Despite intensive research efforts, the pathophysiology of the enigmatic clinical disorder, chronic fatigue syndrome (CFS) remains obscure and curative therapies are not available. The substantial heterogeneity in cross-sectional samples of patients fulfilling the diagnostic criteria for CFS has been identified as an important contributor to the inconclusive and inconsistent research findings (Wilson et al., 2001, Sullivan et al., 2002 and Vollmer-Conna et al., 2006). In response to this conundrum, some groups have shifted their research focus to post-infective fatigue as a model for CFS. Prospective cohort studies have empirically verified the existence of a post-infective fatigue syndrome (PIFS) consistent with CFS, triggered by infection with Epstein-Barr virus (EBV), Ross River virus (RRV, epidemic polyarthritis), or Coxiella burnetii (the causative agent of Q fever) ( White et al., 1998, Buchwald et al., 2000, Candy et al., 2003, Hickie et al., 2006 and Katz et al., 2009). At 6 months post-infection, PIFS cases constitute a subset of the broader CFS group. Like all patients with CFS, they fulfill international diagnostic criteria ( Fukuda et al., 1994); however patients with PIFS are distinct in that their CFS follows directly upon a documented acute infective illness. Thus PIFS constitutes a valid disease model for CFS, which permits examination of pathophysiological hypothesis in a well-defined, homogeneous patient group.
Previous research examining autonomic dysfunction in CFS has provided inconsistent support for functional disturbances in autonomic cardiac regulation associated with orthostatic challenges (e.g. Rowe and Calkins, 1998, Rowe et al., 2001, Poole et al., 2000, Winkler et al., 2004, Jones et al., 2005 and Wyller et al., 2008). Additionally, there is some evidence suggesting sympathetic hyper-arousal [increased resting heart rate (HR) and reduced HR variability] that persists even during sleep (Vollmer-Conna et al., 2006 and Boneva et al., 2007). The precise nature and extent of autonomic system dysregulation in CFS are still unclear.
A fresh perspective of the role of the autonomic nervous system in health and disease was provided by the delineation of an interoceptive pathway within the afferent nervous system (Craig, 2002). Converging evidence from functional anatomy and neuroimaging studies (Craig, 2002, Craig, 2003, Critchley et al., 2004 and Harrison et al., 2009) has established that fibres of the lamina I spinothalamocortical system merge with vagus nerve afferents to convey signals from essentially all physiological systems and microenvironments (including inflammatory, metabolic, hormonal) to autonomic and homeostatic centres, and then to higher limbic and cortical regions (including the anterior cingulate cortex, the insular and orbitofrontal cortex). This sequential cortical processing endows the brain with conscious awareness of the physiological condition of the entire body, termed interoception. In response to perceived homeostatic imbalances the brain adjusts emotions, motivated behaviours and descending autonomic responses in order to maintain body integrity (Craig, 2002).
These new insights into interoception and its neural substrates have redefined our understanding of modalities such as pain, which was conventionally thought of as ‘exteroceptive’, somatosensory and distinct from visceral sensations that were labeled ‘interoceptive’. This categorisation however neglects the inherent emotional and motivational qualities that pain shares with all feelings from the body (Rainville et al., 1997 and Craig, 2003). A series of novel findings (Craig, 2002 and Craig, 2003) suggested that in humans, pain may be best understood as part of an integrated homeostatic network providing both a distinct sense of the physiological condition of the body (i.e. interoception) and a specific behavioural motivation.
Although the potential pathophysiological importance of a functional disturbance in the afferent homeostatic system providing the brain with dynamic representations of the state of the body is widely acknowledged (Craig, 2002, Thayer and Brosschot, 2005, Vollmer-Conna et al., 2008, Thayer, 2009 and Harrison et al., 2009), this possibility has not been explored in CFS. Interoceptive sensitivity can be assessed experimentally by recording awareness of ongoing physiological activity (e.g. heartbeat, pressure) and has been linked to more intense emotional processing and increased autonomic reactivity to stressors (Pollatos et al., 2007, Wiens et al., 2000 and Barrett et al., 2004).
In this study, we examine the hypothesis that following exposure to a significant physiological stressor (e.g. an acute infective illness) PIFS/CFS is associated with sensitization in neurovisceral regulatory circuits, resulting in abnormally heightened perception of symptoms and sensations from the body (physiological hyper-vigilance) in conjunction with autonomic hyper-reactivity to perceived challenges.
