Search

Objective: Many sleep disorders involve frequent, brief arousals, not appreciated during conventional sleep stage scoring due to lack of electroencephalogram (EEG) desynchronization. We evaluated the temporal relation between heart rate (HR) changes, an index of autonomic activation, and EEG in seven healthy subjects during sleep., Methods: We identified bouts of tachycardia-bradycardia and performed spectral analysis of EEG during these. We also identified cortical arousals by the appearance of EEG alpha activity. This allowed us to dichotomize bouts of tachycardia-bradycardia by presence or absence of cortical arousal., Results: During non-rapid eye movement (REM) sleep, bouts with or without cortical arousal occurred with approximately equal frequency. Those with cortical arousals usually preceded onset of EEG changes. Those without cortical arousals were followed by increases in delta but not alpha power. EEG did not change during bouts in REM sleep., Conclusions: Capturing bouts of tachycardia-bradycardia is relatively easy via computerized algorithm. Bouts occur with cortical arousal or with slow wave synchronization suggestive of subcortical arousal. Thus, changes in HR may be useful index of arousal., Significance: These brief bursts of tachycardia-bradycardia are consistent with autonomic arousal. Such a measure may be among the first in a continuum of arousal ending with frank awakening.

Objective: The objective of this study was to examine whether inappropriate cardiovascular responses to stressors may underlie symptoms in Gulf War veterans with chronic fatigue., Methods: Psychophysiological stress testing was performed on 51 Gulf War veterans with chronic fatigue (using the 1994 case definition of the Centers for Disease Control and Prevention) and 42 healthy veterans. Hemodynamic responses to cold pressor, speech, and arithmetic stressors were evaluated using impedance cardiography., Results: Veterans with chronic fatigue had diminished blood pressure responses during cognitive (speech and arithmetic) stress tests due to unusually small increases in total peripheral resistance. The cold pressor test, however, evoked similar blood pressure responses in the chronic fatigue and control groups. Low reactivity to cognitive stressors was associated with greater fatigue ratings among ill veterans, whereas an opposite relation was observed among healthy veterans. Self-reported neurocognitive decline was associated with low reactivity to the arithmetic task., Conclusions: These results suggest a physiological basis for some Gulf War veterans' reports of severe chronic fatigue. A greater deficit with responses processed through cerebral centers, as compared with a sensory stimulus (cold pressor), suggests a defect in cortical control of cardiovascular function. More research is needed to determine the specific mechanisms through which the dissociation between behavioral and cardiovascular activities identified in this study may be contributing to symptoms in Gulf War veterans.

Posttraumatic stress disorder (PTSD) may occur in humans exposed chronically to stressors or after a single exposure to a traumatic event. A distinguishing feature of patients with PTSD is an exaggerated startle response, evident long after the traumatic event. We have observed similar abnormalities in our animal model of a chronic stress state. Rats exposed to 3 days (3DS) of our stress regimen (2-hr sessions of 40, 2 mA tailshocks) have exhibited a consistent pattern of persistent physiological and behavioral abnormalities including an exaggerated startle response several days after stressor cessation. In contrast, rats exposed to a single stress session (1DS) have exhibited many, but not all, of the persistent abnormalities displayed by 3DS rats. The present experiment compared the startle responding of 3DS and 1DS rats 4, 7, and 10 days after stressor cessation. Consistent with previous work, stressed rats exhibited elevated basal plasma corticosterone (CORT) levels the first day poststressor. These CORT levels were sensitive to the number of stressor exposures with higher CORT levels in 3DS rats than in 1DS rats. As for startle responding, the 1DS rats exhibited an exaggerated startle response 7 days poststressor, whereas startle sensitization was apparent 10 days poststressor in 3DS rats. Thus, the appearance of an exaggerated startle response after stressor cessation appears to be related to the number of stress session exposures. These animal models, the 3DS and 1DS rats, may be useful to gain insight into the neurobehavioral changes associated with PTSD.

For 5 days, rats were exposed to shocks that were signalled by a light 0, 33, 66, or 100% of the time. Basal hormone levels and responses to a light-shock pair were measured daily. Greater predictability was associated with higher basal plasma corticosterone and norepinephrine levels indicative of chronic stress. Habituation of the corticosterone response was also less in the groups with greater predictability. However, predictability did not affect plasma prolactin or epinephrine responses. Because the endocrine systems responded differently, it is unlikely that the changes were due to a unitary process. Greater predictability appeared to be more stressful in this paradigm. Both associative and nonassociative factors have major roles in determining the hormonal responses to repeated presentation of stressors.

We assessed the functional adrenocortical and behavioral state of rats previously exposed to repeated stressor presentations. In Experiment 1, the whole-body startle response to threshold (91 dB) and suprathreshold (96 dB) stimuli was assessed in rats given 3 daily sessions (3DS) of 40, 2-mA tailshocks. The 3DS rats showed an exaggerated startle response to the threshold auditory stimulus 4 days poststressor compared to nonshocked controls (CON). An exaggerated startle response in stressed rats was not evident either 1 day or 10 days poststressor. In Experiment 2, adrenocortical sensitization and behavioral reactivity were assessed in rats exposed to 1 day (1DS) or 3 days of our stress regimen. Stressed rats exhibited elevated basal plasma corticosterone (CORT) levels 1 day poststressor which recovered by 9 days poststressor. Stressed rats also exhibited suppressed open-field activity 4 days poststressor. On the 10th day poststressor, rats were exposed to a single tailshock. The 1DS and 3DS rats showed both a sensitized and prolonged CORT response to stressor reexposure compared to control rats which received only the single tailshock. In addition, on the 11th day poststressor 3DS rats exhibited a moderate recapitulation of the elevated basal CORT levels seen after the initial stressor exposures. Thus, exposure to our stress regimen produces a chronic stress state in rats characterized by persistent behavioral and adrenocortical sensitization, as well as suppressed open-field activity and elevated basal CORT levels. Rats exhibiting a chronic stress state may be appropriate as a model for the study of stress-related psychophysiological illnesses, such as posttraumatic stress disorder.

Typically, stress-related elevations in rat plasma cholesterol (CHOL) require preexposure to diets high in fats or cholesterol and lengthy stressor protocols. We report on two studies in which we measured plasma CHOL 22-h poststressor in rats fed Purina Laboratory Rodent Chow and exposed to 3 (3-day) or 1 (1-day) daily stressor sessions [40, 2 mA tailshocks]. In the first study, both the 3-day and 1-day groups exhibited moderately elevated morning plasma CHOL 22-h poststressor compared to nonshocked controls. Along with the groups in the first study, a second study included a restricted food control, rats transferred to the stressor environment, and rats simply transferred to an adjacent room. Neither restricted feeding nor the room transfers had an effect on morning plasma CHOL. However, the 3-day and 1-day groups again exhibited moderately elevated CHOL. Previous reports did not find elevated plasma CHOL in rats given a single stressor exposure when sampled at the end of the stressor session. Thus, the persistently elevated morning CHOL exhibited by the 1-day group may develop over time. The relatively slow development of plasma CHOL elevations may be related to the time course of stressor-induced thyroid suppression.

The chronic stress state has previously been defined as persistent visceral arousal coupled with behavioral abnormalities. To determine the number of stressor exposures necessary to induce a chronic stress state, male rats were given 2 hours of inescapable shock on 10, 7, 4, or 3 consecutive days. The 3-day stress group had the most pervasive changes in the variables measured: persistently elevated basal plasma corticosterone (CORT), continued weight loss in the post-stressor period, and abnormal behavior. More exposures to the stress regimen did not produce higher CORT levels or greater behavioral changes. Acutely stressed rats, exposed to 1 day of inescapable shock, had persistent CORT elevations without the other changes seen in the 3-day stress group. The data suggest that 3 days of our stress regimen are sufficient to produce a state of chronic stress and that some signs of this state begin to appear as early as the first exposure to our inescapable stress regimen.

This experiment was designed to study the effect of stressor intensity on habituation/sensitization of the adrenocortical stress response in rats. Rats were given 18 shocks in 3-hr daily sessions for 8 days, and a single shock probe before the sessions was used to determine how adrenocortical responsiveness changed with repeated exposure to the stress sessions. When lower intensity shock was given, the changes in plasma corticosterone response to shock probes followed a U-shaped curve--with a response that first habituated to no-shock control levels but later returned to the same magnitude as seen on the 1st probe day. Plasma corticosterone responses in rats given higher intensity shock never habituated and instead demonstrated an increased response indicative of sensitization; a temporal delay of 1 week occurred before sensitization developed. Responsiveness to exogenous adrenocorticotropin 24 hr after the last stress session was monotonically related to the intensity of the stressor presented during the experimental sessions. These data are consistent with the rule from the habituation literature that stimulus intensity is inversely related to the magnitude of habituation. Thus the data extend the dual process theory of Groves and Thompson (1970) to an endocrine respondent. The data also suggest that an explanation as to discrepancies in the literature concerning adrenocortical response to repeated presentation of stressors may relate to differences in the stressor parameters used.

This study measured plasma corticosterone levels in male rats during repeated daily presentations of two intensities of restraint stress. The corticosterone response to a stress session was defined as the change from pre-stress levels to levels after 60 minutes of restraint. With the relatively intense stress imposed by four limb prone restraint, the corticosterone response partially habituated over seven days due to increasing basal corticosterone levels. However, even on day 7, there was still a large corticosterone response. With the milder stress of immobilization in a tube, the corticosterone response did not habituate at all over 21 days of repeated stress despite rising basal levels. Stress levels of corticosterone did not show significant change over days in either of the two restraint groups. Further, rising basal corticosterone levels suggest that repeated restraint produced a chronic stress state in these rats which may vary in some qualitative way with stressor intensity. Control rats placed in the same room as the stressed rats during the two stresses initially had increased corticosterone levels that matched the levels achieved in the stressed rats. The responses in control rats for the intense stress did not habituate completely in 7 days, whereas those in the control rats for the mild stress habituated completely within 3 days. These data suggest intraspecific communication of the intensity of stress.

We have developed an apparatus and techniques that permit repeated, undisturbed blood sampling and concurrent assessment of activity in rats. The apparatus also allows experimental control of conditioning stimuli and contingencies without the need to transfer the rat to a separate chamber. In the experimental apparatus, body weights remain stable at approximately 90% of the original body weight. Plasma corticosterone and prolactin levels in the apparatus are comparable to levels obtained in undisturbed free-ranging rats and remain at basal levels for the 7 day duration of this experiment. Additionally, circadian activity rhythms in the apparatus are similar to those seen in free-ranging rats. This technique has potential applications for investigators who need to be able to control shock delivery, monitor activity, and sample blood without disturbing rats.

A disagreement exists in the literature as to whether plasma glucocorticoids are a sensitive index of emotional arousal. In order to provide further data on this subject, arousal in adult male rhesus monkeys was produced by classical appetitive conditioning done once every 48 hr. Monkeys showed significantly more aroused behavior during CS+ sessions than during CS- sessions. Concurrent with these behavioral changes, appetitive conditioning suppressed the increase in plasma cortisol that took place in control conditions. This dissociation between cortisol and arousal provides additional data for the conclusion that plasma glucocorticoids are an insensitive index of arousal. The fact that glucocorticoids decrease dramatically under similar experimental conditions in rats suggests that hormonal regulatory mechanisms for this rodent species may differ from that for primates.

Although it is known that the number of presentations of a stressor can influence the adrenocortical stress response, relatively little information exists on how stressor intensity affects this process. To evaluate this, we repeatedly presented rats with stressors of 3 different intensities and sampled blood for corticosterone. The first major finding was that the rat's initial adrenocortical responsiveness regardless of the stressor employed was a critical variable. Rats that showed a small corticosterone response showed no evidence of habituation or of differences due to stressor intensity. Rats that showed an initial robust response all showed partial habituation of their corticosterone response over time but the patterns varied with stressor intensity. Handled and prone restrained rats showed the same pattern but rats subjected to the more intense stressor of supine restraint showed delay in habituation and tonically elevated responses. These data indicate that individual differences in reactivity to stressors as well as stressor intensity can influence the pattern of the stress response over the course of repeated administration of the stressor.

Plasma growth hormone (GH), cortisol, and glucose were measured every 20 min in the last 2 h of a 12-h dark cycle and the first 4 h of a 12-h light cycle in eight environmentally limited rhesus monkeys; additionally, ongoing behavior was scored every 20 min in the last 4 h when the lights in the booths housing the monkeys were on. Episodic fluctuations in levels of GH, cortisol, and glucose occurred. Onset of booth illumination was associated with a significant number of GH secretory bursts (6 of 18), and more than twice as many bursts per hour occurred in the light than in the dark (L:D = 0.44:0.19). The onset of illumination was also associated with significant increases in glucose for the eight animals. In addition, plasma glucose increased concurrently with the onset of 13 of 18 bursts of GH secretion. Monkeys were rated as significantly more alert or aroused when plasma levels of GH and glucose were increasing than when they were decreasing. In contrast plasma cortisol showed small, rhythmic fluctuations over time that did not correlate with booth illumination or degree of behavioral arousal. This latter finding challenges the traditional assumption that cortisol is a sensitive index of behavioral arousal.

Following instrumentation with pneumatic cuffs around the inferior vena cava and the descending aorta, dogs were studied either following differential classical conditioning or in a control state. The cuffs functioned to raise and lower blood pressure for the construction of baroreflex curves for heart rate. Conditioned dogs received 8 trials each day with each CS+ (tone paired with flank shock) and CS- (a different tone without shock). Curves were constructed from cuff inflations timed to coincide with the maximum conditioned heart rate response. These curves were constructed from data acquired during infusion of saline, methyl atropine, or propranolol. Comparison of these curves revealed that the CS+ shifted the curves toward higher heart rates while the CS- curve was shifted toward lower heart rates without a change in gain. The amount of shift was comparable to that of the conditioned heart rate response. This suggested that the responses were independent and additive. Neither propranolol nor atropine eliminated this separation between the curves induced by the conditioning. These observations lead us to conclude that classically conditioned stress and baroreceptor stimulation exert independent control over heart rate that are mediated by both sympathetic and parasympathetic influences.

Research in chronic stress has been hampered by the absence of an operational definition for that condition. To explore possible criteria for chronic stress, we repeatedly exposed rats to 2 hr of tail shock per day. After several days, we found elevated prestress corticosterone levels and abnormal behavior, including decreased food consumption, fear-like suppression of activity immediately before stress, greater hesitancy to drop from a suspended wire, and decreased exploratory behavior in a novel environment. A less intensely stressed group of rats also had elevated prestress corticosterone levels, but not the abnormal behaviors that persisted in shocked rats after the stress sessions were discontinued. We propose that abnormalities in both adrenocortical function and behavior are a better marker for chronic stress than abnormalities in either of these systems alone. The animal model we have described may be useful for studying factors that contribute to development of chronic stress or PTSD.

The commonly believed hypothesis that increases in adrenocorticoid levels sensitively reflect behavioral arousal was tested by subjecting monkeys to repeated sessions of free-operant avoidance; these sessions produced varying degrees of behavioral arousal over time, which were quantified by a behavioral scoring technique. Cortisol was reliably elevated only in the most aroused subjects early in the first avoidance session. Although subjects were still aroused later in the session, cortisol had returned to basal levels. During subsequent avoidance sessions, cortisol returned to basal levels and did not increase significantly even when arousal was further manipulated by the superimposition of unavoidable shock during the final avoidance session. The addition of unavoidable shock was associated with a significant correlation between arousal, as reflected by increases in response rate, and magnitude of change, usually decreases, in mean cortisol levels. The frequent occurrence of dissociations between cortisol levels and behavioral arousal, as reflected by behavioral score, operant rate, and shock frequency, indicates that cortisol levels are of little use as a neuroendocrine index of arousal.