More appraisal please: A commentary on Pfaff et al. (2007) “Relations between mechanisms of CNS arousal and mechanisms of stress”

Abstract

This article provides a brief commentary on Pfaff et al's timely review of the relations between mechanisms of CNS arousal and mechanisms of stress. Pfaff and colleagues use the review as a platform to propose the existence of a coherent stress-arousal state. We suggest that this proposal is, on a number of grounds, flawed. In turn, we counter that the while the states of stress and arousal are related they are as entities fundamentally separate. Moreover, we propose that any productive attempt to unite the two states must acknowledge the importance of and therefore centrally include higher order integrative phenomena, such as, appraisal.

• Stress
• appraisal
• arousal

It is appropriate that the centenary of Hans Selye's birth should be commemorated with a paper focused on concepts. Undoubtedly, Selye's most enduring contribution was to introduce the concept of stress and, in this issue of Stress, Pfaff et al. provide a timely analysis of the relationship between the concepts of arousal and stress, compare the organisation of the relevant control systems, and propose the existence of a coherent stress-arousal state. But while their effort is admirable, we believe that a significant advance in our understanding of how stress and arousal fit together will require a more detailed treatment of what stress researchers now know about stress.

Stress and arousal: Overlapping but different states

As is well-known by researchers in this field, achieving consensus concerning the concept of stress has been extremely elusive. Indeed the story still circulates, perhaps apocryphal, of one leading stress researcher who refused to attempt a definition of stress in a plenary session as they knew that there was no definition that would not invite attack. Against such background we found it difficult, but unsurprisingly, to determine exactly what Pfaff et al. see as the relationship between stress and arousal. In their introduction they hypothesise that the initial “alarm” stage of Selye's General Adaptation Syndrome—which most would now refer to as an acute stress response—corresponds to “generalised arousal”. However, this is at odds with a later statement (with which we agree) that stress and arousal are not parallel, stress always being associated with increased arousal, but arousal not always being associated with stress. But even this position is then undermined by their subsequent suggestion that stress can be caused by either too much or too little arousal, the latter seeming to imply that you can have stress without increased arousal.

We believe that the development of a better understanding of the relationship between stress and arousal will ultimately need to be grounded in a clearer recognition of the ways in which stress differs from arousal.

Stress differs from arousal in terms of the qualitative appraisal that precedes it

Pfaff et al. (2007) indicate that, although the relationship may not be linear, they see arousal as being proportional to “input”. In other words, an arousal state is a function of an appraisal process that is predominantly (although not necessarily exclusively) quantitative. In contrast we see stress as being a state that is initiated only after a predominantly qualitative appraisal—an appraisal of factors such as threat type and context, past experience and current resources available to deal with the threat, an appraisal that thereby encompasses controllability and escapability (Ursin and Eriksen 2004; Maier et al. 2006). Accordingly, stimuli that are arousing are not necessarily stressful. Pfaff et al. (2007) implicitly acknowledge this issue of appraisal when they use the example of a man becoming more alert but not stressed as a result of his wife entering the room. However, Pfaff et al. then lose sight of the centrality of qualitative appraisal to the elicitation of a stress response stating, for example, that “A considerable proportion of stressful inputs signal through gigantocellular neurons in the medullary reticular formation … whose extreme levels of activation would signal panic.” They further propose that too much or even too little arousal can be stressful. We disagree. Based on what is now known about stress processing we suggest that it is not the level of arousal per se that determines whether a stress response will be triggered, but rather the qualitative appraisal of the information that is feeding in to the corresponding state of arousal. We are particularly suspicious of claims that low levels of arousal per se trigger stress (as in Figure 3, Pfaff et al 2007) and note that neither of the two papers that Pfaff et al. cite to support this proposition offer any direct evidence that this occurs (Parasuraman and Purohit 2000; Gilman and Anderman 2006).

Stress differs from arousal in being elicited only by aversive challenges

Most current literature interprets stress as a response to an aversive (threatening) challenge. Selye (1978), however, held the view that the stress response could be elicited by both negative (aversive) and positive (appetitive) stimuli. In our view, the logic of Selye's position was irredeemably flawed. On the one hand, he wished to emphasise that the core stress response was the same, regardless of the identity of the stressor. Yet, on the other hand, he distinguished between the responses to aversive and appetitive challenges by referring to them as “distress” and “eustress”, respectively, and argued that while distress was damaging, eustress was not, or at least less so. Regrettably, Pfaff et al. endorse Selye's position, stating that “it makes no difference whether the stressor is pleasant or not”. We suggest that it is now not merely commonplace, but in fact logical to adopt the view that stress differs from arousal in that it is only elicited by aversive challenges, whereas arousal can be increased by both appetitive and aversive challenges, some of the latter being such as to also trigger a stress response.

Stress differs from arousal in terms of the physiological state that it entails

Just as stress differs from arousal in terms of the range of challenges that can trigger it, stress also differs from arousal in terms of the physiological state that it entails, and hence its potential pathophysiological consequences. Our understanding of these differences remains far from complete, but an intriguing example comes from the field of learning and memory, where it has been found that stress and arousal can differ significantly in their effects on memory (Maroun and Akirav 2007). Interestingly, these differences appear to be glucocortoicoid-independent. Thus, while it has been demonstrated that an aversive and stressful challenge (predator exposure) can impair spatial memory, an appetitive challenge (presentation with a sexually receptive female) does not, this is despite the fact both challenges elicit similar increases in plasma glucocorticoid levels (Woodson et al. 2003). These particular results also serve to make the point that activation of the hypothalamic pituitary adrenal (HPA) axis is not a distinguishing feature of stress vs. arousal, which leads us now to comment on the way in which Pfaff et al. have chosen to define stress and characterise the mechanisms that control it.

Defining stress and characterising the mechanisms that control it: Beyond the HPA axis

Pfaff et al. (2007) propose an operational definition of stress wherein a stressor is said to be a stimulus that “causes the release of corticotrophin releasing factor (CRF) in a concentration that raises the release rate of ACTH”. Most stress researchers would now regard this as an inadequate definition, if only because of evidence that not all stressors elicit significant HPA axis activation (Goldstein and Kopin 2007) and that not all stimuli that elicit HPA axis activation are stressors (e.g. as in the case of exposure to a sexually receptive female). More importantly, however, this definition reflects an out-moded HPA axis-centric view of stress that also colours their characterisation of stress control mechanisms. Thus, Pfaff et al. (2007) argue that stress control mechanisms possess an organisational structure referred to as a “bow tie” and state that “the central ‘knot’ of the bow tie for stress can be thought of as comprising the CRF neurons that control the release of ACTH”. However, it is our view that most researchers have moved well beyond seeing the HPA axis, or the CRF neurons at its apex, as the pivot point of the stress response. Rather, HPA axis activation is now seen as just one of multiple stress response elements. Indeed, if one wished to argue for a “bow tie” structure in stress control systems, we would suggest that a much more compelling argument could be presented for the role of the amygdala as the pivot point of the stress response (LeDoux 2003).

It is possible that Pfaff et al. mean to refer to CRF neurons generally as the pivot point of the stress response, thus encompassing both hypophysiotropic and non-hypophysiotropic CRF neurons. Certainly a number of influential figures in the stress field have placed a great deal of emphasis on the involvement of CRF as a signalling agent in multiple stress response pathways, such as those involved in behaviour. This is perhaps best seen as part of a tradition in some quarters (particularly in the field of neuroendocrinology) of trying to understand brain function by appreciating the integrative role of particular signalling agents. Such an approach is very apparent in the section of Pfaff et al. (2007) entitled “Three specific examples linking arousal and stress” where it seems to be suggested that arousal and stress can be understood by appreciating how peripherally generated hormones regulate central neuropeptide systems. This approach is apparent again when they mention “the arousal-related transmitters norepinephrine and dopamine”. While it is important to appreciate that signalling agents are sometimes deployed at multiple sites in the endocrine and nervous systems to (apparently) a common purpose, an over emphasis on this approach can also blind us to the fact that these same agents will sometimes be employed in unrelated or even mutually opposing functions. This approach can also restrict our ability to fully appreciate the significance of other less visible signalling agents, sometimes less visible simply because of their ubiquity, as in the case of GABA and glutamate.

Conclusion

Although our mechanistic understanding of the states of stress and arousal is clearly advancing, it is becoming ever more apparent that we have made few significant inroads into understanding how these phenomena are initially instantiated and integrated. Pfaff et al. should be applauded for their attempt but, unfortunately, we feel that we are not yet there. Indeed, it is our view that the current bottom-up approach used by most biomedical scientists to understand global phenomena, and how they are integrated, may have reached its upper bound. As implicitly acknowledged by Pfaff, and explicitly stated in our commentary, appraisal is crucial to modifications in the arousal state and the stress response. The judgment that some perceived internal or external event is salient and necessitates a change in physiological operating conditions must, in most situations, precede engagement of either arousal or stress states. If we accept this position we necessarily find ourselves in a difficult situation, no longer in close proximity to discovering the nature of the relationship between stress and arousal. Moreover, our extensive, but highly localized, topographical knowledge is currently insufficient for us to easily redirect ourselves to such an understanding. We must begin to examine more seriously the mechanisms responsible for higher-order integrative phenomena and perhaps create a new field of study focused on the neurobiology of appraisal.