اثر تروما در اوایل دوران کودکی بر روی هیپوتالاموس-هیپوفیز-آدرنال (HPA) عملکرد محور در بیماران مبتلا به سندرم خستگی مزمن

Background There is a paucity of studies that have investigated the assumption that early childhood trauma is associated with hypothalamic–pituitary–adrenal (HPA) axis dysfunction in Chronic Fatigue Syndrome (CFS). The current study is the first to simultaneously investigate relationships among early childhood trauma, cortisol activity, and cortisol stress reactivity to psychosocial stress in a sample of well-screened CFS patients. We also examined whether self-critical perfectionism (SCP) plays a mediating role in the potential relationship between early trauma and neurobiological stress responses. Methods A total of 40 female patients diagnosed with CFS were asked to provide morning saliva cortisol samples (after awakening, 30 min later, and 1 h later) for seven consecutive days as a measure of cortisol activity. In addition, patients were exposed to the Trier Social Stress Test, a well-validated stress test, to investigate the relationship between early childhood trauma and cortisol stress reactivity. Before the start of the study, patients completed the Childhood Trauma Questionnaire-Short form (CTQ-SF) as a measure of early childhood trauma (i.e. sexual, physical and emotional traumatic experiences). SCP was measured with the Depressive Experiences Questionnaire (DEQ). Data were analyzed by calculating several indices of cortisol secretion (i.e. Cortisol Awakening Response and Area Under the Curve). Results There was no association between early childhood trauma and cortisol as measured over the 7-day period. However, emotional neglect was significantly negatively related to cortisol reactivity in the TSST. SCP did not significantly mediate this association. Conclusion Findings of this study suggest that emotional neglect is associated with blunted HPA axis reactivity, congruent with the assumption that CFS may reflect loss of adaptability of the neuroendocrine stress response system in at least a subgroup of patients.

Chronic Fatigue Syndrome (CFS) is characterized by chronic, medically unexplained fatigue and physical and/or mental fatigability in response to exertion in particular (Fukuda et al., 1994 and Carruthers et al., 2011). It is a highly debilitating condition that most often affects women (Jason et al., 1999) and that is associated with high psychosocial and economic costs (Collin et al., 2011). A considerable proportion of CFS patients also suffers from chronic pain symptoms, and studies increasingly suggest that CFS may be part of a broader spectrum of chronic pain and fatigue disorders (Kanaan et al., 2007, Van Houdenhove et al., 2010 and Ablin et al., 2012). There is accumulating evidence that impairments in stress regulation may play a key role in the development and perpetuation of CFS (Silverman et al., 2010, Luyten et al., 2011 and Nater et al., 2011). Most research in this context has focused on hypothalamic–pituitary–adrenal (HPA) axis function in CFS as measured by the stress hormone cortisol. In general, studies have found evidence for reduced cortisol activity and lower cortisol stress reactivity in CFS (Cleare, 2003, Van Den Eede et al., 2007, Papadopoulos and Cleare, 2011, Tak et al., 2011 and Nijhof et al., 2014), which may reflect a dysregulation of the stress response system after a prolonged period of chronic physical and/or mental stress (Van Houdenhove and Luyten, 2010, Van Houdenhove et al., 2009 and Van Houdenhove et al., 2013). However, it is important to note that previous studies on HPA-axis function in CFS have also yielded inconsistent results (for an overview see Papadopoulos and Cleare, 2011). Differences in study results may be in part explained by the fact that CFS is a multi-factorial and etiologically heterogeneous condition (Van Houdenhove and Luyten, 2008). Hence, there is a need to unravel the mechanisms that may underlie HPA-axis alterations in carefully screened CFS patients (Van Houdenhove et al., 2013). There is a growing body of evidence to suggest that early life stress, and early childhood trauma in particular, may explain in part HPA axis dysregulation in CFS (Luyten et al., 2008, Van Houdenhove et al., 2009 and Nater et al., 2011). Both animal and human studies indicate that early adversity, especially during so-called “critical time windows”, may affect brain structures and the expression of genes that have been shown to regulate the stress system, leading to a neurobiological ‘switch’ from HPA axis hyperactivity to hypoactivity in the long run (e.g., Heim et al., 2000, Heim et al., 2001, Miller et al., 2007, Luecken et al., 2009, Lupien et al., 2009 and Trickett et al., 2010). Congruent with these findings, a number of studies have shown that CFS is associated with a high prevalence of early childhood trauma (for an overview see Borsini et al., 2013, Kempke et al., 2013a and Afari et al., 2014). In a recent study, we found that more than half of the patients with CFS reported a history of childhood trauma (Kempke et al., 2013a), replicating earlier findings in both tertiary care settings and in a population-based study (Van Houdenhove et al., 2001, Heim et al., 2006 and Heim et al., 2009). Moreover, we demonstrated that early childhood trauma, and emotional trauma in particular, was associated with the core symptoms of CFS (Kempke et al., 2013a). Thus, research suggests that early trauma is an important risk factor for CFS. Yet, to the best of our knowledge, only two studies have investigated the relationship between early childhood trauma and HPA axis function in CFS patients. Heim et al. (2009), in a population-based survey, investigated the association between exposure to childhood trauma as determined by the Childhood Trauma Questionnaire Short Form (CTQ-SF) (Bernstein et al., 2003) and cortisol levels after awakening (i.e. between awakening and 60 min post-awakening) as collected on a regular workday. Results showed that only CFS patients with a history of trauma had lower mean cortisol levels after awakening compared with control subjects. This finding is consistent with more basic research demonstrating a relationship between early life stress and reduced cortisol responses (Heim et al., 2000, Carpenter et al., 2007, Carpenter et al., 2009 and Miller et al., 2007). In contrast to these findings, however, Van Den Eede et al. (2008) found that CFS patients without a history of early adversity showed lower cortisol responses to a stress challenge test (i.e. dexamethasone/corticotropin-releasing factor test) compared with age- and education-matched healthy controls. Thus, more research is clearly needed to investigate the effects of early adversity on HPA axis functioning in CFS given the paucity of studies and the contradictory findings in the few available studies. Moreover, as far as we know, there is no study that has simultaneously investigated HPA-axis activity and reactivity in CFS patients. For instance, in a study of depressed patients, Dienes et al. (2013) studied both naturalistic cortisol secretion and cortisol reactivity to a laboratory stressor. There are also no studies that have investigated whether early childhood trauma is associated with impaired HPA-axis reactivity to psychosocial stress in CFS. Gaab et al., 2002 and Gaab et al., 2005 found no differences in cortisol responses to a standardized psychosocial stress test, i.e. the Trier Social Stress Test (TSST) ( Kirschbaum et al., 1993), in CFS patients compared to healthy controls, but they did not account for the impact of early trauma on cortisol responses. Further, while most studies on the effects of early life adversity on HPA axis activity have collected cortisol levels over multiple days ( Cicchetti and Rogosch, 2001, Tarullo and Gunnar, 2006, Weissbecker et al., 2006, Gonzalez et al., 2009 and Klaassens et al., 2009), studies in CFS patients have only assessed cortisol levels for one day. However, as pointed out by Hellhammer et al. (2007), single-time-point assessments of cortisol are largely influenced by situational factors and only to a small extent by trait factors. Hence, cortisol measurements of multiple days are needed to evaluate HPA axis activity in CFS. Finally, it has been hypothesized that self-critical perfectionism (SCP) (i.e. a personality configuration characterized by a combination of high personal standards and self-criticism), which has been implicated in the development and maintenance of CFS ( Kempke et al., 2013b), may be an important factor in explaining the relationship between early trauma and HPA axis dysregulation. Specifically, SCP may reflect attempts to compensate for low self-esteem associated with early childhood adversities, and has been associated with chronic stress and neurobiological alterations in CFS ( Luyten et al., 2011 and Kempke et al., 2013b). Recently, we found a significant relationship between SCP and reduced HPA-axis reactivity after experimental stress induction in CFS (S. Kempke, P. Luyten, L.C. Mayes, B. Van Houdenhove, and S. Claes, unpublished observations). Moreover, there is empirical evidence to suggest that early childhood trauma, and emotional traumatic experiences (e.g., excessive criticism or rejection) in particular, may give rise to a self-critical personality style ( Dunkley et al., 2010 and Kopala-Sibley and Zuroff, 2014). Hence, it is reasonable to hypothesize that SCP may mediate the relationship between early childhood trauma and cortisol responses in CFS. The current study therefore aims to address these gaps in knowledge by investigating relationships among early childhood trauma as assessed with the Childhood Trauma Questionnaire-SF (Bernstein et al., 2003), cortisol activity (morning cortisol) over a period of 7 consecutive days, and cortisol response to the Trier Social Stress Test (Kirschbaum et al., 1993), in a sample of carefully screened CFS patients. We expected, in line with extant theories and findings concerning the long-term effects of early childhood trauma on the HPA axis (Heim et al., 2009 and Lupien et al., 2009), that higher levels of self-reported early childhood trauma would be negatively associated with both cortisol activity and cortisol responses to experimentally-induced psychosocial stress. Also, we investigated the possible mediating role of SCP in the relationship between early childhood trauma and the HPA-axis stress response.