University Department of Psychiatry, and MRC Brain Metabolism Unit, Royal Edinburgh Hospital, Edinburgh
University Department of Psychiatry, Warneford Hospital, Oxford
Correspondence: Professor K. P. Ebmeier, Department of Psychiatry, Edinburgh University, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK
Declaration of interest Study funded by the Scottish Home and Health Department and the Wellcome Trust.
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ABSTRACT |
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Aims To test the hypothesis that patients with CFS have abnormal cerebral perfusion, that differs from that in patients with depressive illness.
Method We recruited 30 patients with CFS who were not depressed, 12 depressed patients and 15 healthy volunteers. Regional cerebral perfusion at rest was assessed using region of interest (ROI) and voxel-based statistical parametric mapping (SPM) techniques.
Results On SPM analysis there was increased perfusion in the right thalamus, pallidum and putamen in patients with CFS and in those with depressive illness. CFS patients also had increased perfusion in the left thalamus. Depressed patients differed from those with CFS in having relatively less perfusion of the left prefrontal cortex. The results were similar on ROI analysis.
Conclusions Abnormal cerebral perfusion patterns in CFS subjects who are not depressed are similar but not identical to those in patients with depressive illness. Thalamic overactivity may be a correlate of increased attention to activity in CFS and depression; reduced prefrontal perfusion in depression may be associated with the greater neuropsychological deficits in that disorder.
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INTRODUCTION |
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METHOD |
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Depressed patients
Twelve hospital in-patients with a diagnosis of major depressive episode
with melancholia and no history of (hypo-) mania (DSM-III-R;
American Psychiatric Association,
1987) were recruited. The mean duration of their present episode
was 12 months (range 2-64). Two patients were medication-free at the time of
imaging. Of the remaining 10, three were prescribed neuroleptics, two lithium
carbonate, eight antidepressants, three hypnotics or anxiolytics, and one
endocrine replacement (thyroxine). Patients were excluded if there had been
any changes in their drug regime in the previous 3 weeks. Five patients had
received electroconvulsive therapy (ECT) more than 6 months ago. Patients had
two scans within 24 hours, and data on diurnal variations of mood in this
group have been reported previously
(Ebmeier et al, 1997).
The morning scan was chosen for all depressed patients, and only patients
randomised into the morning first group were included, to make
scanning times comparable with those of the other groups.
Healthy volunteers
Fifteen healthy volunteers, who were matched in aggregate for age and
gender, were recruited as a control group from hospital staff and friends of
patients. Any significant medical and psychiatric conditions were excluded by
thorough evaluation, as outlined above, including screening blood tests and
psychiatric interview. Three subjects were receiving regular medication in the
form of hormone replacement therapy or oral contraception.
The study followed protocols approved by the local ethics committee and the Administration of Radioactive Substances Advisory Committee (ARSAC) at the UK Department of Health.
Imaging protocol
All subjects were imaged with a single-slice 12-detector head scanner with
an in-slice and z-axis resolution of 8.5 mm full-width half-maximum
(FWHM) and a sensitivity of 15 000 counts/s/mCi/ml, using the intermediate
572-hole collimators (Neuro 900, Strichman Medical Equipment Inc., Boston,
USA). Healthy volunteers and patients with depression received 250 MBq as part
of a split-dose scanning procedure (Ebmeier et al,
1991,
1997). CFS patients received
500 MBq of technetium-99m hexamethyl propylamineoxime
(99m-Tc-HM-PAO). The scanning time for the first two groups was
doubled to 5 min per slice in order to compensate for the reduced dose. Data
on the satisfactory reliability of half-dose as compared with full-dose scans
have been published previously (Ebmeier
et al, 1991).
Subjects rested comfortably on the imaging table with eyes closed and covered and environmental noise kept to a minimum, while the tracer injection was administered over a 30 s period. The subject's head was then positioned in a moulded head-holder and aligned with the help of two crossed positioning lights. During the scan, the head was fixed with pressure pads over the zygomatic arches. Slices were acquired parallel to the orbito-meatal plane, starting at a level approximately 2 cm above the orbito-meatal line and at 1 cm intervals above this level; further details of the method have been described previously (Ebmeier et al, 1995). Images were reconstructed using software supplied by Strichmann Medical Equipment (SME) for the Apple Macintosh. The SME reconstruction algorithm selects an enveloping ellipse, derived from an oversmoothed image of the brain. This, together with the absorption length parameter (95 mm), determines the Chang-like attention correction which was done with one iteration. Count distributions were deconvoluted into the radio-isotope concentrations responsible, using a Wiener filter with a correlation length of 6 mm.
Image analysis
Two transverse slices were chosen for the ROI analysis, approximately 4 and
6 cm above the orbito-meatal line. A standard template was prepared by drawing
regions of interest over corresponding brain atlas slices
(Talairach et al,
1988). Although this atlas is oriented to an internal anatomical
reference (the line between anterior and posterior commissures), the
orbito-meatal line is almost parallel with it
(Szikla et al, 1977).
The ROIs included, in the lower slice, frontal, anterior and posterior
cingulate, anterior temporal, posterior temporal, calcarine and occipital
cortex, as well as caudate, putamen and thalamus. The corresponding template
for the higher slice contained frontal, anterior and posterior cingulate,
parietal and occipital cortex. The templates are linearly and symmetrically
deformed to fit different brain sizes and shapes, using the 20% isocontour
line to define the cortical edge. ROI were thus preserved in their relative
position to each other, and no additional adjustments were made for single
regions that appeared to be out of position
(Ebmeier et al, 1991).
Regional count densities were normalised by proportional scaling to whole
brain blood flow (derived from the two slices examined). The reliability of
this ROI method has been examined previously, in both control and patient
groups, with between-rater errors approximating 10%
(Ebmeier et al,
1991).
Images were further processed using Analyze (CNS Software) with custom-written software developed in the MAT-LAB (The Mathworks, Inc.) on a Sun SPARC workstation. SPM of regional cerebral tracer uptake were derived using the SPM96 software supplied by K. J. Friston and colleagues at the Wellcome Department of Cognitive Neurology. The SPM data were processed as follows:
Statistics
Significant group effects are reported for the ROI analysis using analysis
of variance (ANOVA) followed by post hoc
Scheffé-tests (P<0.05), and for
the SPM analysis using peak z-values with P-values corrected
for multiple comparisons. SPM significance at cluster level is based on
simultaneous consideration of: (a) the peak effect size within a contiguous
volume with voxel z-values greater than 2.33; (b) the size of this
volume; (c) the smoothness of the data-set; and (d) the overall size of the
search volume. Only regions significant at both voxel and cluster level were
accepted. Data were analysed using an analysis of covariance (ANCOVA) design
with age as a confounding covariate. In order to exclude medication effects, a
subgroup analysis was performed, removing the CFS patients who were prescribed
psychotropic medications. As this did not alter the findings of statistical
significance, the result for the whole group is reported.
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RESULTS |
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Table 2 lists the peak differences in perfusion between the three diagnostic groups using SPM. Figure 1 illustrates perfusion differences between patient groups and healthy volunteers in a slice 40 mm above the orbitomeatal line. Uptake was greater, mainly in the right thalamus (as well as pallidum and putamen), both in subjects with CFS and those with depression, than in healthy controls. CFS patients also showed increased perfusion in the left thalamus. In comparison with the CFS group, in the patients with depression perfusion was decreased in the left prefrontal cortex. The remaining foci in Fig. 1 did not achieve statistical significance at the cluster (volume) level.
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The results of the ROI analysis are shown in Table 3. The pattern of results in the thalamus and putamen is similar to the patterns obtained with SPM, although the differences are non-significant, apart from in the left thalamus and right caudate and putamen in unmedicated CFS patients. The significant ROI differences in caudate nuclei could be due to the cortical rim fitting of the template, which can result in partial volume effects between central structures and ventricular cerebrospinal fluid.
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DISCUSSION |
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Limitations
The main limitation of the present study is that our CFS subjects had high
levels of depression: almost half were on psychotropic medication and five had
a previous history of depression. This reflects the rarity of CFS without
comorbid psychiatric disturbance, and is only evident because we characterised
our subjects so carefully. Our rigorous screening and inclusion of self-help
group members may, of course, mean that our CFS subjects are not
representative of people with CFS in clinics and in the community. Almost all
our depressed subjects were medicated, and psychotropic medication may well
alter cerebral perfusion, although the findings in our CFS subjects do not
appear to be explained by medication effects. It should also be noted that our
controls were recruited as staff or friends and may not therefore be
representative of the normal population.
Methodological issues
This is the first study to report SPM analysis of the pattern of cerebral
perfusion in patients with CFS compared with well-matched groups of depressed
and normal controls. SPM was originally used in positron emission tomography
(PET) and has only recently been applied to SPECT data. As the previous SPECT
studies in this area have used ROI analysis, we report both ROI results and
the SPM analysis for comparison and validation. The trends shown in the ROI
analysis were generally in agreement with the SPM results. ROI analysis is
potentially prone to human error, as the technique requires the fitting by an
operator of a standard template to each individual brain. Only 20% of the
volume available from the scan was utilised in the ROI analysis. SPM analysis,
in contrast, uses an objective approach to analysis, with information from the
whole brain, allowing for the detection of smaller effects. In particular,
small structures such as the head of the caudate may be missed or captured
incompletely by an ROI method that fits the whole slice template to the outer
brain boundary. The central grey nuclei are particularly prone to such errors,
because they lie adjacent to the lateral ventricles. Ventricular dilatation
may thus appear to reduce basal ganglia perfusion, due to partial volume
effects. Specifically, the reduction of perfusion in caudate ROIs in
depression may be due to ventricular dilatation, while the absence of such a
reduction in caudate perfusion in the more reliable SPM analysis probably
reflects the absence of real tissue perfusion changes. The veracity of this
interpretation can, of course, only be tested by parallel structural and
functional imaging.
Implications
The relatively strong and statistically significant association of
increased perfusion in the right thalamus in the subjects with CFS and
depression is consistent with the clinical and biological overlap between the
two disorders. Both conditions are associated with low mood and inactivity,
but these are unlikely to result in increased thalamic perfusion. The
similarities in disturbances of motor function
(Lawrie et al, 2000)
and effort perception (Lawrie et
al, 1997) in CFS and depression are more likely explanations.
The thalamus is generally regarded as a sensory relay station for afferent
connections with the cortex. However, recent work with primates and in
vivo imaging in humans increasingly suggests its involvement with motor
function and planning in a system that links cerebellum and prefrontal cortex
(Percheron et al,
1996). Thalamic output on the cerebral cortex is modulated in
response to levels of sleep and wakefulness
(Steriade & Contreras,
1995), and recent work has demonstrated its relevance to general
attention and vigilance (Kinomura et
al, 1996; Roland,
1996) and to the discrimination of painful stimuli
(Lenz et al, 1995).
Some authors have proposed a dynamic role for the thalamus in modulating
information transmission to the cortex
(Sherman & Guillery,
1996). Others have suggested a crucial role for the thalamus in
the modulation of motor and cognitive coordination
(Roland, 1996). Importantly
for CFS, the lateral ventral nucleus of the thalamus receives input from
muscle afferents and the cerebellum that provide critical information about
motor state. There is an intriguing overlap between these sensorimotor
functions and the core symptoms reported in CFS. Thalamic overactivity in CFS
(and depression) may, therefore, reflect increased attention to motor and
cognitive tasks, with previously automatic tasks requiring higher levels of
vigilance and thereby becoming effortful. Many similar disturbances and
symptoms are evident in depression, but we found that prefrontal perfusion
distinguishes the disorders. This is in keeping with our findings, in the same
group of patients, that patients with depression have similar motor but more
profound cognitive deficits than patients with CFS
(Lawrie et al, 2000). These important similarities and differences in the patterns of cerebral
perfusion between patients with depression and those with CFS may, therefore,
be associated with their similar but different clinical presentations.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Chalder, T., Berelowitz, G., Pawlikowska, T., et al (1993) Development of a fatigue scale. Journal of Psychosomatic Research, 37, 147-153.[CrossRef][Medline]
Costa, D.C., Tannock, C. & Brostoff, J. (1995) Brainstem perfusion is impaired in chronic fatigue syndrome. Quarterly Journal of Medicine, 88, 767-773.[Abstract]
Ebmeier, K. P., Dougall, N.J., Austin, M.-P., et al (1991) The split-dose technique for the study of psychological and pharmacological activation with the cerebral blood flow marker exametazime and single photon emission computed tomography (SPECT): reproducibility and rater reliability. International Journal of Methods in Psychiatric Research, 1, 27-38.
Ebmeier, K. P., Steele, J. D., MacKenzie, D. M., et al (1995) Cognitive brain potentials and regional cerebral blood flow equivalents during two- and three-sound auditory "oddball tasks". Electroencephalography & Clinical Neurophysiology, 95, 434-443.[CrossRef][Medline]
Ebmeier, K. P., Cavanagh, J. T. O., Moffoot, A. P. R., et al (1997) Cerebral perfusion correlates of depressed mood. British Journal of Psychiatry, 170, 77-81.[Abstract]
Endicott, J. & Spitzer, R. L. (1978) A diagnostic interview the schedule for affective disorders and schizophrenia. Archives of General Psychiatry, 35, 837-844.[Abstract]
Fischler, B., D'Haenen, H., Cluydts, R., et al (1996) Comparison of 99mTc HMPAO SPECT scan between chronic fatigue syndrome, major depression and healthy controls: an exploratory study of clinical correlates of regional cerebral blood flow. Neuropsychobiology, 34, 175-183.[Medline]
Friston, K. J., Holmes, A. P., Worsley, K. J., et al (1995) Statistical parametric maps in functional imaging: a general linear approach. Human Brain Mapping, 2, 189-210.
Fukuda, K., Straus, S., Hickie, I., et al
(1994) The chronic fatigue syndrome: approach to its
definition and study. Annals of Internal Medicine,
121,
953-959.
Goldstein, J. A., Mena, I., Jouanne, E., et al (1995) The assessment of vascular abnormalities in late life chronic fatigue syndrome by brain SPECT: comparison with late life major depressive disorder. Journal of Chronic Fatigue Syndrome, 1, 55-79.
Goodwin, G. M. (1997) Neuropsychological and neuroimaging evidence for the involvement of the frontal lobes in depression. Journal of Psychopharmacology, 11, 115-122.[Medline]
Hamilton, M. (1960) Rating Scale for Depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-62.[Medline]
Ichise, M., Salit, I. E., Abbey, S. E., et al (1992) Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nuclear Medicine Communications, 13, 767-772.[Medline]
Kendell, R. E. (1991) Chronic fatigue, viruses, and depression. Lancet, 337, 160-162.[Medline]
Kinomura, S., Larsson, J., Gulyás, B., et al (1996) Activation by attention of the human reticular formation and thalamic intralaminar nuclei. Science, 271, 512-515.[Abstract]
Lawrie, S. M., MacHale, S. M., Power, M. J., et al (1997) Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort? Psychological Medicine, 27, 959-999.
Lawrie, S. M., MacHale, S. M., Cavanagh, J. T. O., et al (2000) The difference in patterns of motor and cognitive function in chronic fatigue syndrome and severe depressive illness. Psychological Medicine (in press).
Lenz, F. A., Gracely, R. H., Romanoski, A. J., et al (1995) Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain. Nature Medicine, 1, 910-913.[Medline]
Nelson, H. E. (1982) National Adult Reading Test for the Assessment of Premorbid Intelligence in Patients with Dementia: Test Manual. Windsor: NFERNelson.
Percheron, G., Francois, C., Talbi, B., et al (1996) The primate motor thalamus. Brain Research Reviews, 22, 93-181.[Medline]
Peterson, P. K., Sirr, S. A., Grammith, F. C., et al (1994) Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. Clinical and Diagnostic Laboratory Immunology, 1, 222-226.[Abstract]
Roland, P. E. (1996) The system for regulating general attention in the human brain. Molecular Psychiatry, 1, 303-304.[Medline]
Schwartz, R. B., Komaroff, A. L., Garada, B. M., et al (1994) SPECT imaging of the brain: Comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. American Journal of Roentgenology, 162, 943-951.[Abstract]
Sherman, S. M. & Guillery, R. W. (1996)
Functional organization of thalamocortical relays. Journal of
Neurophysiology, 76,
1367-1395.
Steriade, M. & Contreras, D. (1995) Relations between cortical and thalamic cellular events during transition from sleep patterns to paroxysmal activity. Journal of Neuroscience, 15, 623-642.[Abstract]
Szikla, G., Bouvier, G., Hori, T., et al (1977) Angiography of the Human Brain Cortex. New York: Springer.
Talairach, J., Zilkha, G., Tournoux, P., et al (1988) Atlas d'Anatomie stéréotactique du Télencéphale. Paris: Masson.
von Zerssen, D., Strian, F. & Schwarz, D. (1974) Evaluation of depressive states, especially in longitudinal studies. In Psychological Measurements in Psychopharmacology (ed. P. Pichot). Paris: Karger.
Zigmond, A. S. & Snaith, R. P. (1983) The Hospital Anxiety and Depression Scale. Acta Psychiatrica Scandinavica, 67, 361-370.[Medline]
Received for publication July 5, 1999. Revision received November 4, 1999. Accepted for publication November 10, 1999.