Chronic fatigue syndrome (CFS) is a disabling disorder that is marked by persistent or relapsing fatigue (Fukuda et al. Reference Fukuda, Straus, Hickie, Sharpe, Dobbins and Komaroff1994). CFS has often been linked to a disturbance in the central nervous system. In line with this hypothesis, previous studies have identified both functional (de Lange et al. Reference de Lange, Kalkman, Bleijenberg, Hagoort, Van der Werf, van der Meer and Toni2004; Lange et al. Reference Lange, Steffener, Cook, Bly, Christodoulou, Liu, Deluca and Natelson2005; Caseras et al. Reference Caseras, Mataix-Cols, Giampietro, Rimes, Brammer, Zelaya, Chalder and Godfrey2006; Tanaka et al. Reference Tanaka, Sadato, Okada, Mizuno, Sasabe, Tanabe, Saito, Onoe, Kuratsune and Watanabe2006; Cook et al. Reference Cook, O'Connor, Lange and Steffener2007) and structural (Okada et al. Reference Okada, Tanaka, Kuratsune, Watanabe and Sadato2004; de Lange et al. Reference de Lange, Kalkman, Bleijenberg, Hagoort, van der Meer and Toni2005) alterations in the brain of CFS patients (for a review, see e.g. Cho et al. Reference Cho, Skowera, Cleare and Wessely2006; Prins et al. Reference Prins, van der Meer and Bleijenberg2006).

Caseras et al. (Reference Caseras, Mataix-Cols, Rimes, Giampietro, Brammer, Zelaya, Chalder and Godfrey2008) contribute to the growing literature of functional cerebral changes in CFS patients by using a novel fatigue provocation procedure. They measured cerebral activity, using fMRI, while CFS patients and healthy control subjects had to imagine fatigue-provoking events (e.g. ‘imagine yourself doing your shopping and carrying home heavy bags’). To enhance the vividness of the imagination, participants concurrently watched video clips depicting the to-be-imagined event, shown from a first-person perspective. An anxiety-provoking condition was added to the experiment as a control for any non-specific emotional effects on brain activation.

The authors observed larger activity in the medial parietal cortex and precuneus in CFS patients during the fatigue-provocation task. Recent functional imaging findings in healthy subjects suggest a role for this area in imagery, episodic memory retrieval and self-processing operations like first-person perspective taking and experience of agency (Cavanna & Trimble, Reference Cavanna and Trimble2006). As such, the larger activity in the precuneus in CFS patients during fatigue provocation could well reflect the more vivid capability of CFS patients to imagine themselves in a fatiguing situation, as well as the greater identification that CFS patients experience with fatigue-inducing events.

Fatigue provocation did not only result in areas showing larger brain activity in CFS patients. Interestingly, CFS patients exhibited lower cerebral activity in the dorsolateral prefrontal cortex during the fatigue-provocation task. An earlier study, looking at brain morphology in CFS, found a reduction of grey matter in this cortical area (Okada et al. Reference Okada, Tanaka, Kuratsune, Watanabe and Sadato2004). The dorsolateral prefrontal cortex is essential for the implementation of executive functions like selecting and initiating behaviour, as has been demonstrated by experimental work from neuropsychology, functional imaging in humans, as well as lesion and single-cell recording studies in the monkey (Miller & Cohen, Reference Miller and Cohen2001). Lesions in lateral prefrontal cortex often lead to significant reductions in the generation of appropriate goal-directed voluntary behaviour (Jacobsen, Reference Jacobsen1935; Goldman-Rakic, Reference Goldman-Rakic, Plum and Mountcastle1987; Passingham, Reference Passingham1993), which become clinically manifest as apathy (Levy & Dubois, Reference Levy and Dubois2006). As such, there is converging evidence for combined functional and structural alterations in the lateral prefrontal cortex of CFS patients.

Although the study of Caseras and colleagues (Reference Caseras, Mataix-Cols, Rimes, Giampietro, Brammer, Zelaya, Chalder and Godfrey2008) shows an interesting difference between CFS patients and healthy controls in the experience of fatigue, the relationship between causes and symptoms is many to one, and it therefore remains an open question whether this difference is specific to CFS. Moreover, it will be important for future studies to assess the dynamics of these functional differences. A recent study in our laboratory showed that the grey-matter volume reduction in the lateral prefrontal cortex could be partly reversed by successful cognitive behavioural therapy (de Lange et al. Reference de Lange, Koers, Kalkman, Bleijenberg, Hagoort, van der Meer and Toni2008). It would be interesting to see if the functional changes observed by Caseras and colleagues would follow a similar pattern as a function of disease recovery. Future longitudinal studies will be extremely helpful to address these important questions.