Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans

Circadian rhythms of core body temperature and melatonin are commonly used as phase markers of the circadian clock. Melatonin is a more stable marker of circadian phase when measured under constant routine conditions. However, little is known about the variability of these phase markers under less controlled conditions. Moreover, there is little consensus about the preferred method of analysis. The objective of this study was to assess various methods of calculating melatonin and temperature phase in subjects with regular sleep schedules living in their natural environment. Baseline data were analyzed from 42 healthy young subjects who were studied on at least two occasions. Each hospital admission was separated by at least 3 weeks. Subjects were instructed to maintain a regular sleep schedule, which was monitored for 1 week before admission by sleep logs and actigraphy. Subjects spent one habituation night under controlled conditions prior to collecting baseline temperature and melatonin measurements. The phase of the melatonin rhythm was assessed by 9 different methods. The temperature nadir (Tmin) was estimated using both Cleveland and Cosine curve fitting procedures, with and without demasking. Variability between admissions was assessed by correlation analysis and by the mean absolute difference in timing of the phase estimates. The relationship to sleep times was assessed by correlation of sleep onset or sleep offset with the various phase markers. Melatonin phase markers were more stable and more highly correlated with the timing of sleep than estimates of Tmin. Of the methods for estimating Tmin, simple cosine analysis was the least variable. In addition, sleep offset was more strongly correlated with the various phase markers than sleep onset. The relative measures of melatonin offset had the highest correlation coefficients, the lowest study-to-study variability, and were more strongly associated with sleep timing than melatonin onsets. Concordance of the methods of analysis suggests a tendency for the declining phase of the melatonin profile to be more stable and reliable than either markers of melatonin onset or measures of the termination of melatonin synthesis.     

Sloped muscle excitation waveforms improve the accuracy of forward dynamic simulations

Mathematical models of the muscle excitation are useful in forward dynamic simulations of human movement tasks. One objective was to demonstrate that sloped as opposed to rectangular excitation waveforms improve the accuracy of forward dynamic simulations. A second objective was to demonstrate the differences in simulated muscle forces using sloped versus rectangular waveforms. To fulfill these objectives, surface EMG signals from the triceps brachii and elbow joint angle were recorded and the intersegmental moment of the elbow joint was computed from 14 subjects who performed two cyclic elbow extension experiments at 200 and 300 deg/s. Additionally, the surface EMG signals from the leg musculature, joint angles, and pedal forces were recorded and joint intersegmental moments were computed during a more complex pedaling task (90 rpm at 250 W). Using forward dynamic simulations, four optimizations were performed in which the experimental intersegmental moment was tracked for the elbow extension tasks and four optimizations were performed in which the experimental pedal angle, pedal forces, and joint intersegmental moments were tracked for the pedaling task. In these optimizations the three parameters (onset and offset time, and peak excitation) defining the sloped (triangular, quadratic, and Hanning) and rectangular excitation waveforms were varied to minimize the difference between the simulated and experimentally tracked quantities. For the elbow extension task, the intersegmental elbow moment root mean squared error, onset timing error, and offset timing error were less from simulations using a sloped excitation waveform compared to a rectangular excitation waveform (p<0.001). The average and peak muscle forces were from 7% to 16% larger and 20-28% larger, respectively, when using a rectangular excitation waveform. The tracking error for pedaling also decreased when using a sloped excitation waveform, with the quadratic waveform generating the smallest tracking errors for both tasks. These results support the use of sloped over rectangular excitation waveforms to establish greater confidence in the results of forward dynamic simulations.     

Evaluation of performance criteria for simulation of submaximal steady-state cycling using a forward dynamic model.

The objectives of this study were twofold. The first was to develop a forward dynamic model of cycling and an optimization framework to simulate pedaling during submaximal steady-state cycling conditions. The second was to use the model and framework to identify the kinetic, kinematic, and muscle timing quantities that should be included in a performance criterion to reproduce natural pedaling mechanics best during these pedaling conditions. To make this identification, kinetic and kinematic data were collected from 6 subjects who pedaled at 90 rpm and 225 W. Intersegmental joint moments were computed using an inverse dynamics technique and the muscle excitation onset and offset were taken from electromyographic (EMG) data collected previously (Neptune et al., 1997). Average cycles and their standard deviations for the various quantities were used to describe normal pedaling mechanics. The model of the bicycle-rider system was driven by 15 muscle actuators per leg. The optimization framework determined both the timing and magnitude of the muscle excitations to simulate pedaling at 90 rpm and 225 W. Using the model and optimization framework, seven performance criteria were evaluated. The criterion that included all of the kinematic and kinetic quantities combined with the EMG timing was the most successful in replicating the experimental data. The close agreement between the simulation results and the experimentally collected kinetic, kinematic, and EMG data gives confidence in the model to investigate individual muscle coordination during submaximal steady-state pedaling conditions from a theoretical perspective, which to date has only been performed experimentally.     

Investigations of timing during the schedule and reinforcement intervals with wheel-running reinforcement

Across two experiments, a peak procedure was used to assess the timing of the onset and offset of an opportunity to run as a reinforcer. The first experiment investigated the effect of reinforcer duration on temporal discrimination of the onset of the reinforcement interval. Three male Wistar rats were exposed to fixed-interval (FI) 30-s schedules of wheel-running reinforcement and the duration of the opportunity to run was varied across values of 15, 30, and 60s. Each session consisted of 50 reinforcers and 10 probe trials. Results showed that as reinforcer duration increased, the percentage of postreinforcement pauses longer than the 30-s schedule interval increased. On probe trials, peak response rates occurred near the time of reinforcer delivery and peak times varied with reinforcer duration. In a second experiment, seven female Long-Evans rats were exposed to FI 30-s schedules leading to 30-s opportunities to run. Timing of the onset and offset of the reinforcement period was assessed by probe trials during the schedule interval and during the reinforcement interval in separate conditions. The results provided evidence of timing of the onset, but not the offset of the wheel-running reinforcement period. Further research is required to assess if timing occurs during a wheel-running reinforcement period.     

Differential responses of circadian activity onset and offset following GABA-ergic and opioid receptor activation

The circadian pacemaker in the mammalian suprachiasmatic nuclei is responsive to photic and nonphotic stimuli. In the present study, the authors have investigated the response of activity onset and offset to application of nonphotic stimuli: the benzodiazepine midazolam and the opioid receptor agonist fentanyl. In correspondence with previous studies, both stimuli induced phase advances of the activity onset when given in the mid- to late subjective day. In contrast, activity offset did not phase advance following these injections. Injections during the early subjective day induced small phase delays of the activity onset, while large phase delays occurred in activity offset. Phase shifts, induced at both circadian time zones, were paralleled by an increase in the length of daily activity (alpha). The increase in a remained present during several days after the injection. The different kinetics in phase shifting of the activity onset and offset indicate complexity in phase-shifting behavior of the circadian pacemaker in response to nonphotic stimuli. Moreover, the data show responsiveness of the circadian system to GABA-ergic and opioid receptor activation, not only during the mid- to late subjective day but also during the early subjective day. The data implicate that the early subjective day is an interesting phase for analysis of molecular and biochemical processes involved in nonphotic phase shifting.     

Light exposure among adolescents with delayed sleep phase disorder: a prospective cohort study

The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n=16, 15.3±1.8 yrs) and unaffected controls (n=22, 13.7±2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00 h and 05:00 to 14:00 h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p< .02, 22:00-02:00 h) and less morning (p .05, 08:00-09:00 h and 10:00-12:00 h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p< .03, 5-7 h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p< .001 and p= .02, respectively) and morning (p= .01 and p< .001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p< .001). Increased total sleep time also correlated with increased exposure during the 9 h before sleep onset (p= .01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p< .001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD.     

The between-day reliability of peroneus longus EMG during walking

The peroneus longus (PL) is a rearfoot evertor, important in frontal plane foot motion. Studying PL function has been limited by previous electromyography (EMG) studies reporting poor between-day reliability. Due to its close proximity to adjacent muscles, EMG measures of PL may be susceptible to crosstalk, thus correct electrode placement is vital. The aim of this study was to use ultrasound to aid placement of small surface EMG electrodes and determine the between-day reliability of PL EMG in healthy participants’ walking. Ten participants walked barefoot and shod at a controlled, self-selected speed. Six trials per condition, per session, were recorded over two days (mean (SD): 5 (3) days apart). The muscle belly was located using ultrasound. EMG was recorded with surface electrodes (Trigno™ Mini, Delsys, Inc.) at 2000 Hz. Amplitude was normalized to the peak per gait cycle and time normalized to the gait cycle. Reliability of discrete variables were primarily assessed with the standard error of measurement (SEM), plus the coefficient of multiple correlation (CMC), the coefficient of variation (CV) and the intra-class correlation coefficient (ICC). The pattern of the EMG profile was consistent. The SEM of peak amplitude was 4% (3–8%) and 3% (2–5%) for barefoot and shod respectively. For timing of the peak the SEM was 2% (1–3%) and 1% (1–2%) for barefoot and shod respectively. Low SEM of discrete variables suggests good reliability of PL EMG during walking supporting the future use of this protocol. Therefore activation of PL can be confidently studied in repeated-measures study designs.     

Real-time determination of the optimal reconstruction phase to control ECG pulsing in spiral cardiac CT

The reconstruction phase providing optimal image quality in coronary CT angiography is dependent on the heart rate but additionally displays substantial patient-dependent variation. The purpose of this study was to provide online identification of the patient-specific optimal reconstruction phase during CT coronary angiography data acquisition and to allow adaptation of tube current modulation for the individual patient. A raw data-based cardiac motion signal (kymogram) was used for the detection of the optimal reconstruction phase. The individual motion curve of each patient was correlated with dedicated template curves to reduce signal noise. Data sets of 90 consecutive patients were used for validation purposes. The reliability of our approach increased with scan time and provided highest correlation with the visually identified optimal reconstruction phase already after half of the total scan time indicated by a difference value of 13.2% and 8.2%, respectively. A high correlation of the computed and the visually identified optimal reconstruction phase was assured in most cases providing a dose reduction of 36% compared to conventional TCM application for a confidence interval of 80%. Our method is a fully automatic computer-assisted approach identifying the optimal reconstruction phase with high reliability while online capability can be ensured. We conclude that our method can identify cardiac phases providing highest image quality already during CT scanning. Reduction of the tube current by a patient-specific optimization providing a minimal dose level is the major benefit for the patients.     

Normal contractile algorithm of swallowing related muscles revealed by needle EMG and its comparison to videofluoroscopic swallowing study and high resolution manometry studies: A preliminary study

The purpose of this study was to investigate the function and importance of infrahyoid muscles with the suprahyoid muscles during swallowing, and to investigate swallowing sequences using kinematic analysis, high-resolution manometry (HRM) and electromyography (EMG). As a preliminary study, ten healthy subjects were prospectively enrolled. A needle EMG evaluated the onset latency, peak latency and duration of the suprahyoid and infrahyoid muscles. HRM measured the time intervals among the velopharynx, tongue base, and upper esophageal sphincter. We also evaluated hyoid motion using an automated kinematic analysis software® (AKAS). All of these parameters were synchronized with a tilting motion of the epiglottis. In the EMG analysis, the activations of the suprahyoid muscles developed about 300 ms earlier than that of the infrahyoid muscles. There was a significant relationship between the differences of suprahyoid and infrahyoid muscles’ latency and total duration of the hyoid motion (p < 0.05). The interval time of anterior hyoid motion has a significant correlation in the upper esophageal sphincter (UES) opening time. In conclusions, the functions of the infrahyoid muscles are also as important as that of the suprahyoid muscles for prolonged laryngeal elevation and UES opening. Moreover, kinematic analysis of videofluoroscopic swallowing study (VFSS) and HRM studies could reflect results of needle EMG study and replace EMG study.     

Representation of motion onset and offset in an augmented Barlow-Levick model of motion detection

Kinetic occlusion produces discontinuities in the optic flow field, whose perception requires the detection of an unexpected onset or offset of otherwise predictably moving or stationary contrast patches. Many cells in primate visual cortex are directionally selective for moving contrasts, and recent reports suggest that this selectivity arises through the inhibition of contrast signals moving in the cells’ null direction, as in the rabbit retina. This nulling inhibition circuit (Barlow-Levick) is here extended to also detect motion onsets and offsets. The selectivity of extended circuit units, measured as a peak evidence accumulation response to motion onset/offset compared to the peak response to constant motion, is analyzed as a function of stimulus speed. Model onset cells are quiet during constant motion, but model offset cells activate during constant motion at slow speeds. Consequently, model offset cell speed tuning is biased towards higher speeds than onset cell tuning, similarly to the speed tuning of cells in the middle temporal area when exposed to speed ramps. Given a population of neurons with different preferred speeds, this asymmetry addresses a behavioral paradox—why human subjects in a simple reaction time task respond more slowly to motion offsets than onsets for low speeds, even though monkey neuron firing rates react more quickly to the offset of a preferred stimulus than to its onset.     

Light Exposure Among Adolescents With Delayed Sleep Phase Disorder: A Prospective Cohort Study

The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n?=?16, 15.3?±?1.8 yrs) and unaffected controls (n?=?22, 13.7?±?2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00?h and 05:00 to 14:00?h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p?<?.02, 22:00–02:00?h) and less morning (p?<?.05, 08:00–09:00?h and 10:00–12:00?h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p?<?.03, 5–7?h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p?<?.001 and p?=?.02, respectively) and morning (p?=?.01 and p?<?.001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p?<?.001). Increased total sleep time also correlated with increased exposure during the 9?h before sleep onset (p?=?.01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p?<?.001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD. (Author correspondence: auger.raymond1@mayo.edu)     

Activation of upper airway muscles before onset of inspiration in normal humans

Animal studies have shown activation of upper airway muscles prior to inspiratory efforts of the diaphragm. To investigate this sequence of activation in humans, we measured the electromyogram (EMG) of the alae nasi (AN) and compared the time of onset of EMG to the onset of inspiratory airflow, during wakefulness, stage II or III sleep (3 subj), and CO2-induced hyperpnea (6 subj). During wakefulness, the interval between AN EMG and airflow was 92 +/- 34 ms (mean +/- SE). At a CO2 level of greater than or equal to 43 Torr, the AN EMG to airflow was 316 +/- 38 ms (P < 0.001). During CO2-induced hyperpnea, the AN EMG to airflow interval and AN EMG magnitude increased in direct proportion to CO2 levels and minute ventilation. During stages II and III of sleep, the interval between AN EMG and airflow increased when compared to wakefulness (P < 0.005). We conclude that a sequence of inspiratory muscle activation is present in humans and is more apparent during sleep and during CO2-induced hyperpnea than during wakefulness.     

Direction of visual apparent motion driven solely by timing of a static sound

In temporal ventriloquism, auditory events can illusorily attract perceived timing of a visual onset [1-3]. We investigated whether timing of a static sound can also influence spatio-temporal processing of visual apparent motion, induced here by visual bars alternating between opposite hemifields. Perceived direction typically depends on the relative interval in timing between visual left-right and right-left flashes (e.g., rightwards motion dominating when left-to-right interflash intervals are shortest [4]). In our new multisensory condition, interflash intervals were equal, but auditory beeps could slightly lag the right flash, yet slightly lead the left flash, or vice versa. This auditory timing strongly influenced perceived visual motion direction, despite providing no spatial auditory motion signal whatsoever. Moreover, prolonged adaptation to such auditorily driven apparent motion produced a robust visual motion aftereffect in the opposite direction, when measured in subsequent silence. Control experiments argued against accounts in terms of possible auditory grouping, or possible attention capture. We suggest that the motion arises because the sounds change perceived visual timing, as we separately confirmed. Our results provide a new demonstration of multisensory influences on sensory-specific perception [5], with timing of a static sound influencing spatio-temporal processing of visual motion direction.     

Assortative mating by flowering time and its effect on correlated traits in variable environments

Reproductive timing is a key life‐history trait that impacts the pool of available mates, the environment experienced during flowering, and the expression of other traits through genetic covariation. Selection on phenology, and its consequences on other life‐history traits, has considerable implications in the context of ongoing climate change and shifting growing seasons. To test this, we grew field‐collected seed from the wildflower Mimulus guttatus in a greenhouse to assess the standing genetic variation for flowering time and covariation with other traits. We then created full‐sib families through phenological assortative mating and grew offspring in three photoperiod treatments representing seasonal variation in daylength. We find substantial quantitative genetic variation for the onset of flowering time, which covaried with vegetative traits. The assortatively‐mated offspring varied in their critical photoperiod by over two hours, so that families differed in their probability of flowering across treatments Allocation to flowering and vegetative growth changed across the daylength treatments, with consistent direction and magnitude of covariation among flowering time and other traits. Our results suggest that future studies of flowering time evolution should consider the joint evolution of correlated traits and shifting seasonal selection to understand how environmental variation influences life histories.     

Abdominal muscle activation changes if the purpose is to control pelvis motion or thorax motion

The aim of this study was to compare trunk muscular recruitment and lumbar spine kinematics when motion was constrained to either the thorax or the pelvis. Nine healthy women performed four upright standing planar movements (rotations, anterior–posterior translations, medial–lateral translations, and horizontal circles) while constraining pelvis motion and moving the thorax or moving the pelvis while minimizing thorax motion, and four isometric trunk exercises (conventional curl-up, reverse curl-up, cross curl-up, and reverse cross curl-up). Surface EMG (upper and lower rectus abdominis, lateral and medial aspects of external oblique, internal oblique, and latissimus dorsi) and 3D lumbar displacements were recorded. Pelvis movements produced higher EMG amplitudes of the oblique abdominals than thorax motions in most trials, and larger lumbar displacements in the medial–lateral translations and horizontal circles. Conversely, thorax movements produced larger rotational lumbar displacement than pelvis motions during rotations and higher EMG amplitudes for latissimus dorsi during rotations and anterior–posterior translations and for lower rectus abdominis during the crossed curl-ups. Thus, different neuromuscular compartments appear when the objective changes from pelvis to thorax motion. This would suggest that both movement patterns should be considered when planning spine stabilization programs, to optimize exercises for the movement and muscle activations desired.     

The sit-up: complex kinematics and muscle activity in voluntary axial movement.

This paper describes the kinematics and muscle activity associated with the standard sit-up, as a first step in the investigation of complex motor coordination. Eight normal human subjects lay on a force table and performed at least 15 sit-ups, with the arms across the chest and the legs straight and unconstrained. Several subjects also performed sit-ups with an additional weight added to the head. Support surface forces were recorded to calculate the location of the center of pressure and center of gravity; conventional motion analysis was used to measure segmental positions; and surface EMG was recorded from eight muscles. While the sit-up consists of two serial components, 'trunk curling' and 'footward pelvic rotation', it can be further subdivided into five phases, based on the kinematics. Phases I and II comprise trunk curling. Phase I consists of neck and upper trunk flexion, and phase II consists of lumbar trunk lifting. Phase II corresponds to the point of peak muscle contraction and maximum postural instability, the 'critical point' of the sit-up. Phases III-V comprise footward pelvic rotation. Phase III begins with pelvic rotation towards the feet, phase IV with leg lowering, and phase V with contact between the legs and the support surface. The overall pattern of muscle activity was complex with times of EMG onset, peak activity, offset, and duration differing for different muscles. This complex pattern changed qualitatively from one phase to the next, suggesting that the roles of different muscles and, as a consequence, the overall form of coordination, change during the sit-up.     

Fractal modeling of human isochronous serial interval production

The Hurst exponent (H) was estimated for series of 256 time intervals produced by human participants, collected in 5 sessions performed on different days. Each series was obtained during the continuation phase following synchronization with 25 isochronous intervals generated by a computer and presented through headphones. Dispersional analysis yielded estimates of H > 0.5. These were sufficiently stable to yield statistically significant differences between participants and between each target interval duration (0.5, 0.8, 1.1, and 1.5s). The results indicate that variability in isochronous serial interval production (ISIP) can be modeled as fractional Gaussian noise, which corroborates and qualifies previous research indicating positive serial dependency or long memory in ISIP data in terms of drift and 1/f noise characteristics. It is concluded that ISIP is a more complex process than is assumed by influential timing models and theories, and that realistic modeling of human timing must account for nonlinear variability patterns.Abbreviations Bm Brownian motion - f frequency - fGn fractional Gaussian noise - H Hurst exponent - ISIP isochronous serial interval production - IOI inter onset interval     

Termination of upper limb movement by cutaneous afferents.

We tested whether cutaneous afferents from the skin field close to an upper limb muscular region would carry information to spinal neurons at the onset or at the offset of a voluntary elbow extension movement lasting 1 s. We detected a depression of EMG activity both at onset and at the offset of the reaching movement but in the latter case depression was significantly larger and immediate. The marked depression of EMG activity suggests an inhibition, via spinal neurons, of the descending excitation to the motoneurones supplying the triceps brachii. This spinal control might be a very efficient mechanism for the termination of voluntary movement.