observations). Differences in the two sets of results may be due to the timing of stimulus presentation: in the latter study, the stimulus was presented between 1900 and 2100, while in the present study, the stimulus was presented from 0100 to 0300, when subjects normally do not experience such cues. Thus whether the stimulus is arousing or relaxing remains to be clarified. Other possible putative mechanisms include nonspecific correlates of behavioral state such as hormonal changes (reviewed in Ref. 55).

At present, the neuroanatomical pathways mediating auditory stimuli's effects on the circadian system are unknown. Auditory stimuli are transduced from the ear to the auditory cortex through a well-characterized multisynaptic pathway, including the cochlear nucleus, superior olivary nucleus, the inferior colliculus (IC), and the medial geniculate nucleus (27). Some of these nuclei have connections to the SCN in rodents. For example, the IC projects directly to the suprachiasmatic nuclei (SCN) in rats (43) and indirectly to the SCN via the lateral geniculate nucleus in common moles (21, 45). The intergeniculate leaflet (IGL) also projects directly to the SCN. The IGL mediates nonphotic stimuli such as wheel access and triazolam in hamsters (59); however, it does not mediate all nonphotic information, and thus its role may vary by species and/or stimulus (28). Notably, both the IGL and SCN in rats contain the orphan nuclear receptor, ROR{beta}, which regulates genes whose products are involved in both sensory input integration and circadian timing (65). Finally, the paraventricular thalamic nucleus and raphe nucleus both project to the SCN directly in rats and have been implicated in nonphotic entrainment (1, 57).

Perspectives

Beyond providing information about the formal properties of the human biological clock, this study's results have valuable applications for facilitating adaptation of circadian rhythms. The auditory stimulus used in this study may be useful for phase-advanced elderly subjects who cannot tolerate bright light treatment and may be advantageous in situations where light is improperly timed or insufficient, such as following transmeridian travel or shift work or during space travel. Furthermore, the auditory stimulus may benefit the blind and those with circadian rhythm-based sleep disorders, such as advanced sleep phase syndrome. Finally, the auditory stimulus may serve as an easily administered adjuvant to light or exercise, since these latter two stimuli also phase delay circadian rhythms during the early subjective night.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This research was supported in part by National Institutes of Health Grant AG-16113 (N. Goel).


   ACKNOWLEDGMENTS
 
Thanks to the following individuals for excellent assistance in data collection: Deborah Clark, Damion Grasso, Hyungsoo Kim and Ying-Ju Lai. I also thank three anonymous reviewers for constructive and helpful comments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: N. Goel, Dept. of Psychology, 207 High St., Judd Hall, Wesleyan Univ., Middletown, CT 06459 (E-mail: ngoel{at}wesleyan.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Amir S and Stewart J. Conditioning in the circadian system. Chronobiol Int 15: 447–456, 1998.[ISI][Medline]
  2. Aschoff J, Fatranska M, Giedke H, Doerr P, Stamm D, and Wisser H. Human circadian rhythms in continuous darkness: entrainment by social cues. Science 171: 213–215, 1971.[Abstract/Free Full Text]
  3. Baehr EK, Eastman CI, Revelle W, Olson SH, Wolfe LF, and Zee PC. Circadian phase-shifting effects of nocturnal exercise in older compared with young adults. Am J Physiol Regul Integr Comp Physiol 284: R1542–R1550, 2003.[Abstract/Free Full Text]
  4. Baehr EK, Revelle W, and Eastman CI. Individual differences in the phase and amplitude of the human circadian temperature rhythm: with an emphasis on morningness-eveningness. J Sleep Res 9: 117–127, 2000.[CrossRef][ISI][Medline]
  5. Baker MA, Cronin MJ, and Mountjoy DG. Variability of skin temperature in the waking monkey. Am J Physiol 230: 449–455, 1976.[Abstract/Free Full Text]
  6. Barger LK, Wright KP Jr, Hughes RJ, and Czeisler CA. Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light. Am J Physiol Regul Integr Comp Physiol 286: R1077–R1084, 2004.[Abstract/Free Full Text]
  7. Boivin DB and Czeisler CA. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light. Neuroreport 9: 779–782, 1998.[ISI][Medline]
  8. Brown EN, Choe Y, Shanahan TL, and Czeisler CA. A mathematical model of diurnal variations in human plasma melatonin levels. Am J Physiol Endocrinol Metab 272: E506–E516, 1997.[Abstract/Free Full Text]
  9. Buxton OM, Copinschi G, Van Onderbergen A, Karrison TG, and Van Cauter E. A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag. Sleep 23: 915–927, 2000.[ISI][Medline]
  10. Buxton OM, Frank SA, L'Hermite-Balériaux M, Leproult R, Turek FW, and Van Cauter E. Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms. Am J Physiol Endocrinol Metab 273: E536–E542, 1997.[Abstract/Free Full Text]
  11. Buxton OM, L'Hermite-Balériaux M, Turek FW, and Van Cauter E. Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion. Am J Physiol Regul Integr Comp Physiol 278: R373–R382, 2000.[Abstract/Free Full Text]
  12. Buxton OM, Lee CW, L'Hermite-Balériaux M, Turek FW, and Van Cauter E. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am J Physiol Regul Integr Comp Physiol 284: R714–R724, 2003.[Abstract/Free Full Text]
  13. Cagnacci A, Soldani R, Laughlin GA, and Yen SS. Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin. J Appl Physiol 80: 25–29, 1996.[Abstract/Free Full Text]
  14. Cain JR and Wilson WO. The influence of specific environmental parameters on the circadian rhythms of chickens. Poult Sci 53: 1438–1447, 1974.[ISI][Medline]
  15. Carr DB, Reppert SM, Bullen B, Skrinar G, Beitins I, Arnold M, Rosenblatt M, Martin JB, and McArthur JW. Plasma melatonin increases during exercise in women. J Clin Endocrinol Metab 53: 224–225, 1981.[Abstract]
  16. Cohen J. Statistical Power Analysis for the Behavioral Sciences (2nd ed). Hillsdale: Lawrence Erlbaum Associates, 1988.
  17. Cutrera R, Pedemonte M, Vanini G, Goldstein N, Savorini D, Cardinali DP, and Velluti RA. Auditory deprivation modifies biological rhythms in the golden hamster. Arch Ital Biol 138: 285–293, 2000.[ISI][Medline]
  18. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW, Ronda JM, Silva EJ, Allan JS, Emens JS, Dijk DJ, and Kronauer RE. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284: 2177–2181, 1999.[Abstract/Free Full Text]
  19. Danilenko KV, Cajochen C, and Wirz-Justice A. Is sleep per se a zeitgeber in humans? J Biol Rhythms 18: 170–178, 2003.[Abstract]
  20. Davidson AJ and Menaker M. Birds of a feather clock together—sometimes: social synchronization of circadian rhythms. Curr Opin Neurobiol 13: 765–769, 2003.[CrossRef][ISI][Medline]
  21. Doron N and Wollberg Z. Cross-modal neuroplasticity in the blind mole rat Spalax ehrenbergi: a WGA-HRP tracing study. Neuroreport 5: 2697–2701, 1994.[ISI][Medline]
  22. Eastman CI, Hoese EK, Youngstedt SD, and Liu L. Phase-shifting human circadian rhythms with exercise during the night shift. Physiol Behav 58: 1287–1291, 1995.[CrossRef][Medline]
  23. Eastman CI, Martin SK, and Hebert M. Failure of extraocular light to facilitate circadian rhythm reentrainment in humans. Chronobiol Int 17: 807–826, 2000.[CrossRef][ISI][Medline]
  24. Erkert HG and Schardt U. Social entrainment of circadian activity rhythms in common marmosets, Callithrix j. jacchus (Primates). Ethology 87: 189–202, 1991.
  25. Etwaroo GR and Goel N. Bright light, negative ions and auditory stimuli: effects of short-term exposure on transient mood and sleepiness in depressed and nondepressed young adults. Chronobiol Int 21: 785–786, 2004.
  26. Fuller CA, Lydic R, Sulzman FM, Albers HE, Tepper B, and Moore-Ede M. C. Auditory entrainment of primate drinking rhythms following partial suprachiasmatic nuclei lesions. Physiol Behav 31: 573–576, 1983.[CrossRef][Medline]
  27. Gilman S, Winans Newman S, Manter JT, and Gatz AJ. Manter and Gatz's Essentials of Clinical Neuroanatomy and Neurophysiology. Philadelphia: F. A. Davis, 2002.
  28. Goel N, Governale MM, Jechura TJ, and Lee TM. Effects of intergeniculate leaflet lesions on circadian rhythms in Octodon degus. Brain Res 877: 306–313, 2000.[CrossRef][ISI][Medline]
  29. Goichot B, Weibel L, Chapotot F, Gronfier C, Piquard F, and Brandenberger G. Effect of the shift of the sleep-wake cycle on three robust endocrine markers of the circadian clock. Am J Physiol Endocrinol Metab 275: E243–E248, 1998.[Abstract/Free Full Text]
  30. Gordijn MC, Beersma DG, Korte HJ, and van den Hoofdakker RH. Effects of light exposure and sleep displacement on dim light melatonin onset. J Sleep Res 8: 163–174, 1999.[CrossRef][ISI][Medline]
  31. Gronfier C, Wright KP Jr, Kronauer RE, Jewett ME, and Czeisler CA. Efficacy of a single sequence of intermittent bright light pulses for delaying circadian phase in humans. Am J Physiol Endocrinol Metab 287: E174–E181, 2004.[Abstract/Free Full Text]
  32. Gwinner E. Periodicity of a circadian rhythm in birds by species-specific song cycles (Aves, Fringillidae: Carduelis spinus, serinus serinus). Experientia 22: 765–766, 1966.[CrossRef]
  33. Holand S, Girard A, Laude D, Meyer-Bisch C, and Elghozi JL. Effects of an auditory startle stimulus on blood pressure and heart rate in humans. J Hypertens 17: 1893–1897, 1999.[CrossRef][ISI][Medline]
  34. Honma K, Honma S, Nakamura K, Sasaki M, Endo T, and Takahashi T. Differential effects of bright light and social cues on reentrainment of human circadian rhythms. Am J Physiol Regul Integr Comp Physiol 268: R528–R535, 1995.[Abstract/Free Full Text]
  35. Horne JA and Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 4: 97–110, 1976.[Medline]
  36. Khalsa SB, Jewett ME, Cajochen C, and Czeisler CA. A phase response curve to single bright light pulses in human subjects. J Physiol 549: 945–952, 2003.[Abstract/Free Full Text]
  37. Klein KE and Wegmann HM. The resynchronization of human circadian rhythms after transmeridian flights as a result of flight direction and mode of activity. In: Chronobiology, edited by Scheving LE, Halberg F, and Pauly JE. Tokyo: Igaku, 1974, p. 564–570.
  38. Klerman EB, Gershengorn HB, Duffy JF, and Kronauer RE. Comparisons of the variability of three markers of the human circadian pacemaker. J Biol Rhythms 17: 181–193, 2002.[Abstract]
  39. Klerman EB, Rimmer DW, Dijk DJ, Kronauer RE, Rizzo JF III, and Czeisler CA. Nonphotic entrainment of the human circadian pacemaker. Am J Physiol Regul Integr Comp Physiol 274: R991–R996, 1998.[Abstract/Free Full Text]
  40. Kräuchi K, Cajochen C, Mori D, Graw P, and Wirz-Justice A. Early evening melatonin and S-20098 advance circadian phase and nocturnal regulation of core body temperature. Am J Physiol Regul Integr Comp Physiol 272: R1189–R1196, 1997.[Abstract/Free Full Text]
  41. Kräuchi K, Cajochen C, Werth E, and Wirz-Justice A. Functional link between distal vasodilation and sleep-onset latency? Am J Physiol Regul Integr Comp Physiol 278: R741–R748, 2000.[Abstract/Free Full Text]
  42. Kräuchi K, Cajochen C, Werth E, and Wirz-Justice A. Alteration of internal circadian phase relationships after morning versus evening carbohydrate-rich meals in humans. J Biol Rhythms 17: 364–376, 2002.[Abstract]
  43. Krout KE, Kawano J, Mettenleiter TC, and Loewy AD. CNS inputs to the suprachiasmatic nucleus of the rat. Neuroscience 110: 73–92, 2002.[CrossRef][ISI][Medline]
  44. Kubota T, Uchiyama M, Suzuki H, Shibui K, Kim K, Tan X, Tagaya H, Okawa M, and Inoué S. Effects of nocturnal bright light on saliva melatonin, core body temperature, and sleep propensity rhythms in human subjects. Neurosci Res 42: 115–122, 2002.[CrossRef][ISI][Medline]
  45. Kudo M, Moriya M, and Mizuno N. Auditory projections from the IC to the SCN by way of the LG in the mole, Mogera. Neuroreport 8: 3405–3409, 1997.[ISI][Medline]
  46. Lewy AJ, Bauer VK, Ahmed S, Thomas KH, Cutler NL, Singer CM, Moffit MT, and Sack RL. The human phase response curve (PRC) to melatonin is about 12 hours out of phase with the PRC to light. Chronobiol Int 15: 71–83, 1998.[ISI][Medline]
  47. Lewy AJ and Sack RL. The dim light melatonin onset as a marker for circadian phase position. Chronobiol Int 6: 93–102, 1989.[ISI][Medline]
  48. Lewy AJ and Sack RL. Exogenous melatonin's phase-shifting effects on the endogenous melatonin profile in sighted humans: a brief review and critique of the literature. J Biol Rhythms 12: 588–594, 1997.[Abstract/Free Full Text]
  49. Lockley SW, Brainard GC, and Czeisler CA. High sensitivity of the human circadian melatonin rhythm to resetting by short wavelength light. J Clin Endocrinol Metab 88: 4502–4505, 2003.[Abstract]
  50. Lohmann M and Enright JT. The influence of mechanical noise on the activity rhythms of finches. Comp Biochem Physiol A 22: 289–296, 1967.[CrossRef]
  51. McNair DM, Lorr M, and Droppleman LF. Profile of Mood States (Manual). San Diego: Educational and Industrial Testing Service, 1992.
  52. Menaker M and Eskin A. Entrainment of circadian rhythms by sound in Passer domesticus. Science 154: 1579–1581, 1966.[Abstract/Free Full Text]
  53. Middleton B, Arendt J, and Stone BM. Complex effects of melatonin on human circadian rhythms in constant dim light. J Biol Rhythms 12: 467–477, 1997.[CrossRef][ISI][Medline]
  54. Minors DS, Waterhouse JM, and Wirz-Justice A. A human phase-response curve to light. Neurosci Lett 133: 36–40, 1991.[CrossRef][ISI][Medline]
  55. Mistlberger RE and Skene DJ. Social influences on mammalian circadian rhythms: animal and human studies. Biol Rev Camb Philos Soc 79: 533–556, 2004.[Medline]
  56. Miyazaki T, Hashimoto S, Masubuchi S, Honma S, and Honma KI. Phase-advance shifts of human circadian pacemaker are accelerated by daytime physical exercise. Am J Physiol Regul Integr Comp Physiol 281: R197–R205, 2001.[Abstract/Free Full Text]
  57. Moga MM and Moore RY. Organization of neural inputs to the suprachiasmatic nucleus in the rat. J Comp Neurol 389: 508–534, 1997.[CrossRef][ISI][Medline]
  58. Monteleone P, Maj M, Fusco M, Orazzo C, and Kemali D. Physical exercise at night blunts the nocturnal increase of plasma melatonin levels in healthy humans. Life Sci 47: 1989–1995, 1990.[CrossRef][ISI][Medline]
  59. Mrosovsky N. Locomotor activity and nonphotic influences on circadian clocks. Biol Rev Camb Philos Soc 71: 343–372, 1996.[Medline]
  60. Oishibashi Y, Kakizawa T, Otsuka A, Kawama K, Sato Y, Suzuki M, and Sasaki H. Disturbances of sleep and waking in handicapped children (II): Trend of circadian rhythm disorders in deaf children. Jpn J Psychiatry Neurol 47: 464–465, 1993.[Medline]
  61. Reebs SG. Acoustical entrainment of circadian activity rhythms in house sparrows: constant light is not necessary. Ethology 80: 171–181, 1989.
  62. Rüger M, Gordijn MC, Beersma DG, de Vries B, and Daan S. Acute and phase-shifting effects of ocular and extraocular light in human circadian physiology. J Biol Rhythms 18: 409–419, 2003.[Abstract]
  63. Rüger M, Gordijn MC, Beersma DG, de Vries B, and Daan S. Nasal versus temporal illumination of the human retina: effects on core body temperature, melatonin, and circadian phase. J Biol Rhythms 20: 60–70, 2005.[Abstract]
  64. Savory CJ. Effects of different lighting regimes on diurnal feeding patterns of the domestic fowl. Br Poult Sci 17: 341–350, 1976.
  65. Schaeren-Wiemers N, Andre E, Kapfhammer JP, and Becker-Andre M. The expression pattern of the orphan nuclear receptor ROR{beta} in the developing and adult rat nervous system suggests a role in the processing of sensory information and in circadian rhythm. Eur J Neurosci 9: 2687–2701, 1997.[CrossRef][ISI][Medline]
  66. Schiffman SS, Sattely Miller EA, Suggs MS, and Graham BG. The effect of pleasant odors and hormone status on mood of women at midlife. Brain Res Bull 36: 19–29, 1995.[CrossRef][ISI][Medline]
  67. Shanahan TL, Kronauer RE, Duffy JF, Williams GH, and Czeisler CA. Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker. J Biol Rhythms 14: 237–253, 1999.[Abstract]
  68. Sharkey KM and Eastman CI. Melatonin phase shifts human circadian rhythms in a placebo-controlled simulated night-work study. Am J Physiol Regul Integr Comp Physiol 282: R454–R463, 2002.[Abstract/Free Full Text]
  69. Smith JL and Noon J. Objective measurement of mood change induced by contemporary music. J Psychiatr Ment Health Nurs 5: 403–408, 1998.[CrossRef][Medline]
  70. Stupfel M, Busnel MC, Molin D, Thierry H, and Gourlet V. Respiratory behavior in groups of deaf and nondeaf GFF male mice. Physiol Behav 32: 823–830, 1984.[CrossRef][Medline]
  71. Unwin MM, Kenny DT, and Davis PJ. The effects of group singing on mood. Psychol Music 30: 175–185, 2002.
  72. Van Cauter E, Moreno-Reyes R, Akseki E, L'Hermite-Balériaux M, Hirschfeld U, Leproult R, and Copinschi G. Rapid phase advance of the 24-h melatonin profile in response to afternoon dark exposure. Am J Physiol Endocrinol Metab 275: E48–E54, 1998.[Abstract/Free Full Text]
  73. Van Cauter E, Sturis J, Byrne MM, Blackman JD, Leproult R, Ofek G, L'Hermite-Balériaux M, Refetoff S, Turek FW, and Van Reeth O. Demonstration of rapid light-induced advances and delays of the human circadian clock using hormonal phase markers. Am J Physiol Endocrinol Metab 266: E953–E963, 1994.[Abstract/Free Full Text]
  74. Van Reeth O, Sturis J, Byrne MM, Blackman JD, L'Hermite-Balériaux M, Leproult R, Oliner C, Refetoff S, Turek FW, and Van Cauter E. Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men. Am J Physiol Endocrinol Metab 266: E964–E974, 1994.[Abstract/Free Full Text]
  75. Wechselberger E. Phase-shifting effects of arousal on circadian activity rhythms in Callithrix j. jacchus. In: Current Primatology, vol. 3, edited by Anderson JR, Roeder JJ, Thierry B, and Herrenschmidt N. Strasbourg: Universite Louis Pasteur, 1994, p. 223–226.
  76. Wever RA. The Circadian System of Man. Results of Experiments Under Temporal Isolation. New York: Springer-Verlag, 1979.
  77. Wever RA. Light effects on human circadian rhythms: a review of recent Andechs experiments. J Biol Rhythms 4: 161–185, 1989.[ISI][Medline]
  78. Wirz-Justice A, Kräuchi K, Cajochen C, Danilenko KV, Renz C, and Weber JM. Evening melatonin and bright light administration induce additive phase shifts in dim light melatonin onset. J Pineal Res 36: 192–194, 2004.[CrossRef][ISI][Medline]
  79. Wright KP Jr, Hughes RJ, Kronauer RE, Dijk DJ, and Czeisler CA. Intrinsic near-24-hour pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans. Proc Natl Acad Sci USA 98: 14,027–14,032, 2001.[Free Full Text]
  80. Youngstedt SD, Kripke DF, and Elliott JA. Circadian phase-delaying effects of bright light alone and combined with exercise in humans. Am J Physiol Regul Integr Comp Physiol 282: R259–R266, 2002.[Abstract/Free Full Text]
  81. Zaidan R, Geoffriau M, Brun J, Taillard J, Bureau C, Chazot G, and Claustrat B. Melatonin is able to influence its secretion in humans: description of a phase-response curve. Neuroendocrinology 60: 105–112, 1994.[ISI][Medline]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
N. Goel
An arousing, musically enhanced bird song stimulus mediates circadian rhythm phase advances in dim light
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R822 - R827.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/1/R209    most recent
00754.2004v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Goel, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Goel, N.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.