The vast majority of people do not develop psychopathology after exposure to highly stressful or life-threatening events (Feder et al. Reference Feder, Nestler and Charney2009). Fascinatingly, having experienced some adversity may even have advantages for mental health and well-being (Seery et al. Reference Seery, Holman and Silver2010). Although research into stress-related disorders historically has focused on identifying factors that confer vulnerability, it is becoming increasingly clear that resilience is not simply the absence of vulnerability. In their target article, Kalisch et al. therefore propose a paradigm shift in research into risk factors for stress-related mental disorders to redirect attention to factors that uniquely determine resilience. This is a welcome development because an understanding of resilience factors is critical for the promotion of mental health, one of the most urgent contemporary challenges for modern societies (Malenka & Deisseroth Reference Malenka and Deisseroth2014).

The theoretical framework proposed by the authors draws on an ongoing shift toward transnosological understanding of stress-related mental disorders as heterogeneous clusters of dysfunctions in multiple cognitive-neurobiological systems. Kalisch et al. invoke the classical concept of appraisal (Lazarus Reference Lazarus1993b; Scherer Reference Scherer, Ekman and Davidson1994) as a causal factor determining whether a given situation triggers a stress response. They acknowledge the possibility that a variety of appraisal processes may occur in parallel in different neural and cognitive systems, which even may lead to conflicting appraisals. Nonetheless, they propose a single mediating mechanism that constitutes the final common path to resilience: a positive “appraisal style.”

Kalisch et al. define this concept as a stable trait that determines how a person generally interprets threatening situations. This theoretical framework is reminiscent of cognitive models of vulnerability to stress-related disorders (Beck Reference Beck2008), which assume that development and maintenance of psychopathology ultimately is determined by maladaptive beliefs and cognitive biases, albeit in interaction with biological factors. We think that this strong emphasis on cognitive factors falls short in appreciating the heterogeneity of the cognitive-neurobiological determinants of resilience and may therefore potentially hamper progress. Below, we will illustrate our point by examining the paradoxical role of corticosteroids in adaptation and resilience to stressors.

It is becoming increasingly clear that corticosteroids, which are released through activation of the hypothalamus-pituitary-adrenal (HPA) axis and are commonly seen as the hallmark of the stress response, play a dual role in regulating the central response to stressors. Corticosteroids can act centrally in concert with faster-acting agents such as catecholamines to produce a state of heightened arousal and vigilance (Hermans et al. Reference Hermans, van Marle, Ossewaarde, Henckens, Qin, van Kesteren, Schoots, Cousijn, Rijpkema, Oostenveld and Fernández2011; Joëls & Baram Reference Joëls and Baram2009). Effects that last beyond the time window of concurrent catecholaminergic activation, however, can be different and even go in an opposite direction (de Kloet et al. Reference de Kloet, Joëls and Holsboer2005; Hermans et al. Reference Hermans, Henckens, Joëls and Fernández2014).

For example, administration of synthetic corticosteroids (hydrocortisone) in humans can reduce fear responses to phobic stimuli (Soravia et al. Reference Soravia, Heinrichs, Aerni, Maroni, Schelling, Ehlert, Roozendaal and de Quervain2006). Hydrocortisone administration furthermore leads to reduced vigilance for threat-related stimuli, even when these stimuli are presented below conscious perceptual thresholds by means of backward visual masking (Putman et al. Reference Putman, Hermans, Koppeschaar, van Schijndel and van Honk2007). Similar administrations prior to induction of acute stress have furthermore been shown to have a protective effect on mood changes elicited by stress (Het & Wolf Reference Het and Wolf2007). In line with these experimental findings, another study demonstrated that pretreatment with hydrocortisone increased the efficacy of exposure therapy for acrophobia (fear of heights; de Quervain et al. Reference de Quervain, Bentz, Michael, Bolt, Wiederhold, Margraf and Wilhelm2011). Further clinical studies have provided initial evidence for the effectiveness of hydrocortisone in preventing stress-related mental disorders such as posttraumatic stress disorder (Schelling et al. Reference Schelling, Briegel, Roozendaal, Stoll, Rothenhäusler and Kapfhammer2001; Weis et al. Reference Weis, Kilger, Roozendaal, de Quervain, Lamm, Schmidt, Schmölz, Briegel and Schelling2006). A recent review even concluded that hydrocortisone is so far the only effective drug for this indication (Amos et al. Reference Amos, Stein and Ipser2014). For this reason, the ability to contain and terminate the central stress response through corticosteroid signaling may form an important biological resilience factor.

Such dynamic effects of corticosteroids and other stress-sensitive neuromodulators on appraisal processes can be understood within a neurobiological framework of fear and safety learning. Whereas acquisition of conditioned fear requires the amygdala, extinction of conditioned fear underlying safety learning depends on the prefrontal cortex (Milad & Quirk Reference Milad and Quirk2012). Rather than replacing a fear memory, extinction training appears to produce a new memory that competes for expression whenever a cue is encountered that previously was associated with the threat (Bouton Reference Bouton2004). Increasing evidence shows how the amygdala and prefrontal cortex are part of distinct larger neural systems that are differentially affected by stress (Arnsten Reference Arnsten2009; Hermans et al. Reference Hermans, Henckens, Joëls and Fernández2014). Induction of acute stress (Cousijn et al. Reference Cousijn, Rijpkema, Qin, van Marle, Franke, Hermans, van Wingen and Fernández2010; van Marle et al. Reference van Marle, Hermans, Qin and Fernández2009), as well as elevation of central levels of norepinephrine using reboxetine (Onur et al. Reference Onur, Walter, Schlaepfer, Rehme, Schmidt, Keysers, Maier and Hurlemann2009), enhances amygdala responsiveness to biologically threat-relevant stimuli such as negative facial expressions. Similar stress induction procedures impair prefrontal cortex function (Qin et al. Reference Qin, Hermans, van Marle, Luo and Fernández2009). This shift in dominance between these two systems may explain why acute stress blocks recall of extinction memory (Deschaux et al. Reference Deschaux, Zheng, Lavigne, Nachon, Cleren, Moreau and Garcia2013; Raio et al. Reference Raio, Brignoni-Perez, Goldman and Phelps2014) and impairs the ability to apply previously learned strategies for cognitive reappraisal of conditioned stimuli (Raio et al. Reference Raio, Orederu, Palazzolo, Shurick and Phelps2013).

In line with the dual role of corticosteroids explained above, slow effects of corticosteroids (i.e., beyond the time window of concurrent catecholaminergic activity) on these neural systems are the opposite of the rapid effects. Administration of hydrocortisone decreases amygdala responsiveness to threat-relevant stimuli (Henckens et al. Reference Henckens, van Wingen, Joëls and Fernández2010) and increases prefrontal cortex function (Henckens et al. Reference Henckens, van Wingen, Joëls and Fernández2011). Hence, resilience to stressors can be understood as the ability to adaptively engage stress-related neuromodulators to balance neural systems that produce conflicting appraisals.

In conclusion, we strongly endorse the research agenda focusing on resilience factors put forward by Kalisch and colleagues. The assumption that a positive “appraisal style” is the final common path to resilience may prove too narrow, however. Our example of research on corticosteroids is just one illustration of how neurobiological investigations are beginning to reveal the intricate complexity of the biology of stress resilience (Enman et al. Reference Enman, Sabban, McGonigle and Van Bockstaele2015; McEwen et al. Reference McEwen, Gray and Nasca2015). We are optimistic that this effort will lead to the emergence of an integrated understanding of the cognitive and neurobiological determinants of resilience.