Cognitive flexibility: A distinct element of performance impairment due to sleep deprivation.

In around-the-clock operations, reduced alertness due to circadian misalignment and sleep loss causes performance impairment, which can lead to catastrophic errors and accidents. There is mounting evidence that performance on different tasks is differentially affected, but the general principles underlying this differentiation are not well understood. One factor that may be particularly relevant is the degree to which tasks require executive control, that is, control over the initiation, monitoring, and termination of actions in order to achieve goals. A key aspect of this is cognitive flexibility, i.e., the deployment of cognitive control resources to adapt to changes in events. Loss of cognitive flexibility due to sleep deprivation has been attributed to "feedback blunting," meaning that feedback on behavioral outcomes has reduced salience - and that feedback is therefore less effective at driving behavior modification under changing circumstances. The cognitive mechanisms underlying feedback blunting are as yet unknown. Here we present data from an experiment that investigated the effects of sleep deprivation on performance after an unexpected reversal of stimulus-response mappings, requiring cognitive flexibility to maintain good performance. Nineteen healthy young adults completed a 4-day in-laboratory study. Subjects were randomized to either a total sleep deprivation condition (n = 11) or a control condition (n = 8). Athree-phase reversal learning decision task was administered at baseline, and again after 30.5 h of sleep deprivation, or matching well-rested control. The task was based on a go/no go task paradigm, in which stimuli were assigned to either a go (response) set or a no go (no response) set. Each phase of the task included four stimuli (two in the go set and two in the no go set). After each stimulus presentation, subjects could make a response within 750 ms or withhold their response. They were then shown feedback on the accuracy of their response. In phase 1 of the task, subjects were explicitly told which stimuli were assigned to the go and no go sets. In phases 2 and 3, new stimuli were used that were different from those used in phase 1. Subjects were not explicitly told the go/no go mappings and were instead required to use accuracy feedback to learn which stimuli were in the go and nogo sets. Phase 3 continued directly from phase 2 and retained the same stimuli as in phase 2, but there was an unannounced reversal of the stimulus-response mappings. Task results confirmed that sleep deprivation resulted in loss of cognitive flexibility through feedback blunting, and that this effect was not produced solely by (1) general performance impairment because of overwhelming sleep drive; (2) reduced working memory resources available to perform the task; (3) incomplete learning of stimulus-response mappings before the unannounced reversal; or (4) interference with stimulus identification through lapses in vigilant attention. Overall, the results suggest that sleep deprivation causes a fundamental problem with dynamic attentional control. This element of performance impairment due to sleep deprivation appears to be distinct from vigilant attention deficits, and represents a particularly significant challenge for fatigue risk management.

Total sleep deprivation does not significantly degrade semantic encoding.

Sleep deprivation impairs performance on cognitive tasks, but it is unclear which cognitive processes it degrades. We administered a semantic matching task with variable stimulus onset asynchrony (SOA) and both speeded and self-paced trial blocks. The task was administered at the baseline and 24 hours later after 30.8 hours of total sleep deprivation (TSD) or matching well-rested control. After sleep deprivation, the 20% slowest response times (RTs) were significantly increased. However, the semantic encoding time component of the RTs remained at baseline level. Thus, the performance impairment induced by sleep deprivation on this task occurred in cognitive processes downstream of semantic encoding.

Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.

CONTEXT: The neuraminidase inhibitor zanamivir, a sialic acid analog administered directly to the respiratory tract, has been demonstrated in clinical studies to be effective in treatment of type A and B influenza. It has also been shown to prevent influenza infection and disease in an experimental model. OBJECTIVE: To examine the efficacy of zanamivir, administered once daily, in the prevention of influenza infection and disease. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Two midwestern university communities. PARTICIPANTS: A total of 1107 healthy adults (mean age [range], 29 [18-69] years) were recruited in November 1997, before the influenza season. INTERVENTION: At the start of the influenza outbreak, 554 subjects were randomized to receive placebo and 553 to receive zanamivir. The drug, 10 mg once per day, or identical placebo was administered by oral inhalation for a 4-week period. MAIN OUTCOME MEASURES: Illness occurrence was recorded by participants daily and records were evaluated weekly. Specimens were collected for viral isolation when symptoms were reported within 3 days of illness onset. Infection was also identified by testing paired serum samples for rise in antibody titer against the circulating influenza viruses. RESULTS: Zanamivir was 67% efficacious (95% confidence interval [CI], 39%-83%; P<.001) in preventing laboratory-confirmed clinical influenza meeting the case definition and 84% efficacious (95% CI, 55%-94%; P=.001) in preventing laboratory-confirmed illnesses with fever. All influenza infections occurring during the season, with or without symptoms, were prevented with an efficacy of 31% (95% CI, 4%-50%; P=.03). The nature and incidence of adverse events in the zanamivir group did not differ from placebo. Compliance with the once-daily dosage was high. CONCLUSIONS: Zanamivir administered once daily is efficacious and well tolerated in the prevention of influenza for a 4-week period in healthy adults.

Range effects and dimensional organization in visual discrimination.

Pigeons were trained to discriminate two types of visual forms that could vary in two orthogonal dimensions. One set of stimuli was designed to have relatively integral dimensions, while the other set of stimuli was intended to have relatively separable dimensions, for the pigeon. A first experiment provided evidence that the dimensions of our two stimulus sets differed in the degree of separability. The second experiment examined the effect of increased stimulus range on discrimination of the two stimulus sets. Results from this experiment indicated that increases in range in either relevant or irrelevant dimensions reduced discrimination for the integral stimulus set. For the separable stimulus dimensions, however, performance declined only with increased stimulus range along a relevant dimension. In the third experiment, stimulus range was increased along either one or two dimensions of the stimulus. Correlated changes in stimulus range along two dimensions had an impact only for integral stimuli. In summary, these experiments demonstrate that the organizational structure of stimulus dimensions determines the impact of increases in stimulus range, probably due to the attentional properties of different stimulus forms.

A preliminary examination of some effects of cocaine on within-session patterns of responding.

Two experiments examined within-session changes in operant responding when cocaine or cocaine plus food served as the reinforcer. In Experiment 1, male rats self-administered intravenous cocaine according to several fixed interval schedules. The within-session patterns of responding differed for the different schedules early in the session, but they converged by 50 minutes into the session. Because this convergence occurred regardless of the amount of cocaine consumed, it questions the response-stereotypy and dopamine-loading explanations for within-session changes in responding for cocaine reinforcers. In Experiment 2, rats responded for sweetened condensed milk during baseline sessions. During experimental sessions, responding produced cocaine in addition to the condensed milk. The addition of cocaine altered the pattern of responding during the early (first 15 minutes), but not the later (last 45 minutes), parts of the session. These results suggest that different factors produce the early-session increases and late-session decreases in responding. They are also consistent with the idea that the early-session changes in responding represent changes in'arousal'.

The effects of transtracheal gas delivery on central inspiratory neuromuscular drive.

Previous studies have shown transtracheal delivery of low-flow oxygen (TTO) decreases inspired minute ventilation (Veinsp) and have postulated that this would result in a decrease in the work of breathing (WOB). We hypothesized that a fall in central inspiratory neuromuscular drive (CIND) with TTO would reflect a fall in WOB. We measured resting ventilatory parameters (RVP) and CIND by the mouth occlusion pressure technique (MOP) at different gas flow rates through the catheter in 21 subjects (13 men, 8 women; mean age, 60 +/- 10.6 years) with severe COPD with a mature intratracheal oxygen catheter (ITOC). We also constructed a lung/chest wall analog (LCA) to determine if flow through the catheter would alter pressure changes during inspiration. Inspiratory tidal volume (Vtinsp) and minute ventilation (Veinsp) decreased proportionally to the gas flow rate through the catheter. However, with increasing flow through the catheter, P0.1 increased in the LCA, presumably due to the Bernoulli effect. The lack of a similar change in the subject group suggests that CIND does, in fact, fall, and that possibly there is a decrease in WOB. This effect may be of benefit to patients with severe COPD.

Dobutamine, but not dopamine, augments the normal chronotropic response to acute hypoxemia.

Infusion of exogenous dopamine has been shown to alter both the hypoxic and the hypercapnic ventilatory response, but its effects on the hypoxic and the hypercapnic cardiac response have not been reported. The purpose of this study was to determine if cardiac responses to hypoxemia and hypercapnia are altered by infusion of either dopamine (DOP) or its analog dobutamine (DBT). Baseline mean arterial blood pressure (MAP) and heart rate (HR) were measured in 7 normal male subjects while normal saline was infused intravenously (NS1) for 30 min. Each subject then underwent both a eucapnic hypoxemic challenge (EHC), and a hyperoxic hypercapnic challenge (HHC). In a double-blinded randomized fashion either DOP1 or DBT1 was selected and infused at 5 micrograms/kg/min for 30 min. EHC and HHC were again performed. This sequence was then repeated following a second NS infusion (NS2) and the alternate vasopressor. On a second study day, the dose of dopamine (DOP2) selected was that sufficient to induce a similar rise in MAP as seen with DBT1. Following NS and DOP1 there was a reproducible significant linear increase in HR with progressive hypoxemia seen in all subjects. This response was significantly augmented following infusion of DBT1 (p < 0.03), but no such augmentation was noted with DOP2. No significant change in HR was noted during HHC. The mechanisms responsible for this augmentation of hypoxemic response during dobutamine infusion are unclear, and do not appear to be related to a rise in MAP. We speculate that it is due to an effect of dobutamine on beta 1-receptor activity.

Range effects in transient and maintained generalization gradients.

In three experiments pigeons were trained to discriminate visual flicker rate stimuli. The stimulus set was varied so that the effects of overall stimulus range and border separation between positive and negative stimuli could be assessed. Experiments 1 and 2 showed that transient generalization gradients were lower in height and flatter with increases in either border separation or overall stimulus range. Border separation and overall range interacted in that the effect of range was greatest with relatively greater border stimulus separation. Experiment 3 showed that increased overall stimulus range reduced the magnitude of positive dimensional contrast in maintained gradients. Flattening of the maintained gradient with increases in stimulus range was similar to flattening of post-discrimination gradients found in Experiments 1 and 2. The results from all experiments indicate that increases in overall stimulus range do not decrease discriminability of unchanged stimulus values. Instead, increases in stimulus range may increase the variability of response or criterial factors in discrimination.

Patterns of responding within sessions.

Rates of responding changed systematically across sessions for rats pressing levers and keys and for pigeons pressing treadles and pecking keys. A bitonic function in which response rates increased and then decreased across sessions was the most common finding, although an increase in responding also occurred alone. The change in response rate was usually large. The function relating responding to time in session had the following general characteristics: It appeared early in training, and further experience moved and reduced its peak; it was flatter for longer sessions; and it was flatter, more symmetrical, and peaked later for lower than for higher rates of reinforcement. Factors related to reinforcement exerted more control over the location of the peak rate of responding and the steepness of the decline in response rates than did factors related to responding. These within-session changes in response rates have fundamental theoretical and methodological implications.

Strut fixation of an extensive flail chest.

The indications for and preferred approaches to operative stabilization of posttraumatic chest wall instability are uncertain. We suggest this simple, rapid, and effective approach to surgical stabilization by Luque rod strutting of the flail segment when operation is required.

Discrete and continuous measures of dimensional stimulus control.

In two sets of experiments, we examined dimensional stimulus control of pigeons' responses to a visual flicker-rate continuum. In the first experiment, responses to a single key were reinforced periodically during stimuli from one half of the stimulus continuum, and responses during other stimuli were extinguished. In the second experiment, two response keys were simultaneously available, with reinforcement for each response alternative associated with different halves of the stimulus continuum. Conditions of the second experiment involved either free-operant or discrete-trial stimulus presentations. Results from these experiments show that positive dimensional contrast appeared in discrimination tasks with one or two response alternatives, but only with free-operant procedures. In addition, discrimination between stimulus classes established by differential reinforcement was assessed as accurately by continuous rate measures as by discrete response choice in the two-alternative situation. The general implication of these experiments is that response rate measures, when properly applied, may reveal sources of variation within stimulus classes, such as dimensional contrast, that are not evident with discrete measures.

Absolute and relative measures of dimensional contrast.

Two sets of experiments examined the discriminative performance of pigeons on a visual flicker-rate continuum using a maintained generalization procedure. In the first experiment, responses during the intermediate stimulus value were not reinforced, whereas responses during all other stimuli were reinforced periodically. In the second experiment, training was similar to the first, with the exception of one condition in which stimuli adjacent to the negative stimulus border were eliminated from the discrimination set. Results from both experiments show that positive dimensional contrast seems to represent a relative enhancement of discrimination gradient form, rather than an absolute increase in responding with respect to prior baseline. Further, the form and magnitude of positive dimensional contrast are not predictable from the form and magnitude of baseline response rates. Results from the second experiment indicate that eliminating border stimuli increased response-rate differences between positive and negative stimuli, but did not necessarily diminish the magnitude of positive dimensional contrast.

Massed and spaced stimulus sequences in dimensional discrimination.

In two experiments, pigeons' responding to a visual flicker-rate continuum was established by a maintained generalization procedure. For both experiments, variable-interval reinforcement was available for responses during stimuli from one half of the stimulus continuum while responses during other stimuli were extinguished. The first experiment compared gradients of dimensional stimulus control produced by randomly presented positive and negative stimuli with gradients produced by massed positive and negative stimuli. The second experiment alternated the order of massed stimulus sequences. In both cases, massing of stimulus sequences diminished positive dimensional contrast effects, without seriously disturbing discrimination between positive and negative stimuli. The results indicate that stimulus sequences can have an important role in the production of dimensional contrast effects.

Momentary and global maximizing.

Four adult females responded at a computer console, on three constant probability concurrent variable-interval reinforcement schedules. The subjects were instructed to try to obtain as many reinforcers as possible, but were not given any instructions on how to accomplish this task. Three of the four subjects typically allocated responses to the schedule offering the higher reinforcement probability. These results show that some subjects trying to maximize overall reinforcement may respond in accordance with a momentary maximizing strategy.

Bronchial responsiveness to nonantigenic bronchoconstrictors in awake sheep.

The experiments were designed to further characterize pulmonary responsiveness to nonantigenic aerosol bronchoconstrictors in unanesthetized sheep. The distribution of aerosol histamine responsiveness was described among 55 sheep. Within day reproducibility of aerosol histamine (n = 18) and carbachol (n = 8) responsiveness was studied and aerosol histamine and carbachol responsiveness were compared (n = 9). The effects of cyclooxygenase inhibition with meclofenamate (n = 7) and ibuprofen (n = 8) on pulmonary responsiveness to aerosol histamine was studied as was the effect of ibuprofen (n = 6) on pulmonary responsiveness to aerosol carbachol. A log normal unimodal distribution of pulmonary responsiveness to aerosol histamine was described. Within day pulmonary responsiveness to aerosol histamine was highly reproducible while pulmonary responsiveness to aerosol carbachol decreased slightly, but not significantly, on the second challenge. Pulmonary responsiveness to aerosol histamine correlated with pulmonary responsiveness to aerosol carbachol (r = 0.85, P less than 0.05). Meclofenamate did not significantly attenuate pulmonary responsiveness to aerosol histamine. Ibuprofen attenuated pulmonary responsiveness to aerosol histamine (P less than 0.05) but not to aerosol carbachol. These experiments supply basic information related to pulmonary responsiveness to nonantigenic bronchoconstrictors in awake sheep.

Range effects in successive discrimination.

In two sets of experiments we examined pigeons' discrimination performance with a visual flicker-rate continuum, using a conventional successive discrimination procedure. In the first experiment, responses during the intermediate stimulus value were never reinforced, while responses during stimuli on either end of the continuum were reinforced periodically. In the second experiment, responses during stimuli from one end of the continuum were never reinforced, while responses during stimuli from the other end of the continuum were reinforced periodically. Results from both experiments show that discrimination between unchanged positive and negative stimulus values is a function of the range over which the total stimulus set varies. These range effects are comparable to effects found in absolute judgment tasks in human and animal psychophysics. In addition, the range effects reported here are not due to channel capacity, but may depend instead on variability in judgment criteria.

Nonexertional heatstroke. Physiologic management and cooling in 14 patients.

Fourteen patients with nonexertional heatstroke were evaluated in a general hospital during the summer of 1980. They were managed according to a prospectively devised protocol designed to effect heat dissipation primarily via convection and evaporation rather than by conduction. The time from entry into the emergency room to the first recorded rectal temperature of less than 103 degrees F (39.4 degrees C) ranged from 34 to 89 minutes (median, 60 minutes). Only one patient died; none had residual neurologic deficits. The use of these methods can result in a low incidence of permanent neurologic impairment and a low fatality rate.

Effects of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia.

The effect of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia was studied in eight unanesthetized sheep. Platelets were depleted with rabbit anti-sheep platelet antibodies (APA). Bolus injections of APA alone caused marked pulmonary hypertension (PPA increased from 21 +/- 2 to 62 +/- 5 cm H2O +/- SE) and alterations in lung mechanics (dynamic compliance of the lung [Cdyn] decreased to 38.5 +/- 4.6% and resistance to air flow across the lung [RL] increased to 705 +/- 162% +/- SE of control), which were attenuated by pretreatment with meclofenamate. It was possible to deplete platelets before endotoxemia through a slow continuous infusion of APA without altering base-line values of the measured variables. Platelet depletion did not significantly attenuate the alterations in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, or the normal increase in lung lymph concentrations of thromboxane B2 or 6-keto-PGF1 alpha observed following endotoxemia in the sheep. We conclude that normal circulating platelet counts are not required for the full expression of the sheep's response to endotoxemia.

Effects of granulocyte depletion on pulmonary responsiveness to aerosol histamine.

The effects of granulocyte depletion with hydroxyurea on pulmonary responsiveness to aerosol histamine were studied in 10 chronically instrumented unanesthetized sheep. Sheep were studied when granulocyte counts were normal (B), after 3 days of hydroxyurea but before granulocyte counts had dropped below 700 cells/mm3 (H), and after granulocyte counts had fallen below 200 cells/mm3 (D). Hydroxyurea itself had no effect on aerosol histamine responsiveness and the results were unaffected by the order of experimentation. All 10 sheep were less responsive (P less than 0.05) to aerosol histamine when granulocyte depleted effective dose of histamine that caused a reduction to 65% of control dynamic compliance (ED65Cdyn = 23.98 +/- 4.70 mg/ml) compared with base line (ED65Cdyn = 7.06 +/- 1.86 mg/ml). Those sheep initially most responsive to aerosol histamine had the greatest attenuation in their airway responsiveness to aerosol histamine (P less than 0.05). There was a significant negative correlation between absolute granulocyte counts in peripheral blood and pulmonary responsiveness to aerosol histamine during base-line (B) condition (r = -0.74, P less than 0.05) and for the data as a whole [r = -0.69, P less than 0.05 (B + H + D)]. Circulating granulocytes and/or pulmonary inflammation may contribute to pulmonary responsiveness to bronchial challenge.

Matching, maximizing, and hill-climbing.

In simple situations, animals consistently choose the better of two alternatives. On concurrent variable-interval variable-interval and variable-interval variable-ratio schedules, they approximately match aggregate choice and reinforcement ratios. The matching law attempts to explain the latter result but does not address the former. Hill-climbing rules such as momentary maximizing can account for both. We show that momentary maximizing constrains molar choice to approximate matching; that molar choice covaries with pigeons' momentary-maximizing estimate; and that the "generalized matching law" follows from almost any hill-climbing rule.