Biomedical subjects

T A Wehr

Publications and source records attributed to T A Wehr.

At least 19 recordsLinked to original sources

PubMed2001

Band-specific electroencephalogram and brain cooling abnormalities during NREM sleep in patients with winter depression.

BACKGROUND: We previously reported that delta wave activity and facial skin temperatures, an index of brain cooling activity, were both abnormal during sleep in patients with winter depression (SAD). Because other electroencephalographic (EEG) frequencies may also convey relevant thermal, homeostatic, and circadian information, we sought to spectrally analyze delta, theta, alpha, and sigma frequencies during sleep from 23 patients with SAD and 23 healthy control subjects. METHODS: We computed means for delta, theta, alpha, and sigma power during both NREM and REM sleep. We also generated 22 cross-correlation functions for each group by crossing facial and rectal temperature with each other, as well as with delta, theta, alpha, and sigma frequencies. RESULTS: We found that delta, theta, and alpha frequency activities were all increased during NREM, but not REM sleep, in patients with SAD. In addition, there were significant and abnormal cross-correlations between facial temperatures and delta and theta frequencies during NREM sleep in patients with SAD. CONCLUSIONS: Patients with winter depression exhibit correlated abnormalities of sleep homeostasis and brain cooling during NREM sleep. Their EEG profiles during NREM sleep resemble the EEG profiles of subjects who have been sleep deprived. Further studies of NREM sleep homeostasis in patients with SAD seem warranted.

Adult↗

PubMed2001

Evidence for a biological dawn and dusk in the human circadian timing system.

1. Because individuals differ in the phase angle at which their circadian rhythms are entrained to external time cues, averaging group data relative to clock time sometimes obscures abrupt changes that are characteristic of waveforms of the rhythms in individuals. Such changes may have important implications for the temporal organization of human circadian physiology. 2. To control for variance in phase angle of entrainment, we used dual internal reference points--onset and offset of the nocturnal period of melatonin secretion--to calculate average profiles of circadian rhythm data from five previously published studies. 3. Onset and/or offset of melatonin secretion were found to coincide with switch-like transitions between distinct diurnal and nocturnal periods of circadian rhythms in core body temperature, sleepiness, power in the theta band of the wake EEG, sleep propensity and rapid eye movement (REM) sleep propensity. 4. Transitions between diurnal and nocturnal periods of sleep-wake and cortisol circadian rhythms were found to lag the other transitions by 1-3 h. 5. When the duration of the daily light period was manipulated experimentally, melatonin-onset-related transitions in circadian rhythms appeared to be entrained to the light-to-dark transition, while melatonin-offset-related transitions appeared to be entrained to the dark-to-light transition. 6. These results suggest a model of the human circadian timing system in which two states, one diurnal and one nocturnal, alternate with one another, and in which transitions between the states are switch-like and are separately entrained to dawn and dusk. 7. This description of the human circadian system is similar to the Pittendrigh-Daan model of the rodent circadian system, and it suggests that core features of the system in other mammals are conserved in humans.

Body Temperature↗

PubMed2001

Dynamics of electroencephalographic slow wave activity and body temperature during monophasic and biphasic human sleep.

Dynamics of electroencephalographic (EEG) slow wave activity (0.5-4.5 Hz) and body temperature, as estimates, respectively, of the process S and process C, regulating sleep and waking alternate occurrence, were measured during monophasic and biphasic sleep patterns that occurred spontaneously in a 35-year-old woman who lived for 105 days in a winter-type photoperiod (10-14 h light-dark). In monophasic nights, rate of EEG synchronization showed a decreasing trend across the first three non-rapid eye movement (NREM) periods. In biphasic nights, rate of EEG synchronization increased during the third NREM period which precedes the nocturnal awakening. Temperature cycle was not different between biphasic and monophasic nights. Those results confirm that EEG dynamics reflects homeostatic sleep regulatory mechanism, and suggest that the period of prolonged wakefulness in the middle of biphasic night is pre-programmed.

Adult↗

PubMed2001

A circadian signal of change of season in patients with seasonal affective disorder.

BACKGROUND: In animals, the circadian pacemaker regulates seasonal changes in behavior by transmitting a signal of day length to other sites in the organism. The signal is expressed reciprocally in the duration of nocturnal melatonin secretion, which is longer in winter than in summer. We investigated whether such a signal could mediate the effects of change of season on patients with seasonal affective disorder. METHODS: The duration of melatonin secretion in constant dim light was measured in winter and in summer in 55 patients and 55 matched healthy volunteers. Levels of melatonin were measured in plasma samples that were obtained every 30 minutes for 24 hours in each season. RESULTS: Patients and volunteers responded differently to change of season. In patients, the duration of the nocturnal period of active melatonin secretion was longer in winter than in summer (9.0 +/- 1.3 vs 8.4 +/- 1.3 hours; P=.001) but in healthy volunteers there was no change (9.0 +/- 1.6 vs 8.9 +/- 1.2 hours; P=.5). CONCLUSIONS: The results show that patients with seasonal affective disorder generate a biological signal of change of season that is absent in healthy volunteers and that is similar to the signal that mammals use to regulate seasonal changes in their behavior. While not proving causality, this finding is consistent with the hypothesis that neural circuits that mediate the effects of seasonal changes in day length on mammalian behavior mediate effects of season and light treatment on seasonal affective disorder.

Adult↗

PubMed2001

Evidence from the waking electroencephalogram that short sleepers live under higher homeostatic sleep pressure than long sleepers.

We used the waking electroencephalogram to study the homeostatic sleep regulatory process in human short sleepers and long sleepers. After sleeping according to their habitual schedule, nine short sleepers (sleep duration < 6 h) and eight long sleepers (> 9 h) were recorded half-hourly during approximately 40 h of wakefulness in a constant routine protocol. Within the frequency range of 0.25-20.0 Hz, spectral power density in the 5.25-9.0 and 17.25-18.0 Hz ranges was higher in short sleepers than in long sleepers. In both groups, increasing time awake was associated with an increase of theta/low-frequency alpha activity (5.25-9.0 Hz), whose kinetics followed a saturating exponential function. The time constant did not differ between groups and was similar to the previously obtained time constant of the wake-dependent increase of slow-wave activity (0.75-4.5 Hz) in the sleep electroencephalogram. In addition, the time constant of the decrease of slow-wave activity during extended recovery sleep following the constant routine did not differ between groups. However, short sleepers showed an abiding enhancement of theta/low-frequency alpha activity during wakefulness after recovery sleep that was independent of the homeostatic process. It is concluded that, while the kinetics of the homeostatic process do not differ between the two groups, short sleepers live under and tolerate higher homeostatic sleep pressure than long sleepers. The homeostat-independent enhancement of theta/low-frequency alpha activity in the waking electroencephalogram in the short sleepers may be genetically determined or be the result of long-term adaptation to chronically short sleep.

Adult↗

PubMed2001

Assembling a clock for all seasons: are there M and E oscillators in the genes?

The hypothesis is advanced that the circadian pacemaker in the mammalian suprachiasmatic nucleus (SCN) is composed at the molecular level of a nonredundant double complex of circadian genes (per1, cry1, and per2, cry2). Each one of these sets would be sufficient for the maintenance of endogenous rhythmicity and thus constitute an oscillator. Each would have slightly different temporal dynamics and light responses. The per1/cry1 oscillator is accelerated by light and decelerated by darkness and thereby tracks dawn when day length changes. The per2 /cry2 oscillator is decelerated by light and accelerated by darkness and thereby tracks dusk. These M (morning) and E (evening) oscillators would give rise to the SCN's neuronal activity in an M and an E component. Suppression of behavioral activity by SCN activity in nocturnal mammals would give rise to adaptive tuning of the endogenous behavioral program to day length. The proposition-which is a specification of Pittendrigh and Daan's E-M oscillator model-yields specific nonintuitive predictions amenable to experimental testing in animals with mutations of circadian genes.

Animals↗

PubMed2001

Photoperiodism in humans and other primates: evidence and implications.

Most of the anatomical and molecular substrates of the system that encodes changes in photoperiod in the duration of melatonin secretion, and the receptor molecules that read this signal, have been shown to be conserved in monkeys and humans, and the functions of this system appear to be intact from the level of the retina to the level of the melatonin-duration signal of change of season. While photoperiodic seasonal breeding has been shown to occur in monkeys, it remains unclear whether photoperiod and mediation of photoperiod's effects by melatonin influence human reproduction. Epidemiological evidence suggests that inhibition of fertility by heat in men in summer contributes to seasonal variation in human reproduction at lower latitudes and that stimulation of fertility by lengthening of the photoperiod in spring contributes to the variation at higher latitudes. Parallels between the seasonality of human reproduction and seasonal affective disorder suggest that they may be governed by common biological processes. Historical and experimental evidence indicates that human responses to seasonal changes in the natural photoperiod may have been more robust prior to the Industrial Revolution and that subsequently they have been increasingly suppressed by alterations of the physical environment.

Animals↗

PubMed2000

Ultradian oscillations in cranial thermoregulation and electroencephalographic slow-wave activity during sleep are abnormal in humans with annual winter depression.

The level of core body, and presumably brain temperature during sleep varies with clinical state in patients with seasonal affective disorder (SAD), becoming elevated during winter depression and lowered during clinical remission induced by either light treatment or summer. During sleep, brain temperatures are in part determined by the level of brain cooling activity, which may be reflected by facial skin temperatures. In many animals, the level of brain cooling activity oscillates across the NREM-REM sleep cycle. Facial skin temperatures during sleep in patients with winter depression are abnormally low and uncorrelated with rectal temperatures, although their relationship to EEG-defined sleep stages remains unknown. We therefore measured the sleep EEG, core body and facial skin temperatures in 23 patients with winter depression and 23 healthy controls, and tested the hypothesis that ultradian oscillations in facial skin temperatures exist in humans and are abnormal in patients with winter depression. We found that facial skin temperatures oscillated significantly across the NREM-REM sleep cycle, and were again significantly lower and uncorrelated with rectal temperatures in patients with winter depression. Mean slow-wave activity and NREM episode duration were significantly greater in patients with winter depression, whereas the intraepisodic dynamics of slow-wave activity were normal in patients with winter depression. These results suggest that brain cooling activity oscillates in an ultradian manner during sleep in humans and is reduced during winter depression, and provide additional support for the hypothesis that brain temperatures are elevated during winter depression.

Activity Cycles↗

PubMed2000

Glucocorticoid replacement is permissive for rapid eye movement sleep and sleep consolidation in patients with adrenal insufficiency.

There is a well described temporal relation between hormonal secretion and sleep phase, with hormones of the hypothalamic-pituitary-adrenal (HPA) axis possibly playing a role in determining entry into and duration of different sleep stages. In this study sleep features were studied in primary Addison's patients with undetectable levels of cortisol treated in a double blind, randomized, cross-over fashion with either hydrocortisone or placebo supplementation. We found that REM latency was significantly decreased in Addison's patients when receiving hydrocortisone at bedtime, whereas REM sleep time was increased. There was a trend toward an increase in the percentage of time in REM sleep and the number of REM sleep episodes. Waking time after sleep onset was increased, whereas no differences were observed between the two conditions when total sleep time or specific non-REM sleep parameters were evaluated. Our results suggest that in Addison's patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep. These effects may be mediated either directly by the central effects of glucocorticoids and/or indirectly through CRH and/or ACTH.

Addison Disease↗

PubMed1999

Serotonin hypothesis of winter depression: behavioral and neuroendocrine effects of the 5-HT(1A) receptor partial agonist ipsapirone in patients with seasonal affective disorder and healthy control subjects.

Winter depressions in seasonal affective disorder (SAD) are associated with central serotonergic (5-HT) dysfunction. SAD patients demonstrate rather specific, state-dependent, abnormal increases in 'activation-euphoria' ratings following intravenous infusion of the 5-HT receptor agonist meta-chlorophenylpiperazine (m-CPP). Several studies are also consistent with abnormal serotonergic regulation of the hypothalamic-pituitary-adrenal (HPA) axis in SAD. Here, we investigated the effects of the 5-HT1A receptor partial agonist ipsapirone, which produces behavioral effects and HPA-axis activation, to further characterize the 5-HT receptor subtype-specificity of these disturbances in SAD. Eighteen SAD patients and 18 control subjects completed two drug challenges (ipsapirone 0.3 mg/kg and placebo) separated by 3-5 days in randomized order. We measured behavioral responses with the NIMH self-rating scale, and plasma ACTH, cortisol, and prolactin concentrations. Compared with placebo, ipsapirone was associated with significant increases in self-rated 'functional deficit' and 'altered self-reality', and in each of the hormones. There were no differences between groups on any measures. The level of depression in SAD patients was inversely correlated with their ipsapirone-induced cortisol responses. There were significant drug x order effects on baseline 'anxiety' scores, ACTH and cortisol concentrations, such that subjects were significantly more stressed (higher 'anxiety', ACTH and cortisol) prior to their first challenge compared with their second. In conclusion, post-synaptic 5-HT1A receptors appear to function normally in SAD. The previously observed m-CPP-induced behavioral abnormality may be mediated by either 5-HT2C or 5-HT7 receptors.

Adrenocorticotropic Hormone↗

PubMed1999

5-HT agonist-induced phase-advances of the circadian pacemaker are diminished by chronic antidepressant drug treatment.

Serotonin (5-HT) and its agonists alter the timing of the circadian pacemaker. Previous research has shown that when they are injected 4 h before or after the onset of wheel-running, they phase-advance or delay, respectively, the timing of the pacemaker. Because serotonergic interventions alter 5-HT receptor number in the hypothalamus, we asked whether chronic treatment with an antidepressant drug (AD) that modifies serotonergic function could alter the phase-shifting effects of the 5-HT agonist 8-hydroxydipropylaminotetralin (8-OH-DPAT). Hamsters were treated chronically with the monoamine oxidase inhibitor (MAOI), clorgyline, and then injected with 8-OH-DPAT or vehicle (VEH) either 4 h before or after the onset of wheel-running. MAOI treatment decreased the magnitude of both 8-OH-DPAT- and VEH-induced phase advances, but not the magnitude of 8-OH-DPAT-induced phase-delays. The results indicate that 8-OH-DPAT-induced phase-advances and delays are functionally distinct with regard to adaptive changes during chronic AD treatment.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1999

Monorhinal odor identification and depression scores in patients with seasonal affective disorder.

BACKGROUND: Visual and olfactory pathways are interconnected. Olfactory deafferentation unmasks photoperiodic responsiveness in some nonphotoperiodic animals such as laboratory rats. By analogy, we hypothesized that olfactory deficits may unmask seasonal rhythms in certain individuals, namely those with seasonal affective disorder (SAD). Since previous studies suggest lateralized hemispheric dysfunction in SAD, and since olfactory neurons' primary projections are largely ipsilateral, we assessed olfactory identification performance on both the right and left side of the nose. METHODS: Twenty-four patients with SAD and 24 matched controls were studied using a phenyl ethyl alcohol detection threshold test bilaterally and the University of Pennsylvania Smell Identification Test unilaterally. Subjects rated their mood using the Self Assessment Mood Scale for SAD. Patients' testing was done in both 'depressed' and 'improved on light' states. RESULTS: No difference in olfactory performance was found between patients and controls or between patients before and after light treatment. However, right-side identification scores were negatively correlated with 'typical' depression scores (r = -0.56, P = 0.006), while left-side olfactory scores were not. Atypical depression scores were unrelated to olfactory performance. Similar correlations emerged between the olfactory identification laterality quotient (Right - Left)/(Right + Left) and typical depressive scores (r = - 0.64, P < 0.001) and total depression scores (r = - 0.59, P < 0.004). LIMITATIONS: We studied a demographically heterogeneous sample and did not control for menstrual factors. DISCUSSION: Our results add to previous evidence of lateralized hemispheric involvement in SAD and suggest that olfaction may be related to seasonal emotional rhythms in humans.

Adult↗

PubMed1999

Free thyroxine and thyroid-stimulating hormone levels in patients with seasonal affective disorder and matched controls.

Seasonal affective disorder (SAD) is characterized by recurrent episodes of depression in the fall and winter that alternate with nondepressed periods in the spring and summer. Because some symptoms of SAD, such as decreased energy and weight gain, also occur in hypothyroidism, it is possible that individuals with SAD have a subtle decrease in thyroid function. To test this hypothesis, we studied blood levels of free thyroxine (T4) and thyroid-stimulating hormone (TSH) in SAD patients and matched controls in the winter. We found that free T4 blood levels were slightly but significantly lower in patients than in healthy volunteers. The difference between TSH levels in SAD patients and controls was not statistically significant. Future research will be needed to determine whether the difference in thyroid function between SAD patients and controls is an epiphenomenon or is related to the biological mechanisms that cause symptoms of SAD.

Adult↗

PubMed1999

Two circadian rhythms in the human electroencephalogram during wakefulness.

The influence of the circadian pacemaker and of the duration of time awake on the electroencephalogram (EEG) was investigated in 19 humans during approximately 40 h of sustained wakefulness. Two circadian rhythms in spectral power density were educed. The first rhythm was centered in the theta band (4.25-8.0 Hz) and exhibited a minimum approximately 1 h after the onset of melatonin secretion. The second rhythm was centered in the high-frequency alpha band (10.25-13.0 Hz) and exhibited a minimum close to the body temperature minimum. The latter rhythm showed a close temporal association with the rhythms in subjective alertness, plasma melatonin, and body temperature. In addition, increasing time awake was associated with an increase of power density in the 0.25- to 9.0-Hz and 13.25- to 20. 0-Hz ranges. It is concluded that the waking EEG undergoes changes that can be attributed to circadian and homeostatic (i.e., sleep-wake dependent) processes. The distinct circadian variations of EEG activity in the theta band and in the high-frequency alpha band may represent electrophysiological correlates of different aspects of the circadian rhythm in arousal.

Adult↗

PubMed1998

Treatment of rapidly cycling bipolar patient by using extended bed rest and darkness to stabilize the timing and duration of sleep.

BACKGROUND: The modern practice of using artificial light to extend waking activities into the nighttime hours might be expected to precipitate or exacerbate bipolar illness, because it has been shown that modifying the timing and duration of sleep can induce mania in susceptible individuals. With this possibility in mind, we treated a patient with rapidly cycling bipolar illness by creating an environment that was likely to increase and to stabilize the number of hours that he slept each night. METHODS: We asked the patient to remain at bed rest in the dark for 14 hours each night (later this was gradually reduced to 10 hours). Over a period of several years, his clinical state was assessed with twice-daily self-ratings, once-weekly observer ratings, and continuous wrist motor activity recordings. Times of sleeping and waking were recorded with sleep logs, polygraphic recordings, and computer-based event recordings. RESULTS: The patient cycled rapidly between depression and mania and experienced marked fluctuations in the timing and duration of sleep when he slept according to his usual routine, but his sleep and mood stabilized when he adhered to a regimen of long nightly periods of enforced bed rest in the dark. CONCLUSIONS: Fostering sleep and stabilizing its timing by scheduling regular nightly periods of enforced bed rest in the dark may help to prevent mania and rapid cycling in bipolar patients.

Bed Rest↗

PubMed1998

Homeostatic regulation of REM sleep in humans during extended sleep.

Benington and Heller (1994) recently proposed a sleep-dependent model for the homeostatic control of REM sleep in which the amount of REM sleep propensity discharged in each bout of REM sleep affects the timing of the subsequent REM episode. Consistent with their hypothesis, they reported that in rats the duration of a REM episode was positively correlated with the duration of the succeeding NREM episode and not with the duration of the preceding NREM episode. To assess this hypothesis in humans, we used 308 sleep records from 11 subjects who remained at bedrest in the dark and slept ad libitum during 14-hour periods each night for 4 weeks. The timing of the onset of the first REM episode of the long night was linked to the timing of sleep onset. NREM-REM cycle duration decreased progressively throughout the night as a result of a progressive decrease in duration of the NREM component. Durations of REM sleep episodes correlated significantly with durations of subsequent NREM episodes in three out of the eight rank cycles analyzed (p < .0031, Bonferroni corrected); positive correlation coefficients were found for all the remaining cycles, but were not statistically significant when the conservative Bonferroni correction of the alpha level was applied. With the exception of the first sleep cycle, durations of REM sleep episodes did not correlate with durations of preceding NREM sleep episodes. According to the present results, the amount of REM sleep in one episode controls the time of occurrence of the next REM episode when the impact of other possible regulating factors are at a low level. We hypothesize that the extended dark/rest period, by increasing the time window allowed for sleep, provided a condition under which the systems governing REM sleep expression were free of the masking imposed by the conventional 16 hours light/8 hours dark schedule that consolidates and compresses sleep.

Adult↗

PubMed1998

Disruption of the activity-rest cycle by MAOI treatment: dependence on light and a secondary visual pathway to the circadian pacemaker.

The disruptive effects on the activity-rest cycle of the monoamine oxidase inhibitor (MAOI) clorgyline and of continuous light were examined in Syrian hamsters. When administered in dim and moderate light intensities, clorgyline delayed the daily onset of wheel-running. When administered in bright light, it dissociated the circadian rhythm of wheel-running. This dissociation was prevented by lesions of the intergeniculate leaflet of the ventral lateral geniculate nucleus. Constant darkness restored the circadian rhythm of wheel-running in hamsters with disrupted circadian rhythms. The phase of the restored rhythm of wheel-running was shifted 6-12 h later than the phase of wheel-running prior to dissociation. Our results suggest that MAOI treatment weakens the coupling between oscillators that comprise the circadian pacemaker, and augments the disruptive effects of continuous light acting via the intergeniculate leaflet region of the ventral lateral geniculate nucleus. These effects on the circadian pacemaker may be responsible for disruptions of the sleep-wake cycle that occur as side effects when MAOIs are used clinically to treat depression and might play a role in the induction of mania and rapid cycling by antidepressants.

Analysis of Variance↗

PubMed1998

Serotonin 1A receptors, melatonin, and the proportional control thermostat in patients with winter depression.

BACKGROUND: In patients with seasonal affective disorder, light treatment lowers core temperature during sleep in proportion to its antidepressant efficacy. The regulation of the level of core temperature during sleep is linked with a proportional control thermostat in the central nervous system whose operation appears abnormal in patients with seasonal affective disorder. Because both melatonin and serotonin 1A receptor activation also lower core temperature, we investigated the relationship between (1) endogenous melatonin and core temperature profiles, (2) the proportional control thermostat, and (3) the core hypothermic response to the serotonin 1A receptor partial agonist ipsapirone hydrochloride in patients with seasonal affective disorder and healthy controls. METHODS: Eighteen patients with seasonal affective disorder and 18 controls first completed a 24-hour study in which their melatonin profiles were characterized. Subjects then returned 3 to 5 days later for the first of 2 drug challenges (ipsapirone hydrochloride, 0.3 mg/kg, or placebo), each separated by 3 to 5 days. Overnight rectal and facial temperatures were recorded before and after each drug challenge. RESULTS: The magnitudes of the core hypothermic responses to ipsapirone were (1) not different between groups and (2) independently correlated with both the levels of the previous nights' core temperature minima (P=.002) and the amounts of nocturnal melatonin secreted (P<.001). CONCLUSION: The daytime regulation of core temperature by serotonin 1A receptors appears normal in seasonal affective disorder. The magnitude of serotonin 1A receptor-activated hypothermia is governed by a central nervous system proportional control thermostat whose operation appears modulated by both melatonin and the level of the core temperature minimum.

Adult↗