This study received Institutional Review Board approval from the Centers for Disease Control and Prevention (CDC) and collaborating institutions. Administration of protocols adhered to U.S. Department of Health and Human Services human experimentation guidelines. All participants were over 21 years of age and provided written informed consent.
The present study, conducted between January and July of 2003, evaluated participants with CFS and healthy controls followed from 1997 through 2000 in the Wichita CFS Surveillance Study [8
]. The Wichita CFS Surveillance Study employed a random digit-dialing telephone survey to screen 56,146 adult residents, 18 to 69 years of age, living in Wichita in 1997. That survey identified 5,295 persons with fatigue persisting one month's duration or longer. Those individuals were asked to participate in a detailed telephone interview; 3,528 agreed to participate, along with a subset of 3,634 randomly selected non-fatigued (NF) controls. The detailed interview was used to identify cases with fatigue of 6 months duration or longer, who did not feel better after rest, who did not report any fatigue-associated medical or psychiatric conditions, and who reported at least four of the eight CFS case-defining symptoms (CFS-like cases) [1
]. CFS-like cases were invited to participate in a clinical examination to confirm CFS by 1994 criteria [1
]. Two Randomly selected NF controls matched to CFS-like cases based on age, sex, race, and body mass index were also asked to participate in the clinical evaluation. We followed this telephone interview cohort in 1998, 1999, and 2000 with telephone interviews and clinical evaluations.
In-hospital study participants
In 2002, all subjects ever having met criteria for clinically confirmed CFS during the surveillance study were invited to participate in the current study. Thus, we invited the 70 people, who were classified as having CFS at least once during the 4-year surveillance study, to participate in the current study and 58 (83%) agreed. We randomly selected an equal number of surveillance participants who had unexplained fatigue for at least six months or longer, at least once during the 4-year surveillance study, but who did not meet full CFS criteria, and 59 (84%) were enrolled. Finally, we enrolled 60 non-fatigued control subjects who had participated in the same surveillance program, but did not exhibit any medical or psychiatric exclusion, and had never reported fatigue of at least 1-month duration. They were matched to CFS cases based on sex, age, race, and body mass index.
All subjects were admitted to a Wichita hospital research unit for 2 days. On admission, subjects underwent reevaluation in terms of current CFS symptoms and exclusionary conditions. At the hospital, 43 current CFS cases were confirmed. These consisted of past CFS cases that still had CFS, as well as new onset CFS cases derived from chronically fatigued persons who previously did not meet CFS criteria. Persons with insufficient symptoms of fatigue to be considered CFS, at the time of the in hospital study, were not included in this report. Because NF controls were individually matched to cases with a CFS diagnosis during the prior surveillance study, and this in-hospital study occurred two years later, and subjects were classified according to current diagnostic status, individual matching could not be maintained. However, the groups were demographically comparable. The mean age of the sample was 50.5 years and mean body mass index was 29.2.
Participants were admitted to a Wichita hospital research unit for 2 days where they underwent a standardized review of past medical history, a standardized physical examination, and provided blood and urine for routine analysis [1
]. To identify psychiatric conditions exclusionary for CFS, specifically trained and licensed psychiatric interviewers administered the Diagnostic Interview Schedule for current Axis I disorders. Subjects with no exclusionary conditions were considered to be CFS if they met criteria of the 1994 CFS case definition [1
], as applied following recommendations of the International Chronic Fatigue Syndrome Study Group [8
]. Subjects completed a series of rating scales to assess functional impairment (SF-36), fatigue severity (MFI), and occurrence, frequency and severity of the 8 CFS defining symptoms [13
]. Classification as a current CFS case was based on cutoff scores in these rating scales with respect to the 3 dimensions of CFS specified in the case definition, i.e., impairment, fatigue, and accompanying symptoms [13
]. Subjects meeting these criteria at the time of the study were classified as having CFS (n = 35) and those who met no criteria were classified as well (n = 40).
Polysomnographic and Multiple Sleep Latency Techniques
Detailed descriptions of data collection techniques and protocols for nocturnal PSG and daytime multiple sleep latency testing (MSLT) have been described elsewhere [9
]. Briefly, all PSG procedures were conducted within a 4-bed laboratory established at Wesley Medical Center, Wichita, KS. Each subject had a standard nocturnal PSG performed on the first night in the Medical Center, followed by MSLT the next day and a second PSG performed on the second night. Subjects were asked to arrive three hours before their typical bedtime on Night 1 to allow adequate time for electrode application and standard biocalibrations. Lights out and lights on times were standardized at 22:00 and 07:00, respectively, for all subjects.
During the PSG, standard gold cup electrodes were employed for the recording of electroencephalography (EEG), electroencephalography (EOG), and electromyography (EMG) in the following montage: central EEGs (C3-A2//C4-A1), occipital EEGs (O1-A1//O2-A2) EEGs, left and right monopolar EOGs, surface mentalis EMGs, and a three lead electrocardiogram. These signals were collected at a sampling rate of 200 Hz. Respiration was measured with inductance plethysmography-like belts placed around the chest and abdomen. A nasal cannula, attached to a pressure transducer, was positioned in close approximation to the nares to provide indices of airflow. A pulse oximeter probe, to measure hemoglobin oxygen saturation (Sp02), was applied to either the right or left index finger. Leg movement activity was measured via surface EMG electrodes applied to both the right and left anterior tibialis muscles.
Scoring of polysomnography data
All PSG data was scored by a single registered polysomnology technologist who was blinded to each subjects' enrollment classification. Each PSG recording was manually scored in 30 second epochs, with each epoch scored as either wake, Stages 1, 2, slow wave, or rapid eye movement (REM) sleep. Criteria for scoring sleep and respiratory variables were upon based definitions used by the Sleep Heart Health Study [14
Fast Fourier Transformation of EEG Data
Following manual scoring of each subject's night one and two PSG recordings, the night two PSG was prepared for spectral analyses. Each 30-second epoch was assessed for the presence of EEG artifact (random high frequency noise attributed to movement arousal, etc), which was marked as movement artifact and excluded from further analysis. Removing entire epochs insured that the final FFT data output would be appropriately synchronized with each scored, artifact free, PSG epoch.
Following identification of all epochs containing artifact, we utilized the FFT algorithm within Somnologica Science (Embla, Denver Co., USA) to determine the spectral analysis profile of the EEG signal obtained between electrodes placed at the C3-A2 region of the scalp. The FFT algorithm was adjusted to deconstruct the EEG signal into the primary frequency domains described in Table (Table ). Since EEG signals were recorded at 200 Hz, each thirty second epoch contained 6,000 EEG data points per channel.
The FFT analysis window processed 256 samples of EEG data as a signal unit, with each "unit" representing 1.28 seconds of EEG data. As the FFT analysis window progressed along the EEG signal, the final 128 data points within the preceding analysis window were included with the next 128 EEG data points, to be analyzed. This analysis routine produced 23.44 discrete FFT values for each 30 second epoch of EEG data. These 23.44 FFT values were then averaged into one FFT value representing the entire 30 second epoch. This methodological approach enabled us to define both the "power" within the alpha, delta, theta, beta and sigma frequency bands (Table ) as well as the relative contribution that the power within each frequency provided to the overall power of the EEG signal.
Clinic staff reviewed all current medications (prescription and over the counter) that study participants were taking. All participants continued their medication use throughout the study. CDC CFS research program staff classified these medications as those affecting sleep (i.e., inducing sleep, inhibiting sleep or with mixed effects) or not affecting sleep. Medications that we encountered during this study included analgesics (e.g., hydrocodone, Lortab, oxycodone, Propoxyphene), antidepressants (e.g., Celexa™, amitriptyline, imipramine, Lexapro™, Wellbutrin™, Effexor, Prozac™, Zoloft™, Paxil™, fluoxetine), antianxiety (Alprazolam), antihistamines (e.g., diphenhydramine, chlorpheneramine, benadryl, promethazine), decongestants (e.g., pseudoephedrine, guaifenesen), anticonvulsants (e.g., Topamax, Neurotin, clonazepam), anti-sleep phase disorder (melatonin), blood pressure controlling (e.g., Clonidine, Proamatine), antipsychotics (e.g., Seroquel, Zyprexa, Fluvoxamine), stimulants (e.g., methylphenidate, Provigil), peristaltic stimulants (Metoclopramide), and muscle relaxants (cyclobenzaprine). Medications affecting sleep were handled as a binary measure (i.e., they used or did not use one or more of those named above). Analyses took into account use of sleep affecting medications.
Spectral power for each frequency domain was determined for each 30 second epoch of sleep as well as wakefulness prior to sleep onset. Independent samples t-tests were employed to assess values of alpha, delta, theta, beta and sigma between control subjects with CFS subjects. Group differences were considered significant at a two-tailed significance of 0.05.