Download A functional magnetic resonance study

Abnormal functional connectivity with mood regulating circuit in unmedicated
individual with major depression: a resting-state functional magnetic resonance
study
PENG Daih-uia, FANG Yi-rua, XU Yi-fengb,c, SHEN Tingb, ZHANG Jiea, HUANG
Jiaa, LIU Jund, LIU Shu-yonge and JIANG Kai-dab
a Division of Mood Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University
School of Medicine, Shanghai 200030, China (PENG Daih-ui, FANG Yi-ru, ZHANG Jie,
HUANG Jia)
b Clinic Medical Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School
of Medicine, Shanghai 200030, China (XU Yi-feng, SHEN Ting, JIANG Kai-da)
c Huashan Hospital, Medical School of Colleague, Fudan University, Shanghai 200032, China
(XU Yi-feng)
d Department of Medical Imaging, Shanghai Pu Tuo People’s Hospital 200062, Shanghai, China
(LIU Jun)
e Department of Medical Imaging, Taian People’s hospital, Shangdong 271021, PR China (LIU
Shu-yong)
Correspondence to: Dr. JIANG Kai-da, Clinic Medical Center, Shanghai Mental Health Center,
Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China (Tel:
86-21-34289888 ext. 3528. Fax: 86-21-64387986. Email: jiangkaida66@126. com); Dr. FANG
Yi-ru, Division of Mood Disorder, Shanghai Mental Health Center, Shanghai Jiao Tong University
School of Medicine, Shanghai 200030, China (Tel: 86-21-34289888 ext. 3529. Fax:
86-21-64387986. Email: [email protected])
This work was partly supported by the grant (114119a5500) from Science and Technology
Commission of Shanghai municipality.
Key words: depression; anterior cingulate cortex; thalamus; functional connectivity; functional
magnetic resonance imaging
Background Reports on mood regulating circuit (MRC) indicated different activities between
depressed patients and healthy controls. The functional networks based on MRC have not been
described in major depression disorder (MDD). Both the anterior cingulate cortex (ACC) and
thalamus are all the key regions of MRC. This study was to investigate the two functional
networks related to ACC and thalamus in MDD.
Methods Sixteen patients with MDD on first episode which never got any medication and
sixteen matched health controls were scanned by 3.0 T functional magnetic resonance imaging
(fRMI) during resting-state. The pregenual anterior cingulate cortex (pgACC) was used as seed
region to construct the functional network by cortex section. The thalamus was used as seed
region to construct the functional network by limbic section. Paired-t tests between-groups were
performed for the seed-target correlations based on the individual fisher z-transformed correlation
maps by SPM2.
Results Depressed subjects exhibited significantly greater functional connectivity (FC) between
pgACC and the parahippocampus gyrus in one cluster (size 923) including left parahippocampus
gyrus (-21,-49,7), left parietal lobe (-3,-46,52) and left frontal lobe (-27,-46,28). The one cluster
(size 962) of increased FC on thalamus network overlapped the precuneus near to right parietal
lobe (9,-52,46) and right cingulate gyrus (15,-43,43) in health controls.
Conclusions Abnormal functional networks exist in earlier manifestation of MDD related to
MRC by both cortex and limbic sections. The increased functional connectivity of pgACC and
decreased functional connectivity of thalamus is mainly involved in bias mood processing and
cognition.
The major depression disorder (MDD) shows the bias negative mood processing,
cognition deficits and physical symptoms. Abnormal brain function is one mechanism
of the depressed symptoms, which are likely to be present in functional connectivities
(FCs) between brain regions, rather than within brain regions.1,2 These brain regions
should involve in negative emotion, cognition and physical symptoms.3,4,5
The emotion processing is dependent on a distributed neuronal network.6 The mood
regulating
circuit
(MRC)
should
be
composed
of
a
putative
prefrontal-amygdalar-pallidostriatal-mediothalamic.7 Bias mood processing is related
with abnormal MRC in depression.8,9 The decreased correlations between the anterior
cingulate cortex (ACC) and thalamus are consistent with the hypothesis that
decreased cortical regulation of limbic activation in response to negative mood stimuli
may be present in depression.9,10
Both ACC and thalamus are all the key regions of MRC. The pregenual anterior
cingulate cortex (pgACC) has always been focused on same as the subgenual ACC,
which is involved in abnormal mood.11 Through its connections with the emotion
processing regions, including the hypothalamus, middle thalamus (MTHAL), and
other limbic structures, it regulates the relationship of depressed emotion, autonomic
and visceral function.12 Some researches showed ACC increased its contributions in
resting-state FCs in MDD.13,14 Other researches showed thalamus decreased its
spontaneous activity in MDD during resting-state.15,16 The thalamus has been found to
be abnormal structure and function, related to the visceral function of depression.4,5
The MRC is related with the cognition network and default mode network
(DMN).17,18 Previous studies characterized the MRC as a homogenous network, but
few examined the differential contributions of MRC in MDD. The previous method to
construct the MRC is to analyze the relationship among specific regions of interest
(ROI) by emotion-activation experiment task or resting state.9,10 The functional
networks based on MRC have not been described across global brain in MDD to date.
In functionally related regions of the brain during resting state, low frequency
fluctuations (LFFs) (< 0.08 Hz) are synchronous and exhibit high temporal coherence,
defined as resting state functional connectivity (RSFC) 19,20. By RSFC analysis based
on global brain signal, it’s benefit to explore the potential implications of MRC in
MDD.
In this study, the objective was to investigate the two functional networks from both
cortex and limbic sections of MRC in MDD. The hypothesis is that the two functional
networks should alter in early manifestation of MDD. Specifically, (1) the FC in
MDD has the enhance tendency from seed pgACC of cortex; (2) the FC in MDD will
be decreasing from seed thalamus of limbic region. In order to test the hypothesis, the
RSFC analysis was performed across whole brain, which measured the correlations of
spontaneous LFF signal between seed region and global brain voxels. Then to
investigate the differences of the two functional networks between medication-naïve
patients with MDD on first episode and healthy control subjects.
METHODS
MDD patients were recruited from the outpatient clinic at Huashan Hospital and
Shanghai mental health centre. Healthy subjects matched for age, sex, education level
were recruited via advertisement. Inclusive criteria for depressed subjects were: ages
ranged from 25 to 50 years, satisfy DSM-IV diagnosis criteria of MDD, first episode,
medication-naïve, Hamilton rating scale for depression 24 (24-HAMD)21 score>20,
Hamilton anxiety scale 14 (14-HAMA) score<7. Exclusion criteria for depressed
patients were: meeting criteria of any current or past Axis I disorder of diagnostic and
statistical manual of mental disorders IV (DSM-IV) such as schizophrenia,
schizoaffective disorder, bipolar disorder or an anxiety disorder as a primary
diagnosis, acutely suicidal, homicidal or requiring inpatient treatment, meeting criteria
for substance dependence within the past year, except caffeine or nicotine, serious
medical or neurological illness, current pregnancy or breastfeeding, and metallic
implants or other contraindications to MRI.
Inclusive criteria for healthy subjects were: ages ranged from 25 to 50 years, no
history of psychiatric illness or substance abuse or dependence, no family history of
major psychiatric or neurological illness in first degree relatives, and no serious
medical or neurological illness. Exclusion criteria for healthy subjects were: pregnant
or breastfeeding, and metallic implants or other contraindication to MRI.
Sixteen depressed patients and sixteen healthy subjects were recruited. All
participants were right-handed. All subjects signed an informed consent form
approved by the Investigational Review Board (IRB) at Shanghai mental health centre,
and were paid 200 yuans for their participation. There were not significant differences
between the two groups in age, gender distribution and education level. The clinic
status of all subjects is showed in table 1.
Fuctional MRI Acquisition
Structural images and functional images were acquired on a 3.0 T General Electric
Signa scanner (USA) by using a standard General Electric whole-head coil. T1
weighed structural images with a horizontal axis acquired using the SE sequence in a
level position with parameters: repeat time (TR) = 500 ms, echo time (TE) = 14ms,
flip angle = 15°, 5.0 mm thickness, no interval. Whole-brain functional images
acquired using multislice echo planar imaging (EPI) sequence with parameters: TR =
3000 ms, TE = 30 ms, flip angle = 90°, 5.0 mm thickness, no interval, field of vision
(FOV) = 240 mm × 240 mm, matrix size is 64 × 64, spatial resolution is 3.75 × 3.75×
5.0. The 3 D reconstruction by rapid interference phase gradient echo flip recovery
(FSPGRIR) pulse sequence (T1 weighed) scanning, with parameters: TR = 6.4 ms,
TE = 1.6 ms, TI = 40 ms, 1.0 mm thickness, no interval, FOV = 240 mm × 240 mm,
bandwidth = 31.25, 256 × 256 × 1.0 spatial resolution, including the anatomical
images with 146 layers. Each brain volume was comprised of 22 axial slices parallel
to anterior cortex - posterior cortex. The functional run contained 104 volumes. The
fMRI instruction: lie and remain motionless, to keep your eyes closed and relax as
possibly. The scanning time of resting state: 5 min and 12 secs.
Data preprocessing
The first 4 time points of the resting state were discarded because of the
magnetization equilibrium of the initial MRI signal leaving 100 time points. The data
were firstly preprocessed (motion correction, slice timing, realignment, spatial
normalization to the standard MNI space and re-sampled at 3mm3) using SPM2
(www.fil.ion.ucl.ac.uk/spm). The data were spatially smoothed using a 6-mm FWHM
Gaussian kernel. After these, a low-pass frequency filter (0.01 < f < 0.08 Hz) was
applied to reduce physiological high frequency noise using the 3d bandpass program
of AFNI (http://www.afni.nimh.nih.gov/).22 To reduce the effects of confounding
factors, six motion parameters, mean time series of white matter, cerebrospinal fluid
and all voxels in global brain and linear drift were extracted and removed from the
data by linear regression using SPM2(www.fil.ion.ucl.ac.uk/spm).23,24
Seed region selection
Two seeds were chosen from cortex and limbic regions of MRC separately, the
pgACC and thalamus. The two gray matter structures are potential to emotion
processing and relative symptoms in MDD.16,25 The pgACC [12 41 13] was chosen
based on the literature25. The seed was near to the subgeneual ACC reported in the
literatures (Fig.1)
9,10
. The thalamus [−7.5 −17.5 5.5] was identified based on
decreased spontaneous activity brain area in MDD according to the primary paper16.
Seed region analysis and test of functional correlations
Extraction of the time series of the seed regions (pgACC and thalamus) was generated
using SPM2 (www.fil.ion.ucl.ac.uk/spm). The blood-oxygen-level-dependent (BOLD)
time series of the voxels within each seed were averaged to generate the reference
time series for this seed region. A correlation map was produced by computing the
correlation coefficients (Pearson's r) between the reference time series and the time
series of every voxel in the global brain. After application of Fisher’s r-to-z transform
{z = 0.5 Ln [(1 + r)/(1 − r)]}, which yielded variates that were approximately
normally distributed26, fisher z maps were combined across subjects by using a
random-effects analysis (within group t-test for the two groups, separately). After the
seeds were applied to test the connectivity analysis, paired t-test between-groups was
calculated for the seed-target correlations based on the individual fisher z-transformed
correlation maps as described above. The paired t values between two groups were
converted to equally fisher z scores and thresholded by P < 0.05.
RESULTS
Using pgACC (12,41,13) and thalamus (−7.5,−17.5,5.5) as the two seed regions
shown in Fig. 1, we determined significant differences in mean correlation
coefficients between depressed and control subjects for each network. The locations
of seed regions were circle-coded by seed origin (Fig. 1).
The regions of altered FCs in depression were identified in pgACC network maps and
thalamus network maps separately (Fig. 2 and Fig.3). Depressed subjects exhibited
significantly greater FCs between pgACC and the parahippocampus gyrus in one
cluster (size 923) including left sub-lobar (-21,-49,7), left parietal lobe (-27,-46,28)
and left frontal lobe (-3,-46,52) (Fig. 2 and Table 2).
The FCs analysis on thalamus network showed increased connectivity in health
control compared with depressed subjects in one cluster (size 962) overlapping the
right precuneus near to parietal lobe(9,-52,46)
and right cingulate gyrus (15,-43,43)
(Fig. 3 and Table 2).
There were no clusters that showed significantly greater FCs in the health control
compared to depressed subjects in pgACC network (Table 2). And there were also no
clusters that showed significantly greater FCs in depressed subjects compared to the
health control in thalamus network (Table 2).
DISCUSSION
In this study, one finding showed increased FCs in depressed subjects between
pgACC with the left parahippocampus gyrus, parietal lobe and frontal lobe. Another
finding showed decreased FCs in depressed subjects between thalamus with right
precuneus and right cingulate gyrus. The earlier two studies on MRC showed
decreased correlations between cortex such as ACC and limbic regions such as
MTHAL. Decreased connectivity was used to insist their hypothesis that decreased
cortical regulation of limbic activation in response to negative mood stimuli may be
present.9,10 However, different analysis procedures focus on different research objects.
In previous two studies, the functional connectivity was constructed by analyzing the
defined regions of interests (ROI) in pgACC, dorsomedial thalamus (DMTHAL),
pallidostriatum (PST) and amygdale (AMYG). It’s to explore the regulation
relationship between brain areas by ROI-ROI analysis. In this study, the analysis of
seed-target correlations was based on the global brain signals. It’s benefit to explore
the physical implication of global FCs.19,22
The findings from seed pgACC in this study were consistent with recent studies, in
which ACC increased its contributions in resting-state FCs in MDD.13,14 Tryptophan
depletion in patients with remitted depression, as precursor for 5-hydroxytryptamine
(5-HT), resulted in change of metabolism in several regions including ACC.27 The
potential biochemical issue on depression is that abnormal serotonergic (5-HT) nerve
system should be responsible for bias mood processing, which could regulate the
interaction between ACC and other brain areas.28 These studies suggest ACC might
be related with bias mood on MDD.13
Recent mapping studies support individual has variability in connections between
brain nodes,29 which can indicate pathological implications.30 The finding of
increasing FCs between pgACC and left parahippocampus might implicate episodic
memory processing and partly visceral monitoring, which are compromised of
cognition symptoms in depression.12,18 Some studies reported participants with
elevated depression symptoms showed weaker activation in parietal regions by
cognitive control test.31 Depressive patients decreased activity in parietal region as
prefrontal cortex, and anterior cingulated gyrus et al by face-profession pairs test.32
These studies showed the coherence of function between ACC and parietal lobe,
frontal lob. Thus, increasing FCs between pgACC and parietal lobe, frontal lobe in
this study should be related with the cognitive dysfunction on MDD. However, how
this increasing alteration occurs is not clear. It might involve early developmental
changes related with structure and biochemical paradigms especially for depressive
“trait”.33
The results from seed thalamus supported some previous studies, in which it showed
abnormal structure and function of thalamus.4,5 In this study, thalamus was chose as
seed region based on a latest interesting finding, which showed significantly lower
regional homogeneity in the left thalamus in MDD than health control.16 The
decreased hemodynamic responses indicated abnormal function of local neural
activity.15,16 In this study, the findings indicated decreased FCs in depressed subjects
between thalamus and the right precuneus and right cingulate gyrus in health control
compared with depressed subjects. The decreased spontaneous activity within
thalamus should be responsible for the decreasing FCs to other areas. Thalamus was
involved in the serotonergic (5-HT) mechanism of depression.34 The altered
functional network might implicate somatic symptoms of depression, such as
characterized insomnia, lack of appetite and lower libido.4,5
In this study, the decreased FCs between thalamus with right precuneus and cingulate
gyrus are not agreement with some prior literatures. One earlier study identified over
connectivity in thalamus related to depression by independent component analysis
(ICA).13 Another study showed there was not significantly altered FCs between
precuneus and thalamus in depression patients.35 Actually, there are some different
findings if post analysis is different. The differences of patients sample were also
confounding factors between medicine- naïve and ever taking medicine subjects.
Precuneus plays an important role in executive-function to attentional targets. The
FCs of thalamus to precuneus and cingulate gyrus have implicated cognition
symptoms due to bias mood processing, such as the focus of self-relevant thought,36
declining episodic memory and executive function, 31 et al.
In this study, two seeds were separately used to construct the functional networks
from cortex and limbic regions of MRC. The patients sample is first episode, and
never got any psychotropic medicine, which is ideal to explore the intrinsic character
related with depression. However, the present findings may be limited by the small
sample size of participants. The strait or trait signatures related with disease
mechanism could not be investigated by this cross section study. Future studies need
larger number sample to indicate the issue by following up.
In summary, the present results confirm altered functional network related with MRC
in MDD. The increased functional connectivity of pgACC and decreased functional
connectivity of thalamus is mainly involved in bias mood processing and cognition.
The two networks would be combined to explore the abnormal functional signatures
in depression. The present findings may be limited by the small sample size of
participants. Actually, the fMRI also received the influence of age. In the future, the
larger sample on different age level needs to be explored. Additionally, the following
up study would be necessarily to explore the implications of abnormal FCs in MDD.
ACKNOWLEDGEMENTS
The authors thank Yuan Zhou for their valuable suggestions on the data analysis
(Center for Social and Economic Behavior, Institute of Psychology, Chinese
Academy of Sciences, Beijing, PR China). The authors thank Yi Jin, Jianyin Qiu and
Chunbo Li for their suggestions on manuscript (Shanghai Mental Health Center).
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Table 1. Demographic and Clinical characteristics
Depressed
Patients
(n = 16)
Healthy Subjects
(n = 16)
t
P
33.445.77
9/7
33.255.09
9/7
0.09
0.92
-0.27
15.482.69
15.723.03
33.135.74
3.081.30
32.26
31.192.95
2.631.96
8.18
5.620.72
3.310.87
HAMD: Hamilton Depression Rating Scale. HAMA: Hamilton Anxiety Scale.
0.78
Age (years)
Gender (male/female)
Education level (years)
Age on set (years)
Duration of illness (months)
24-item HAMD Score
14-item HAMA Score
0.00
0.00
Table 2. Significant Clusters in the Paired t-Tests Comparing Functional Connectivity
of ACC and Thalamus in MDD subjects versus Controls
Cluster Location
(BA)
Primary Peak Location
Cluster
Size
T -Score
923
3.97
pgACC
MDD versus Controls
parahippocampus
gyrus
-21
-49
7
Parietal
Prefrontal
-3
-27
-64
-46
52
28
3.59
3.33
Controls versus MDD
No significant cluster
Thalamus
MDD versus Controls
No significant cluster
Controls versus MDD
Parietal
9
15
-52
-43
46
43
962
4.89
3.92
cingulate gyrus
Listed are the Talairach coordinates (MNI), voxel number (Cluster size), and
significance level for primary peak of each region. Height and extent thresholds of P
< 0.05 were used to determine significant clusters. Abbreviations: MDD, major
depression disorder. BA, Broadmann’s Area. pgACC, pregenual anterior cingulate
cortex
Figure 1. Location of seed regions. Red open circle corresponds to a seed region in
the pgACC [12 41 13], and blue open circle corresponds to a seed region in the
thalamus [−7.5 −17.5 5.5]
Figure 2. Comparison of connectivity maps for depressed and control subjects across
the FCs of the pgACC. X, Y and Z are the Talairach coordinates (MNI) of primary
peak in significantly different clusters. The color bar indicates that images were
thresholded at P < 0.05
Figure 3. Comparison of connectivity maps for depressed and control subjects across
the FCs of the thalamus. X, Y and Z are the Talairach coordinates (MNI) of primary
peak in significantly different clusters. The color bar indicates that images were
thresholded at P < 0.05.