Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression

Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, 610041, PR China.
Journal of Affective Disorders (Impact Factor: 3.38). 03/2009; 117(3):157-61. DOI: 10.1016/j.jad.2009.01.003
Source: PubMed
Studies on treatment resistant depression (TRD) using advanced magnetic resonance imaging techniques are very limited.
A group of 15 patients with clinically defined TRD and 15 matched healthy controls underwent magnetization transfer imaging (MTI) and T1-weighted (T1W) imaging. MTI data were processed and analyzed voxel-wised in SPM2. A voxel based morphometric (VBM) analysis was performed using T1W images.
Reduced magnetization transfer ratio was observed in the TRD group relative to normal controls in the anterior cingulate, insula, caudate tail and amygdala-parahippocampal areas. All these regions were identified within the right hemisphere. VBM revealed no morphological abnormalities in the TRD group compared to the control group. Negative correlations were found between MRI and clinical measures in the inferior temporal gyrus.
The cross-sectional design and small sample size.
The findings suggest that MTI is capable of identifying subtle brain abnormalities which underlie TRD and in general more sensitive than morphological measures.


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Research report
Magnetization transfer imaging reveals the brain decit in patients with
treatment-refractory depression
Ti-Jiang Zhang
, Qi-Zhu Wu
, Xiao-Qi Huang
, Xue-Li Sun
, Ke Zou
, Su Lui
, Fei Liu
Jun-Mei Hu
, Wei-Hong Kuang
, Dong-Ming Li
, Fei Li
, Hua-Fu Chen
, Raymond C.K. Chan
Andrea Mechelli
, Qi-Yong Gong
Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, PR China
Afliated Hospital of Zunyi Medical College, Guizhou, PR China
Department of Psychiatry, West China Hospital of Sichuan University, Chengdu, PR China
School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, PR China
Department of Forensic Psychiatry, School of Primary Medicine and Forensic Medicine, Sichuan University, Chengdu, PR China
Neuropsychology and Applied Cognitive Neuroscience Laboratory & Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences,
Beijing, PR China
Section of Neuroimaging, Division of Psychological Medicine, Institute of Psychiatry, King's College London, UK
Division of Medical Imaging, Faculty of Medicine, University of Liverpool, UK
article info abstract
Article history:
Received 25 November 2008
Received in revised form 4 January 2009
Accepted 5 January 2009
Available online 10 February 2009
Background: Studies on treatment resistant depression (TRD) using advanced magnetic
resonance imaging techniques are very limited.
Methods: A group of 15 patients with clinically dened TRD and 15 matched healthy controls
underwent magnetization transfer imaging (MTI) and T1-weighted (T1W) imaging. MTI data
were processed and analyzed voxel-wised in SPM2. A voxel based morphometric (VBM)
analysis was performed using T1W images.
Results: Reduced magnetization transfer ratio was observed in the TRD group relative to normal
controls in the anterior cingulate, insula, caudate tail and amygdala-parahippocampal areas. All
these regions were identied within the right hemisphere. VBM revealed no morphological
abnormalities in the TRD group compared to the control group. Negative correlations were
found between MRI and clinical measures in the inferior temporal gyrus.
Limitations: The cross-sectional design and small sample size.
Conclusions: The ndings suggest that MTI is capable of identifying subtle brain abnormalities
which underlie TRD and in general more sensitive than morphological measures.
© 2009 Elsevier B.V. All rights reserved.
Treatment resistant/refractory depression
Magnetization transfer imaging
Magnetization transfer ratio
Limbic system
Striatal nucleus
1. Introduction
Despite the progress made over the years in the develop-
ment of treatments for depressive disorders, treatment
refractory depression (TRD) remains a common condition
which accounts for approximately 1530% of the depressed
population and results in signicant social costs (Petersen
et al., 2001). Recent advances in imaging techniques make it
feasible to explore the structural and functional abnormalities
associated with TRD; this in turn may lead to a greater
understanding of the neuropathology of this condition and
facilitate the development of effective treatments (Fagiolini
and Kupfer, 2003).
A number of structural MRI studies have been performed
on TRD patients and identied structural or anatomical
abnormalities in the so-called LCSPT tract (limbiccortical
Journal of Affective Disorders 117 (2009) 157161
Corresponding author. Huaxi MR Research Center (HMRRC), Department
of Radiology, West China Hospital. Guo Xuexiang 37#, Chengdu, 610041, PR
China. Tel: +86 28 81812593, fax: +86 28 85423503.
E-mail address: (Q.-Y. Gong).
Drs. Ti-Jiang Zhang and Qi-Zhu Wu contributed to the work equally.
0165-0327/$ see front matter © 2009 Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
Journal of Affective Disorders
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striatalpallidalthalamic; Nauta, 1972). Specically, treat-
ment resistance has been associated with hyperintensity in
subcortical gray matter (Steffens et al., 2001) and white
matter (Hickie et al., 1995), and with atrophy in the right
frontostriatal structures ( Shah et al., 2002), the frontal lobe
(Coffey et al., 1993) and the temporal lobe (Shah et al., 1998).
The hippocampus has also been frequently implicated in TRD
(Axelson et al., 1993; Baldwin and Simpson, 1997; Fagiolini
and Kupfer, 2003; Mervaala et al., 2000; Simpson et al., 1998).
In addition to conventional structural MRI, other MRI
techn iques, such as the magne tization transfer imaging
(MTI), have been applied to the investigation of depressive
disorders in recent years (Gunning-Dixon et al., 2008; Kumar
et al., 2004; Wyckoff et al., 2003). MTI is sensitive to subtle
neuropathological alterations in which the macromolecular
concentration changes, thus it also provides complementary
disease information to conventional MRI (Filippi and Agosta,
20 07; Henkelman et al., 2001).
Currently, there have been very few MTI studies of human
depressive disorders. The only three aforementioned studies
have all foc used on geriatric depression and observed
consistently reduced magnetization transfer ratio (MTR) in
specic cerebral regions (Gunning-Dixon et al., 2008; Kumar
et al., 2004; Wyckoff et al., 2003). To our best knowledge, no
MTI study targeting the TRD population has been reported to
date. Therefore, in the present study we examined a group of
adult patients with TRD using the MTI technique. Our aim was
to validate the effectiveness of MTI in characterizing neuro-
biological abnormalities in TRD. We hypothesized that MTI
would be able to detect subtle abnormalities within the LCSPT
tract in the brain of patients with TRD relative to matched
2. Materials and methods
2.1. Subjects
Fifteen depressed patients and 15 healthy controls took
part in the whole study. Demographic data are p resented in
Table 1. Depressed subjects were originally recruited for a
clinical trail from the Mental Health Center of our university
afliated hospital. Major depression was diagnosed by two
qualied psychiatrists using the Structured C linical Inter-
view according to the DSM-IV criter ia (American Psychiatric
Association, 1994) and th e Research Diagnostic Criteria for
major depressive disorder. Exclusion criteria included
bipolar disorder, any history of major illness, previous
psychiatric therapy before being included in the study,
cardiovascular disease, and younger than 18 years or older
than 60 years. The severity of depression was assessed using
the 17-item Hamilton Rating Scale for Depression (HRSD;
Hamilton, 1967) and to be elig ible for t he study, only
patients who scored 18 or greater were included. All p atients
were taking antidepressant drugs at the time of the MRI sc an
and treatment resistance was dened as non-responsiveness
to at least two adequate trails (in terms of dosage, duration
(6 weeks for each trail), and compliance) of different clas ses
of antidepressants in consistence with previous studies
(Furtado et al., 2008; Shah et al., 20 02). The non-respon-
siveness was dened as a less than 50% reduction in HRSD
score (Nierenberg and Amsterdam, 1990) after a trea tment
at a minimum dose of 150 mg/day of imipramine equiva-
len ts (dose converted using a conversion table; Iidaka et al.,
1997) for 6 weeks. Healthy controls had no history of
neuropsychiatric illness or brain injury and were individu-
ally ma tched with the patients for age, sex, handedness and
years of educa tion. The s tudy was approved by the local
ethical committee, and written informed consent was
obtained from a ll participants.
2.2. MRI acquisition
MR scanning was carried out on a 3.0T MR scanner (EXCITE,
GE Signa, Milwaukee, USA). Whole brain MT images were
acquired using a 3-dimensional fast low angle shot sequence.
One acquisition was performed with, and another without, the
magnetization saturation pulse at 1.5 kHz off-resonance, thus
generating MT-weighted and non-MT-weighted images sepa-
rately. Other sequence parameters were: TR/TE =37/5 ms; ip
angle (FA)=15°; 50 contiguous axial slices with slice
thickness= 3 mm; Field of View (FOV)= 24×24 cm
matrix=320×192. After MTI, high resolution 3-dimensional
T1-weighted (T1W) images were acquired employing a spoiled
gradient recalled (SPGR) sequence with TR/TE=8.5/3.4 ms,
FA = 12
, 156 axial slices with thickness=1 mm, axial FOV
24 × 24 cm
and data matrix=256× 256.
2.3. Image processing and analysis
MR images from all the subjects were rst reviewed to
ensure that there were no structural abnormalities or quality
aws. Then data processing and analysis were carried out
using the statistical parametric mapping software SPM2,
(Wellcome Department of Imaging Neuroscience, London).
For each subject, the MT-weighted and non-MT-weighted
images were rst co-registered using a mutual information
registration algorithm. MTR was then calculated on a voxel-
by-voxel basis as follows:
× 100;
where M
and M
are the signal intensities without and with
the saturation pulse applied. Because the non-MT images are
partially T1-weighted, we directly normalized them to the MNI
T1W template; and then the transformation parameters were
used to normalize the co-registered MTR map. The normalized
non-MT images were skull-stripped using the brain extraction
tool (BET,, and then used
as masks to remove the non-brain tissues on the normalized
MTR maps. Finally, MTR maps were smoothed with a Gaussian
Table 1
Demographic information and disease severity for treatment refractory
depression (TRD) and control subjects.
Demographic data TRD patients (n= 15) Control subjects (n =15)
10/5 10/5
Age (years) 33.5 10.2), range 1851 33.4 10.2), range 1852
HRSD score 21.1 2.4), range 1826
Illness duration
10.3 4.8), range 220
158 T.-J. Zhang et al. / Journal of Affective Disorders 117 (2009) 157161
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kernel of 6-mm full-width half-maximum. After these pre-
processing steps, group comparison of MTR maps was
performed using the AnCova (analysis of covariates) and the
age was used as the nuisance covariate. Then the individual
MTR from the AnCova-derived signicant clusters were entered
into SPSS (SPSS Inc.) for a two-way ANOVA with gender and
depression/healthy as two xed factors. Correlation analysis
was made between patients' MTR maps and clinical measures,
including the HRSD score and illness duration.
To identify whether subtle morphological abnormalities
could be detected in the TRD patients, T1W SPGR images were
used to conduct an optimized voxel-based morphometry
(VBM) analysis (Good et al., 2001) in SPM2. AnCova was
performed to compare group differences in terms of the
volumes and concentrations of the gray and white matter
with the age and intracranial volume as nuisance covariates,
separately. We also performed a voxel-based correlative
analysis between gray matter volume (GMV) and HRSD
score and illness duration.
3. Results
The TRD group and normal controls were well-matched
for gender, age and handedness (Table 1). When we set the
statistical thresh old at voxel level p b 0.01 (uncorrected) and
a cluster extent (κ) of 150 voxels, the group analysis
revealed four clusters with reduced MTR (Fig. 1a, Table 2),
Fig. 1. Panel (a) shows the axial view of the four brain regions with lower MTR in TRD group superimposed on a T1W template. These regions include the ACC, the
parahippocampal gyrus and amygdala, the insula and the tail of the caudate nucleus. The color bar signies the T value of the group analysis. The right panels show
signicant correlations between MTR and HRSD score (b1), between MTR and duration of illness (b2), and between gray matter volume and HRSD score (b3). All
the correlations are negative. The statistical threshold for all correlation analyses was set at cluster level p b 0.005, uncorrected; κ N 100. The superimposed color
indicates the strength of the correlation.
Table 2
Clusters present MTR reductions in TRD group compared with healthy
(Brodmann area)
Cluster-level Voxel-level Talairach
of peak voxels
Cingulate gyrus, (32) 284 0.030 4.74 b 0.001 0 23 29
Anterior cingulate,
4.10 b 0.001 0 30 16
R anterior cingulate,
2.83 0.004 3 32 3
R parahippocampal
gyrus, (34)
215 0.055 4.01 b 0.001 21 1 15
R uncus, (28) 3.94 b 0.001 28 3 20
R insula, (13) 167 0.087 3.49 0.001 43 12 2
R transverse temporal
gyrus, (41)
3.45 0.001 46 20 13
R caudate tail 296 0.028 3.48 0.001 25 32 21
R caudate tail 3.44 0.001 30 39 13
R caudate body 3.29 0.001 19 18 23
159T.-J. Zhang et al. / Journal of Affective Disorders 117 (2009) 157161
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including (1) the anterior cingulate cortex (ACC) and,
adjacent, a small part of the corpus callosum; (2) th e right
amygdala, the right uncus and an adjacent portion of the
para hippocampal gyrus; (3) th e right posterior insula and
connecting transverse temporal gyrus; and (4) the right
cau date tail and adjacent subgyral white matter. At voxel
level, the signicance was not preserved after multiple
comparison correction (p b 0.05,FWEorFDR).Atthecluster
level, clusters ( 1) and (4) reached the signicance level of
pb 0.05, uncorrected, but clusters (2) and (3) did not. In
AnCova, when age was allowed to take effect as covariate,
only the identied cluster sizes were slightly cha nged but
the coord inates of peak voxels and sign icance level were
not affected . The 2-way ANOVA revealed no signicant
gender or interaction effects in all four clusters. No marked
regional MTR increase in the TRD group compared to the
controls was found. Correlative analysis showed that MTR
was negatively c orrelated with HRSD in the bilateral inf erior
temporal gyrus (Fig. 1b-1), and n egatively correlated with
illness duration in white ma tter areas of the left fron tal lobe
(Fig. 1b-2).
VBM analysis revealed no signicant difference between
groups no matter with or without the age and intracranial as
covariates. A negative correlation between GMV and HRSD
score was found in the right medial inferior temporal gyrus
(Fig. 1b-3).
4. Discussion
To our knowledge, this is the rst MTI study to examine
TRD using voxel-based analysis. We found MTR to be lower in
the TRD group relative to healthy controls in several right-
sided limbic and striatal regions. These results are consistent
wi th our hypothesis that MTI is able to detect subtle
abnormalities in the LCSPT tract in TRD brain.
MTI is frequently used in studies of white matter because
MTR changes are thought to reect dys/demyelination or axon
loss (Henkelman et al., 2001; Wozniak and Lim, 2006).
Recently, however, MTR reductions in gray matter have been
consistently reported in MS (Filippi and Agosta, 2007)anda
number of psychiatric disorders (Kabani et al., 2002; Kumar
et al., 2004). The present study further demonstrates the
sensitivity of MTI in revealing gray matter MTR reductions in
young and middle-aged TRD patients. Previous MTI investiga-
tions into human depressive disorders have focused on geriatric
depression (Kumar et al., 2004; Gunning-Dixon et al., 2008;
Wyckoff et al., 2003) but our results are not directly comparable
due to differences in data analysis.
Using optimized VBM, we did not detect any morpholo-
gical changes in TRD, although a negative correlation was
found between GMV and HRSD score in the right inferior
temporal region. In contrast, a recent VBM study found
regional gray matter reductions in patients with major
depression com pared to normal controls (Vasic et al.,
20 08). This inconsistency may be due to the focus of the
present investigation on patients with TRD or the use of a
small sample size; the correlation between GMV and HRSD
however indicates that VBM could potentially be sensitive to
gray matter decits in the TRD group if larger sample size
was employed in future studies. Taken collectively, our
ndings indicate the sensitivity of MTI in detecting altera-
tions in patients' brain with TRD without apparent morpho-
logical abnormalities.
ACC is thought to play an important role in cognitive
processing and mood regulation as it is anatomically linked
with both dorsal neocortical and ventral paralimbic regions
(Mayberg et al., 1997). Consistent with our nding of
decreased MTR in the ACC, previous studies of TRD have
revealed hypermetabolism using PET (Mayberg et al., 1997)
and a change in tissue composition using VBM-MRI (Shah
et al., 2002) in this region. The observation of decreased MTR
in the amygdala-parahippocampal area is also consistent with
previous reports of hippocampal abnormalities (Mervaala
et al., 2000; Shah et al., 2002). Negative correlations have also
been reported between the chronicity of depressive illness
and amygdalahippocampus volume (Axelson et al., 1993). A
SPECT study observed increased cerebral blood ow in the
hippocampusamygdala area in medication-free TRD patients
(Hornig et al., 1997). More recently, a study compared female
TRD patients to healthy controls and found a volume
reduction in the e ntorh inal cortex which has intimate
anatomical and functional connections with the parahippo-
campal gyrus (Furtado et al., 2008). In contrast, the altera-
tions in the insula and the caudate tail have not been reported
by previous studies of TRD, although the insular cortex and
caudate have been found to be abnormal in major depression
(Drevets, 2000). However, because of the lack of a control
group of patients with major depression who were responsive
to medication, we were unable to assess whether the
observed pattern of abnormalities is specic to TRD or is a
common feature of major depression. This limitation of our
study should be taken into account when interpreting the
Generally, studies of TRD using different imaging mod-
alities have yielded inconsistent results. For example, two
independent investigations identied the amygdala-hippo-
campal area ( Hornig et al., 1997) and the rostral ACC (Mayberg
et al., 1997) respectively as the unique anatomical site to
differentiate TRD patients from depressed patients without
TRD. Here we observed MTR reductions in limbic structures
and striatal nucleus, which have been reported by some but
not all previous studies of TRD. The inconsistency can be
explained by different patient recruitment criteria and the use
of different imaging methodologies and analytical techniques.
Of note is that all the brain regions we identied with reduced
MTR are in the right hemisphere, whereas previous TRD
studies reported bilateral differences (Kumar et al., 2004;
Mayberg et al., 1997; Shah et al., 2002). We speculate that the
laterality of our ndings may result from limited statistical
power due to the small sample size rather than the lateraliza-
tion of TRD neuropathology.
In summary, although preliminary, the present investiga-
tion supports the feasibility and capability of MTI in detecting
subtle pathological abnormalities in normal appearing brain
tissues in TRD brain, and provides additional evidence for the
implication of the LCSPT circuit in TRD. Future studies should
adopt a longitudinal design with a larger sample size and a
control group of patients with major depression who are
responsive to medication, in order to better characterize the
neurobiological mechanisms of treatment resistance, and
then to help the development of effective therapeutic
interventions targeting TRD patients.
160 T.-J. Zhang et al. / Journal of Affective Disorders 117 (2009) 157161
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Role of funding source
The funders of this work had no role in the data collection, analysis and
interpretation and writing the manuscript.
Conict of interest
No conict of interest declared.
This study was supported by National Natural Science
Foundation of China (Grant Nos. 30625024 and 30728017),
Programs from the State Education Ministry (Grant Nos.
NCET-0 4-0866; SRFDP-20060 610 073), National Basic
Research Program (Program No: 2007CB512305/2), Key
Technology R&D Program (Grant No. 2004BA720A21-01)
and National High Technology Program of China (Program
No: 2008AA02Z408).
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    • "Some years later, the same authors did another data analysis and noted enlarged cerebroventricles and reduced gray matter in several regions of the left and right hemisphere in TRD subjects compared to the other two groups combined (Shah et al., 2002). Zhang et al. (2009) also examined brain structure in subjects who were already known to suffer from TRD. Using magnetization transfer imaging, they noted differences between TRD subjects and healthy individuals in several regions in the right hemisphere. "
    [Show abstract] [Hide abstract] ABSTRACT: The search for potential biomarkers of psychiatric disorders is a central topic in biological psychiatry. This review concerns published studies on potential biomarkers of treatment-resistant depression (TRD). The search for biomarkers of TRD in the bloodstream has focused on cytokines and steroids as well as brain-derived neurotropic factor. Additional approaches to identifying biomarkers of TRD have dealt with cerebrospinal fluid analysis, magnetic resonance imaging, and positron emission tomography. Some studies have also investigated potential genetic and epigenetic factors in TRD. Most studies have, however, used a post hoc experimental design that failed to determine the association between biomarkers and the initial risk of TRD. Particular attention in future studies should be on shifting the experimental paradigm toward procedures that can determine the risk for developing treatment resistance in untreated depressed individuals.
    Full-text · Article · Jun 2013 · Frontiers in Psychiatry
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    • "Major depression is a common condition and a leading cause of disability worldwide [1]. Approximately 5% of American adults are affected by depression each year, 30% of whom fail to respond to two or more types of antidepressant, a phenomenon termed treatment-resistant depression (TRD) [2-7]. The pathogenesis of major depressive disorder (MDD) and the pathogenic mechanism of TRD remain unclear. "
    [Show abstract] [Hide abstract] ABSTRACT: Background White matter abnormalities can cause network dysfunction that underlies major depressive disorder (MDD). Diffusion tensor imaging (DTI) is used to examine the neural connectivity and integrity of the white matter. Previous studies have implicated frontolimbic neural networks in the pathophysiology of MDD. Approximately 30% of MDD patients demonstrate treatment-resistant depression (TRD). However, the neurobiology of TRD remains unclear. Methods We used a voxel-based analysis method to analyze DTI data in young patients with TRD (n = 30; 19 males, 11 females) compared with right-handed, age- and sex-matched healthy volunteers (n = 25; 14 males, 11 females). Results We found a significant decrease in fractional anisotropy (FA) (corrected, cluster size >50) in the left middle frontal gyrus (peak coordinates [−18 46–14]), left limbic lobe uncus (peak coordinates [−18 2–22]), and right cerebellum posterior lobe (peak coordinates [26–34 -40]). There was no increase in FA in any brain region in patients. We also found a significant negative correlation between mean regional FA values in the three areas and Beck Depression Inventory symptom scores. Conclusions We found significant differences in white matter FA in the frontal lobe, limbic lobe and cerebellum between TRD patients and controls. These data suggest that abnormalities of cortical-limbic-cerebellar white matter networks may contribute to TRD in young patients.
    Full-text · Article · Mar 2013 · BMC Psychiatry
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    • "Shan et al. have identified gray matter density or volume reductions in ACC, frontal, temporal, and parahippocampal areas [Shah et al., 2002]. In our previous study of TRD using magnetization transfer imaging [Zhang et al., 2009], reduced magnetization transfer ratio, indicative of abnormalities of brain tissue composition, was observed in the ACC, insular and parahippocampal areas. Other attempts to find metabolic or functional alterations in TRD have revealed increased blood flow in hippocampus-amygdala in TRD compared to both NDD and healthy controls [Hornig et al., 1997], and hypometabolism in cingulate, insula, frontal, and temporal areas in TRD, in association with different components of the severity and course of illness [Kimbrell et al., 2002]. "
    [Show abstract] [Hide abstract] ABSTRACT: Treatment-refractory depression (TRD) represents a large proportion of the depressive population, yet has seldom been investigated using advanced imaging techniques. To characterize brain dysfunction in TRD, we performed resting-state functional MRI (rs-fMRI) on 22 TRD patients, along with 26 matched healthy subjects and 22 patients who were depressed but not treatment-refractory (NDD) as comparison groups. Results were analyzed using a data-driven approach known as Regional Homogeneity (ReHo) analysis which measures the synchronization of spontaneous fMRI signal oscillations within spatially neighboring voxels. Relative to healthy controls, both depressed groups showed high ReHo primarily within temporo-limbic structures, and more widespread low ReHo in frontal, parietal, posterior fusiform cortices, and caudate. TRD patients showed more cerebral regions with altered ReHo than did NDD. Moderate but significant correlations between the altered regional ReHo and measures of clinical severity were observed in some identified clusters. These findings shed light on the pathophysiological mechanisms underlying TRD and demonstrate the feasibility of using ReHo as a research and clinical tool to monitor persistent cerebral dysfunction in depression, although further work is necessary to compare different measures of brain function to elucidate the neural substrates of these ReHo abnormalities.
    Full-text · Article · Aug 2011 · Human Brain Mapping
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