The present study provides the first report of focal gray-matter atrophy in the prefrontal cortex of CFS patients. Previous MRI studies of CFS revealed non-specific abnormalities: hyperintense small punctuated subcortical white-matter foci were observed predominantly in the frontal lobes [16
] and their prevalence did not differ from an age-matched control group [17
]. Ventricular enlargement was also reported [19
]. Usually, MRI abnormalities in CSF patients cause the physician to conclude that the symptoms might be secondary to another medical condition [20
Prefrontal pathology has been reported in MS with pathological fatigue [21
]. Roelcke and colleagues [21
] reported that MS patients with fatigue had a reduction of the cerebral metabolic rate of glucose (CMRGlu) in the bilateral prefrontal areas compared with MS patients without fatigue. Moreover, scores on the fatigue-severity scale were inversely related to CMRGlu levels in the right prefrontal cortex, suggesting that fatigue in MS is associated with prefrontal dysfunction due to the demyelination of frontal white matter [21
]. Although the Talairach's coordinates reported by Roelcke and colleagues (x = 18, y = 42 and z = 20) were more medial and ventral than those observed here (x = 48, y = 32 and z = 41), both results suggest that prefrontal hypofunction might underlie pathological fatigue. Although MS should be excluded in the diagnosis of CFS, as in the present study, the similar clinical manifestations of the illnesses suggest that a common pathogenesis underlies the symptoms of fatigue in both disorders. This speculation is supported by the fact that the administration of L-carnitine, which improves fatigue in CFS patients, was effective for treating fatigue in MS patients [22
In the present study, right dorsolateral prefrontal-cortex atrophy was significantly correlated with the severity of fatigue, as measured by the performance-status scores. As the performance status rates the daily activities that trigger or aggravate fatigue, this correlated volume reduction might reflect a functional deficiency that makes patients susceptible to fatigue.
A single site in the dorsolateral prefrontal cortex revealed the parallel between volume reduction and fatigue severity. This does not necessarily mean that it is fatigue-specific; instead, this area might be the part of the network that, when functioning sub-normally, results in pathological fatigue. Fatigue is also a symptom of diseases that affect the basal ganglia, and that interrupt the connection between the prefrontal cortex and thalamus [3
]. Hence, frontal-subcortical circuits might be important contributors to the sense of fatigue.
The dorsolateral prefrontal cortex has dense widespread subcortical and cortical connections [23
]. A series of parallel frontal-subcortical circuits have been described that link specific regions of the frontal cortex to the striatum, globus pallidus and thalamus [24
]. These originate in the prefrontal cortex, project into the striatum (caudate, putamen and ventral striatum), connect to the globus pallidus and substantia nigra, and from there connect to the thalamus. There is then a final link back to the frontal cortex in each circuit, forming a closed loop [25
]. Corticostriatal and thalamocortical connections use excitatory glutamatergic projections [25
]. Frontal-subcortical circuits serve as organizational axes, integrating related information from widespread areas of the brain and mediating diverse behaviors. The three principal behaviorally-relevant circuits originate in the dorsolateral prefrontal, orbitofrontal and anterior cingulate cortices [26
]. The marker behaviors specific to each circuit are executive dysfunction (dorsolateral prefrontal-subcortical circuit), disinhibition (orbitofrontal-subcortical circuit) and apathy (medial frontal-subcortical circuit), respectively [26
]. Hence, these circuits are capable of concurrent participation in separate functions, including motor, cognitive and limbic processing [3
The dorsolateral prefrontal cortex also has widespread reciprocal corticocortical connections with posterior temporal, parietal and occipital association areas [23
]. Furthermore, at the level of the frontal lobes, the orbitofrontal, anterior cingulate and dorsolateral prefrontal cortices are linked to each other without cross connections at subcortical levels [26
]. Therefore, the dorsolateral prefrontal cortex is poised to serve as a principal site for the integration of information.
These anatomical and functional characteristics of the frontal-subcortical circuits suggest that the large decrease in acetyl-L-carnitine uptake in the dorsolateral prefrontal, anterior cingulate and temporal cortices [9
] represents hypofunction of the frontal-subcortical circuits. Furthermore, this decrease might be due to the remote effects of the pathology in the dorsolateral prefrontal cortex [27
]. Recently, Fillippi et al. [28
] underwent fMRI with MS patients with fatigue using simple motor task. They found inverse correlation between fatigue severity score and the task-related activity of the thalamus, concluding that fatigue could be secondary to dysfunction of corticosubcortical circuits. Thus, according to the model by Chaudhuri and Behan [3
], hypofunction of the dorsolateral prefrontal cortex might interrupt the associated striato-thalamo-cortical loop, resulting in enhanced fatigability.