Bob Cheung

Etiologic significance of arginine vasopressin in motion sickness.

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146‐D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose‐response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.

Working memory training is associated with lower prefrontal cortex activation in a divergent thinking task

Working memory (WM) training has been shown to lead to improvements in WM capacity and fluid intelligence. Given that divergent thinking loads on WM and fluid intelligence, we tested the hypothesis that WM training would improve performance and moderate neural function in the Alternate Uses Task (AUT)-a classic test of divergent thinking. We tested this hypothesis by administering the AUT in the functional magnetic resonance imaging scanner following a short regimen of WM training (experimental condition), or engagement in a choice reaction time task not expected to engage WM (active control condition). Participants in the experimental group exhibited significant improvement in performance in the WM task as a function of training, as well as a significant gain in fluid intelligence. Although the two groups did not differ in their performance on the AUT, activation was significantly lower in the experimental group in ventrolateral prefrontal and dorsolateral prefrontal cortices-two brain regions known to play dissociable and critical roles in divergent thinking. Furthermore, gain in fluid intelligence mediated the effect of training on brain activation in ventrolateral prefrontal cortex. These results indicate that a short regimen of WM training is associated with lower prefrontal activation-a marker of neural efficiency-in divergent thinking.

Investigation of Anti‐Motion Sickness Drugs in the Squirrel Monkey

Early attempts to develop an animal model for anti‐motion sickness drugs, using dogs and cats, were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti‐motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800–1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti‐motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3–6. 0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Influence of body roll on visually induced sensations of self-tilt and rotation.

Illusory self-tilt and illusory self-motion (vection) produced by rotation of a 360° visual scene about the subjects roll axis was measured as a function of the presence or absence of actual rotation of the subject during acceleration of the visual scene. Rotation of the subject to a tilt of 15° was at two levels of acceleration (onset) and with or without a delay between initial rotation and subsequent return (washout) to the vertical position. In one set of conditions, visual motion and subject motion were in opposite directions (concordant) and in another set they were in the same direction (discordant). In two control conditions, the subject was rotated while the visual scene remained stationary. For concordant motion the main effect of body rotation was to reduce the time taken by the subject to indicate self-tilt as compared with the response time to visual motion alone. The magnitude of estimated self-tilt was increased by actual body tilt as could be expected from addition of the perceived actual body tilt and the illusory body tilt induced by visual rotation. This effect of augmented body tilt did not persist after the body was returned to the vertical. The magnitude of vection was not markedly influenced by body rotation and washout. For discordant motion of body and the visual scene, subjects were confused and their responses were very variable, suggesting a nonlinear visual-vestibular interaction.

Coriolis-induced cutaneous blood flow increase in the forearm and calf

Using venous occlusion plethysmography, Sunahara et al. reported that Coriolis-induced nausea was accompanied by an increase in forearm blood flow, suggesting a decrease in sympathetic activity to this vascular bed. No significant blood pressure and heart rate changes were observed. Vasodilation of the limbs theoretically impairs orthostatic tolerance, particularly if blood flow is shown to increase simultaneously in the lower limbs. This study examined the latter possibility. Seventeen subjects were exposed to the Coriolis cross-coupling effects induced by 20 RPM yaw rotation, and a simultaneous 45 degrees pitch forward head movement in the sagittal plane every 12 s. Forearm and calf skin blood flow were monitored in real-time using laser Doppler flowmetry (PeriFlux 4001). Our results indicated a significant (p < 0.001) simultaneous forearm and calf skin blood flow increase as a result of Coriolis cross-coupling across all 15 susceptible subjects. No significant changes in blood pressure and heart rate were observed. Coriolis-induced cardiovascular changes may confound previous reports on reduced G tolerance using ground-based centrifuges that invariably evoke cross-coupling effects.

Human ocular torsion during parabolic flights: an analysis with scleral search coil

SummaryRotation of the eyes about the visual axis is known as ocular torsion. A lateral inclination (a “roll”) of the head induces ocular torsion in the opposite direction, a response known as ocular counterrolling. For six subjects, we recorded the static (head still) and dynamic (head in oscillatory roll motion) ocular torsion in normal 1 g condition and also during the microgravity and hypergravity periods of parabolic flight, using the electromagnetic scleral search coil technique. With the head still, the direction and magnitude of torsion that occured in response to microgravity and hypergravity differed substantially from one individual to another, but there was a significant difference in torsional magnitude between the microgravity and hypergravity periods, for all static head positions including the upright position. Under normal 1 g conditions, counterrolling compensated for about 16% of (voluntary) static head roll, while dynamic counterroll was much larger, up to 36% of head roll at 0.55 Hz. With increasing frequency of head oscillation between 0.33 Hz and 0.55 Hz, the gain of counter rolling increased and there was no change in the phase relationship. The gain of dynamic counterroll (in response to voluntary head rolling) was not significantly less in hypogravity, suggesting that on the ground at these frequencies the contribution of gravity and gravity receptors to this reflex is redundant: this reflex is probably driven by the semicircular canals. In some subjects, the torsional displacement in microgravity is accompanied by micro-torsional oscillatory motion.

A Review of Psychophysiological Stressors on Pharmacokinetics

We conducted a comprehensive literature review on the effects of psychophysiological stressors on the pharmacokinetics of drugs commonly used by the Canadian Forces. These stressors may change the physiological status of an individual and subsequently may alter the drugs pharmacokinetics. The effects of isolated physical activities on pharmacokinetics have been well documented. However, the findings are inconsistent due to variations in the intensity and duration of the activity, and the routes and timing of drug administration. The effects of other environmental stressors, such as temperature extremes, hypobaric, hyperbaric, hyperoxic conditions, and the effects of multiple stressors are less well known. There are limited studies describing the effects of psychological stressors on drug pharmacokinetics. Further studies are necessary to understand the clinical implications of pharmacokinetic changes. We also discussed the advantage of using a physiologically based pharmacokinetic model to predict the effects of a single or multiple stressors.

The effects of a single night of sleep deprivation on fluency and prefrontal cortex function during divergent thinking.

The dorsal and ventral aspects of the prefrontal cortex (PFC) are the two regions most consistently recruited in divergent thinking tasks. Given that frontal tasks have been shown to be vulnerable to sleep loss, we explored the impact of a single night of sleep deprivation on fluency (i.e., number of generated responses) and PFC function during divergent thinking. Participants underwent functional magnetic resonance imaging scanning twice while engaged in the Alternate Uses Task (AUT) – once following a single night of sleep deprivation and once following a night of normal sleep. They also wore wrist activity monitors, which enabled us to quantify daily sleep and model cognitive effectiveness. The intervention was effective, producing greater levels of fatigue and sleepiness. Modeled cognitive effectiveness and fluency were impaired following sleep deprivation, and sleep deprivation was associated with greater activation in the left inferior frontal gyrus (IFG) during AUT. The results suggest that an intervention known to temporarily compromise frontal function can impair fluency, and that this effect is instantiated in the form of an increased hemodynamic response in the left IFG.

Alterations of proprioceptive function in the weightless environment.

T he alterations of proprioceptive function in the weightless environment will be discussed. The proprioceptive function is the function of those sensory systems that have their sensory receptors in muscles, tendons, and joints. These receptors function as part of the system that gives us perception of where limbs are, positions, angles and motions, and so on. Proprioceptors also assist, independently of anything that is conscious, to provide reflex control of limbs generally, in the aid of maintaining body balance and posture. Most sensory cells work because there is an ion pump in the wall of the cell; these pumps are fueled by cell metabolism and, with this energy, the pumps pump ions out of the sensory cell. In some cases they also pump ions into the cell, but mostly it is a matter of pumping ions out. The major ions involved are sodium and potassium, and in some cases calcium. When many of these ions get pumped out, they move around to another place along the cell surface where there are holes and there the ions diffuse back in again. Ions also re-enter because of electrical forces to provide a continuous current that is on going all the time, even when the sensory receptor is not functional. The effective stimulus acts on the cell, not really “to prod or stimulate” the cell, but to adjust the size of the holes through which the ions are returning into the cell. This basically explains why some cells are enormously sensitive, because the stimulus does not really have to prod the cell; all it does is “turn a valve” to decrease a flow of ions. In the eye, for example, light causes a series of chemical reactions that change the chemical structure of the holes, and as a result, there is a change in the current carried by sodium ions. This is why the eye is so sensitive to light. In fact, it is believed that one quantum of light can have a perceivable effect on the eye,

A physiologically based pharmacokinetics model for melatonin—Effects of light and routes of administration

Physiologically based pharmacokinetic (PBPK) models were developed using MATLAB Simulink(®) to predict diurnal variations of endogenous melatonin with light as well as pharmacokinetics of exogenous melatonin via different routes of administration. The model was structured using whole body, including pineal and saliva compartments, and parameterized based on the literature values for endogenous melatonin. It was then optimized by including various intensities of light and various dosage and formulation of melatonin. The model predictions generally have a good fit with available experimental data as evaluated by mean squared errors and ratios between model-predicted and observed values considering large variations in melatonin secretion and pharmacokinetics as reported in the literature. It also demonstrates the capability and usefulness in simulating plasma and salivary concentrations of melatonin under different light conditions and the interaction of endogenous melatonin with the pharmacokinetics of exogenous melatonin. Given the mechanistic approach and programming flexibility of MATLAB Simulink(®), the PBPK model could provide predictions of endogenous melatonin rhythms and pharmacokinetic changes in response to environmental (light) and experimental (dosage and route of administration) conditions. Furthermore, the model may be used to optimize the combined treatment using light exposure and exogenous melatonin for maximal phase advances or delays.