Cortisol circadian rhythms and response to stress in children with autism

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Summary

Background: Autism is a severe neurodevelopmental disorder characterized by impairment in communication, social interaction, repetitive behaviors and difficulty adapting to novel experiences. The Hypothalamic-Pituitary-Adrenocortical (HPA) system responds consistently to perceived novel or unfamiliar situations and can serve as an important biomarker of the response to a variety of different stimuli. Previous research has suggested that children with autism may exhibit dysfunction of the HPA system, but it is not clear whether altered neuroendrocrine regulation or altered responsiveness underlies the differences between children with and without autism. In order to provide preliminary data concerning HPA regulation and responsiveness, we compared circadian rhythms and response to a non-social, environmental stressor in children with and without autism.

Methods: Circadian rhythms of cortisol were estimated in children with (N=12) and without (N=10) autism via analysis of salivary samples collected in the morning, afternoon and evening on 2 consecutive days. HPA responsiveness was assessed by examining the time course of changes in salivary cortisol in response to a mock MRI.

Results: Both groups showed expected circadian variation with higher cortisol concentration in morning than in the evening samples. The children with autism, but not typical children, showed a more variable circadian rhythm as well as statistically significant elevations in cortisol following exposure to a novel, nonsocial stimulus.

Conclusions: The results suggest that children with autism process and respond idiosyncratically to novel and threatening events resulting in an exaggerated cortisol response.

Introduction

Autism is a severe neurodevelopmental disorder characterized by qualitative impairment before the age of three in verbal and nonverbal communication, reciprocal social interaction, and a markedly restricted repertoire of activities and interests (APA, 1994). In addition to these features, children with autism have been described as experiencing difficulty tolerating novelty and environmental stressors (Kanner, 1943). Amongst the two most frequently used indices of the response to stress have been observable changes in the behavior of an individual experiencing stress and the marked increase in the stress related hormones. When the behavior and the endocrine markers of stress are concordant there is little problem in interpreting the outcome. However, there are examples of dissociation between these behavioral and endocrine measures (e.g. Wiener et al., 1988). In children with autism, there are excessive behavioral reactions to stressful circumstances, but it is less clear whether or not this is accompanied by a corresponding increase in neuroendocrine activity.

The hypothalamic-pituitary-adrenal (HPA) axis is the classical endocrine stress system. Although the label HPA is still used to describe this system, it is abundantly clear that the regulation of the HPA axis involves a complex neural system involving many different anatomical structures and neurochemical events that are required to activate and/or inhibit the HPA axis. Adrenocorticotropic hormone (ACTH) is regulated by two primary molecules at opposing ends of the system, which are corticotropin releasing hormone (CRH) in the brain, which activates both behavioral and hormonal stress responses and glucocorticoids (cortisol in humans) secreted from the adrenal which acts primarily to inhibit the release of CRH, ACTH and cortisol through its action on the glucocorticoids receptors in the brain and the pituitary. Thus, one of the most widely used biological markers of stress is the release of cortisol from the adrenal since elevations often occur in response to novel and unpredictable situations (Gunnar and Donzella, 2002, Hennessey and Levine, 1979).

It has been established that the regulation of the HPA axis is different depending on the type of stress the organism is exposed to. The most recent descriptions of these differences have been elaborated by Herman and Cullinan (1997). Thus, although seemingly disparate stimuli activate the HPA axis they utilize different pathways. Systemic stressors are physical and context-independent and are capable of activating the HPA system in unconscious animals. In general, systemic stimuli usually involve a life-threatening event. In the case of systemic stimuli, the information required to activate the HPA system is relayed to the periventricular nuclei (PVN) of the hypothalamus via the brain stem. In contrast, processive stimuli are context dependent, requiring the comparison of current information with past experience and the assignment of emotional meaning. Limbic system structures are the primary mediators of processive stimuli. Thus the bed nucleus of the stria terminalis (BNST) preoptic nucleus, lateral and medial septum, the amygdala, prefrontal cortex and hippocampus all are involved in either activation or inhibition of the stress response to processive stimuli. Given the importance of the limbic system in the regulation of the stress response it has become more common to refer to the stress responsive system as the LHPA axis. The ‘L’ refers to the limbic system.

There is evidence that regulation of the HPA system may be dysfunctional in children with autism (Nir et al., 1995, Richdale and Prior, 1992, Yamazaki et al., 1975). Most of the published reports examining HPA responsiveness in children with autism have serious methodological flaws, which include a lack of appropriate controls, invasive sampling techniques, mixed diagnosis and very small samples. Children with autism have been shown to exhibit an exaggerated stress response as evidenced by increases in ACTH and beta-endorphin following an injection of insulin (Maher et al., 1975). In this investigation, there were no controls for the effects of venipuncture per se. Tordjman et al., 1997, Curin et al., 2003 report higher levels of ACTH in autism. These data were interpreted as indicating that individuals with autism have a chronic level of anxiety. However, in these studies cortisol was not different or lower than controls. Insofar as the release of ACTH is much more rapid than cortisol, it appears more likely that the higher ACTH levels observed in the subjects with autism was a result of the response to venipuncture and restraint required to obtain blood samples. Richdale and Prior (1992) provide additional support for the hypothesis that children with autism may be hyperresponsive to environmental stress. Subjects with autism who were integrated into the regular school system showed hypersecretion of cortisol suggesting an environmental stress response in the school environment. In contrast, a recent report showed a lack of salivary cortisol elevation or ‘hyporesponsiveness’ in a group of autistic-like children diagnosed with Multiple Complex Developmental Disorder (MCDD; Jansen et al., 2000). These investigators exposed children diagnosed as MCDD to a stressor involving public speaking (a modified Trier Social Stress Test) and hypothesized that these children may be processing social stimuli differently and, therefore, tend to show a diminished salivary cortisol response. In a more recent investigation, Jansen et al. (2003) demonstrated that unlike the reduced cortisol response shown in the MCDD children, the children with autism showed a relatively elevated cortisol response to psychosocial stress but were not significantly different from neurotypical children.

Although the data are by no means consistent, alterations in the normal circadian patterns of cortisol have been reported in children with autism (Aihara and Hashimoto, 1989, Hill et al., 1977, Hoshino et al., 1987, Richdale and Prior, 1992, Tordjman et al., 1997, Yamazaki et al., 1975). In general, where alterations in circadian rhythms are reported in children with autism, they seem to be more apparent in children identified as being low functioning (Jensen et al., 1985). It has also been reported that children with autism show poor negative feedback regulation. In one study, Hoshino and colleagues (Hoshino et al., 1987) indicated that some children with autism showed abnormal diurnal rhythm and/or a failure to suppress cortisol in response to dexamethasone, a synthetic glucocorticoid that serves as a potent negative feedback signal (Jensen et al., 1985). The results suggest that negative feedback mechanisms of the HPA axis may be inefficient in children with autism, which would be expected to result in prolonged cortisol elevations following activation of the stress response. It is possible, therefore, that some claims of increased HPA responsivity in children with autism are actually due to decreased negative feedback.

The current study was undertaken to evaluate the responsiveness and regulation of the HPA axis in a group of relatively high functioning children with autism. In order to avoid stress associated with collection of blood samples, we measured cortisol in saliva, a noninvasive method for obtaining multiple samples (Kirschbaum and Hellhammer, 1994). It has been determined that cortisol is sequestered in saliva, exists in the unbound form and shows detectable changes after about 20 min. Resting levels of cortisol vary predictably as a function of the diurnal cycle. Thus, in using cortisol as a measure of stress responsiveness we deemed it necessary to examine the basic regulatory aspects of the system by obtaining diurnal cortisol samples for comparison. Samples obtained over a 48-h cycle were used to characterize circadian rhythms. This also provided a stable basal level by which to compare the response to arrival at the laboratory. The response to stress was examined by exposing the children for twenty minutes to a mock MRI scanner. We reasoned that this manipulation would include exposure to novelty as well as mild restraint that would result in the activation of the HPA axis. Finally, cortisol measures were obtained for an extended period of time following the termination of the stressor to evaluate negative feedback. This design also makes it possible to study the relationship between presumed basal cortisol levels obtained in the home to the adrenocortical response to stress in the laboratory. Based upon the results of previous experiments we predicted that children with autism would: (1) exhibit normal circadian patterns of cortisol, (2) show an exaggerated response to stress reflecting enhanced activation, and (3) would return to basal levels more slowly reflecting diminished negative feedback.

Section snippets

Subjects

Twenty-four male children entered the study and participants met criteria for categorization into the two groups: Autism or typically developing (Typical). Two typically developing children were dropped from the study due to parental noncompliance with procedures. Thus, the subjects consisted of 22 male children between 6- and 11-years of age (mean age 8.8 years), 12 diagnosed with autism (mean age=8.5) and 10 neurotypical children (mean age=9.2 years). The children with autism were diagnosed

Results

Fig. 1 illustrates the mean patterns of salivary cortisol levels (log transformed) for children in the Autism and Typical groups, and Fig. 2 illustrates the mean stress and recovery patterns for these groups.

Results of the mixed-effects analysis pertaining to fixed effects are shown in Table 1. Both groups demonstrated the expected decline in cortisol over the day, with significant decreases for both time of day contrasts (p<0.00001; all p-values are from the Wald test unless otherwise noted).

Discussion

In the present experiment, our primary purpose was to investigate the hypothesis proposed originally by Kanner (1943) that children with autism were more responsive to changes in their environment. Insofar as the LHPA axis appears to be activated in response to novelty, we specifically chose as our stimuli a situation where the stimuli represented primarily novel events that did not involve any social parameters. It has been well established that one of the features of children with autism is a

Acknowledgements

The authors wish to thank the children and families who participated in this study and assisted in the collection of home samples. We also express our gratitude to Christine Brennan who ran the cortisol assays for the project.

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