Department of Psychiatry, University of Edinburgh, UK
Unit on Integrative Neuroimaging, Clinical Brain Disorders Branch, National Institute of Mental Health, Bethesda, Maryland, USA
University Department of Psychiatry, Warneford Hospital, Oxford
Department of Psychiatry, University of Edinburgh, UK
Correspondence: Professor K. P. Ebmeier, Department of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Morningside Park, Edinburgh EH10 5HF, UK. Tel/Fax: 0131 5376505; e-mail: k.ebmeier{at}ed.ac.uk
Declaration of interest Support from the Royal College of Physicians (Edinburgh) and the Medical Research Council Brain Metabolism Unit.
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ABSTRACT |
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Method Magnetic resonance images of 20 patients with TRD were compared with images of 20 recovered patients and 20 healthy controls. Images were compared using a voxel-based analysis (VBA) method; the results were validated by conventional volumetric analysis. The clinical associations of magnetic resonance imaging (MRI) changes with illness duration and severity were examined by VBA.
Results Only the TRD group exhibited right fronto-striatal atrophy, and subtle MRI changes in the left hippocampus on VBA. Atrophy was confirmed on volumetric analysis, the degree correlating with the cumulative number of electroconvulsive therapy (ECT) treatments received, suggesting an acquired deficit.
Conclusions This is the first study to demonstrate fronto-striatal atrophy in patients with depression with poor outcome; the atrophy is more marked in those with more severe illness.
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INTRODUCTION |
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METHOD |
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In reality, all patients exceeded the minimum criteria for treatment resistance. Many were on multiple and/or combination treatments. All patients were on a stable medication regime for at least 2 weeks prior to the study. Patients had not received ECT for at least 3 months prior to the study and had no history of intracranial pathology or surgery.
Twenty recovered patients who previously fulfilled DSM-IV criteria for a major depressive disorder and 20 normal healthy volunteers with no lifetime history of psychiatric illness were also examined. Subjects from both of these groups were individually matched with patients with TRD for age, gender, premorbid IQ and years of education. Recovered patients were matched for age of onset and for onset of the index episode with the treatment-resistant group. The recovered group all had had severe illness episodes (details below). Recovery was defined as scoring 5 or less on the Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) for at least 3 months prior to the study, and subjects were either medication-free or on stable medication for at least 2 weeks prior to the study.
Clinical assessment
All subjects were interviewed using the lifetime version of the Schedule
for Affective Disorders and Schizophrenia (SADS-L;
Endicott & Spitzer, 1978).
All available psychiatric case notes were reviewed in detail, providing RDC
diagnoses and allowing lifetime histories of psychiatric illness and treatment
histories to be reconstructed. The total number of hospitalisations,
cumulative length of psychiatric hospitalisation and cumulative number of ECT
treatments were used as indices of cumulative illness severity. Estimated
total lifetime illness duration was derived from psychiatric case-note
histories. Healthy volunteers had no lifetime history of significant
psychiatric illness, established by the SADS-L interview schedule.
Exclusion criteria were previous manic episodes, other organic cerebral pathology, significant alcohol or substance misuse, head injury associated with significant loss of consciousness, or concurrent use of steroids.
All subjects had standardised neuropsychological and clinical testing within 1 day of each other and within 1 week of the MRI. Symptom severity was measured using the HRSD, the severity of psychomotor retardation was measured using the observer-rated Widlöcher Scale (Widlöcher, 1983) and cerebral dominance was measured with a handedness scale (Annett, 1970). Subjects also performed the revised National Adult Reading Test (Nelson & Willison, 1991), which estimated premorbid IQ.
Magnetic resonance image acquisition
Subjects were imaged within 1 week of clinical assessment. Images were
acquired on a 1.0 Tesla Siemens Magnetom SPE system, with subjects undergoing
a magnetisation-prepared rapid-acquisitiongraded echo (MPRAGE) sequence,
acquired perpendicular to a line connecting the anterior and posterior
commissure (AC-PC). This yielded high-resolution T1-weighted images with good
contrast between white and grey matter (repetition time=10 ms, delay time=500
ms, inversion time=200 ms, flip angle=12°, block size=240 mm, 128
contiguous slices with an effective slice thickness of 1.875 mm).
Voxel-based analysis
Image analysis was performed on a SPARC workstation (Sun Microsystems
Europe Inc., Surrey, UK) using ANALYZE software (version 7.5.5, 1995;
Biomedical Imaging Resource, Mayo Foundation, Rochester, Minnesota, USA), and
SPM'96 software for spatial normalisation and statistical parametric mapping
(Wellcome Functional Imaging Laboratory, Institute of Neurology, Queen Square,
London, UK), running in MATLAB (version 4.2c, 1994; The Mathworths Inc.,
Matick, Massachusetts, USA). The technique is fully described by Shah et
al (1998). An ANCOVA
model was applied, removing the global density of each tissue compartment for
each subject. Differences between groups were displayed as statistical
parametric maps (SPMs), with a 1% threshold probability. Statistical clusters
were also projected onto the T1-weighted grey matter density template to
facilitate interpretation of the results. Corrected probability values take
into account the volume examined, the smoothness of the data, the size of the
cluster with P < 0.01 and the peak effect (Z value).
Volumetric analysis
Images were analysed using ANALYZE (CNS Software) running on a Unix-based
Sun workstation (Sun Microsystems). Images initially were converted to 8-bit
images. The threshold voxel intensity between grey matter and cerebrospinal
fluid (CSF) was ascertained. Tissue below this threshold (surrounding CSF) and
exterior to this rim of CSF (skull, scalp and meninges) was excluded.
Meningeal tissue abutting on cerebral tissue was removed manually using an
anatomical atlas as a guide. Within ANALYZE, images were corrected for minor
degrees of tilt, roll and yaw. Partial volume effects at the exterior edge of
cerebral tissue were removed using a 1-bit image template multiplier,
re-orientated in an identical manner to the original image using
nearest-neighbour interpolation. Total cerebral volume thus remained unchanged
after re-orientation.
Landmarks used to delineate cerebral structures
The landmarks defined by Shenton et al
(1992) and Suddath et
al (1990) were used as a
guide to dissection. The criteria used are available from the authors upon
request. The hippocampus was divided into anterior and posterior portions,
using the mamillary bodies as a landmark. No attempt was made to measure
amygdala volume separately. Caudate and putamen were measured bilaterally, as
was prefrontal tissue, posterior frontal tissue and the temporal
lobes.
Segmentation of magnetic resonance images
Two investigators received training to identify landmarks accurately and to
segment images reliably into object maps. A third investigator then removed
identifying information from the magnetic resonance images. He randomly chose
half of the images from each subject group to be mirrored in the midsagittal
plane so that the left and right sides were exchanged. The two investigators
who segmented the magnetic resonance images were thus blind to left-right
orientation and the diagnostic group of the images. Each investigator
independently analysed the images from half of the total subjects. Five random
images were analysed independently by both investigators, allowing a
measurement of interrater reliability. One of the investigators performed a
repeat analysis of the same five images 2 months later, producing a measure of
intrarater reliability. Onetailed t-tests were used (SPSS for
Macintosh, version 4.0) because the direction of change was predicted, and no
correction for multiple comparison was used because there were specific
hypotheses about the regions expected to show volumetric reductions in
patients with TRD. Because the total cerebral tissue volume did not differ
between the three groups, controlling for total cerebral volume was not
required.
Group demographics and clinical data were compared using univariate
analysis of variance and post hoc independent t-tests to
identify specific group differences. Noncontinuous variables were compared
using the Mann-Whitney U and 2 tests, with
correlations made using Spearman nonparametric correlation as appropriate.
Data reduction was done with the appropriate programs of SPSS 10.0 for
Windows.
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RESULTS |
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All TRD patients were taking anti-depressant drugs. Additionally, twelve patients took regular neuroleptic medication, five took lithium and three took benzodiazepines. Eleven patients in the recovered group were medication-free. Nine of the recovered patients were prescribed antidepressants; one also received neuroleptics and one lithium.
Both the patients with TRD and the recovered patients had, or previously had, melancholic depressive episodes. The TRD group had endogenous symptoms as measured by the Newcastle Scale (Carney et al, 1965) and fulfilled the DSM-IV criteria for a depressive episode with melancholic features (American Psychiatric Association, 1994). The recovered patients also previously fulfilled DSM-IV criteria for having depressive episodes with melancholic features.
The TRD group had moderately severe depressive symptoms and psychomotor retardation. Although not clinically depressed, the recovered patients had significantly more depressive symptoms and more observable motor retardation than the controls.
Voxel-based analysis
The three-group comparison of increases and decreases in each of the three
tissue compartments yielded 18 SPMs. Only the TRD group had changes in all
three tissue compartments in comparison with the other two groups. Because the
areas of differences were virtually identical when comparing the TRD group
with controls and recovered patients, and because there was no significant
tissue difference between the recovered group and the controls, the TRD group
was compared against the pooled recovered and control groups.
Limbic and striatal changes in compartmental densities in TRD
The TRD group had reduced tissue density in the right putamen and a
corresponding increase in right lateral ventricular CSF overlying the right
striatum, not reaching statistical significance because of the small volumes
involved but complementing the volumetric analysis. In addition, a pattern of
reciprocal grey matter reductions with overlapping apparent white matter
increases was found in bilateral hippocampal and parahippocampal areas,
particularly anteriorly, and more markedly on the left
(Fig. 1), upon VBA but not
volumetric analysis. Reciprocal changes in grey and white matter, with no
increase in CSF, suggest that volumetric change in these areas will not be
detected easily.
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Cortical change (Fig.
1)
The TRD group had reduced grey matter density in the right superior frontal
gyrus, with large reductions in white matter density in the right medial and
superior frontal gyri. There were corresponding large CSF increases over the
right medial and superofrontal cortex (see
Table 2). These changes predict
right prefrontal atrophy in volumetric analysis. The large grey matter density
reductions in the left superior and medial temporal gyri did not have
associated CSF changes, suggesting that this change would not be detected by
volumetry. Finally, an unpredicted finding upon VBA was increased grey matter
density in the left cuneus, precuneus and lingual gyrus in the TRD group, with
a lesser increase in bilateral cerebellar grey density (see
Shah et al,
1998).
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Volumetric object mapping
The TRD patients had less right prefrontal lobe tissue than controls (65.18
cm3 v. 71.17 cm3, t=-2.34,
P=0.012, effect size=0.74) and less right caudate tissue than both
controls (3.51 v. 3.77 cm3, t=-1.7,
P=0.048, effect size=0.54) and recovered patients (3.51 v.
3.80 cm3, t=-1.77, P=0.04, effect size=0.56).
Interrater reliability of volumetric object mapping varied from 0.85 (right
anterior hippocampus) to 0.99 (posterior frontal tissue), and intrarater
reliability from 0.76 (left anterior hippocampus) to 0.98 (posterior frontal
tissue).
Correlation of grey matter density in TRD with selected clinical
variables
Severity of illness over time was thought to be represented best by the
total number of ECT treatments administered, the total duration of
hospitalisation and the total number of admissions. Data reduction with the
number of ECT treatments in both patient groups, duration of hospitalisation,
number of admissions and treatment resistance entered as (dummy) variables in
a principal-components analysis with subsequent varimax rotation, resulted in
two rotated factors: one represented the two patient groups and accounted for
35% of the overall variance and loading on duration of hospitalisation (0.86)
and treatment resistance (-0.83); and the other accounted for the majority of
the variance (53%) and loaded on number of ECT treatments (0.96) and number of
hospital admissions (0.98). Electroconvulsive therapy at the Royal Edinburgh
Hospital is usually reserved for severely depressed patients requiring
admission and for those unresponsive to conventional pharmacotherapy. Although
variability in its use between consultants cannot be neglected, the variations
observed within the hospital are probably less than those observed nationwide.
Nevertheless, the use of ECT as a measure of illness severity clearly has its
limitations. As the total number of ECT treatments, total duration of
hospitalisation and total number of admissions were highly inter-correlated,
we elected to use the total number of ECT treatments as the measure of
cumulative illness severity, aware that a significant association of ECT with
cortical tissue reductions may have alternative interpretations.
Increasing cumulative ECT correlated extensively with reduced bilateral superior frontal gyri, bilateral superior frontal and inferior parietal gyri, bilateral medial and superior temporal gyri and bilateral caudate grey matter density in the TRD group (Fig. 2) upon VBA. The reduced grey matter density correlations with ECT were unaffected, even after accounting for the current severity of depression (using the HRSD score as a covariate). Thus, neocortical and striatal grey matter reductions appeared to be proportional to the cumulative severity of depression. We repeated the group comparison of grey matter density between the TRD and recovered groups, controlling for age and the number of ECT treatments administered, and found that only reductions in grey density in the left hippocampus remained. Thus, reduced hippocampal grey matter density in TRD seemed to be unrelated to the cumulative severity (or cumulative ECT received) or duration of illness. Additionally, the estimated total duration of illness did not correlate with neocortical grey density reductions.
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DISCUSSION |
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Methods of analysis
Conventional volumetry has a number of limitations. It involves manual
segmentation of brain regions, reducing spatial precision and reliability. It
assumes functional and structural homogeneity and, because regions are
constrained by a priori hypotheses, only examines parts of the data
set (or image). Only volumetric aspects of the data are examined, making the
assumption that MRI reflects structure. Because T1-weighted images are
cross-sectional measurements of water distribution and chemistry, they are
influenced by tissue characteristics (e.g. fat content), regional metabolism
and blood flow. Thus, they may reflect both state-dependent and anatomical
differences.
In contrast, VBA detected a range of MRI changes. With atrophy, CSF replaces grey and white matter. Thus, atrophy is represented by reductions in grey and/or white matter together with a corresponding increase in CSF. If, however, water density decreased without cell loss, then the voxel signals may be brighter. In areas where grey and white matter are in close proximity, brighter voxels have a higher probability of being assigned to the white matter compartment instead of grey, producing reduced grey matter density but an overlapping apparent increased white matter density. Thus, the reciprocal grey and white matter changes seen in the anterior hippocampus, rostral anterior cingulate (Brodmann area 24) and posterior cingulate/precuneus are not likely to be frank atrophy but, rather, indicative of a change in tissue composition.
Fronto-striatal atrophy
Our findings of fronto-striatal atrophy are consistent with previous
studies (Husain et al,
1991; Coffey et al,
1993; Dupont et al,
1995). Reduced metabolism in the rostral anterior cingulate in
treatment non-responsive patients has also been shown
(Mayberg et al,
1997). However, findings of temporal lobe changes have been more
equivocal (Coffey et al,
1993).
At present, there is no clear hypothesis as to which neuronal systems are involved with the atrophy. However, a brain morphometric study (Rajkowska et al, 1999) of patients with major depression found cell atrophy in cortical layers of the rostral orbito-frontal cortex (Brodmann areas 10-47) associated with serotonergic neurons, and in layers associated with dopaminergic and glutaminergic neurons in dorso-lateral prefrontal cortex (Brodmann area 9), extensively connected with striatum. We also found right frontal atrophy in these Brodmann areas. Interestingly, in vivo studies have found reduced striatal dopamine release in depression, proportional to the severity of motor slowing (Ebert et al, 1994; Shah et al, 1997) and that the mood-activating properties of psychostimulants are particularly linked to dopamine (Swerdlow & Koob, 1987). The characteristics of possibly irreversible cognitive deficits in depression also support fronto-striatal involvement, raising the possibility of a fronto-striatal dementia (reviewed in Robbins et al, 1992). Thus, it could be speculated that treatment resistance in depression may be related to a loss of dopamine neurons or their function.
Fronto-striatal atrophy, however, is not diagnosis-specific; similar frontostriatal changes are found in schizophrenia, and may be related to the poverty syndrome characterised by poverty of affect, movement and initiation. At a speculative level, such atrophy may be the final common pathway for severe melancholia, also characterised by poverty of affect, movement and initiation, and for chronic schizophrenia.
Tissue changes in hippocampal and rostral anterior cingulate
Much attention has been paid to hippocampal changes in depression owing to
the notion that stress may produce cellular damage. We did not find volumetric
change, in contrast to other studies (e.g.
Sheline et al, 1999),
but rather evidence of change in tissue composition, which appeared to be
unrelated to illness severity (or to ECT). Our rostral anterior cingulate
changes (Brodmann area 24) also agree with Mayberg's
(1997) notion of specific
metabolic changes in this area in treatment-resistant patients. Our results
suggest that this may represent metabolic rather than structural change.
Limitations
Although it could be argued that the differences were the effects of ECT,
there is little current evidence that ECT can produce permanent hippocampal or
other structural brain changes (Devanand
et al, 1994). Because of this, and because the total
number of ECT treatments, total duration of in-patient stay and total number
of hospitalisations were closely inter-correlated, it seemed reasonable to
regard the total number of ECT treatments administered as being an index of
cumulative severity. However, the possibility that the findings are
ECT-related cannot be discounted. Similarly, all the patients with TRD were
medicated, as were about half of the recovered patients. It was not possible
to withdraw medication on these subjects.
Because the study is cross-sectional in design, it is not possible to distinguish between state-dependent, acquired and permanent changes, especially as apparent atrophy on MRI has been found to be partially reversible with illness resolution in conditions such as anorexia nervosa and alcohol dependence. Patients with depression often lose weight, which could produce a general effect. However, it is difficult to see how this would produce specific focal brain changes. The exact time course of these changes in relation to the illness needs to be determined. One possibility is that these brain differences are present prior to illness and confer vulnerability to treatment resistance. However, given that the TRD group had no clinical evidence of premorbid impairment and that the atrophy was more severe in those with the most severe illness, it is more likely that these differences were acquired.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication March 22, 2001. Revision received January 2, 2002. Accepted for publication January 14, 2002.
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