Circadian rhythm of brain self-stimulation behavior.

Under constant conditions of light, sound, temperature, and humidity, rats exhibited circadian rhythmicity in rate of bar-pressing with hypothalamic and septal reinforcing brain stimulation. Variations in reinforcer magnitude aflected absolute levels of operant response emission but not the frequency of the circadian rhythm. In long sessions, the time of peak responding deviated systematically from a strict 24-hour period. Such data show marked similarity to free-running rhythms of motor activity.

A controlled trial of timed bright light and negative air ionization for treatment of winter depression.

BACKGROUND: Artificial bright light presents a promising nonpharmacological treatment for seasonal affective disorder. Past studies, however, have lacked adequate placebo controls or sufficient power to detect group differences. The importance of time of day of treatment--specifically, morning light superiority--has remained controversial. METHODS: This study used a morning x evening light crossover design balanced by parallel-group controls, in addition to a nonphotic control, negative air ionization. Subjects with seasonal affective disorder (N = 158) were randomly assigned to 6 groups for 2 consecutive treatment periods, each 10 to 14 days. Light treatment sequences were morning-evening, evening-morning, morning-morning, and evening-evening (10,000 lux, 30 min/d). Ion density was 2.7 x 10(6) (high) or 1.0 x 10(4) (low) ions per cubic centimeter (high-high and low-low sequences, 30 min/d in the morning). RESULTS: Analysis of depression scale percentage change scores showed low-density ion response to be inferior to all other groups, with no other group differences. Response to evening light was reduced when preceded by treatment with morning light, the sole sequence effect. Stringent remission criteria, however, showed significantly higher response to morning than evening light, regardless of treatment sequence. CONCLUSIONS: Bright light and high-density negative air ionization both appear to act as specific antidepressants in patients with seasonal affective disorder. Whether clinical improvement would be further enhanced by their use in combination, or as adjuvants to medication, awaits investigation.

Circadian time of morning light administration and therapeutic response in winter depression.

BACKGROUND: We investigated a possible mechanism of action for the antidepressant response to light-phase advances of the circadian clock-by measuring the onset of melatonin secretion before and after light treatment in the morning or evening. METHODS: Plasma melatonin was sampled in 42 patients with seasonal affective disorder, in the evening or overnight while depressed and after 10 to 14 days of light therapy (10 000 lux for 30 minutes) when symptoms were reassessed. RESULTS: Morning light produced phase advances of the melatonin rhythm, while evening light produced delays, the magnitude depending on the interval between melatonin onset and light exposure, or circadian time (morning, 7.5 to 11 hours; evening, 1.5 to 3 hours). Delays were larger the later the evening light (r = 0.40), while advances were larger the earlier the morning light (r = 0.50). Although depression ratings were similar with light at either time of day, response to morning light increased with the size of phase advances up to 2.7 hours (r = 0.44) regardless of baseline phase position, while there was no such correlation for evening light. In an expanded sample (N = 80) with the sleep midpoint used as a reference anchor for circadian time, early morning light exposure was superior to late morning and to evening exposure. CONCLUSION: The antidepressant effect of light is potentiated by early-morning administration in circadian time, optimally about 8.5 hours after melatonin onset or 2.5 hours after the sleep midpoint.

The visual input stage of the mammalian circadian pacemaking system: II. The effect of light and drugs on retinal function.

Acute light pulses as well as long-term light exposure may not only modulate photoreceptive properties, but also induce reversible or irreversible damage to the retina, depending on exposure conditions. Illuminance levels in laboratory animal colonies and manipulations of lighting regimens in circadian rhythm research can threaten retinal structure and physiology, and may therefore modify zeitgeber input to the central circadian system. Given the opportunity to escape light at any time, the nocturnal rat self-selects a seasonally varying "naturalistic skeleton photoperiod" that protects the eyes from potential damage by nonphysiological light exposures. Both rod rod-segment disk shedding and behavioral circadian phase shifts are elicited by low levels of twilight stimulation. From this vantage point, we hypothesize that certain basic properties of circadian rhythms (e.g., Aschoff's rule and splitting) may reflect modulation of retinal physiology by light. Pharmacological manipulations with or without the addition of lighting strategies have been used to analyze the neurochemistry of circadian timekeeping. Drug modulation of light input at the level of the retina may add to or interact with direct drug modulation of the central circadian pacemaking system.

The visual input stage of the mammalian circadian pacemaking system: I. Is there a clock in the mammalian eye?

Threads of evidence from recent experimentation in retinal morphology, neurochemistry, electrophysiology, and visual perception point toward rhythmic ocular processes that may be integral components of circadian entrainment in mammals. Components of retinal cell biology (rod outer-segment disk shedding, inner-segment degradation, melatonin and dopamine synthesis, electrophysiological responses) show self-sustaining circadian oscillations whose phase can be controlled by light-dark cycles. A complete phase response curve in visual sensitivity can be generated from light-pulse-induced phase shifting. Following lesions of the suprachiasmatic nuclei, circadian rhythms of visual detectability and rod outer-segment disk shedding persist, even though behavioral activity becomes arrhythmic. We discuss the converging evidence for an ocular circadian timing system in terms of interactions between rhythmic retinal processes and the central suprachiasmatic pacemaker, and propose that retinal phase shifts to light provide a critical input signal.

Photic entrainment in hamsters: effects of simulated twilights and nest box availability.

Entrainment of wheel-running activity rhythms was compared in hamsters exposed to daily light-dark (LD) cycles with abrupt transitions between 0 and 10 lux or with artificial twilights simulating summer solstice conditions at 41 degrees N latitude but truncated at 10 lux. The photoperiod in LD-rectangular was set at 16.24 h, equating the total light (in lux.min) emitted under the two schedules. The LD cycles were maintained for 35 days and were followed by 14 days of constant darkness (DD). Half the animals in each condition had access to a dark nest box connected to the outer compartment by a tunnel, the remaining animals being confined to a single compartment. Body temperature and locomotor activity inside the nest boxes were recorded by telemetry. Movements between the nest box and the outer compartment were monitored and the data were used to calculate light exposure at different times of the day. In all groups, the phase angle difference between wheel-running onset and dusk was more positive than that between activity offset and dawn. Hamsters with access to nest boxes, however, had later onsets, earlier offsets, and shorter activity durations (alpha s) than those without. These effects could be accounted for by the difference in light exposure between the nest and no-nest animals, particularly light exposure in the morning. The inclusion of twilights also resulted in later onsets and shorter alpha s, but the differences were relatively small and were only observed in the nest animals. The day-to-day variability in activity onset was negatively correlated with onset time and was smaller in the twilight/nest animals than in the other three groups. Most animals showed an expansion of alpha during the first few days of DD, resulting from a rapid advance of activity onsets relative to offsets. The period of the rhythms, determined from the first five activity onsets in DD, was negatively correlated with the balance of evening and morning light exposure. These results are discussed in the context of nonparametric entrainment of compound pacemakers.

Light treatment for sleep disorders: consensus report. I. Chronology of seminal studies in humans.

Examination of the influence of the light-dark cycle on circadian rhythmicity has been a fundamental aspect of chronobiology since its inception as a scientific discipline. Beginning with Bünning's hypothetical phase response curve in 1936, the impact of timed light exposure on circadian rhythms of literally hundreds of species has been described. The view that the light-dark cycle was an important zeitgeber for the human circadian system, as well, seemed to be supported by early studies of blind and sighted subjects. Yet, by the early 1970s, based primarily on a series of studies conducted at Erling-Andechs, Germany, the notion became widely accepted that the light-dark cycle had only a weak influence on the human circadian system and that social cues played a more important role in entrainment. In 1980, investigators at the National Institute of Mental Health reported that bright light could suppress melatonin production in humans, thereby demonstrating unequivocally the powerful effects of light on the human central nervous system. This finding led directly to the use of timed bright light exposure as a tool for the study and treatment of human circadian rhythms disorders.

Light treatment for sleep disorders: consensus report. II. Basic properties of circadian physiology and sleep regulation.

The rationale for the treatment of sleep disorders by scheduled exposure to bright light in seasonal affective disorder, jet lag, shift work, delayed sleep phase syndrome, and the elderly is, in part, based on a conceptual framework developed by nonclinical circadian rhythm researchers working with humans and other species. Some of the behavioral and physiological data that contributed to these concepts are reviewed, and some pitfalls related to their application to bright light treatment of sleep disorders are discussed. In humans and other mammals the daily light-dark (LD) cycle is a major synchronizer responsible for entrainment of circadian rhythms to the 24-h day, and phase response curves (PRCs) to light have been obtained. In humans, phase delays can be induced by light exposure scheduled before the minimum of the endogenous circadian rhythm of core body temperature (CBT), whereas phase advances are induced when light exposure is scheduled after the minimum of CBT. Since in healthy young subjects the minimum of CBT is located approximately 1 to 2 h before the habitual time of awakening, the most sensitive phase of the PRC to light coincides with sleep, and the timing of the monophasic sleep-wake cycle itself is a major determinant of light input to the pacemaker. The effects of light are mediated by the retinohypothalamic tract, and excitatory amino acids play a key role in the transduction of light information to the suprachiasmatic nuclei. LD cycles have direct "masking" effects on many variables, including sleep, which complicates the assessment of endogenous circadian phase and the interpretation of the effects of light treatment on sleep disorders. In some rodents motor activity has been shown to affect circadian phase, but in humans the evidence for such a feedback of activity on the pacemaker is still preliminary. The endogenous circadian pacemaker is a major determinant of sleep propensity and sleep structure; these, however, are also strongly influenced by the prior history of sleep and wakefulness. In healthy young subjects, light exposure schedules that do not curtail sleep but induce moderate shifts of endogenous circadian phase have been shown to influence the timing of sleep and wakefulness without markedly affecting sleep structure.

Light treatment for sleep disorders: consensus report. III. Alerting and activating effects.

In addition to the well-established phase-shifting properties of timed exposure to bright light, some investigators have reported an acute alerting, or activating, effect of bright light exposure. To the extent that bright light interventions for sleep disturbance may cause subjective and/or central nervous system activation, such a property may adversely affect the efficacy of treatment. Data obtained from patient samples and from healthy subjects generally support the notion that exposure to bright light may be associated with enhanced subjective alertness, and there is limited evidence of objective changes (EEG, skin conductance levels) that are consistent with true physiological arousal. Such activation appears to be quite transient, and there is little evidence to suggest that bright light-induced activation interferes with subsequent sleep onset. Some depressed patients, however, have experienced insomnia and hypomanic activation following bright-light exposure.

Light treatment for sleep disorders: consensus report. IV. Sleep phase and duration disturbances.

Advanced and delayed sleep phase disorders, and the hypersomnia that can accompany winter depression, have been treated successfully by appropriately timed artificial bright light exposure. Under entrainment to the 24-h day-night cycle, the sleep-wake pattern may assume various phase relationships to the circadian pacemaker, as indexed, for example, by abnormally long or short intervals between the onset of melatonin production or the core body temperature minimum and wake-up time. Advanced and delayed sleep phase syndromes and non-24-h sleep-wake syndrome have been variously ascribed to abnormal intrinsic circadian periodicity, deficiency of the entrainment mechanism, or--most simply--patterns of daily light exposure insufficient for adequate phase resetting. The timing of sleep is influenced by underlying circadian phase, but psychosocial constraints also play a major role. Exposure to light early or late in the subjective night has been used therapeutically to produce corrective phase delays or advances, respectively, in both the sleep pattern and circadian rhythms. Supplemental light exposure in fall and winter can reduce the hypersomnia of winter depression, although the therapeutic effect may be less dependent on timing.

Light treatment for sleep disorders: consensus report. V. Age-related disturbances.

Sleep maintenance insomnia is a major complaint among the elderly. As a result, an inordinate proportion of sleeping pill prescriptions go to individuals over 65 y of age. Because of the substantial problems associated with use of hypnotics in older populations, efforts have been made to develop nondrug treatments for age-related sleep disturbance, including timed exposure to bright light. Such bright light treatments are based on the assumption that age-related sleep disturbance is the consequence of alterations in the usual temporal relationship between body temperature and sleep. Although studies are limited, results strongly suggest that evening bright light exposure is beneficial in alleviating sleep maintenance insomnia in healthy elderly subjects. Less consistent, but generally positive, findings have been reported with regard to bright light treatment of sleep and behavioral disturbance in demented patients. For both groups, it is likely that homeostatic factors also contribute to sleep disturbance, and these may be less influenced by bright light interventions.

Light treatment for sleep disorders: consensus report. VI. Shift work.

The unhealthy symptoms and many deleterious consequences of shift work can be explained by a mismatch between the work-sleep schedule and the internal circadian rhythms. This mismatch occurs because the 24-h zeitgebers, such as the natural light-dark cycle, keep the circadian rhythms from phase shifting to align with the night-work, day-sleep schedule. This is a review of studies in which the sleep schedule is shifted several hours, as in shift work, and bright light is used to try to phase shift circadian rhythms. Phase shifts can be produced in laboratory studies, when subjects are kept indoors, and faster phase shifting occurs with appropriately timed bright light than with ordinary indoor (dim) light. Bright light field studies, in which subjects live at home, show that the use of artificial nocturnal bright light combined with enforced daytime dark (sleep) periods can phase shift circadian rhythms despite exposure to the conflicting 24-h zeitgebers. So far, the only studies on the use of bright light for real shift workers have been conducted at National Aeronautics and Space Administration (NASA). In general, the bright light studies support the idea that the control of light and dark can be used to overcome many of the problems of shift work. However, despite ongoing practical applications (such as at NASA), much basic research is still needed.

Light treatment for sleep disorders: consensus report. VII. Jet lag.

Sleep disturbances are an all-too-familiar symptom of jet lag and a prime source of complaints for transmeridian travelers and flight crews alike. They are the result of a temporary loss of synchrony between an abruptly shifted sleep period, timed in accordance with the new local day-night cycle, and a gradually reentraining circadian system. Scheduled exposure to bright light can, in principle, alleviate the symptoms of jet lag by accelerating circadian reentrainment to new time zones. Laboratory simulations, in which sleep time is advanced by 6 to 8 h and the subjects exposed to bright light for 3 to 4 h during late subjective night on 2 to 4 successive days, have not all been successful. The few field studies conducted to date have had encouraging results, but their applicability to the population at large remains uncertain due to very limited sample sizes. Unresolved issues include optimal times for light exposure on the first as well as on subsequent treatment days, whether a given, fixed, light exposure time is likely to benefit a majority of travelers or whether light treatment should be scheduled instead according to some individual circadian phase marker, and if so, can such a phase marker be found that is both practical and reliable.

The human circadian pacemaker can see by the dawn's early light.

The authors' previous experiments have shown that dawn simulation at low light intensities can phase advance the circadian rhythm of melatonin in humans. The aim of this study was to compare the effect of repeated dawn signals on the phase position of circadian rhythms in healthy participants kept under controlled light conditions. Nine men participated in two 9-day laboratory sessions under an LD cycle 17.5:6.5 h, < 30:0 lux, receiving 6 consecutive daily dawn (average illuminance 155 lux) or control light (0.1 lux) signals from 0600 to 0730 h (crossover, random-order design). Two modified constant routine protocols before and after the light stimuli measured salivary melatonin (dim light melatonin onset DLMOn and offset DLMOff) and rectal temperature rhythms (midrange crossing time [MRCT]). Compared with initial values, participants significantly phase delayed after 6 days under control light conditions (at least -42 min DLMOn, -54 min DLMOff, -41 min MRCT) in spite of constant bedtimes. This delay was not observed with dawn signals (+10 min DLMOn, +2 min DLMOff, 0 min MRCT). Given that the endogenous circadian period of the human circadian pacemaker is slightly longer than 24 h, the findings suggest that a naturalistic dawn signal is sufficient to forestall this natural delay drift. Zeitgeber transduction and circadian system response are hypothesized to be tuned to the time-rate-of-change of naturalistic twilight signals.

Food availability and daily biological rhythms.

Restricted daily feeding schedules result in the partial or complete synchronization of a wide range of rhythmic biological functions in rodents. In some cases, exemplified by drinking behavior and liver tyrosine transaminase activity, this represents primarily a direct, exogenous influence of food intake. In others, synchronization is achieved by entrainment of a circadian time-keeping mechanism distinct from that which underlies free-running rhythms in these functions. This food-entrained mechanism is responsible for the timing of anticipatory increases in locomotor and lever-pressing activity immediatley prior to food delivery, and may also underlie similar anticipatory increases in body temperature, corticosterone secretion, and in the activities of some intestinal enzymes. It is suggested that such a mechanism may enable an animal to recognize and take advantage of the periodic recurrence of significant events in its biotic environment.

Photopic and scotopic light detection in patients with seasonal affective disorder and control subjects.

BACKGROUND: Retinal sensitivity may play a role in the pathogenesis of seasonal affective disorder (SAD) and response to light therapy. METHODS: Using a dark adaptation procedure, SAD patients and normal control subjects were tested in the winter and summer, with patients retested after light treatment. The eyes were preadapted to bright light followed by 30 min in darkness, during which subjects detected a dim signal titrated around the detection threshold. Photopic (cone-mediated) and scotopic (rod-mediated) components of the data were identified by nonlinear exponential curve fits to successive threshold estimates. RESULTS: Patients (n = 24) showed significantly lower cone and rod thresholds in the summer than winter, while control subjects (n = 12) showed a similar trend. Relative to the control subjects, however, patients were supersensitive in winter (lower cone final threshold, faster rod recovery). Clinical responders to morning light showed a small summer-like increase in cone sensitivity, whereas nonresponders became subsensitive. In comparison to darker-eyed patients, blue-eyed patients showed a larger summertime increase in cone sensitivity and a similar trend after response to morning light. CONCLUSIONS: Heightened retinal sensitivity with increased light exposure, and supersensitivity of patients relative to control subjects in winter, may play roles in the pathogenesis of winter depression and the action of therapeutic light.

Predictors of response and nonresponse to light treatment for winter depression.

OBJECTIVE: The authors' goal was to determine whether the pattern and severity of depressive symptoms predict response to light treatment for seasonal affective disorder. METHOD: Subjects with winter depression (N = 103) were given bright light treatment. Seventy-one were classified as responders, 15 as nonresponders, and 17 as partial responders. Using depression rating scale data and correlational and multivariate analysis, the authors sought predictors of response in baseline symptom and scale scores. RESULTS: Responders were characterized by atypical symptoms, especially hypersomnia, afternoon or evening slump, reverse diurnal variation (evenings worse), and carbohydrate craving. By contrast, nonresponders were characterized mainly by melancholic symptoms, retardation, suicidality, depersonalization, typical diurnal variation (mornings worse), anxiety, early and late insomnia, appetite loss, and guilt. The ratio of atypical to classical symptoms of depression, rather than severity per se, best predicted treatment outcome for the group as a whole. Pretreatment expectations were positively correlated with improvement on the Hamilton Depression Rating Scale but not on a supplementary scale of atypical symptoms. CONCLUSIONS: Light-responsive seasonal affective disorder is distinguished by a dominant atypical symptom profile closely associated with depressed mood. Nonresponders from a clinically distinct group with melancholic features. The patient's symptom profile, therefore, should be considered when diagnosing seasonal affective disorder and selecting treatment.

Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial.

OBJECTIVE: The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag. METHOD: This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting schedule) for jet lag. The subjects were 257 Norwegian physicians who had visited New York for 5 days. Jet lag ratings were made on the day of travel from New York back to Oslo (6 hours eastward) and for the next 6 days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, that identifies prominent daytime symptoms of jet lag distress. RESULTS: There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next 5 days. However, there were no significant group differences or group-by-time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r = 0.54 on the day of travel to a high of r = 0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study. CONCLUSIONS: The use of melatonin for preventing jet lag needs further study.

Light therapy for seasonal affective disorder. A review of efficacy.

Bright artificial light has been found effective in reducing winter depressive symptoms of Seasonal Affective Disorder, although conclusions about the true magnitude of treatment effect and importance of time of day of light exposure have been limited by methodologic problems. Individual subjects' data from 14 research centers studying 332 patients over 5 years were analyzed with a pooled clustering technique. Overall, 2500-lux intensity light exposure for at least 2 hours daily for 1 week resulted in significantly more remissions--Hamilton Depression Rating Scale (HAM-D) score reduction of 50% or more to a level under 8--when administered in the early morning (53%) than in the evening (38%) or at midday (32%). All three times were significantly more effective than dim light controls (11%). Dual daily exposures (morning-plus-evening light) provided no benefit over morning light alone. In morning-evening crossovers, remission rates were 62% under morning light alone, compared with 28% under evening light alone, with a differential morning-evening response present in 59% of morning responders compared with 10% of evening responders (p less than 0.001). Remission rates with morning light were highest given low severity at baseline (HAM-D score of 10-16: 67% remission), as compared with moderate-to-severe cases (HAM-D score above 16: approximately 40% remission) where no morning-evening differences were found. Firmer conclusions await treatment studies with larger sample sizes and full assessment of atypical vegetative symptoms seen in winter depression but underrepresented in the Hamilton scale. Longer treatment course and greater light intensity may help clarify clinical response despite the impossibility of achieving a conventional blind placebo control.

Chronic fatigue syndrome and seasonal affective disorder: comorbidity, diagnostic overlap, and implications for treatment.

This study aimed to determine symptom patterns in patients with chronic fatigue syndrome (CFS), in summer and winter. Comparison data for patients with seasonal affective disorder (SAD) were used to evaluate seasonal variation in mood and behavior, atypical neurovegetative symptoms characteristic of SAD, and somatic symptoms characteristic of CFS. Rating scale questionnaires were mailed to patients previously diagnosed with CFS. Instruments included the Personal Inventory for Depression and SAD (PIDS) and the Systematic Assessment for Treatment Emergent Effects (SAFTEE), which catalogs the current severity of a wide range of somatic, behavioral, and affective symptoms. Data sets from 110 CFS patients matched across seasons were entered into the analysis. Symptoms that conform with the Centers for Disease Control and Prevention (CDC) case definition of CFS were rated as moderate to very severe during the winter months by varying proportions of patients (from 43% for lymph node pain or enlargement, to 79% for muscle, joint, or bone pain). Fatigue was reported by 92%. Prominent affective symptoms included irritability (55%), depressed mood (52%), and anxiety (51%). Retrospective monthly ratings of mood, social activity, energy, sleep duration, amount eaten, and weight change showed a coherent pattern of winter worsening. Of patients with consistent summer and winter ratings (n = 73), 37% showed high global seasonality scores (GSS) > or = 10. About half this group reported symptoms indicative of major depressive disorder, which was strongly associated with high seasonality. Hierarchical cluster analysis of wintertime symptoms revealed 2 distinct clinical profiles among CFS patients: (a) those with high seasonality, for whom depressed mood clustered with atypical neurovegetative symptoms of hypersomnia and hyperphagia, as is seen in SAD; and (b) those with low seasonality, who showed a primary clustering of classic CFS symptoms (fatigue, aches, cognitive disturbance), with depressed mood most closely associated with irritability, insomnia, and anxiety. It appears that a subgroup of patients with CFS shows seasonal variation in symptoms resembling those of SAD, with winter exacerbation. Light therapy may provide patients with CFS an effective treatment alternative or adjunct to antidepressant drugs.