Source: Clinical Physiology Functional Imaging Vol. 26, #2, pp 83-86 Date: March 2006 URL: http://www.blackwell-synergy.com/doi/abs/10.1111/j.1475-097X.2006.00649.x Patients with chronic fatigue syndrome have reduced absolute cortical blood flow --------------------------------------------------------------------------- Kazuhiro Yoshiuchi(1,2), Jeffrey Farkas(3) and Benjamin H. Natelson(1) 1 Department of Neurosciences, Fatigue Research Center, UMDNJ-New Jersey Medical School, Newark, NJ, USA, 2 Department of Psychosomatic Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan, and 3Department of Radiology, Fatigue Research Center, UMDNJ-New Jersey Medical School, Newark, NJ, USA Correspondence Kazuhiro Yoshiuchi, Department of Psychosomatic Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 113-8655 E-mail: kyoshiuc-tky@umin.ac.jp Accepted for publication Received 22 July 2005; accepted 6 October 2005 Summary Prior studies on brain blood flow in chronic fatigue syndrome (CFS) did not find consistent results. This may be because they used single-photon emission computed tomography to measure brain blood flow, which could not measure absolute blood flow. Therefore, the aim of this study was to test the hypothesis that patients with CFS have reduced absolute cerebral blood flow. Xenon-computed tomography blood flow studies were done on 25 CFS patients and seven healthy controls. Analyses were done after stratifying the CFS patients based on the presence or absence of a current psychiatric disorder. Flow was diminished in both groups as follows: patients with no current psychiatric disorders had reduced cortical blood flow in the distribution of both right and left middle cerebral arteries (P<0.05 for both) while those with current psychiatric disorders had reduced blood flow only in the left middle cerebral artery territory (P<0.05). These data indicate that patients with CFS have reduced absolute cortical blood flow in rather broad areas when compared with data from healthy controls and that those devoid of psychopathology had the most reductions in cortical flow. These data support, in part, our earlier findings that patients devoid of psychopathology are the group most at risk of having some of the symptoms of CFS due to brain dysfunction. Key words depression; medically unexplained illness; middle cerebral artery; psychiatric disorders; xenon computed tomography Introduction Chronic fatigue syndrome (CFS) is a medically unexplained illness characterized by debilitating fatigue accompanied by infectious, rheumatological and neuropsychiatric symptoms. While earlier work had suggested that the severe fatigue of CFS was due to problems in the muscle, recent work does not confirm this (McCully et al., 2003). Our own findings of impaired neuropsychological function (DeLuca et al., 1995) and abnormal brain magnetic resonance scans (Lange et al., 1999) in CFS patients without comorbid psychiatric illness pointed to the brain as the target organ producing fatigue. A number of early studies using single-photon emission computed tomography (SPECT) have reported global cerebral hypoperfusion (Ichise et al., 1992; Schwartz et al., 1994). However, these studies did not divide CFS patients into those with and without co-morbid psychiatric diseases. Subsequent studies in a more homogeneous sample of CFS patients without comorbid depression reported diametrically opposite results in subcortical sites; one group found decreases in brain stem perfusion (Costa et al., 1995) while another group found increased perfusion in the thalamus. In contrast, at least three studies - one in carefully matched monozygotic twins discordant for CFS - found no differences in cerebral blood flow (CBF) between patients and controls (Peterson et al., 1994; Fischler et al., 1996; Lewis et al., 2001). Therefore, sample heterogeneity does not appear to be an adequate explanation for these discrepancies. An alternative explanation is a methodological issue. SPECT scanning provides information about the whole brain blood flow relative to some other site - usually the cerebellum. If some CFS patients had reduced blood flow to cerebellum, this occurrence might greatly confound the results. Therefore, the aim of this study was to test the hypothesis that patients with CFS have reduced absolute CBF using Xenon computed tomography (CT), a method that provides absolute measures of CBF. In addition, a stratification strategy was used as recommended by the Centers for Disease Control to reduce heterogeneity in the patient sample by dividing CFS patients into those with and without comorbid Axis I psychiatric disorders. Our previous use of that strategy had produced a subset of patients with neuropsychological dysfunction and increased numbers of brain magnetic resonance imaging (MRI) abnormalities relative to patients with comorbid psychopathology (Natelson, 2001). Methods Subjects The subjects studied were nine healthy controls and 32 patients who fulfilled the 1994 case definition for CFS, which required six or more months of severe unexplained fatigue-producing substantial reduction in activities and four or more symptoms from a list specified in the case definition (Fukuda et al., 1994). The patients were all self- or physician-referred to our Center, and control subjects responded to media advertisements or community-wide postings. Of these subjects, four patients dropped out of the study prior to imaging due to claustrophobia and one patient with problems related to mask fitting; data from two other patients and two healthy subjects were collected but were unusable due to motion artifact. Therefore, we analysed seven healthy controls (five men and two women) and 25 patients (seven men and 18 women). Patients taking medica- tions such as antidepressants, including low-dose tricyclics or opiates were excluded from participation. Based on laboratory blood screening and on a psychiatric diagnostic interview (Marcus et al., 1990), no patient had any medical or psychiatric conditions that could explain their symptoms (Schluederberg et al., 1992), and none had a history of a head trauma that resulted in loss of consciousness for more than 5 min. Healthy controls were sedentary, who did not exercise regularly. All subjects signed informed consent approved by the New Jersey Medical School's Institutional Review Board. Following the psychiatric diagnostic evaluation, CFS patients were divided into those with a current co-morbid psychiatric diagnosis, usually depression (n=9) and those free from psychiatric comorbidity (n=16). All of the controls were free from psychiatric illness. Xenon-computed tomography scanning Xenon-CT scan cerebral blood flow values were obtained by having patients inhale a mixture of 28% xenon p/m 1.25% and oxygen (XeScan/Xenon in Oxygen USP; Praxair Pharmaceutical Gases, Danbury, CT, USA) while undergoing conventional CT scan. The Xenon mixture was prepared from a multidose cylinder containing 80% xenon in oxygen USP and a separate source of 100% oxygen. All CBF studies were obtained using the same scanner and equipment in all subjects. Prior to Xenon-CT imaging, 15 ml of blood was withdrawn via venipuncture to allow for correction based on haematocrit in computing the final CBF value. The imaging protocol consisted of two baseline CT scans followed by six stable xenon enhanced scans, which were obtained during 4.25 min of Xenon gas inhalation. A complete Xenon-CT study consisted of four levels; each level was a 10-mm thick cross-section (Fig. 1a). The first level was always obtained through the basal ganglia and thalamus. All scans were angled to exclude the orbits in a plane that was parallel to the orbital meatal line. All CT studies were obtained on a multi-slice CT scanner (GE Lightspeed QXI; GE Healthcare Technologies, Waukesha, Wisconsin, USA), and images were obtained in axial mode. Prior to the performance of this study, phantom calibration controls provided by GE were instituted so that consistent results would be available throughout the study period. The primary data collector and physician who created the data maps and recorded the data were blinded to the clinical history of the patients. Data analysis and statistics The extent and time course of the increased houndsfield attenuation secondary to the inhaled xenon and the end tidal xenon were used to calculate cerebral blood flow maps using a modified Kety-Schmidt equation (Kety & Schmidt, 1948). The cerebral cortex was divided into six fan-shaped regions of interest for each hemisphere at each of the four levels. CBF for each of these regions was automatically calculated by the system. The six cortical regions correspond to the six vascular territories of the brain as follows: right anterior cerebral, right middle cerebral, right posterior cerebral, left anterior cerebral, left middle cerebral and left posterior cerebral. Additional regions of interest were obtained from the left and right caudate, putamen and thalamus on each of the three levels (panel b of Fig. 1 depicts all the regions of interest). We averaged the data from levels 1, 2, 3 and 4 of each region in the cortex and six regions in the basal ganglia were averaged in each subject. This left us with six cortical areas (bilateral anterior, middle and posterior cerebral artery territories) and one subcortical area. Analyses among the stratified groups used one-way ANOVA and Tukey's multiple comparison tests. P-values <0.05 were considered significant. Results There was no significant difference in age among the three groups (CFS without axis I, 38.7 p/m 6.5 years; CFS with axis I, 43.0 p/m 7.1 years; controls, 34.9 p/m 9.9 years). Using samples stratified based on presence or absence of psychiatric diagnosis, differences were found among the three groups in cerebral blood flow in left and right middle cerebral artery territories [F(2,29)=3.76, P=0Æ035; F(2,29)=4.58, P=0.019 respectively]. Using the Tukey's multiple comparison test, flow in right middle artery territory was reduced significantly for CFS patients with and without axis I diagnosis when compared with healthy controls (Table 1). Blood flow to left middle cerebral artery territory was significantly lower in CFS patients without axis I diagnosis than in healthy controls (Table 1). Discussion Using a technique that allows measurement of absolute brain blood flow, we found that patients with CFS have reduced global cerebral blood flow in the present study. Our data support and extend earlier studies that reported global hypoperfusion using SPECT brain imaging (Ichise et al., 1992; Schwartz et al., 1994). Such hypoperfusion could have explained reports of localized increases in cerebellum perfusion (Costa et al., 1995; Schmaling et al., 2003) because SPECT provides blood flow relative to cerebellum. However, the results of this study confirm that cortical blood flow is reduced through some regions of the CFS patients relative to controls. Specifically, CFS patients had decreased blood flow in bilateral middle cerebral artery territories. We had hypothesized that one problem with the earlier work lay in the fact that no effort had been made to stratify the patient group to reduce the heterogeneity that comes with the use of clinical case definition to diagnose CFS. Our previous work had supported the value of using stratification strategies to reduce heterogeneity of the patient sample: patients without comorbid psychopathology were those with the most cognitive dysfunction (DeLuca et al., 1997) and had the most brain MRI abnormalities (Lange et al., 1999). While we had expected that stratified subgroups of CFS patients would lead to one group having reduced cortical blood flow but not the other, the data did not support that expectation. However, consonant with our earlier work, we did find the most abnormalities in the group devoid of comorbid psychopathology. Of importance is a recent paper showing that these patients have increased ventricular volume (Lange et al., 2001). Further studies using positron emission tomography on comparison of CFS patients with and without psychiatric disorders, especially depression, are necessary to investigate the effect of CFS itself and psychiatric disorders because recent studies (Yamamoto et al., 2004; Cleare et al., 2005) reported that alterations of the serotonergic system was found in CFS patients without psychiatric disorders. Although we did find a difference based on psychiatric comorbidity, we must reiterate that both patient groups had reduced cortical blood flow. Therefore, we conclude that CFS, itself, is associated with diminished blood flow. Our study suffers from several limitations. The size of our control sample is small and it is comprised of more men than women - the opposite sex distribution as in our patient group. However, differences in rates of psychiatric comorbidity between the sexes do not explain the differences found between those with and without psychiatric diagnoses: rates were similar in male and female patients (P=0.67 using the Fisher's exact test). Moreover, previous cerebral blood flow studies of normal subjects indicate that flow is higher in women than in men (Gur & Gur, 1990). This result would suggest that we might have found an even greater diminution of cerebral and regional blood flow had our control group been sex-matched to our CFS group. In addition, reduction in flow was similar in men and women (interaction of sex and group for left and right middle cerebral artery territories was not significant; P=0.79 and P=0.55 respectively). However, absolute CBF values in the cortex in this study seemed higher than those in previous studies with healthy people (Hagen et al., 1999) while CBF-values in the basal ganglia were comparable to previous studies (Sase, 1998). Therefore, further studies with more controls are needed to confirm the results of this study. In conclusion, CFS patients have lower cortical blood flow than healthy sedentary controls. Those patients devoid of comorbid psychiatric diagnosis had the widest areas of reduced flow. The data support the hypothesis that the symptoms seen in CFS are due, in part, to brain dysfunction. Acknowledgments This work was funded by a grant (NIH U01-34427) from the National Institute for Allergy and Infectious Disorders establishing the New Jersey CFS Cooperative Research Center. Figure Caption Figure 1 Axial images of the brain (a). Computer tomographic images are provided to indicate the approximate anatomic levels imaged during the Xenon computed tomography scan. A total of four levels (10-mm thick) were imaged. The first and second level typically included the deep thalamic gray nuclei such as the thalamus and basal ganglia. Regions of interest were drawn and calculated automatically for each level including cortical gray and deep thalamic and basal ganglion gray nuclei (b). Table 1 Brain blood flow for chronic fatigue syndrome (CFS) and controls [mean ml/100 g min^-1) p/m SD] ---------------------------------------------------------------------------------------- Controls CFS without CFS with Brain area studied (n=7) axis (n=16)I axis (n=9)I ---------------------------------------------------------------------------------------- Left anterior cerebral artery territory 63.8 p/m 30.9 50.9 p/m 13.7 47.6 p/m 8.0 Right anterior cerebral artery territory 71.0 p/m 27.3 58.2 p/m 12.3 52.8 p/m 7.9 Left middle cerebral artery territory 59.7 p/m 23.0 42.1*p/m 12.1 45.0 p/m 8.6 Right middle cerebral artery territory 62.6 p/m 24.8 43.8*p/m 11.1 44.0*p/m 8.0 Left posterior cerebral artery territory 67.4 p/m 27.2 55.0 p/m 11.2 51.5 p/m 8.8 Right posterior cerebral artery territory 64.3 p/m 32.0 52.8 p/m 12.4 47.4 p/m 8.4 Basal ganglia 83.2 p/m 32.9 71.7 p/m 16.5 67.5 p/m 16.2 ---------------------------------------------------------------------------------------- *P<0.01 versus controls using the Tukey's multiple comparison test. 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