Umberto Tirelli* MD, Franca Chierichetti° MD, Marcello Tavio* MD, Cecilia Simonelli* MD, Gianluigi Bianchin€ MD, Pierluigi Zanco° MD and Giorgio Ferlin° MD. 

* Division of Medical Oncology and AIDS, Centro di Riferimento Oncologico, Aviano - Italy. 
° Nuclear Medicine Department - PET Center, General Hospital  - Castelfranco Veneto  - Italy. 
€ Psychiatry Department, General Hospital  - Castelfranco Veneto  - Italy. 

Corresponding author:


Prof. Umberto Tirelli
Division of Medical Oncology and AIDS
Centro di Riferimento Oncologico
Via Pedemontana Occ. 12, 
33081 Aviano (PN) - Italy
Tel. 434/659284
fax: 434/659531


Background and objective: Chronic fatigue syndrome (CFS) has been widely studied by neuroimaging techniques in recent years with conflicting results. In particular, by single photon emission computed tomography (SPECT) and perfusion tracers it has been found hypoperfusion in several brain regions, although the findings vary across the research centres. Objective of the study was to investigate brain metabolism of patients affected by CFS, by using 18Fluorine-deoxygluxose (18FDG) positron emission tomography (PET). 
Methods: We performed 18FDG PET in 18 patients who fulfilled the criteria of working case definition of CFS. Twelve of the 18 patients were females; the mean age was 34 ± 50 (range 15-68) and the median time from CFS diagnosis was 16 months (range 9-138). Psychiatric diseases and anxiety neurosis were excluded in all CFS patients. CFS patients were compared with a group of 6 patients affected by depression (according to DSM IV R) and 6 age matched healthy controls. The CFS patients were not taking any medication at the time of PET, while depressed patients were drug-free for at least one week prior to the PET examination. PET images were examined considering 22 cortical and subcortical areas. 
Results: CFS patients showed a significant hypometabolism in right medium frontal cortex (p = 0.010) and brain stem (p = 0.013) in comparison to the healthy controls. Moreover, comparing patients affected by CFS and depression, the latter group showed a significant and severe hypometabolism of a medium and upper frontal regions bilaterally (p = ranging from 0.037 to 0.001), while the metabolism of brain stem was normal. 
Conclusion: Brain- 18FDG PET showed peculiar metabolism abnormalities in patients with CFS in comparison both with healthy controls and depressed patients. The most relevant result of our study is the brain stem hypometabolism which , as already reported in a perfusion SPECT study, seems to be an marker for the  in vivo  diagnosis of CFS. 

Chronic Fatigue Syndrome (CFS) is a debilitating disorder of unknown etiology characterized by unexplained, deep fatigue lasting more than six months. The cause of CFS has not been identified, and no specific diagnostic tests are available to date. The first case definition of CFS did not effectively help physicians to distinguish CFS from other types of unexplained fatigue (1). For this reason, the revised case definition provided additional guidelines to researchers for subgrouping cases of CFS and other types of unexplained prolonged fatigue (2). Nevertheless CFS is not still recognized as an independent syndrome by most neurologists and psychiatrists, being depression the most common final diagnosis also in patients with genuine CFS (3). Diagnosis of depression is usually based on the neuro-psychological evaluation but, in CFS setting, it is not easy to distinguish between a primary depressive disorder and a secondary, reactive one. Neuro-functional imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have  already been extensively used to study neurologic and psychiatric disorders, especially to differential diagnosis purposes (4). In a recent review CFS has been included in a group of problematic syndromes in which SPECT may be useful in the differential diagnosis (5). 
We herewith present the results of a study aiming to evaluate brain metabolism of CFS patients without signs of depression by using PET and 18Fluorine-deoxygluxose (18FDG) as tracer. The study was based on a previous experience by perfusion SPECT  in a mixed group of CFS, neurological and psychiatric disorders that proved a relevant hypoperfusion of brain stem in CFS (6). As depression is the most frequent neurological diagnosis in cases of CFS, we examined subject suffering from major depression, too, but no other psychiatric patients. The aim of our study was to evaluate glucose brain metabolism to assess a possible role of central nervous system in the pathogenesis of CFS, and to confirm the data of perfusion SPECT by a higher resolution method like PET, able to detect small structures such as brain stem. Patients affected by CFS were evaluated at the Aviano cancer center, meanwhile patients with depression as well as healthy volunteers were evaluated at the Castelfranco general hospital, where PET procedure was performed to all the patients. 

In this preliminary study we enrolled 24 right-handling individuals composed of 18 patients (12 females and 6 males) who fulfilled the criteria of working case definition of CFS and 6 patients (4 females and 2 males) affected by major depression according to the DSM IV R, and we compared both groups with a group of healthy controls. All patients underwent a complete diagnostic work-up that included history, physical and neuropsychiatric examination, and brain CT or MRI. In all CFS cases psychiatric diseases were excluded by BPRS (Brief Psychiatric Rating Scale) and PSE (Present State Examination). We performed also Hamilton Rating Scale for Anxiety and 24-item Hamilton Rating Scale for Depression, before PET study, to exclude depression and anxiety neurosis.  Their mean age was 34 ± 15 years (range, 15 to 68) and they were drug-naive. Patients affected by major depression were older (mean age 48 ± 7 years, range 41 to 59) and the mean duration of the disease was 8 +-4 years. They were drug-free for at least 4 weeks prior to entering the study. Previous head trauma, and/or cerebrovascular diseases were excluded for both. Median time from CFS diagnosis was 16 months (range 9-138). The main symptoms of CFS patients are shown in table I. 
We included a control group comprising 6 age-matched  healthy subjects (4 females and 2 males) (mean age 38 ± 12) who were entirely normal on physical examination, with negative history for neurological and psychiatric diseases. We chose a small group of controls who were composed of a similar percentage of males and females and age matched respect to CFS cases. They were young enough to exclude the effect of age even if this is still controversial as the findings seen on PET in normal aging are not yet unique (7-8). All subjects or their relatives gave informed consent to participate into the study. 
PET studies were performed using a whole-body, high resolution PET scanner (ECAT EXACT 47 Siemens CTI). This 24-ring bismuth germinate tomograph produces 47 simultaneous slices 3.38 mm thick and the resolution (FWHM) is 6.1 mm along the transaxial plane and 4.8 mm along the axial plane. The correct positioning of the head was assessed by a laser device to define the orbitomeatal line. A transmission scan was performed (10 min acquisition) to obtain the attenuation correction, using orbiting 68Ge rod sources. 210-270 MBq of 18FDG were injected into an antecubital vein in resting condition, ear unplugged and eyes closed. Emission scan data were acquired 45 min post injection. In controls, depressed patients and 10 out of 18 CFS subjects we obtained also the cardiac input functions for calculating rCMRgl following a methodology described in a previous experience (9). Transaxial, coronal and sagital slices were reconstructed from raw data both for qualitative (non parametric) and quantitative (parametric) studies. On    6 mm thick transaxial slices (about 16 per study) we performed a region of interest (ROI) analysis positioning several anatomical ROIs, based on isocontour techniques, comparing the PET images to a standard brain atlas (10) and outlining the entire region on each image. The ROIs, 50-54 per study, were used to sample the different brain areas of the cortex, basal ganglia, thalamus, cerebellum and brain stem. At least three contiguous slices were used to obtain information from each area by averaging the data from these planes. The resulting 22 cortical and subcortical areas were: 1. left inferior frontal (comprising orbito-frontal region); 2. right inferior frontal; 3. left medium frontal (comprising medium frontal gyrus and the lower region of superior frontal gyrus); 4. right medium frontal; 5. left superior frontal; 6. right superior frontal; 7. left parietal; 8. right parietal; 9. left inferior temporal (comprising hyppocampus and mesial cortex); 10. right inferior temporal; 11. left superior temporal (comprising primary auditive cortex); 12. right superior temporal; 13. left occipital cortex (included primary visual cortex); 14. right occipital cortex; 15. left nucleus caudate; 16. right nucleus caudate; 17. left putamen; 18. right putamen; 19. left thalamus; 20. right thalamus; 21. brain stem; 22. cerebellum (taken as a whole). The same set of ROIs was used for both parametric and non parametric PET images to obtain the mean values of all areas in rGMRgl and microCi per pixel, respectively. Then, for each study, we computed the mean brain activity (MBA), as mean value of all ROIs, and we normalised each cortical and subcortical area to this mean. E.g. left inferior frontal A = mean value of the ROIs on left inferior frontal cortex/MBA. 
Group means were compared using the two-tailed Student's t test for unpaired comparisons. The level of statistical significance was set at p < 0.05. 

Conventional radiological imaging (MRI and CT) was normal in both groups of patients showing no focal defects or significant brain atrophy. For visual inspection of PET imaging, the reduction of metabolism was considered to be mild (< 10% of the color scale), moderate (10-20% less) or severe (>20%). CFS patients, respect to controls, showed moderate hypometabolism of brain stem, especially pons (fig. 1). In depressed subjects a severely impaired glucose metabolism in frontal areas was evident (fig. 2). Normalised non parametric PET data revealed in CFS a significant hypometabolism of right medium frontal cortex (p = 0.010) and brain stem (p = 0.013) respect to healthy subjects. Comparing major depression and CFS, in the first group of patients the whole frontal cortex was affected (except the left inferior frontal) with p ranging from 0.037 to 0.001, while in CFS patients brain stem was severely and significantly hypometabolic, with p value of 0.009 (table II). Absolute, quantitative 18FDG PET showed normal values for the mean (40± 12 micronmol/100 g/min) rCMRgl both in depressed and CFS patients. The normalization of parametric images, by using the same set of ROIs of the non parametric studies, demonstrated the same involvement of previous reported brain areas. 

To date no diagnostic tests are available for CFS which is currently diagnosed by a history of illness suggestive of CFS along with the systematic exclusion of other possible causes of fatigue. Applications and limitations of functional neuro-imaging in diagnosis of CFS have been recently reviewed (11). Magnetic resonance imaging (MRI) and x-ray computed tomography (CT) are anatomical approaches that gave in CFS conflicting and substantially inconcludent results (12-13). PET and SPECT offer non-invasive in vivo methods to assess directly regional brain functions. Regional brain blood flow, oxygen metabolism and glucose utilisation, blood-brain barrier permeability, and pre-sinaptic and post-sinaptic neuro-receptor density and affinity are some of the neuro-physiologic variables that can be studied by these techniques (14-16). Several studies have been published using SPECT in CFS, although the results vary across research centers, probably reflecting a different selection of the patients. First reported regional SPECT abnormalities involved frontal, parietal, temporal and occipital areas within a widespread cortical hypoperfusion (17). The involvement of frontal and temporal regions was successfully described (18) both in depressed and CFS patients, suggesting important similarities and also arising the question of the differential diagnosis between these disorders. 
Recently Costa et al compared brain perfusion of patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with that of normal volunteers and other patients with major depression (6). The results indicated that in addition to scattered cortical perfusion abnormalities, brain stem hypoperfusion (compared to normals) appeared to be characteristic of ME/CFS patients and it was significantly lower than that of depressed patients. The brain stem hypoperfusion was the lowest in those ME/CFS patients who fulfilled the CDC criteria and had no other psychiatric disorder. 
In order to describe PET- pattern in CFS patients and to study PET usefulness in differential diagnosis between CFS and depression, we measured brain metabolism in patients affected by CFS without depression and in patients affected by depression without CFS, comparing both groups of patients with a control group of healthy subjects. Absolute glucose metabolism data and normalised data showed that the brain glucose metabolism is impaired in selected and different areas both in CFS and depression. In CFS, respect to healthy subjects, we found a significant hypometabolism of right medium frontal cortex, as in agreement with a previous SPECT study by perfusion tracers (18). Our group of depressed patients presented more severe and spread frontal alterations, as already reported in depression (19) and in other psychiatric syndromes, especially schizophrenia, and obsessive-compulsive disorder (20-25). PET and SPECT studies have not yet identified specific patterns for each disease, but, generally, the frontal alterations are not focal as we conversely found in our experience with CFS. We can argue that this limited involvement of frontal cortex  in CFS may be a feature of the disease. Alternatively, we can consider it as an expression of reactive, not yet clinically evident, depression. Hypothetically, taking into account that in our regional analysis, medium frontal cortex comprised brain areas 9 and 46 (association cortex), this derangement of right hemisphere may explain some neurocognitive impairments of the disease. 
More specifically, we found a significant hypometabolism of brain stem, confirming the report of other Authors (see above) and this seems a typical feature of CFS never reported to our knowledge in psychiatric diseases. Previous SPECT studies were able to identify such involvement, even if this technique has an anatomical resolution lower than our high resolution PET. To date this finding has no clear explanation especially in order to define such a damage as primary or secondary to CFS. Brain stem is involved in many functions of the vegetative life. Animal models have shown (26) a predilection for brain stem and diencephalon by some herpes virus, and Epstein-Barr virus and herpes virus type 6 have been often implicated in CFS pathogenesis (12-27). As already suggested by Costa et al. this virus-mediated brain stem impairment might be rather the cause than the consequence of the disease and might explain some manifestations of CFS, by the involvement of the reticular system (i.e. sleep disturbances and consciousness alterations). 
In conclusion, our, even preliminary, study is in agreement with previous neurofunctional imaging studies supporting an organic cause for CFS. Because of its cost, PET procedure should not be considered appropriate for the clinical diagnosis of CFS. Nonetheless, in the near future, PET cuold become extremely useful in testing new pathogenetic hypothesis and new therapeutic approches, especially in selected subsets of patients.

Table - I - 


Number (%)
Fatigue (according to case definition) 18/18 (100)
Insomnia / ipersomnia 18/18 (100)
Headaches 18/18 (100)
Neuropsychological problems 18/18 (100)
Photophobia or transient scotomata 17/18 (94)
Prolonged periods of low-grade fever 14/18 (78)
Migratory artralgia 13/18 (72)
Sore throat 13/18 (72)

Table - II - 


Depression mean st dev CFS 
st dev p
L inferior-F  1.00 0.06729 1.03 0.03912 NS
R inferior-F 0.96 0.04539 1.02 0.05217 0.037
L medium F 0.96 0.05148 1.04 0.0453 0.002
R medium F 0.96 0.05768 1.02 0.03689 0.037
L superior F 0.77 0.048697 1.06 0.04936 0.001
R superior F 0.76 0.048517 1.04 0.04299 0.001
brain stem 0.77 0.13645 0.65 0.06257 0.009
L = left; R = right; F = frontal. 



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Legend figure number 1
CFS patient: PET transaxial and sagittal showing the low up-take in brain stem. 

Legend figure number 2
Depressed patient: PET transaxial and sagittal showing the low frontal up-take and normal glucose metabolism of the brain stem. 

We thank Dr. Maddalena Mosconi for the help with the manuscript