Do diurnal salivary cortisol curves carry meaningful information about the regulatory biology of the HPA axis in healthy humans?

Salivary cortisol stress biomarkers have been extensively used in epidemiological work to document links between stress and ill health. There has been little effort to ground field friendly cortisol measures in the hypothalamic-pituitary-adrenal (HPA) axis regulatory biology that is likely relevant to delineating mechanistic pathways leading from stress exposure to detrimental health outcomes. Here, we utilized a healthy convenience sample (n = 140) to examine normal linkages between extensively collected salivary cortisol measures and available laboratory probes of HPA axis regulatory biology. Participants provided 9 saliva samples per day over 6 days within a month, while engaging in usual activities, and also participated in 5 regulatory tests (adrenocorticoptripin stimulation, dexamethasone/corticotropin-releasing-hormone stimulation, metyrapone, dexamethasone suppression, and Trier Social Stress Test). Logistical regression was used to test specific predictions linking cortisol curve components to regulatory variables and to explore widely for non-predicted associations. We found support for 2 of 3 original hypotheses, showing associations (1) between cortisol diurnal decline and feedback sensitivity as measured by dexamethasone suppression, and (2) between morning cortisol levels and adrenal sensitivity. We did not find links between central drive (metyrapone test) and end of day salivary levels. We confirmed an a priori expectation of limited linkage between regulatory biology and diurnal salivary cortisol measures, beyond those predicted. These data support an emerging focus on measures related to diurnal decline in epidemiological stress work. They raise questions about the biological meaning of other curve components, including morning cortisol levels, and perhaps CAR (Cortisol Awakening Response). If morning cortisol dynamics are linked to stress, more work on adrenal sensitivity in stress adaptation and stress-health links may be warranted.

Childhood maltreatment and within-person associations between cortisol and affective experience.

Glucocorticoids exert profound effects on the brain and behavior, but cortisol concentrations are rarely linked to subjectively reported emotional states in humans. This study examined whether the link between cortisol and subjective anxiety varied by childhood maltreatment history. To do this, 97 individuals (60.8% female) participated in a standardized stress task in the laboratory (Trier Social Stress Test, TSST) while providing serial ratings of their feelings of anxiety as well as cortisol samples in blood. These measurements were collected nine times across the laboratory visit, from immediately before the TSST to 65 minutes after stress initiation. We estimated the within-person association between cortisol concentrations and momentary feelings of anxiety for individuals with and without exposure to childhood maltreatment, measured via self-report on the Childhood Trauma Questionnaire (CTQ). Individuals exposed to maltreatment during childhood reported the greatest feelings of anxiety when cortisol concentrations were lowest. This pattern was exaggerated among female participants, those with posttraumatic stress disorder (PTSD), and those exposed to emotional neglect relative to other forms of maltreatment. Early life adversity, such as parental maltreatment, may alter the role of cortisol in affective experiences. This observation may provide preliminary, translational evidence of a novel pathway through which stress may lead to and maintain internalizing symptoms in humans. More studies accounting for the moderating role of childhood maltreatment in biobehavioral pathways are needed.

The psychology of HPA axis activation: Examining subjective emotional distress and control in a phobic fear exposure model.

The HPA axis plays a key role in mediating the effects of "stress" on health, but clarifying mechanisms requires an understanding of psycho-biological linkages. There has long been an implicit assumption that subjective emotional distress (e.g., fear) should activate the HPA axis. Although this assumption was challenged 25 years ago (Curtis, 1976), laboratory studies in humans are limited. In this study we sought to replicate Curtis' findings and extend it by investigating if presence or absence of stressor control shapes HPA axis reactivity in a phobic fear exposure model. We recruited 19-45-year-old specific phobia participants (n=32 spider/snake phobia; n=14 claustrophobia) and gradually exposed them to their feared object or situation while measuring hormonal (ACTH and cortisol) and subjective (emotional distress, perceived control) responses. Utilizing a dyadic yoked design, we compared HPA reactivity when the pace of exposure was controlled by participants to identical exposure given to matched participants in the absence of control. Results showed that phobic fear exposure generated intense emotional distress without a corresponding increase in HPA axis activity. Although our actual manipulation of control failed to impact HPA responses, perceived control during exposure was associated with lower cortisol, an effect that was moderated by actual availability of stressor control. Our findings replicate Curtis' findings and challenge the still common but unsupported assumption that HPA axis activity reflects subjective distress. These results also highlight the importance of both perceived and actual aspects of stressor control in understanding what is truly "stressful" to the HPA axis system.

Penn State Worry Questionnaire - 10: A new tool for measurement-based care.

The Penn State Worry Questionnaire - Past Week (PSWQ-PW) is an adaptation of the widely used Penn State Worry Questionnaire, measuring pathological worry weekly. However, it contains problematic negatively worded items and has not been validated in a large sample yet. To meet the needs of measurement-based care (MBC), we developed a shortened version (PSWQ-10) based on the PSWQ-PW, retaining only positively worded items, and examined its psychometric properties and clinical utility. Patients with Generalized Anxiety Disorder (GAD), Major Depressive Disorder (MDD), and other anxiety disorders completed the PSWQ-10 and other instruments during routine evaluation in an academic anxiety clinic. A second cohort from a perinatal clinic was evaluated similarly. The PSWQ-10 displayed excellent internal consistency, convergent and discriminant validity, and criterion group validity. Patients with GAD scored significantly higher than those with other anxiety disorders but did not differ from those with MDD. The PSWQ-10 showed sensitivity to change over time and demonstrated excellent psychometric properties in the perinatal population. The PSWQ-10 is a reliable, valid, efficient, and straightforward worry-focused instrument that can be readily used in MBC and help clinicians objectively measure worry as a treatment outcome in broad clinical populations.

Brief cognitive intervention can modulate neuroendocrine stress responses to the Trier Social Stress Test: buffering effects of a compassionate goal orientation.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a critical mediator linking stress to health. Understanding how to modulate its reactivity could potentially help reduce the detrimental health effects of HPA axis activation. Social evaluative threat is a potent activator of this system. Access to control and coping responses can reduce its reactivity to pharmacological activation. Compassionate or affiliative behaviors may also moderate stress reactivity. Impact of these moderators on social evaluative threat is unknown. Here, we tested the hypotheses that interventions to increase control, coping, or compassionate (versus competitive) goals could reduce HPA-axis response to social evaluative threat. METHODS: Healthy participants (n=54) were exposed to social evaluative threat using the Trier Social Stress Test (TSST). They were randomly assigned to receive one of four different instructions prior to the stressor: Standard TSST instructions (SI), standard instructions with access to "control" (SI Control), or one of two cognitive interventions (CI) that (1) increased familiarity and helped participants prepare coping strategies (CI Coping), or (2) shifted goal orientation from self-promotion to helping others (CI Compassionate Goals). ACTH and cortisol were obtained before and after stress exposure via intravenous catheter. RESULTS: Control alone had no effect. CI Compassionate Goals significantly reduced ACTH and cortisol responses to the TSST; CI Coping raised baseline levels. Compassionate Goals reduced hormonal responses without reducing subjective anxiety, stress or fear, while increasing expression of pro-social intentions and focus on helping others. CONCLUSIONS: Brief intervention to shift focus from competitive self-promotion to a goal orientation of helping-others can reduce HPA-axis activation to a potent psychosocial stressor. This supports the potential for developing brief interventions as inoculation tools to reduce the impact of predictable stressors and lends support to growing evidence that compassion and altruistic goals can moderate the effects of stress.

CRH-stimulated cortisol release and food intake in healthy, non-obese adults.

BACKGROUND: There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans. METHODS: We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm. RESULTS: CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption. CONCLUSIONS: These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity.

Effect of time of preparation on pentagastrin-induced symptom, endocrine and cardiovascular responses.

Pentagastrin is a cholecystokinin (CCK)-B agonist and laboratory panicogenic agent that produces endocrine (ACTH and cortisol), symptom (anxiety, panic) and cardiovascular (heart rate) responses. Although in vitro data have supported its chemical stability, preliminary data suggested that increasing time between drug preparation and drug infusion could reduce the magnitude of endocrine and symptom responses. The current study examined this possibility. Twenty-one healthy subjects presented at the University of Michigan General Clinical Research Center (GCRC) and had an intravenous catheter inserted. Heart rate, cortisol levels and subjective anxiety were measured before and after pentagastrin and placebo injections. Pentagastrin was prepared either within 60 min of IV infusion (Normal Preparation group) or at least 3.5 h prior to infusion (Early Preparation group). Relative to the Normal Preparation group, Early Preparation subjects had similar heart rate responses but significantly smaller cortisol and subjective anxiety responses. Early preparation of pentagastrin thus appears to weaken endocrine and subjective anxiety responses, highlighting the importance of attending to often overlooked procedural variables (e.g., time between preparation and administration) in studies of this type. The sensitivity of cortisol and anxiety responses to preparation time, but insensitivity of heart rate, is consistent with previous studies suggesting different thresholds of activation for the three response modalities. These differential sensitivities may suggest different and separable CCK-B stimulated pathways for each response, which combine to produce panic, rather than a single, unified CCK-B mediated panicogenic response.