These data replicate and extend evidence that brief psychological manipulations can alter the HPA response to pharmacological activation in healthy subjects, supporting the hypothesis that novelty/familiarity and access to control or coping responses are highly salient to the HPA axis. They directly replicate our prior report (
23) that a full intervention, incorporating novelty reduction, sense of control and cognitive coping components, can significantly reduce cortisol responses to pentagastrin. They also indicate that cognitive preparation alone, without direct manipulation of control, can modulate the HPA axis as effectively as the more complex intervention. There is also evidence that simply providing access to control, even if it is not utilized, can modulate HPA axis activation, though this effect may be less robust. These results further dissect psychological mechanisms of cortisol modulation in humans, supporting the separable salience of familiarity/coping and access to control.
The impact of ‘Control alone’ across outcome variables appeared less robust (see below), but its impact on cortisol was significant and comparable to that of ‘full CI’ or ‘Coping alone’ (novelty reduction plus coping instructions). Subjective data corroborated that the control manipulation in fact enhanced subjective sense of control. It would thus appear that the mere turning on or off of a light indicating presence or absence of control carried enough meaning to significantly alter cortisol release. This effect persisted with exclusion of the only subject who utilized available control. These findings suggest that believing one can control a potential threat may be a particularly salient modulator of HPA axis activation. However, we must also note that the impact of control alone was perhaps less robust than the impact of coping instructions. The group main effect was not significant when separately comparing ‘Control alone’ to the SI group on cortisol response, whereas this comparison was significant or nearly so for the full CI and Coping alone groups, which both received coping instructions. In addition, ACTH changes for ‘Control alone’ did not parallel cortisol changes. Further study will be needed to determine the true relative potency of “coping” and “control” in modulating HPA axis activation.
Further work is also needed to separate the effects of novelty reduction and coping enhancement, since cognitive coping instructions included both factors – trying to enhance familiarity (via detailed information on expectable experiences) and cognitive coping (by helping subjects interpret these experiences as benign). As a result, these data cannot address the separable potency of these two factors in modulating HPA axis activity.
Alternative explanations for these findings must be considered and addressed in future research. Subjects receiving ‘full CI’ and ‘Coping alone’ spent an extra 9 minutes with the investigator, who was with subjects after pentagastrin injection. This could enhance sense of social support, though our subjective measure of perceived social support did not capture such an effect. Social support is a known modulator of HPA axis activity (
13). Follow-up work controlling for time spent and specifically examining social support is needed. It is also possible that introducing the
idea of control may have made salient the potential for
lack of control and thereby enhanced HPA responding, rather than access to control reducing it. The ‘Coping alone’ group had the indicator light removed and the control concept was never introduced. Their cortisol response reduction was comparable to other intervention groups, but they had less total cortisol secretion on pentagastrin day. This was the only group with a highly significant main effect of group when separately compared to the SI group, because their cortisol levels were low throughout the experiment. We want to attribute this to the power of coping instructions, but it is conceivable that introducing the light and the possibility of control elevated cortisol in the other three groups. Given the complexity and intensity of the most robust and widely used psychosocial HPA activator, the Trier Social Stress Test (TSST, (
30)), significantly elevating cortisol by adding a light and not turning it on seems far-fetched. However, the possibility that simply introducing a potential wish for control but denying it might provide an amplifying signal to the HPA axis warrants further exploration.
Further work is needed to determine if control and coping represent separate processes or two aspects of a single phenomenon. We provided direct control through access to infusion pump buttons, but coping instructions fostered cognitive control of internal responses. The salient experience for both may be a sense of mastery over side effects. In the absence of real control or coping assistance, subjects perhaps just passively endured side effects. The correlation between symptom intensity (which predominantly reflects side effects) and cortisol response, and the impact of control on cortisol via effects on symptoms (in path analysis), suggest that control was a key factor, whether it involved control over the symptom generator (drug infusion) or symptom interpretation (cognitive coping). Extensive data from other human and non-human paradigms support the importance of control, mastery, self-efficacy, and coping as modulators of HPA axis activity (
19–
21). Familiarity, social support, and past experience with a challenge (
11–
14) may all reduce HPA axis activation by enhancing “positive outcome expectancies” (
10,
22). Further work is needed to determine whether these indeed reflect a single underlying psychobiological mechanism or represent separable phenomena.
Future work should attempt to trace the neural pathways through which psychological processes amplify and inhibit HPA axis activity, to reveal underlying mechanisms and help optimize cognitive tools for stress modulation. In our model, pentagastrin side effects may create a signal from insula to hypothalamus that amplifies its direct pituitary effects. The insula helps to process emotion and monitor internal bodily states (
31). Insula activity predicts emotion-induced release of ACTH (
32). It could well mediate side-effect-generated amplification of HPA axis activity. Positive associations between other cortical areas, insula, and ACTH response to emotional activation (
32) suggest pathways through which both somatosensory and cognitive/emotional inputs (e.g., the “idea” of potential need for control discussed above) might amplify HPA axis activity.
Medial prefrontal cortex (mPFC) is a likely source for top-down inhibitory inputs that could dampen HPA responses to an activator like pentagastrin. The mPFC is a critical source for inhibitory input to “stress response” areas such as amygdala in fear conditioning models (
33) and dorsal raphe in stressor control models – via glutamatergic activation of local GABAergic inhibitory neurons (
34,
35) – and has inhibitory control over hypothalamic outputs (
36) via a similar mechanism (
37), suggesting parallel inhibitory circuits from mPFC to multiple brain regions involved in emotion or stress responses. Future work may define specific prefrontal, inhibitory control pathways and ways to specifically increase activity in them, so as to enhance stress resilience (
32).
Our data continue to document clear dissociation between subjective distress and HPA activity – again showing no link between anxiety and cortisol responses – consistent with extensive evidence that negative affect is not a primary driver of HPA axis reactivity in challenge paradigms (
9,
23). Here we report a link not previously noted (
9,
23) between physical symptoms and cortisol release, with path analysis support for the importance of this link. The net HPA response to pentagastrin may involve direct pituitary activation that is amplified by psychological responses to side effects. The combination of direct and indirect activation pathways may provide a particularly useful context for examining psychological modulation of the HPA axis. Psychological factors may be more salient and their impact more detectable when the system has already been turned on directly, through ‘systemic’ pathways (
3). It should be illuminating to study comparable cognitive interventions in a CRH model (
38), where activation is entirely direct, with no “amplifying” side effects.
One caveat in interpreting our results is the randomization failure that led to higher trait anxiety scores in the SI group. We cannot prove that trait anxiety differences did not contribute to cortisol differences, but we think it is extremely unlikely for the following reasons. Intervention groups had smaller cortisol responses to pentagastrin than the SI group even after controlling for trait anxiety. Mean trait anxiety scores were entirely within the normal range and the group difference (8 points) is not clinically meaningful. Groups did not differ on any other pre-pentagastrin measure. No linkages between trait anxiety and cortisol have been seen in any previous pentagastrin data set (
24,
26–
28). Prior work produced strikingly similar group HPA differences without any differences in trait anxiety. We conclude that the randomization failure had no bearing on our HPA results.
These data thus confirm our prior report (
23) that simple psychological manipulations can significantly reduce cortisol responses to pharmacological activation. They extend prior findings by showing that cognitive preparation alone, focusing on enhancing familiarity and preparedness to cope with drug side effects, can reduce cortisol responses. Additionally, they suggest that an ability to control drug exposure may also independently reduce cortisol responses.
Insofar as deleterious health consequences of stress may be mediated through the HPA axis (
1), further dissection of psychological activators and inhibitors of this system may enhance our ability to reduce these negative effects, through laboratory-developed stress reduction and stress preparation techniques (
39). The alteration of HPA axis activity by instruction-sensitive cognitive variables, even in this pharmacological activation model, also suggests that HPA abnormalities in psychiatric patients could be due to disruption in top-down modulatory inputs to the hypothalamus, rather than to fundamental dysregulation at the level of the hypothalamus or below.
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