Dissociation of subjective and physiological stress responses in orexin-deficient narcolepsy

Mental health disorders such as stress, anxiety, and depression are frequently found in patients with narcolepsy [1–3], but their pathophysiologies are still not fully understood. Orexin (also called hypocretin) neurons in the lateral hypothalamus and corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) work synergistically to regulate the hypothalamic–pituitary–adrenal (HPA) axis which represents the central stress response system [4]. CRH neurons in the PVN are considered the primary activators of the HPA axis [5]. Animal studies have shown that acute stress can activate the orexin neurons, and orexins then stimulate CRH neurons to release CRH, which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH), leading to cortisol production by the adrenal glands [4–6]. A recent study found a strong reduction of CRH neurons in the PVN in postmortem tissue of patients with narcolepsy type 1 (NT1) [7]. This suggests that the stress response pathway might be impaired in narcolepsy, potentially contributing to the higher rates of mental health disorders seen in these patients.

The study by Vringer et al. explored the relationship between stress and NT1. The authors found that while patients with NT1 reported higher levels of subjective stress, there were no significant differences in the physiological stress response as measured by levels of ACTH and cortisol compared to healthy controls in an acute stress test [8]. This unexpected finding might be due to the compensation mechanisms, such as the overactivation of the remaining CRH neurons, or the production of vasopressin (AVP) by CRH neurons as AVP can also stimulate the release of ACTH. However, it is also possible that the reduction of CRH neurons observed in the postmortem tissue is a long-term consequence rather than a direct cause of narcolepsy. Since narcolepsy is a chronic neurological disease, the loss of CRH neurons in the brain may develop gradually over time, which is indicated by Vringer’s finding that ACTH negatively correlated with disease duration in their patients [8]. In some cases, NT1 could also have acute disease manifestation which has been related to infections such as 2009–2010 H1N1 influenza viruses [9]. While the immune-mediated response caused by infections can lead to a rapid loss of orexin neurons in several weeks [10, 11], it is unclear whether it also impacts CRH neurons similarly. Future studies replicating the results reported by Vringer et al. in patients with an acute disease manifestation after infections may provide better insights into the neuropathologies of narcolepsy-associated stress response.

Interestingly, this new study found that only men with NT1 had lower cortisol levels immediately after a stressful experience compared to healthy men, and women had a stronger subjective stress response than men [8]. Gender difference in narcolepsy has been recently reported in both human study [12–14] and animal models [15, 16]. The results from Vringer et al. highlight a potentially psychophysiological difference between how men and women with narcolepsy experience and respond to stress. Animal studies found higher expressions of both orexin-1 receptor in hypothalamus and orexin-2 receptor in PVN in female rats than in male rats [17]. The increased PVN orexin-2 receptor expression could suggest increased CRH activity in response to orexins [6], leading to stronger stress-related behaviors in female rats [17, 18]. Considering that orexins are deficient in human narcolepsy, the gender difference in stress response is much more complex and cannot be simply explained by the interaction between orexin and CRH. While the exact mechanisms are unknown, it likely involves complex interactions between the brain regions that regulate stress hormones and those involved in higher-level cognitive functions. Higher cognitive brain regions such as the prefrontal cortex are directly targeted by stress hormones, and their sensitivity and responsiveness can be significantly altered by acute stress exposure [19]. Gender difference in the activities of frontoparietal network measured by fMRI in response to acute stress has been reported in patients with depression [20]. To gain a deeper understanding of gender-related variations in physical stress responses in narcolepsy, we recommended that future research should combine hormone measurements with neuroimaging techniques to investigate brain activity during stress tests. This could provide a more comprehensive understanding of gender-specific stress responses in narcolepsy. Ultimately, this knowledge may help to tailor treatment and disease management strategies to better meet gender-specific unmet needs.

Chronic stress is a known risk factor for mood disorders, such as depression and anxiety. The high prevalence of depression-like symptoms among patients with NT1 may be linked to chronic stress associated with living with narcolepsy. The unexpected absence of difference in NT1 patients’ physiological stress compared to healthy controls reported by Vringer et al. raises intriguing questions about the nature of affective symptoms in narcolepsy. Do depression and narcolepsy truly occur comorbidly, or are depression-like symptoms simply consequences of the chronic sleepiness and fatigue associated with narcolepsy? Given that depression is commonly reported in people with narcolepsy [1–3], these questions are crucial to address. Future studies using multimodal approach and advanced techniques such as unsupervised machine learning [13] could help categorize different subtypes of narcolepsy with varying mental health profiles. Also, new treatment trials with orexin receptor agonists that aim to restore the orexin-signaling will show whether affective symptoms improve with increased vigilance in patients with NT1.

In conclusion, Vringer et al.’s study sheds light on the complex relationship between stress and narcolepsy type 1. While patients with NT1 may experience high levels of subjective stress, this may not be reflected in their physiological stress response. This study highlights the need for further investigation into the role of specific neurons such as CRH neurons in the development of narcolepsy, and the need to develop effective interventions to address the psychological burden of narcolepsy.

Disclosure Statement

Financial disclosure: none. Nonfinancial disclosure: none.