Fatigue is one of the most common presenting complaints, accounting for a 10-25% prevalence of patients presenting to primary care physicians (PCP) . The extensive differential diagnosis of fatigue encompasses a wide spectrum of illnesses including, but not limited to endocrine disorders, infections, cancer, medication side effects, sleep disorders, seizures, autoimmune diseases, obesity, drug abuse, malingering, and depression . Fortunately, most of these illnesses have characteristic clinical presentations often with confirmatory laboratory tests.
Yet there remain significantly fatigued patients where no underlying diagnosis can be securely established. In the past, such patients were often dismissed as having some form of uncertain psychiatric disorder-typically depression with symptoms of somatization. However, within this 'unclassifiable' but severely fatigued patient population a subset stood out with normal pre-morbid personalities and whose pre-morbid lives were successful and fulfilling. These patients, however, had suddenly become unusually fatigued after an undetermined illness and for whom the subsequent disabling weakness and fatigue endured for more than six months (often years) beyond the resolution of the initial illness. Some, but not all, patients would report intermittent lymphadenopathy and/or low grade fever often with corresponding worsening of their fatigue. Yet, no clear etiology could be found. The term Chronic Fatigue Syndrome (CFS) came to be applied to this group where a suspicion of organic etiology persisted but could not be confirmed [2, 3].
Since common psychiatric disorders, particularly depression, often cause fatigue and since psychiatric diagnoses may be difficult to objectively and reliably confirm, many continued to reasonably wonder about the role of an as of yet identified form of depression as the cause of CFS. However, it was found that many patients with CFS suffer from co-existing psychiatric disorders only after becoming ill with CFS. Moreover, in 30-50% of patients no co-existing psychiatric disorders [4, 5] can be demonstrated. In addition, a carefully controlled trial of fluoxetine in patients with CFS failed to improve fatigue, even in those patients with a concomitant major depression .
To better identify this perplexing patient population, the U.S. Centers for Disease Control (CDC) convened a group of experts to establish a set of strict diagnostic criteria for CFS. The resultant criteria have become known as the CDC or Fukuda criteria . These criteria, available as a multi-page evaluation form, serve investigators and clinicians studying CFS to assure that their patient populations are well identified and comparable across studies. CFS is, therefore, not a synonym for prolonged, disabling fatigue although the distinction may be difficult upon initial evaluation. In this paper we use the term CFS to mean CDC-defined CFS.
CFS-which constitutes 0.5-2.5% of primary care referrals and 10-15% of tertiary care referrals for fatigue  -remains without confirmatory laboratory tests and can be difficult to distinguish from depression. Between 1 and 8 in 1000 U.S. adults meet the CDC criteria . The CDC estimates that cost to the U.S. economy from lost productivity alone (not including medical care costs) is $9 billion annually .
There exists published evidence that CFS may have its underpinnings in organic disease especially within the central nervous system (CNS), although not all studies have found such abnormalities. Studies of the CNS in CFS have included psychometric assessment of cognition [9, 10], magnetic resonance imaging [[11–13]], functional MRI [14, 15], in vivo MR spectroscopy [16, 17], single-photon emission computed tomography , positron emission tomography , neuroendocrine studies of hypothalamic function [[20–22]], and studies of the autonomic nervous system [[23–25]].
A link with infection and CFS also has been reported following infection with Epstein-Barr virus, Ross River virus, Coxiella burnetii , Borrelia burgdorferi , parvovirus B19 , human herpesvirus-6 , and enteroviruses . Novel retroviruses may also be involved [31, 32] but that possibility has been challenged . All these infectious agents have the potential to be CNS pathogens. The evidence of neurologic involvement in CFS, and the possible role of infectious agents in triggering and perpetuating CFS, is summarized in a recent review .
Symptoms suggesting the possibility of subtle encephalitis in CFS, along with the documented association of CFS with several neurotropic infectious agents, caused us to examine the role of electroencephalographic (EEG) studies in this illness. However, simple visual inspection of EEG has rarely provided valuable information in CFS, aside from allowing exclusion of epilepsy and classic encephalopathy. A study utilizing EEG Spectral Analysis  reported no significant differences of spectral power in any EEG frequency bands during sleep between subjects with CFS and their non-fatigued co-twins. Only studies requiring stressful conditions such as repetitive muscular exercise  and sleep deprivation  have documented EEG spectral difference in CFS.
Accordingly, we undertook an exploration of spectral coherence, a more complex computational derivative of EEG spectral data, which estimates connectivity between brain regions [[38–40]]. We hypothesized that results would, first, serve to confirm a consistent pattern of brain difference in CFS and, second, provide estimates of the potential for an EEG based diagnostic test for CFS.