Reduced fractional anisotropy in the uncinate fasciculus in patients with major depression carrying the met-allele of the Val66Met brain-derived neurotrophic factor genotype

Department of Psychiatry, Institute of Neuroscience, University of Dublin, Trinity College Dublin, Dublin, Ireland.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 07/2012; 159B(5):537-48. DOI: 10.1002/ajmg.b.32060
Source: PubMed
ABSTRACT
Experimental studies support a neurotrophic hypothesis of major depressive disorder (MDD). The aim of this study was to determine the effect of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism on the white matter fiber tracts connecting hippocampus and amygdala with the prefrontal lobe in a sample of patients with MDD and healthy controls. Thirty-seven patients with MDD and 42 healthy volunteers were recruited. Diffusion tensor imaging (DTI) data with 61 diffusion directions were obtained with MRI 3 Tesla scanner. Deterministic tractography was applied with ExploreDTI and Val66Met BDNF SNP (rs6265) was genotyped. Fiber tracts connecting the hippocampus and amygdala with the prefrontal lobe, namely uncinate fasciculus (UF), fornix, and cingulum were analyzed. A significant interaction was found in the UF between BDNF alleles and diagnosis. Patients carrying the BDNF met-allele had smaller fractional anisotropy (FA) in the UF compared to those patients homozygous for val-allele and compared to healthy subjects carrying the met-allele. A significant three-way interaction was detected between region of the cingulum (dorsal, rostral, and parahippocampal regions), brain hemisphere and BDNF genotype. Larger FA was detectable in the left rostral cingulum for met-allele carriers when compared to val/val alelle carriers. We provide evidence for the importance of the neurotrophic involvement in limbic and prefrontal connections. The met-allele of the BDNF polymorphism seems to render subjects more vulnerable for dysfunctions associated with the UF, a tract known to be related to negative emotional-cognitive processing bias, declarative memory problems, and autonoetic self awareness.

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RESEARCH ARTICLE
Reduced Fractional Anisotropy in the Uncinate
Fasciculus in Patients With Major Depression Carrying
the Met-Allele of the Val66Met Brain-Derived
Neurotrophic Factor Genotype
A. Carballedo,
1
F. Amico,
1
I. Ugwu,
1
A.J. Fagan,
2
C. Fahey,
3
D. Morris,
3
J.F. Meaney,
2
A. Leemans,
4
and T. Frodl
1
*
1
Department of Psychiatry, Institute of Neuroscience, University of Dublin, Trinity College Dublin, Dublin, Ireland
2
Centre of Advanced Medical Imaging, St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
3
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, University of Dublin,
Trinity College Dublin , Dublin, Ireland
4
Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands
Manuscript Received: 12 January 2012; Manuscript Accepted: 18 April 2012
Experimental studies support a neurotrophic hypothesis of
major depressive disorder (MDD). The aim of this study was
to determine the effect of Val66Met brain-derived neurotrophic
factor (BDNF) polymorphism on the white matter fiber tracts
connecting hippocampus and amygdala with the prefrontal
lobe in a sample of patients with MDD and healthy controls.
Thirty-seven patients with MDD and 42 healthy volunteers were
recruited. Diffusion tensor imaging (DTI) data with 61 diffusion
directions were obtained with MRI 3 Tesla scanner. Determin-
istic tractography was applied with ExploreDTI and Val66Met
BDNF SNP (rs6265) was genotyped. Fiber tracts connecting the
hippocampus and amygdala with the prefrontal lobe, namely
uncinate fasciculus (UF), fornix, and cingulum were analyzed. A
significant interaction was found in the UF between BDNF alleles
and diagnosis. Patients carrying the BDNF met-allele had smaller
fractional anisotropy (FA) in the UF compared to those patients
homozygous for val-allele and compared to healthy subjects
carrying the met-allele. A significant three-way interaction
was detected between region of the cingulum (dorsal, rostral,
and parahippocampal regions), brain hemisphere and BDNF
genotype. Larger FA was detectable in the left rostral cingulum
for met-allele carriers when compared to val/val alelle carriers.
We provide evidence for the importance of the neurotrophic
involvement in limbic and prefrontal connections. The met-
allele of the BDNF polymorphism seems to render subjects
more vulnerable for dysfunctions associated with the UF, a
tract known to be related to negative emotionalcognitive proc-
essing bias, declarative memory problems, and autonoetic self
awareness.
2012 Wiley Periodicals, Inc.
Key words: diffusion tensor imaging (DTI); uncinate
fasciculus; fornix; cingulum; Val66Met brain-derived neuro-
trophic factor (BDNF) genotype; major depression (MDD);
neurogenetics
INTRODUCTION
Major depressive disorder (MDD) [Erickson et al., 2011] is a
common, comp lex, and recurrent disorder of geneenvironment
interactions with an estimated heritability of 0.360.66 [Sullivan
et al., 2000] and a lifetime prevalence of 16% [Kessler et al., 2003].
Untreated depression can have severe consequences. Approximate-
ly 800,000 individuals worldwide die from suicide every year, a high
proportion of them related to MDD [Isacsson, 2000; Prince et al.,
2007; Bailey et al., 2011; Thomson, 2012]. The World Health
Grant sponsor: Science Foundation Ireland; Grant sponsor: Health
Research Board Ireland.
None of the authors has a competing financial interest with regard to this
manuscript or has biomedical financial interests or potential conflicts of
interest.
*Correspondence to:
T. Frodl, Department of Psychiatry, Institute of Neuroscience, University
of Dublin, Trinity College Dublin, Dublin 2, Ireland. E-mail: frodlt@tcd.ie
Article first published online in Wiley Online Library
(wileyonlinelibrary.com): 14 May 2012
DOI 10.1002/ajmg.b.32060
How to Cite this Article:
Carballedo A, Amico F, Ugwu I, Fagan AJ,
Fahey C, Morris D, Meaney JF, Leemans A,
Frodl T. 2012. Reduced Fractional Anisotropy
in the Uncinate Fasciculus in Patients With
Major Depression Carrying the Met-Allele of
the Val66Met Brain-Derived Neurotrophic
Factor Genotype.
Am J Med Genet Part B 159B:537548.
2012 Wiley Periodicals, Inc. 537
Neuropsychiatric Genetics
Page 1
Organisation (WHO) estimates that more people die each year
from suicide than in all the armed conflicts worldwide [McKenzie
et al., 2003]. It is then pressing to define the pathophysiological
mechanisms of MDD in order to develop potentially better treat-
ment strategies in the future.
Attempts to elucidate the pathophysiology of depression have
increased over the years and several genetic polymorphisms are
known nowadays to be related to MDD. One of the polymorphisms
found to be associated with MDD is the Val66Met polymorphism of
brain derived neurotrophic factor (BDNF) [Verhagen et al., 2010].
BDNF is part of the neurotrophin family, which also includes
neurotrophin 3, neurotro phin 4/5, their high affinity receptors
(receptor tyrosine kinase A [NTRK1], receptor tyrosine kinase B
[NTRK2], and receptor tyrosine kinase C [NTRK3]), and the low-
affinity nerve growth factor receptor (p75NTR) [Alderson et al.,
2000]. The gene coding for BDNF is located in chromosome 11 [Liu
et al., 2005]. It codes for a precursor peptide (pre-pro-BDNF),
which is successively cleaved to generate pro-BDNF and mature
BDNF, both of which are secreted and extracellularly active [Pang
and Lu, 2004]. A functional single nucleotide polymorphism (SNP)
identified in the BDNF gene (rs6265) results in a methionine (met)
to valine (val) substitution at codon 66 in the pro-region of the
BDNF [Egan et al., 2003]. Interestingly, the met variant has been
associated with impaired intracellular trafficking of pro-BDNF into
dendrites and vesicles as well as a reduction in activity-dependent
secretion, the process that plays a major role in the regulation of
extracellular level of BDNF [Egan et al., 2003]. BDNF is expressed
throughout the brain in cortical and subcortical areas, particularly
in the hippocampus [Lu and Gottschalk, 2000; Dennis and Levi tt,
2005]. BDNF seems to be required for neuroplastic changes and
brain development and further supports the neurotrophic and
neurogenic hypothesis of depression [Frodl et al., 2007]. The
literature describing structural imaging findings related to BDNF
Val66Met polymorphism is not unequivocal. Based on previous
imaging genetics studies, it was suggested that the met-BDNF allele
carriers may be at risk of developing smaller hippocampal volumes
and thus may be more susceptible to developing major depression
as suggested by structural MRI studies [Frodl et al., 2007]. Even
otherwise healthy Met carriers with high trait depression showed a
reduction in gray matter volume of the mean hippocampus when
compared with subjects homozygotic for the val-allele [Joffe et al.,
2009]. Moreover, another study suggested that the met-allele also
affects other brain regions such as the amyg dala and the para-
hippocampal gyrus [Montag et al., 2009]. A very recent study has
provided preliminary evidence of a neuroprotective role of the
val/val genotype. Elderly MDD subjects homozygotic for the BDNF
val-allele BDNF homozygotes had significantly larger right hippo-
campal volumes compare d to nondepressed subjects homozygotic
for the val-allele. However, there was no significant difference
between the depressed and healthy met carriers [Kanellopoulos
et al., 2011].
By contrast, a more recent study found no main effect of this
genetic variant on hippocampal, amygdala, and orbitomedial pre-
frontal cortex volumes, but demonstrated the importance of early
adversity in modifying BDNF effects [Gerritsen et al., 2011].
Similarly, Cole et al. [2011] found no evidence of a genetic effect
for 5HTTLPR or BDNF Val66Met on hippocampal morphology in
either healthy individuals or MDD patients despite very large
sample sizes. Karnik et al. [2010] again found that genotype for
the Val66Met BDNF had no significant effect on hippocampal
structure.
In more recent years, the magneti c resonance imaging technique
called diffusion tensor imaging (DTI) has developed as a significant
advance in our attempts to characterize microstructural changes in
the brain [Basser et al., 1994; Tournier et al., 2011]. DTI is a novel
imaging technique that can evaluate both the direction and the
diffusion characteristics within the white matter tracts in the brain
in vivo and can provide an innovative approach, referred to as fiber
tractography [Mori et al., 1999; Basser et al., 2000], to study white
matter architectural organization in vivo on the submillimeter scale
[Le Bihan, 2003; Mori and Zhang, 2006]. DTI enables quantifica-
tion of the rate of diffusion of water in brain tissue where water
diffusion is not random but rather hindered by barriers such as cell
membranes, cytoskeletal elements, and myelin [Beaulieu, 2002]. In
white matter tracts, where axons are aligned in bundles, water
diffuses more readily along axonal paths than across them. Frac-
tional anisotropy (FA) is a scalar value between zero and one that
measures the directionality of this water diffusion [Frodl et al., 2010;
Nobuhara et al., 2006b]. Reduced FA in the absence of gross
pathological findings may represent microstructural abnormalities
of the white matter tracts [Coplan et al., 2010]. Recent DTI studies
have suggested that patients with MDD show reduced FA values
compared to healthy controls. A significant reduction in FA has
been found in the dorsolateral prefrontal cortex and in widespread
regions of the frontal and temporal lobes [Alexopoulos et al., 2002;
Taylor et al., 2004; Nobuhara et al., 2006a; Ma et al., 2007; Yang
et al., 2007] as well as in the left sagittal stratum [Kaspar et al., 2005]
of patients with MDD compared to healthy controls, indicating
microstructural white matter alterations in MDD (for a detailed
meta-analysis and review, see Murphy and Frodl [2011] and Sexton
et al. [2009]). These results may explain disease-related micro-
stuctural changes taking place during depressive episodes.
The aim of the present study was to converge the two main points
highlighted above. We aimed at determining the effect of the
Val66Met BDNF polymorphism on white matter fiber tracts known
to be implicated in MDD. For this, we used DTI based tractography
to analyze the fiber bundles connecting the hippocampus and
amygdala with the prefrontal lobe, namely the uncinate fasciculus,
fornix, and cingulum, and compared the microstructural proper-
ties of these tracts between patients with MDD and healthy com-
parison subjects.
METHODS
Participants
A cohort 79 volunteers with ages between 18 and 65 years were
included in this study. Patients with MDD (N ¼ 37) were recruited
from inpatient wards and outpatient clinics attached to the De-
partment of Psychiatry at Tallaght Hospital and St. James’ Hospital
in Dublin. Healthy volunteers without history of psychiatric
illness (N ¼ 42) were recruited from the local community via
announcements. The patients had a DSM-IV diagnosis of MDD
at the time of the study without any other comorbidity, confirmed
by two psychiatrists. The sample was carefully screened for medical
538 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Page 2
conditions to ensure that healthy volunteers had no personal
history of neurological or psychiatric disorders (axis I or axis II),
and also no history of severe me dical illness, head injury or
substance and alcohol abuse. Exclusion criteria also included acute
suicidality, previous treatment with hydroco rtisone or electrocon-
vulsive therapy, and previous head injury with loss of conscious-
ness. Demographic variables, inclusion and exclusion criteria, and
clinical details were assessed using a standardized questionnaire as
well as through DSM-IV Structured Clinical Interviews for psychi-
atric disorders and personality (SCID-I, II) [Spitzer et al., 1992;
Williams et al., 1992]. In the patient group, information about
illness duration and treatment information was obtained during the
structured interview. Thirteen of the patients were currently drug-
free, 13 received SSRIs, and 11 dual acting substances venlafaxine or
mirtazapine. There was no significant difference with regards to
these medication groups between patients carrying the met-allele
and those homozygous for the val-allele of the BDNF polymor-
phism (c
2
¼ 0.16, P ¼ 0.93; met allele carriers: none: 5, SSRI: 5, dual:
5, val/val: none; 8, SSRI : 8, dual: 6).
Informed Consent
Written informed consent was obtained from all participants after
having be en given a detailed description of the study. Our study was
designed and performed in accordance to the ethical standards laid
out by the Declaration of Helsinki, and was approved by the ethics
committees from St. James’s and Adelaide and Meath hospitals, the
teaching hospitals of Trinity College Dublin.
Rating Instruments
Self and observer rated scales were also completed for all partic-
ipants included in the study. The rating scales that were used
comprised: the Hamilton Rating Scale for Depression [Hamilton,
1969], Beck’s Depression Inventory (BDI-II) [Beck et al., 1996],
Montgomery Asberg Depression Rating Scale (MADRAS)
[Montgomery and Asberg, 1979], and the Structured Clinical
Interview for DSM-IV (SCID-II) personality questionnaire.
Diffusion Tensor Imaging (DTI)
Magnetic resonance imaging studie s were carried out using an
eight-channel head coil on a Philips Achieva MRI scanner operating
at three Tesla (Best, The Netherlands). High angular resolution
diffusion imaging (HARDI) with 61 (split up in one non-diffusion
weighted image (b ¼ 0 sec/mm
2
) and 60 diffusion weighted images)
diffusion directions was obtained (Field Of View (FOV):
200 257 126 mm
3
, 60 slices, no gap, spatial resolution:
1.8 1.8 2.1 mm
3
, TR/TE ¼ 12,561/59 msec, flip angle ¼ 90
,
half k-space acquisition was used (half scan factor ¼ 0.68), SENSE
parallel imaging factor ¼ 2.5, b-values ¼ 0, 1,200 sec/mm
2
, with
SPIR fat suppression and dynamic stabilization in an image acqui-
sition time of 15 min 42 sec).
DTI Data Pre-Processing
Data were pre-processed with ExploreDTI [Leemans et al., 2009]
(www.exploredti.com/) using the following steps:
- First, data quality assessment was performed by looping through
the individual images to check for gross artifacts, such as signal
dropouts and interleave artefacts caused by sudden subject
motion. No participants had to be exclu ded based on these
data checks.
- Second, each data set was corrected for subject motion and eddy
current induced geometric distortions with the appropriate
reorientation of the diffusion gradient directions [Leemans
and Jones, 2009]. In this correction proced ure, the data were
transformed rigidly to MNI space (voxel size: 2 2 2mm
2
)by
applying cubic interpolation with only a single resampling step
(concatenating the transformation matrices) [Klein et al., 2010;
Leemans et al., 2005; Mori et al., 2008; Rohde et al., 2004]. In
doing so, no additional confounds, such as partial volume effect
(PVE) related modulations of the estimated DTI measures [Vos
et al., 2011b], were introduced in this processing step. In additi on,
by transforming the DTI data to a common atlas space, uni for-
mity of brain angulation was maximized across subjects, which
facilitates the reconstruction of the fiber bundles of interest.
- Finally, the diffusion tensor was estimated with the RESTORE
approach [Chang et al., 2005] and the FA was computed as
described previously [Pierpaoli and Basser, 1996].
Tractography
Deterministic tractography [Basser et al., 2000] was applied as
implemented in ExploreDTI [Leemans et al., 2009]. First, whole
brain tractography was performed on each data set with a uniform
2 mm seed point resolution, 1 mm step size, and an FA tract
termination threshold of 0.2. Then, tracts were isolated by defining
regions of interest (ROI, using the ‘‘AND’’ operator if tr acts passed
or not allowing a tract to pass through with the ‘‘NOT’’ operator).
NOT was consist ently placed, for example, in the midline to avoid
crossing fibers from other bundles, for example, from the corpus
callosum. The ROI definitions were adjusted to recent established,
published research showing good validity and reliability [Malykhin
et al., 2008; Kumar et al., 2010; Luck et al., 2011]. More specifically,
two ROIs per tract were used to extract the uncinate fasciculus (UF)
and crus fornix, and three ROIs were used for the cingulum (rostral,
dorsal and parahipocampal regions; Fig. 1).
For the UF, which connects the anterior temporal lobe with
orbital and polar frontal cortex, the ‘‘AND’’ ROIs were placed on
the most posterior coronal slice in which the temporal lobe is
separated from the frontal lobe. The first ROI included the entire
temporal lobe and the second ROI was placed at the same coronal
level and included the entire projections toward the frontal lobe.
Moreover, a ‘‘NOT’’-ROI was used to avoid fibers from the inferior
fronto-occipital fasciculus and the cingulum.
The cingulum was divided into three regions: rostral (left and
right), dorsal (left and right), and parahippocampal (left and right).
Each region was identified using three ROIs. The length of fibers was
chosen to be less than 8 cm in order to minimize them to partly
overlap. For the rostral cingulum, the first ROI w as placed on the
most inferior axial slic e where the body of the corpus callosum was
clearly seen in full profile. The second ROI was located in the axial
slice corresponding to the middle of the genu. Finally, the third ROI
was placed on the lowest axial slice where the genu was joined across
CARBALLEDO ET AL. 539
Page 3
the midline. NOT regions were placed sagitally to exclude fibers
projecting laterally and/or medially. The dorsal cingu lum was
identified placing the first ROI on the most posterior coronal slice,
where the genu of the corpus callosum was seen in full profile.
The second ROI was located on the most anterior coronal slice
at the midp oint between where the splenium of the corpus
callosum was seen in full profile and the third ROI on the coronal
slice at the midpoint between these two ROIs. NOT regions were
placed axially to exclude fibers branching to the cortex and/or other
limbic areas.
The parahippocampal cingulum was first identified on the
sagittal and coronal slices that provided the clearest profile of
the hippocampus. The first ROI was then traced around the
hippocampus in the sagittal plane. The second and the third
ROI were then traced on the adjacent medial and lateral slices.
NOT regions were placed on the slice below the lower body of the
splenium, excluding the retrosplenial portion and the branches into
retrosplenial cortex.
The crus of the fornix contain fibers from the hippocampus
and the parahippocampal cortex. The first ROI was placed in the
coronal section at the level of the middle hippocampal body;
the second ROI was placed in the coronal section at the level where
the body of the fornix and both crus are clearly visible.
All fiber bundles were drawn separately for each individual on the
directionally color encoded FA maps (examples of which are
presented in Fig. 1 for one subject) and the investigators were blind
to diagnosis. For all subjects, the same numbers and locations of
ROIs were used as a start and these ROIs were predefined in the
anatomical T1 and FA images. Inter-rater reliability was calculated
after two raters independently performed the tractography in
20 participants. Intraclass correlations were between 0.90 and
0.95 for mean FA values in the tracts. After performing the
FIG. 1. DTI images for the left uncinate fasciculus, left fornix, left rostral cingulum, left dorsal cingulum, and left parahippocampal region using
radiological convention. The images depicted here are for a healthy individual. [Color figure can be seen in the online version of this article, available
at http://wileyonlinelibrary.com/journal/ajmgb]
540 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Page 4
tractography for all tracts for all individuals, the mean FA of tracts
were extracted and read into SPSS for further data analysis.
These protocols are described in detail above (two circular AND-
ROIs per tract were used to extract the white matter fiber tracts
of UF and crus fornix, and three circular AND-ROIs were used for
the cingulum (rostral, dorsal, and parahipocampal regions; Fig. 1).
Genotyping
The Val66Met BDNF SNP (rs6265) was genotyped in this sample
using a Taqman
SNP Genotyping Assay on a 7900HT Sequence
Detection System (Applied Biosystems, Carlsbad, CA). The call
rate for the Taqman genotyping was >95% and all samples were in
HardyWeinberg equilibrium (P > 0.05). Along with the test sam-
ples, a number of HapMap CEU DNA sample positive controls
(www.hapmap.org) and non-template negative controls were gen-
otyped for each SNP for quality control purposes. For positive
controls, all genotypes were found to be concordant with available
online HapMap data. All non-template samples returned a negativ e
result.
Statistical Analyses
Morphometric measurements in both groups were normally dis-
tributed (using Kolmogorov Smirnov test) and their variances were
homogenous (using Levine’s test). Differences in demographic
variables were tested using Stude nt’s T-test, Chi-square test for
gender distribution and MannWhitney U-test for differences in
clinical variables. Statistical tests were considered to be significant if
P < 0.05. In the case of the morphometric data the P-threshold was
P < 0.05/3 ¼ 0.016, since three ANCOVAs for different regions
were used.
FA values of UF and fornix tracts were subjected to an analysis of
variance (ANCOVA) to assess the main and interaction effects of
the within-subjects factor hemisphere (left and right), and the
between-subjects factors diagnosis (depression and control), and
BDNF-genotype (met-allele carriers and val/val) using age and
gender as co-variates. For the cingulum, an additional factor was
added for the subregions of the cingulum (rostr al, dorsal, and
parahippocampal). Post hoc tests were performed using Sidak
Bonferroni test following significant interactions between group
variables following the omnibus ANCOVA.
RESULTS
Demographics and Clinical Data
There were no differences in demographic details between patients
and contr ols, the details of which are presented in Table I. Patients
were not more frequently carriers of the met-BDNF allele compared
to healthy control individuals (met/met: 2 patients and 0 controls;
met/val: 13 patients and 8 controls; and val/val: 22 patients and 34
controls; Pearson’s c
2
¼ 5.5, df ¼ 2, P ¼ 0.065). Scores for depres-
sive illness derived from Hamilton Rating Scale, Beck’s Depression
Inventory and MADRS were significantly different between the
patients group and the controls group, as it should be expected.
Scores for depressive illness as well as illness duration, cumulative
illness duration and age of onset did not differ between patients
carrying the met-allele compared to those homozygous for the
val-allele.
Uncinate Fasciculus
No significant main effects of diagnosis (F ¼ 2.0, df ¼ 1.73,
P ¼ 0.17) and of BDNF (F ¼ 1.6, df ¼ 1.73, P ¼ 0.22) alone were
seen in the UF. There was a significant interaction between BDNF
alleles and diagnosis (F ¼ 8.6, df ¼ 1.73, P ¼ 0.004). Post hoc anal-
ysis using SidakBonferroni correction showed that patients car-
rying the BDNF met-allele had smaller FA in the UF compared to
those patients homozyg ous for the val-allele (P ¼ 0.009, corrected)
and compared to healthy subjects carrying the met-allele
(P ¼ 0.015, corrected), whereby it was not significant compared
to healthy subjects being homozygous for the val-allele (P ¼ 0.1,
corrected; Fig. 2). No significant effect was found between patients
being homozygous for the val-allele compared to healthy controls
homozygous for the val-allele (P ¼ 0.72, corrected) or to healthy
controls carrying the met-allele (P ¼ 0.99, corrected). No signifi-
cant main hemisphere effects were found. All results were Sidak
corrected.
TABLE I. Demographic Characteristics for Patients and Controls
Patients (N ¼ 37) Controls (N ¼ 42)
tdfPMean SD Mean SD
Age (years) 40.4 10.3 36.3 13.0 1.5 77 0.13
Gender (f/m) 25/12 25/17
x
2
¼ 0.55 1 0.46
Weight [Gonca Akbulut et al., 2011] 75.4 15.5 71.2 15.8 1.2 77 0.24
Height [Chiang et al., 2011] 171.3 8.3 172.5 10.3 0.54 77 0.59
Total Hamil ton 28.2 6.7 2.5 2.2 23.3 77 <0.001
Total BDI-II 32.7 11.8 2.5 3.4 15.6 77 <0.001
Total MADRS 29.3 6.6 1.5 2.7 25.1 77 <0.001
Met/val allele 15/22 8/34
x
2
¼ 5.5 2 0.065
Illness duration (years) 14.1 11.7
Cumulative illness durat ion (years) 9.5 9.9
CARBALLEDO ET AL. 541
Page 5
Fornix
In the fornix no significant main effects of diagnosis (F ¼ 0.28,
df ¼ 1.73, P ¼ 0.60) and of BDNF (F ¼ 2.9, df ¼ 1.73, P ¼ 0.09)
were found. No significant interaction was found between BDNF
genotype and diagnosis (F ¼ 0.49, df ¼ 1.73, P ¼ 0.49). There was a
main hemisphere effect in the fornix. Left fornix FA w as smaller
than the right fornix FA (F ¼ 8.2, df ¼ 1.73, P ¼ 0.006).
Cingulum
A significant three-way interaction was detected between region of
the cingulum (dorsal, rostral, and parahippocampal regions), brain
hemisphere and BDNF genotype (F ¼ 9.3, df ¼ 1.73, P ¼ 0.003). No
significant diagnosis effect (F ¼ 0.40, df ¼ 1.73, P ¼ 0.54) and no
significant interactions w ere found between diagnosis and BDNF
genotype (F ¼ 0.001, df ¼ 1.73, P ¼ 0.97). No other significant
interactions, including brain hemisphere and region of the cingu-
lum, were detected. Left cingulum FA value though was smaller
than the right cingulum FA (F ¼ 9.1, df ¼ 1.73, P ¼ 0.003).
A significant difference of BDNF alleles was detectable in the left
rostral cingulum (F ¼ 6.9, df ¼ 1.77, P ¼ 0.010) and a tende ncy or
trend in the left dorsal cingulum (F ¼ 2.8, df ¼ 1.77, P ¼ 0.09),
meaning larger FA values for met-allele carriers in those two left
regions of the cingulum when compared to those homozygous for
the val-allele (Fig. 3).
Effects of Medication
There were no significant effects of medication group and no
significant interactions between medication group and BDNF
genotype on the FA of UF, fornix, or cingulum.
Additional Statistical Considerations
Results did not change and no additional results were found when
volumes of tracts were added as covariate in order to correct
for tract volume. Although tract FA values were normally distrib-
uted, we examined the data using the median of FA with non-
parametric Whitney U tests and this confirmed the findings
described above.
DISCUSSION
To our knowledge, this is one of the first studies available to address
the interaction between the BDNF genotype and MDD with the use
of DTI. The BDNF Val66Met (rs6265) nonsynonymous polymor-
phism is the most investigated genetic variant in depression [Licinio
et al., 2009] in human studies. BDNF plays an important role in
neuroplasticity [Grande et al., 2010] and has been repeatedly
associated with reduced brain structures such as the hippocampus,
the brain region where it is mostly expressed [Frodl et al., 2007; Joffe
et al., 2009; Kanellopoulos et al., 2011]. At the same time, the lack of
main effect of this genetic variant on hippocampal volume has also
been described in the literature [Karnik et al., 2010; Cole et al., 2011;
Gerritsen et al., 2011]. The results of our study show that the
Val66Met polymorphism of BDNF plays an important role in
alterations of the UF, which it seems to be altered in MDD.
MDD patients carrying the met-allele have smaller FA in the UF
compared to patients homozygous for the val-allele and compared
to controls either carrying the met-allele or controls homozygous
for the val-allele. Further evidence for changes of the UF in MDD
came from a study showing reduced FA in connections between
the subgenual ant erior cingulate cortex to amygdala in the right
hemisphere and between the right and left uncinate to supragenual
cingulum [Cullen et al., 2010].
The function of the UF is not fully known yet though it is
traditionally considered to be part of the limbic system [Hasan
et al., 2009]. The capacity for autonoetic self-awareness, that is re-
experiencing previous events as part of one’s past as a continuous
entity across time, has been linked to the right UF as has pro ficiency
in auditoryverbal memory and declarative memory to the integ-
rity of the left UF [Levine et al., 1998; Mabbott et al., 2009]. The UF
FIG. 2. FA values for the BDNF met-allele carriers and val/val genotype in the patients and the controls, for the left UF (A) and for the right UF (B)
separately. In the left UF, patients carrying the met-allele showed smaller FA values than those patients homozygous for the val-allele (F ¼ 12.2,
df ¼ 1.35, P ¼ 0.001), met-carrier healthy controls (F ¼ 20.9, df ¼ 1.22, P ¼ 0.001) and healthy controls homozygous for the val-allele (F ¼ 10.0,
df ¼ 1.48, P ¼ 0.003). In the right UF, patients carrying the met-allele show also smaller FA values than those patients homozygous for the
val-allele (F ¼ 8.6, df ¼ 1.35, P ¼ 0.006), met-carrier healthy controls (F ¼ 8.7, df ¼ 1.22, P ¼ 0.008) and healthy controls homozygous for the
val-allele (F ¼ 2.1, df ¼ 1.48, P ¼ 0.015). [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/
journal/ajmgb]
542 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Page 6
connects limbic structures, such as the hippocampus and amygdala,
with frontal regions [Taylor et al., 2007]. In a recent animal study
it was shown that maternal deprivation resulted in a reduction of
BDNF in the amygdala [R
eus et al., 2011] indicating that BDNF is
important in the amygdala in stress related disorders like MDD.
Functional MRI studies have demonstrated di sconnectivity be-
tween prefrontal and limbic brain regions during emotion proc-
essing. A study in 15 unmedicated patients with MDD and 15
healthy volunteers found decreased cortical regulation of limbic
activation in response to negative stimuli [Anand et al., 2005].
Compared to healthy controls, 34 patients with depression showed
significantly redu ced amygdalaprefrontal functional connectivity
[Dannlowski et al., 2009]. Another study showed that patients w ith
MDD had more negative functional connectivity between the
amygdala and frontal cortex than controls, this being corrected
by treatment with SSRIs [Chen et al., 2008]. These functional MRI
studies are consistent with findings of a behavioral processing bias
and support the finding that alterations of the UF play a role in
MDD. Further evidence for this comes from neuropsychological
studies investigating the effect of Val66Met BDNF on cognitive
function in healthy subjects and in patients with MDD [Forlenza
et al., 2010; van Wingen et al., 2010; Erickson et al., 2011; Voineskos
et al., 2011].
The other two tracts studied are closely related to the limbic
system. They are the fimbria/fornix, which projects from the
hippocampus to the septal region and mamillary bodies, and
the cingulum, which connects the enthorinal cortex and the
cingulate gyrus [Concha et al., 2005]. With regards to the cingulum
we found that met-allele carriers have larger FA values than those
homozygous for the val-allele and in particular for the regions of
the fornix and the left dorsal and left rostral cingulum. These
associations with the BDNF genotype seem to be not specific of
patients and thus they may be indicative of strong gene related
neurodevelopmental changes, specific to genotype but independent
of MDD illness status. They are in line with the most recent studies,
which show larger hippocampal volumes in BDNF met-allele
carriers [Gonul et al., 2011]. Worth mentioning is that w ith regards
to structural MRI, studies have also shown no association between
Val66Met polymorphism and hippocampal volume in healthy
controls and in patients with MDD [Jessen et al., 2009; Benjamin
et al., 2010; Soliman et al., 2010; Richter-Schmidinger et al., 2011].
Others have reported reduced hippocampal volumes in subjects
carrying the met allele irrespective of the whether they are depressed
or healthy [Bueller et al., 2006; Frodl et al., 2007].
DTI studies have shown also conflicting results. For example, Lu
et al. [2010] detected an increase in FA values in MDD patients in
areas of the brain associated with mood regulation such as the right
superior frontal gyrus to right pallidum and left superior parietal
gyrus to right superi or occipital gyrus using tractography analysis.
Previous studies did not use tractography and found with voxel-
based or tract-based whole brain methods heterogenous results,
with the majority of studies showing decreased FA, however in
FIG. 3. FA values for the BDNF met-allele and val/val genotype in the left and the right dorsal cingulum and in the left and the right rostral cingulum;
showing the patient group and the control group separately. A significant difference of BDNF alleles was detectable in the left rostral cingulum
(F ¼ 6.9, df ¼ 1.77, P ¼ 0.010) and a tendency or trend in the left dorsal cingulum (F ¼ 2.8, df ¼ 1.77, P ¼ 0.09), meaning larger FA values for
met-allele carriers in those two left regions of the cingulum when compared to subjects homozygous for the val-allele. [Color figure can be seen in
the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmgb]
CARBALLEDO ET AL. 543
Page 7
different brain regions. This heterogeneity in findings may also be
due to differences in the applied approaches, as voxel based DTI
analyses are known to be highly sensitive to the amount and type of
filtering [Jones et al., 2005; Van Hecke et al., 200 9, 2010] and choice
of atlas template [Van Hecke et al., 2008, 2011; Sage et al., 2009].
Some studies in late life depression consistently reported reduced
FA values in prefrontal brain regions [Bae et al., 2006; Nobuh ara
et al., 2006b; Li et al., 2007; Murphy et al., 2007; Yang et al., 2007;
Shimony et al., 2009]. Reduced FA in the cingulate corte x has been
also detected [Murphy et al., 2007; Cullen et al., 2010; Taylor et al.,
2010]. In addition, Yang et al. [2007] and Murphy et al. [2007]
reported a reduction in FA values in the parahippocampal gyrus.
Blood et al. [2010] found increased FA values in the right ventral
tegmental area and redu ced FA values in dorsolateral prefrontal
white matter in MDD patients, whereas Abe et al. [2010] did not
find alterations of FA between patients with MDD and healthy
controls.
Since our study is one of the first to integrate DTI and Val66Met
BDNF polymorphism, our results need further exploration and
replication. Recent attempts to do so have been undertaken by
Chiang et al. They have shown that the Val-BDNF variant was
associated with lower FA values in the splenium of the corpus
callosum, left optic radiation, inferior fronto-occipital fasciculus,
and superior corona radiate but the UF was not one of the main
tracts included on the ana lysis [Chiang et al., 2011]. Montag et al.
[2010] in their recent study of 99 healthy participants cou ld not
find significant differences in DTI derived metrics between the
Met carriers and val/val carriers.
The identification of single candidate genes associated with
MDD has not been easy due to the likelihood of MDD being
a polygenic disorder associated with interactions between genetic
variants and environmental exposures [Uher, 2009]. However,
some studies have concentrated in the study of other relevant
polymorphisms. For instance, the association between the seroto-
nin transporter-linked polymorphism (5-HTTLPR/rs25531) and
MDD [Serretti et al., 2007]. Moreover, microstructural white
matter abnormalities have also been associated with this
5-HTTLPR/rs25531 polymorphism and MDD, both in depressed
and healthy individuals. Pacheco et al. [2009] found a significant
main effect of 5-HTTLPR polymorphism on the microstructure
of the left UF, such that as the number of the S/Lg alleles increased,
the FA in the left UF decreased in healthy individuals. Alexopoulos
et al. [2009] highlighted that depressed elderly S-carriers also had
lower FA values than L-allele homozygotes in frontolimbic brain
areas, including the dorsal and rostral anterior cingulate, posterior
cingulate, dorsolateral prefrontal, and medial prefrontal regions
and thalamus. S-alleles carriers had a lower remission rate than
L-allele homozygotes [MacQueen and Frodl, 2011].
The sample size of such a study needs discussion. The sample
with 79 participants is in the range of similar imaging genetic studies
and importa ntly the results are statistically strong and post hoc tests
survive SidakBonferroni corrections. While there had been some
imaging genetic studies using larger samples our study first looks at
the effects of a genetic variant on DTI in MDD compared to healthy
controls. One could think that one limitation of this study is its case-
control design, which is sensitive to population stratification. This
is unli kely to be problematic here because the patients and controls
with each BDNF allele did not differ for age, gender, origin, illness
duration, age at onset, or medication use. There was a small number
of subjects with the BDNF met-allele. It could be argued that equal
numbers of individuals with the genetic subtype should have been
sampled. This would have required a very large number of subjects.
For issues of sample size, we have used the stratification of met-allele
carrier (met/met and met/val) and val/val homozygotic. Moreover,
patients with MDD were taking antidepressant treatment . Whether
antidepressants affect diffusion parameters in the brain still is a
matter of ongoing research. In the present study we did not detect a
significant effect of medication group (no medication, SSRI, dual
acting substances) on fiber tracts. Moreover, BDNF groups did not
differ with respect to current medication, so that medication is
unlikely to present a major problem. Also there was no significant
effect of medication group and no significant interaction between
medication group and BDNF genotype on the FA measures.
Furthermore, the applied psychopharmacological treatment varied
in the patient group. As little is known about the effect of different
antidepressants on white matter structure, an influence on the
retrieved imaging results cannot be excluded.
Another possible limitation is that with basic deterministic
tracking it is impossible to accurately reconstruct all the major
pathways, especially where fibers branch and cross [Tuch et al.,
2002]. The various methods being developed for resolving fiber-
crossing information are intriguing in that they partly ameliorate
the limitations of the tensor model [Behrens et al., 2007; Wheeler-
Kingshott and Cercignani, 2009; Wobrock et al., 2009; Jeurissen
et al., 2011; Vos et al., 2011a]. The use of HARDI, however, can
resolve more complex diffusion geometri es than standard DTI,
such as in regions where fibers cross or mix and may be a useful
approach for future investigations.
In summ ary, the results of our study are the first to provide
evidence of microstructural white matter changes in MDD, in the
UF connecting amygdala and prefrontal regions, when considering
at the same time the Met66Val BDNF polymorphism that has
previously been described as closely related to MDD. MRI and
neuropsychological studies support the finding of alterations
of the uncinate fasciculus in MDD. We show that the Val66Met
BDNF polymorphism seems to determine whether the UF is altered
in subjects with MDD or not. The met-allele of the BDNF poly-
morphism seems therefore to render subjects more vulnerable for
enduring dysfunctions that can be associated with the UF, an area of
the brain linked to emotional-cognitive processing bias, declarative
memory problems and autonoetic self awareness.
ACKNOWLEDGMENTS
This work was supporte d by the Science Foundation Ireland
(SFI-Stokes Professor Grant to T.F.) and an infrastructure grant
from Health Research Board Ireland for developing of the Centre
of Advanced Medical Imaging at St. James’s Hospital, Dublin.
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    • "Reduced CB FA may represent a state marker for MDD (Huang et al., 2011; Keedwell et al., 2012), but further investigation is required in medication naïve adults with MDD: changes in the CB might be reversed by treatment (Bracht et al., 2015b). UF (Carballedo et al., 2012; de Kwaasteniet et al., 2013; Murphy et al., 2012; Steele et al., 2005; Zhang et al., 2012 ) and slMFB microstructure (Bracht et al., 2014) may be altered during depressive episodes in adult MDD, while the latter might be particularly affected in severe depression (Bracht et al., 2014; de Diego-Adelino et al., 2014; Guo et al., 2012a; Peng et al., 2013). Associations between microstructural changes in the major tracts of the reward system and MDD do not, in themselves, prove a functional contribution towards the development of depression's core symptoms. "
    [Show abstract] [Hide abstract] ABSTRACT: Depressed mood, anhedonia, psychomotor retardation and alterations of circadian rhythm are core features of the depressive syndrome. Its neural correlates can be located within a frontal-striatal-tegmental neural network, commonly referred to as the reward circuit. It is the aim of this article to review literature on white matter microstructure alterations of the reward system in depression. We searched for diffusion tensor imaging (DTI)-studies that have explored neural deficits within the cingulum bundle, the uncinate fasciculus and the supero-lateral medial forebrain bundle/anterior thalamic radiation - in adolescent and adult depression (acute and remitted), melancholic depression, treatment-resistant depression and those at familial risk of depression. The relevant diffusion MRI literature was identified using PUBMED. Thirty-five studies were included. In people at familial risk for depression the main finding was reduced fractional anisotropy (FA) in the cingulum bundle. Both increases and decreases of FA have been reported in the uncinate fasciculus in adolescents. Reductions of FA in the uncinate fasciculus and the anterior thalamic radiation/supero-lateral medial forebrain bundle during acute depressive episodes in adults were most consistently reported. Non-quantitative approach. Altered cingulum bundle microstructure in unaffected relatives may either indicate resilience or vulnerability to depression. Uncinate fasciculus and supero-lateral medial forebrain bundle microstructure may be altered during depressive episodes in adult MDD. Future studies call for a careful clinical stratification of clinically meaningful subgroups. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Jul 2015 · Journal of Affective Disorders
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    • "Being one of the preferred methods to investigate brain structure, diffusion MRI is nowadays being used in a myriad of biomedical and neuroscience applications, including diabetes (e.g., Kodl et al., 2008; Hsu et al., 2012; Reijmer et al., 2013), amyotrophic lateral sclerosis (Wang and Melhem, 2005; Sage et al., 2009; Blain et al., 2011), Alzheimer's Disease (Reijmer et al., 2012), neuroplasticity (De Groof et al., 2006, 2009; Zatorre et al., 2012), performance and learning (e.g., Moseley et al., 2002; Caeyenberghs et al., 2010a; Sisti et al., 2012; Gooijers et al., 2013; Zatorre et al., 2012), depressive disorders (e.g., White et al., 2008; Carballedo et al., 2012), stroke (e.g., O'Sullivan, 2010; Van der Aa et al., 2011), and traumatic brain injury (Caeyenberghs et al., 2010b, 2011a,b; Zappalà et al., 2012). In many of these studies, group comparisons were performed, where it is of paramount importance that data quality itself will not affect the final outcome. "
    [Show abstract] [Hide abstract] ABSTRACT: Diffusion-weighted (DW) magnetic resonance imaging (MRI) is a unique method to investigate microstructural tissue properties noninvasively and is one of the most popular methods for studying the brain white matter in vivo. To obtain reliable statistical inferences with diffusion MRI, however, there are still many challenges, such as acquiring high-quality DW-MRI data (e.g., high SNR and high resolution), careful data preprocessing (e.g., correcting for subject motion and eddy current induced geometric distortions), choosing the appropriate diffusion approach (e.g., diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), or diffusion spectrum MRI), and applying a robust analysis strategy (e.g., tractography based or voxel based analysis). Notwithstanding the numerous efforts to optimize many steps in this complex and lengthy diffusion analysis pipeline, to date, a well-known artifact in MRI - i.e., Gibbs ringing (GR) - has largely gone unnoticed or deemed insignificant as a potential confound in quantitative DW-MRI analysis. Considering the recent explosion of diffusion MRI applications in biomedical and clinical applications, a systematic and comprehensive investigation is necessary to understand the influence of GR on the estimation of diffusion measures. In this work, we demonstrate with simulations and experimental DW-MRI data that diffusion estimates are significantly affected by GR artifacts and we show that an off-the-shelf GR correction procedure based on total variation already can alleviate this issue substantially. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · NeuroImage
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    • "Moreover, a higher level of BDNF has been observed in those Alzheimer's patients showing symptoms of depression compared to those with no depressive symptoms (Hall et al., 2011). Data from individuals with depression suggest that a substitution from valine to methionine, at amino-acid position 66 (BDNF Val66Met), could be responsible for structural alterations in the hippocampus and the prefrontal cortex (Cardoner et al., 2013) and in the uncinate fasciculus, a fiber tract linking these two regions (Carballedo et al., 2012). It has been proposed that these neural alterations in patients with depression, could result in poorer treatment outcomes (Cardoner et al., 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Environmental effects and personal experiences could be expressed in individuals through epigenetic non-structural changes such as DNA methylation. This methylation could up- regulate or down-regulate corresponding gene expressions and modify related phenotypes. DNA methylation increases with aging and could be related to the late expression of some forms of mental disease. The objective of this study was to evaluate the association between anxiety disorders and/or depression in older women and DNA methylation for four genes related to anxiety or depression. Women aged 65 and older with (n = 19) or without (n = 24) anxiety disorders and/or major depressive episode (DSM-IV), were recruited. DNA methylation and single nucleotide variant (SNV) were evaluated from saliva, respectively by pyrosequencing and by PCR, for the following genes: brain-derived neurotrophic factor (BDNF; rs6265), oxytocin receptor (OXTR; rs53576), serotonin transporter (SLC6A4; rs25531), and apolipoprotein E (APOE; rs429358 and rs7412). A greater BDNF DNA methylation was observed in subjects with anxiety/depression compared to control group subjects (Mean: 2.92 SD ± 0.74 vs. 2.34 ± 0.42; p= 0.0026). This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 ± 0.41 vs. 2.27 ± 0.26; p= 0.0006) than those carrying the CC genotype (p= 0.0332); no subjects with the TT genotype were observed. For OXTR, a greater DNA methylation was observed in subjects with anxiety/depression, but only for those carrying the AA genotype of the OXTR rs53576 SNV, more particularly at one out of the seven CpGs studied (7.01 ± 0.94 vs. 4.44 ± 1.11; p= 0.0063). No significant differences were observed for APOE and SLC6A4. These results suggest that DNA methylation in interaction with SNV variations in BDNF and OXTR, are associated with the occurrence of anxiety/depression in older women.
    Full-text · Article · Jun 2015 · Frontiers in Genetics
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