ORIGINAL ARTICLE
Functional and Anatomical Brain Abnormalities and Effects of Antidepressant in Major Depressive Disorder: Combined Application of Voxel-Based Morphometry and Amplitude of Frequency Fluctuation in Resting State Junfang Fang, MS,* Ning Mao, MS,* Xingyue Jiang, MD,* Xuri Li, MD,† Bin Wang, MD,† and Qian Wang, MS† Objective: Convergent studies suggest that functional and morphological abnormalities of the brain circuits may contribute to the pathophysiology of major depressive disorders (MDD). However, few study has been conducted to examine how or whether functional abnormalities are related to anatomical alterations in the brain. We used voxel-based morphometry and amplitude of frequency fluctuation (ALFF) methods to investigate their association. Methods: Twenty MDD participants, 16 treated MDD participants and 18 healthy controls acquired baseline high-resolution structural magnetic resonance imaging and functional magnetic resonance imaging scans. Using SPM8 and REST1.8 software to analyze the imaging data. Results: The MDDs had decreased gray matter volume and ALFF values in different brain regions. Compared to pretreatment, posttreatment MDDs had increased gray matter volume and ALFF values in some brain regions. Conclusions: There is no overlap of brain regions with the functional and anatomical alterations, and they may alter independently in MDDs. Key Words: major depressive disorder, voxel-based morphometry, amplitude of frequency fluctuation, resting state (J Comput Assist Tomogr 2015;39: 766–773)
D
epression is linked to persistent low mood, both in the resting state and in executing cognitive tasks. Functional status in patients with depression compared with normal people is likely to vary and may improve with the relief of symptoms. Positron emission tomography and single photon emission computed tomography are commonly used for resting state research. They reveal that depression patients may have abnormal metabolism inspecific brain neural circuit,1,2 and convergent evidence from functional magnetic resonance imaging (fMRI)3,4 and diffusion tensor imaging5 demonstrate that dysregulation of resting-state brain circuits that involve emotional and cognitive processing6,7 may contribute to the pathophysiology of major depressive disorders (MDD). The fMRI studies suggest that brain dysfunction area mainly in the frontal lobe, temporal lobe, cingulated gyrus, limbic lobe, and basal ganglia region.8 After short-term treatment to clinical cure, most functions can return to normal, but there can remain some brain dysfunctions,9,10 which would be the foundation of recurrent depression.
From the *Department of Radiology, Affiliated Hospital of Binzhou Medical University; and †Binzhou Medical University, Shandong, P.R. China. Received for publication October 31, 2014; accepted March 20, 2015. Correspondence to: Bin Wang, MD, Binzhou Medical University, 346 Guanhai Rd Laishan, Yantai, Shandong 264000, P.R. China (e‐mail: binwang [email protected]). This study was supported by grants from the National Nature Science of Foundation of China (Grant no. 81171303), and a Taishan Scholar's program to Xuri Li and Bin Wang. Ning Mao, who made a great deal of work for this study, is the co-first author. The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RCT.0000000000000264
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Gray matter volume (GMV) deficits have been reported in MDD patients using voxel-based morphometry (VBM), including reductions in the frontal cortex,11,12 temporal gyrus,13 anterior cingulate cortex,14,15 and occipital gyrus.13 After treatment, MDD patients had GMV reduction in the dorsal anterior insula,16 cingulate cortex, and superior frontal gyrus.17 Currently, the findings of amplitude of frequency fluctuation (ALFF) in MDD varies, but most research support the changes of frontal and the default mode network (DMN) that are related to the depression.18,19 Decreased ALFF is found in the frontal cortex (orbitofrontal cortex, ventral prefrontal cortex, and ventral prefrontal cortex) and right superior temporal gyrus18 and the DMN.19 Studies suggested that remitted women with MDDs had low ALFF in the right putamen.20 Therefore, further studies using the ALFF and VBM methods to analyze the whole brain ALFF and GVM changes are necessary to better understand the effects of antidepressants in MDD. In our study, we used the ALFF and VBM methods to investigate the whole brain structural and functional abnormalities in MDDs before and after antidepressant treatment. We hypothesized that compared with healthy controls (HCs), MDD patients with GMV and ALFF abnormalities in resting-state brain circuits, such as DMN, sensorimotor components, executive control components, frontal-parietal components, and temporal-parietal components, these abnormalities would be return to normal after treatment.
MATERIALS AND METHODS Participants Twenty MDD participants were recruited from hospital between April 2012 and August 2014. All MDD participants were diagnosed by 2 trained psychiatrists individually using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV and met the following inclusion criteria: fulfilling Diagnostic and Statistical Manual of Mental Disorders-IV criteria for MDD; Untreated; aged 50 to 70 years; 17-item Hamilton Depression Scale (HAMD-17) greater than 24, after 8 weeks antidepressant treatment with reduction rate of HAMD-17 greater than 75% into treated group; no other mental disorders or drug or alcohol dependent patients; no severe physical illness; no serious infection or operation. Eighteen HCs matched for sex, age, and education were recruited from the local area. Good mental health, no history of mental disorder; no nervous system diseases and serious body disease; no long-term use of painkillers, sedatives, hypnotics, and other special drug history; no history of head trauma and operation; do not meet the criteria for depression. All participants provided written informed consent after receiving detailed description of the study. The study was approved by the Ethics Committee of China Medical University.
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MRI Acquisition Scanning was conducted by Siemens 1.5 T (Munich, Germany). The baseline high-resolution structural MRI was used to get structural MR images for VBM analysis. Using a 3D T1-weighted gradient echo pulse sequence (repetition time, 1940 ms, echo time, 3.08 ms, flip angle 15°, field of view, 250 mm, and voxel dimensions of 1.0 1.0 1.0 mm3). Resting state functional scanning with a gradient echo-Echo planar imaging sequence acquisition (repetition time/echo time = 2000 ms/29 ms, field of view = 192 mm, voxel dimensions of 3.0 3.0 3.0 mm3, 3 mm). The VBM analysis was performed using Matlab R2011b (the Math Works, Natick, MA), Statistical Parametric Mapping (SPM8) software (Wellcome Department of Imaging Neuroscience, London, UK), and VBM8 toolbox (http:// dbm. neuro. uni-jena.de/ vbm.html). All original images were manually aligned on the anterior-posterior commissure line. T1-weighted images were imported into a format that could be used by the VBM8 algorithm. After bias-corrected, images were segmented into gray matter (GM), white matter, and cerebrospinal fluid using the maximum a-posteriori spatial probability segmentation approach extended by partial volume estimation. The segmented images were normalized to Montreal Neurological Institute space using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra method, and then were smoothed with an 8 mm Gaussian filter. Resting-state f MRI data preprocessing was carried out by using SPM8 (http://www.fil.ion.ucl.ac.uk/spm/software/spm8) and the Resting State fMRI Data Analysis Toolkit (REST, V1.5_101101, http://www.restfmri.net). Image preprocessing included slice timing correction, head motion correction, spatial normalization, and smoothing. Before image preprocessing, we need removing the first 6 time points sequence to attained steadystate of longitudinal magnetization. Spatial normalization was performed by using the standard Echo planar imaging template from the Montreal Neurological Institute. Spatial smoothing was done with a 4-mm full-width half-maximum Gaussian filter. The head of translational is less than 2 mm and rotational mobile is less than 2°, which are the subjects' image into subsequent analysis. Then, ALFF was calculated using REST software. Linear detrending and temporal bandpass (0.01–0.08 Hz) filtering were performed to remove low-frequency drifts and physiological high-frequency noise.
Statistical Analysis We conducted a 2-sample t test and χ2 test to examine demographic data (age, sex, IQ, length of illness) and HAMD scores among the MDD and HC groups with SPSS 13.0 software (SPSS Inc, Chicago, IL). We analyzed the imaging data with SPM8 and REST1.8 software. To identify differences in brain volume and ALFF across the entire brain, which were separately compared for every 2 groups (MDD and HC, treated MDD and HC), a 2-sample test was used. Meanwhile pre- and posttreatment MDDs with a model of a paired-sample test were compared. We set the threshold with a corrected P (P < 0. 05). Pearson correlation was performed to determine the correlation between abnormal ALFF or GMV values of detected brain regions and HAMD scores in the MDD patients.
RESULTS Clinical Characteristics Clinical characteristics are presented in Table 1. Analysis of variance showed that there was no significant difference in
Combined Application of VBM and ALFF
TABLE 1. Demographic and Characteristics of Participants MDD (n = 20) HC (n = 18) Age, y Sex (male/female) Years of education HAMD HAMD (treated) Onset age of illness Length of illness, y No. episodes
Mean
SD
59.2 12/8 9.3 26.6 6.4 56.1 3.6 2.1
3.7 1.8 1.9 0.98 5.1 1.1 0.8
Mean SD 59.1 10/8 8.6
P
Statistic
7.5
t = 0.105 0.918 χ2 = 0.77 0.78 2.1 t = 0.674 0.512
age, sex, and years of education among the 2 groups. The mean episode number was 2.1 ± 0.8. The HAMD score in MDD patients was 26.6 ± 1.9. The HAMD score in treated MDD patients was 6.4 ± 0.98.
Group Differences in Brain GM Volumes Table 2 shows that MDD patients displayed significantly smaller GM volumes in the inferior temporal (BA20), left inferior frontal gyrus (BA13), right fusiform gyrus (BA37), and right cuneus (BA18) (Fig. 1). After effective treatment, the treated MDD patients showed increased GMV in the right superior temporal gyrus (BA42), left cuneus (BA18), as well as decreased GMV in the left inferior frontal gyrus (BA13), left middle frontal gyrus (BA8), and right fusiform gyrus (BA37) as shown in Figure 2.
Group Differences in Brain ALFF Values Table 3 shows clusters with decreased ALFF in the left fusiform gyrus (BA37), left posterior cingulated (BA29), right lingual gurus (BA18), right superior frontal (BA10), and right middle frontal (BA9) (Fig. 3). The treated MDD showed a decreased ALFF in the right precuneus, and an increased ALFF in the left middle temporal gyrus (BA21) as shown in Figure 4.
Paired Compared of Pre- and Posttreatment MDDs As shown in Table 4, after treatment, MDDS had decreased GMV in the left rectus, increased GMV in the left putamen, medial frontal gyrus, supper parietal gyrus, precentral, right lingual gyrus (Fig. 5), and increased ALFF in the left fusiform (Fig. 6).
Correlations Between HAMD Scores and Functional or Anatomical Findings As shown in Table 5 and Table 6, the Pearson correlation analyses in the MDD patients showed significantly negative correlations between the HAMD scores and mean GMV values of the right fusiform gyrus (r = −0.519, P = 0.019) and between the HAMD scores and ALFF values of the left fusiform gyrus (r = −0.820, P = 0.001).
DISCUSSION This study was undertaken to elucidate the anatomical and resting-state functional characteristic in the brains of MDD patients before and after treatment. In this study, we present 4 important findings. First, compared to HCs, MDD patients had smaller GMV and ALFF values in some regions of the brain, suggesting that MDD patients had functional and structural abnormalities. Second, after effective treatment, parts of the ALFF and GMV deficits became normal, but still there were areas of the brain in which
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TABLE 2. Brain Regions Showing Gray Matter Volume Abnormalities in MDD and Treated MDD, Compared With HC MNI Coordinates Areas MDD/HC Inferior temporal Inferior frontal gyrus Precuneus Mid-cingulate Fusiform gyrus Inferior temporal Cuneus Treated MDD > HC Superior temporal gyrus Postcentral gyrus Cuneus Treated MDD < HC Inferior frontal gyrus Middle frontal gyrus Parahippocampal Fusiform gyrus
Cluster Size
x
y
z
BA
T Values
R/L
1310 342 188 343 1662 163 109
−46.5 −43.5 −3 6 36 49.5 16.5
−10.5 22.5 −72 −13.5 −31 −7.5 −97.5
−34.5 7.5 16.5 51 −16.5 −27 16.5
20 13/45 31 31 37 20 18
−4.51 −3.24 −3.07 −3.19 −4.40 −2.76 −2.57
L L L R R R R
523 311 116
67.5 49.5 −15
−15 −28.5 −90
7.5 31.5 21
42 2 18
3.78 2.92 3.46
R R L
1015 658 171 769
−43.5 −19.5 −19.5 30
21 2 6 −51
7.5 46.5 −30 −16.5
13/45 8 28 37
−6.31 −3.99 −3.79 −3.83
L L L R
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
FIGURE 1. Statistical maps showing gray matter volume differences between MDD and HC. Blue denotes decreased gray matter volume, and the color bar indicates the T values from 2-sample t tests. Figure 1 can be viewed online in color at www.jcat.org.
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FIGURE 2. Statistical maps showing gray matter volume differences between treated MDD and HC. Blue denotes decreased gray matter volume, and the color bar indicates the T values from 2-sample t tests. Figure 2 can be viewed online in color at www.jcat.org.
ALFF and GMV were reduced. Also, compared to pretreatment MDDs, posttreatment MDDs have more increased GMV and ALFF values. Third, there was no overlap between the brain TABLE 3. Brain Regions Showing ALFF Values Abnormalities in MDD and Treated MDD, Compared With HC
Areas MDD/HC Fusiform gyrus Posterior cingulate Lingual gyrus Superior frontal gyrus Middle frontal gyrus Treated MDD > HC Middle temporal gyrus Treated MDD < HC Precuneus
Cluster Size
MNI Coordinates
T BA Values R/L
x
y
z
133 26 39 35
−54 −12 3 21
−57 −51 −84 69
−21 6 −9 6
28
30
36
42
40
−57
−21
−6 21
41
3
−63
27
−4.50 −3.06 −3.94 −3.14
L L R R
9 −2.82
R
37 29 18 10
7.76
L
−5.41
R
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
regions where the ALFF and GMV were reduced. Finally, as mentioned above, there are significant correlations between the HAMD scores and the mean VBM and ALFF values, suggesting that the severity of depressive illness may play an important role in the brain structures and functional abnormality in depression. As predicted, we found reduced GMV and ALFF values in the resting-state brain circuits. The GMV reductions were found in the parietal-temporal regions (bilateral inferior temporal gyrus, the left inferior frontal gyrus, the left precuneus, and right midcingulate) and visual components (the right fusiform gyrus and right cuneus). Decreased functional activity was mainly found in the frontal-parietal regions (the right middle frontal gyrus, the right superior frontal gyrus and the left posterior cingulate) and the right lingual gyrus. After the treatment, we found GM reduction mainly in the frontal regions (left inferior and middle frontal gyrus), left parahippocampal and right fusiform, and ALFF deficits in the right precuneus. Our results suggest that brain function and structure may alter independently and play a different role in the neurobiology of MDD. Gray matter volume abnormalities measured by VBM may represent a more stable and long time change results, but the functional deficits measured by ALFF may be more present in the disease status. These alterations of GMV and ALFF in posttreatment MDDs may be trait markers of MDD. The cingulated cortex is part of the cingulated system, which is involved in emotion formation and processing and cognitive function, such as learning and memory.21 Previous diffusion tensor imaging results showed that in the cingulum bundle part, there are changes in the structure of belt buckle connectivity. It also
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FIGURE 3. Statistical maps showing ALFF differences between MDD and HC. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 3 can be viewed online in color at www.jcat.org.
has an effect on relieving depression.22 Our data suggest a decreased GMV in the right mid-cingulate and reduced ALFF in the left posterior cingulate. This is also reported in the previous studies.14,23 In the MDD patients in this study, these structural abnormalities also included reduced GMV in the frontal cortex, right temporal fusiform gyrus, and right cuneus. Smaller GMV was observed in the bilateral inferior temporal, which was also observed in the first-episode MDD15 and in the drug-naive MDD patients.24 The superior frontal, middle frontal, and precuneus are recognized as the key regions related to the frontal-parietal network, which is associated with attention, cognitive control, and decision-making
processes.15,25 Previous studies suggested that abnormal function exist in these regions.26 We also found reduced ALFF values in the right superior frontal and right middle frontal of the brains. The lingual gyrus of occipital lobe is part of the visual recognition network, which is thought to play a role in the perception of facial emotion and is crucial for social functioning and individual emotion.27,28 In our results, the MDD patients had reduced ALFF values in the right lingual gyrus compared to HC. The deficits of ALFF values are also found in some other studies,20,29 suggesting that the lingual gyrus activity and short-term change in symptom severity may have a positive correlation. Reduced ALFF values in the fusiform have been found in this study.9 Temporal lobe and fusiform gyrus ALFF anomalies may indicate the presence of interference in the social function and emotional loop circuit. The fusiform cortex is a part of the visual loop and is thought to TABLE 4. Brain Regions Showing ALFF Values and GMV Abnormalities in Treated MDDs, Compared With Pretreatment
Areas VBM Rectus Putamen Lingual gyrus Medial frontal gyrus Supper parietal gyrus Precentral ALFF Fusiform FIGURE 4. Statistical maps showing ALFF differences between treated MDD and HC. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 4 can be viewed online in color at www.jcat.org.
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Cluster Size 359 420 1009 1241
MNI Coordinates x
y
z
−1.5 48 −22.5 −18 18 −10.5 9 −57 3 −1.5 −16.5 54
T BA Values R/L −30.26 18.33 42.62 6 50.37
L L R L
11
355
−13.5
−72
57
7
66.05
L
364
−36
3
33
9
17.28
L
41
−36
−33
−18
36
9.68
L
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
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Combined Application of VBM and ALFF
FIGURE 5. Statistical maps showing gray matter volume differences between pre- and posttreatment MDDs. Blue denotes decreased gray matter volume, and the color bar indicates the T values from paired-sample t tests. Figure 5 can be viewed online in color at www.jcat.org.
be involved in visual emotional facial stimulation neural circuits. Facial emotion stimuli-responsive change is considered as a possible indicator for early diagnosis of MDDs. After 8 weeks of antidepressant treatment, we found a decreased GMV in the left inferior frontal gyrus, left middle frontal gyrus, left parahippocampal, and right fusiform as well as reduced ALFF in the right precuneus compared to HC. The MDD patients with severely impaired hippocampal function and structure, existence of lateralization (left predominant). After short-term antidepressant treatment and clinical recovery, this damage was not effectively reversed.30,31 Precuneus is part of the DMN. It
has been found to have reduced functional in first-episode and treatment-naive MDD patients.32 Other studies also found decreased functional connectivity of precuneus.33 The deficits of ALFF suggest the function abnormalities of precuneus in MDD patients. Based on these results, we conclude that some functional and anatomical abnormalities regions in MDD became normal. However, there are still some regions with VBM and ALFF deficits, and these regions do not overlap. In addition, after antidepressant treatment, we also found increased VBM in the right superior temporal gyrus, right postcentral gyrus, and left cuneus as well as increased ALFF in the left middle
FIGURE 6. Statistical maps showing ALFF differences between pre- and posttreatment MDDs. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 6 can be viewed online in color at www.jcat.org. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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temporal gyrus. The higher ALFF and GMV regions in cured MDD patients may be considered to be a compensatory reallocation, which evokes patients with MDD to function in a relatively effective way. Further studies are needed to clarify how the compensation influences patients with MDD.
TABLE 6. Correlation Between the Mean VBM of the Right Fusiform Gyrus and HAMD Scores in the Patient Group
Study Limitations Several limitations affect the interpretation of our findings. First, although our findings are notable, the relatively small sample size may limit the translational value of our results. More studies with a larger sample size are needed. Second, changes in the brain regions after treatment may be due to different methods used for treatment because we did not restrict the type of treatment. Therefore, in the future, we will study the changes in brain regions with different treatment methods and compare the changes to find deference between them. Finally, the VBM and ALFF methods used in the current study have their own limitations. The ALFF method is used to identify the resting-state functional alterations of GM, and the VBM method is used to investigate the anatomical deficits of GM, they study different aspects of GM in MDDs. Therefore, combined application of different methods is necessary to find the structure and functional abnormalities of depression, the relationship between them, and how they contribute to depression.
CONCLUSIONS To the best of our knowledge, this is the first to investigate anatomical and functional alterations in the same sample. There exists a separation pattern of brain regions with anatomical and functional alterations in pre- and posttreatment depression patients. In summary, our findings support the notion that brain functional and anatomical deficits may contribute independently to the neurobiology of MDD. The functional and morphological abnormalities in the cured MDD patients may be related with
TABLE 5. Correlation Between the Mean ALFF of the Left Fusiform Gyrus and HAMD Scores in the Patient Group
the recurrence of depression. Future studies with combination of functional and morphological MRI methods will clarify the reasons of functional and morphological abnormalities and the separation phenomenon, which will provide new insights into understanding the neurobiology of MDD.
ACKNOWLEDGMENTS The authors thank the Binzhou Medical University and Yantai Affiliated Hospital of Binzhou Medical University.
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Functional and Anatomical Brain Abnormalities and Effects of Antidepressant in Major Depressive Disorder: Combined Application of Voxel-Based Morphometry and Amplitude of Frequency Fluctuation in Resting State Junfang Fang, MS,* Ning Mao, MS,* Xingyue Jiang, MD,* Xuri Li, MD,† Bin Wang, MD,† and Qian Wang, MS† Objective: Convergent studies suggest that functional and morphological abnormalities of the brain circuits may contribute to the pathophysiology of major depressive disorders (MDD). However, few study has been conducted to examine how or whether functional abnormalities are related to anatomical alterations in the brain. We used voxel-based morphometry and amplitude of frequency fluctuation (ALFF) methods to investigate their association. Methods: Twenty MDD participants, 16 treated MDD participants and 18 healthy controls acquired baseline high-resolution structural magnetic resonance imaging and functional magnetic resonance imaging scans. Using SPM8 and REST1.8 software to analyze the imaging data. Results: The MDDs had decreased gray matter volume and ALFF values in different brain regions. Compared to pretreatment, posttreatment MDDs had increased gray matter volume and ALFF values in some brain regions. Conclusions: There is no overlap of brain regions with the functional and anatomical alterations, and they may alter independently in MDDs. Key Words: major depressive disorder, voxel-based morphometry, amplitude of frequency fluctuation, resting state (J Comput Assist Tomogr 2015;39: 766–773)
D
epression is linked to persistent low mood, both in the resting state and in executing cognitive tasks. Functional status in patients with depression compared with normal people is likely to vary and may improve with the relief of symptoms. Positron emission tomography and single photon emission computed tomography are commonly used for resting state research. They reveal that depression patients may have abnormal metabolism inspecific brain neural circuit,1,2 and convergent evidence from functional magnetic resonance imaging (fMRI)3,4 and diffusion tensor imaging5 demonstrate that dysregulation of resting-state brain circuits that involve emotional and cognitive processing6,7 may contribute to the pathophysiology of major depressive disorders (MDD). The fMRI studies suggest that brain dysfunction area mainly in the frontal lobe, temporal lobe, cingulated gyrus, limbic lobe, and basal ganglia region.8 After short-term treatment to clinical cure, most functions can return to normal, but there can remain some brain dysfunctions,9,10 which would be the foundation of recurrent depression.
From the *Department of Radiology, Affiliated Hospital of Binzhou Medical University; and †Binzhou Medical University, Shandong, P.R. China. Received for publication October 31, 2014; accepted March 20, 2015. Correspondence to: Bin Wang, MD, Binzhou Medical University, 346 Guanhai Rd Laishan, Yantai, Shandong 264000, P.R. China (e‐mail: binwang [email protected]). This study was supported by grants from the National Nature Science of Foundation of China (Grant no. 81171303), and a Taishan Scholar's program to Xuri Li and Bin Wang. Ning Mao, who made a great deal of work for this study, is the co-first author. The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/RCT.0000000000000264
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Gray matter volume (GMV) deficits have been reported in MDD patients using voxel-based morphometry (VBM), including reductions in the frontal cortex,11,12 temporal gyrus,13 anterior cingulate cortex,14,15 and occipital gyrus.13 After treatment, MDD patients had GMV reduction in the dorsal anterior insula,16 cingulate cortex, and superior frontal gyrus.17 Currently, the findings of amplitude of frequency fluctuation (ALFF) in MDD varies, but most research support the changes of frontal and the default mode network (DMN) that are related to the depression.18,19 Decreased ALFF is found in the frontal cortex (orbitofrontal cortex, ventral prefrontal cortex, and ventral prefrontal cortex) and right superior temporal gyrus18 and the DMN.19 Studies suggested that remitted women with MDDs had low ALFF in the right putamen.20 Therefore, further studies using the ALFF and VBM methods to analyze the whole brain ALFF and GVM changes are necessary to better understand the effects of antidepressants in MDD. In our study, we used the ALFF and VBM methods to investigate the whole brain structural and functional abnormalities in MDDs before and after antidepressant treatment. We hypothesized that compared with healthy controls (HCs), MDD patients with GMV and ALFF abnormalities in resting-state brain circuits, such as DMN, sensorimotor components, executive control components, frontal-parietal components, and temporal-parietal components, these abnormalities would be return to normal after treatment.
MATERIALS AND METHODS Participants Twenty MDD participants were recruited from hospital between April 2012 and August 2014. All MDD participants were diagnosed by 2 trained psychiatrists individually using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV and met the following inclusion criteria: fulfilling Diagnostic and Statistical Manual of Mental Disorders-IV criteria for MDD; Untreated; aged 50 to 70 years; 17-item Hamilton Depression Scale (HAMD-17) greater than 24, after 8 weeks antidepressant treatment with reduction rate of HAMD-17 greater than 75% into treated group; no other mental disorders or drug or alcohol dependent patients; no severe physical illness; no serious infection or operation. Eighteen HCs matched for sex, age, and education were recruited from the local area. Good mental health, no history of mental disorder; no nervous system diseases and serious body disease; no long-term use of painkillers, sedatives, hypnotics, and other special drug history; no history of head trauma and operation; do not meet the criteria for depression. All participants provided written informed consent after receiving detailed description of the study. The study was approved by the Ethics Committee of China Medical University.
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MRI Acquisition Scanning was conducted by Siemens 1.5 T (Munich, Germany). The baseline high-resolution structural MRI was used to get structural MR images for VBM analysis. Using a 3D T1-weighted gradient echo pulse sequence (repetition time, 1940 ms, echo time, 3.08 ms, flip angle 15°, field of view, 250 mm, and voxel dimensions of 1.0 1.0 1.0 mm3). Resting state functional scanning with a gradient echo-Echo planar imaging sequence acquisition (repetition time/echo time = 2000 ms/29 ms, field of view = 192 mm, voxel dimensions of 3.0 3.0 3.0 mm3, 3 mm). The VBM analysis was performed using Matlab R2011b (the Math Works, Natick, MA), Statistical Parametric Mapping (SPM8) software (Wellcome Department of Imaging Neuroscience, London, UK), and VBM8 toolbox (http:// dbm. neuro. uni-jena.de/ vbm.html). All original images were manually aligned on the anterior-posterior commissure line. T1-weighted images were imported into a format that could be used by the VBM8 algorithm. After bias-corrected, images were segmented into gray matter (GM), white matter, and cerebrospinal fluid using the maximum a-posteriori spatial probability segmentation approach extended by partial volume estimation. The segmented images were normalized to Montreal Neurological Institute space using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra method, and then were smoothed with an 8 mm Gaussian filter. Resting-state f MRI data preprocessing was carried out by using SPM8 (http://www.fil.ion.ucl.ac.uk/spm/software/spm8) and the Resting State fMRI Data Analysis Toolkit (REST, V1.5_101101, http://www.restfmri.net). Image preprocessing included slice timing correction, head motion correction, spatial normalization, and smoothing. Before image preprocessing, we need removing the first 6 time points sequence to attained steadystate of longitudinal magnetization. Spatial normalization was performed by using the standard Echo planar imaging template from the Montreal Neurological Institute. Spatial smoothing was done with a 4-mm full-width half-maximum Gaussian filter. The head of translational is less than 2 mm and rotational mobile is less than 2°, which are the subjects' image into subsequent analysis. Then, ALFF was calculated using REST software. Linear detrending and temporal bandpass (0.01–0.08 Hz) filtering were performed to remove low-frequency drifts and physiological high-frequency noise.
Statistical Analysis We conducted a 2-sample t test and χ2 test to examine demographic data (age, sex, IQ, length of illness) and HAMD scores among the MDD and HC groups with SPSS 13.0 software (SPSS Inc, Chicago, IL). We analyzed the imaging data with SPM8 and REST1.8 software. To identify differences in brain volume and ALFF across the entire brain, which were separately compared for every 2 groups (MDD and HC, treated MDD and HC), a 2-sample test was used. Meanwhile pre- and posttreatment MDDs with a model of a paired-sample test were compared. We set the threshold with a corrected P (P < 0. 05). Pearson correlation was performed to determine the correlation between abnormal ALFF or GMV values of detected brain regions and HAMD scores in the MDD patients.
RESULTS Clinical Characteristics Clinical characteristics are presented in Table 1. Analysis of variance showed that there was no significant difference in
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TABLE 1. Demographic and Characteristics of Participants MDD (n = 20) HC (n = 18) Age, y Sex (male/female) Years of education HAMD HAMD (treated) Onset age of illness Length of illness, y No. episodes
Mean
SD
59.2 12/8 9.3 26.6 6.4 56.1 3.6 2.1
3.7 1.8 1.9 0.98 5.1 1.1 0.8
Mean SD 59.1 10/8 8.6
P
Statistic
7.5
t = 0.105 0.918 χ2 = 0.77 0.78 2.1 t = 0.674 0.512
age, sex, and years of education among the 2 groups. The mean episode number was 2.1 ± 0.8. The HAMD score in MDD patients was 26.6 ± 1.9. The HAMD score in treated MDD patients was 6.4 ± 0.98.
Group Differences in Brain GM Volumes Table 2 shows that MDD patients displayed significantly smaller GM volumes in the inferior temporal (BA20), left inferior frontal gyrus (BA13), right fusiform gyrus (BA37), and right cuneus (BA18) (Fig. 1). After effective treatment, the treated MDD patients showed increased GMV in the right superior temporal gyrus (BA42), left cuneus (BA18), as well as decreased GMV in the left inferior frontal gyrus (BA13), left middle frontal gyrus (BA8), and right fusiform gyrus (BA37) as shown in Figure 2.
Group Differences in Brain ALFF Values Table 3 shows clusters with decreased ALFF in the left fusiform gyrus (BA37), left posterior cingulated (BA29), right lingual gurus (BA18), right superior frontal (BA10), and right middle frontal (BA9) (Fig. 3). The treated MDD showed a decreased ALFF in the right precuneus, and an increased ALFF in the left middle temporal gyrus (BA21) as shown in Figure 4.
Paired Compared of Pre- and Posttreatment MDDs As shown in Table 4, after treatment, MDDS had decreased GMV in the left rectus, increased GMV in the left putamen, medial frontal gyrus, supper parietal gyrus, precentral, right lingual gyrus (Fig. 5), and increased ALFF in the left fusiform (Fig. 6).
Correlations Between HAMD Scores and Functional or Anatomical Findings As shown in Table 5 and Table 6, the Pearson correlation analyses in the MDD patients showed significantly negative correlations between the HAMD scores and mean GMV values of the right fusiform gyrus (r = −0.519, P = 0.019) and between the HAMD scores and ALFF values of the left fusiform gyrus (r = −0.820, P = 0.001).
DISCUSSION This study was undertaken to elucidate the anatomical and resting-state functional characteristic in the brains of MDD patients before and after treatment. In this study, we present 4 important findings. First, compared to HCs, MDD patients had smaller GMV and ALFF values in some regions of the brain, suggesting that MDD patients had functional and structural abnormalities. Second, after effective treatment, parts of the ALFF and GMV deficits became normal, but still there were areas of the brain in which
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TABLE 2. Brain Regions Showing Gray Matter Volume Abnormalities in MDD and Treated MDD, Compared With HC MNI Coordinates Areas MDD/HC Inferior temporal Inferior frontal gyrus Precuneus Mid-cingulate Fusiform gyrus Inferior temporal Cuneus Treated MDD > HC Superior temporal gyrus Postcentral gyrus Cuneus Treated MDD < HC Inferior frontal gyrus Middle frontal gyrus Parahippocampal Fusiform gyrus
Cluster Size
x
y
z
BA
T Values
R/L
1310 342 188 343 1662 163 109
−46.5 −43.5 −3 6 36 49.5 16.5
−10.5 22.5 −72 −13.5 −31 −7.5 −97.5
−34.5 7.5 16.5 51 −16.5 −27 16.5
20 13/45 31 31 37 20 18
−4.51 −3.24 −3.07 −3.19 −4.40 −2.76 −2.57
L L L R R R R
523 311 116
67.5 49.5 −15
−15 −28.5 −90
7.5 31.5 21
42 2 18
3.78 2.92 3.46
R R L
1015 658 171 769
−43.5 −19.5 −19.5 30
21 2 6 −51
7.5 46.5 −30 −16.5
13/45 8 28 37
−6.31 −3.99 −3.79 −3.83
L L L R
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
FIGURE 1. Statistical maps showing gray matter volume differences between MDD and HC. Blue denotes decreased gray matter volume, and the color bar indicates the T values from 2-sample t tests. Figure 1 can be viewed online in color at www.jcat.org.
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FIGURE 2. Statistical maps showing gray matter volume differences between treated MDD and HC. Blue denotes decreased gray matter volume, and the color bar indicates the T values from 2-sample t tests. Figure 2 can be viewed online in color at www.jcat.org.
ALFF and GMV were reduced. Also, compared to pretreatment MDDs, posttreatment MDDs have more increased GMV and ALFF values. Third, there was no overlap between the brain TABLE 3. Brain Regions Showing ALFF Values Abnormalities in MDD and Treated MDD, Compared With HC
Areas MDD/HC Fusiform gyrus Posterior cingulate Lingual gyrus Superior frontal gyrus Middle frontal gyrus Treated MDD > HC Middle temporal gyrus Treated MDD < HC Precuneus
Cluster Size
MNI Coordinates
T BA Values R/L
x
y
z
133 26 39 35
−54 −12 3 21
−57 −51 −84 69
−21 6 −9 6
28
30
36
42
40
−57
−21
−6 21
41
3
−63
27
−4.50 −3.06 −3.94 −3.14
L L R R
9 −2.82
R
37 29 18 10
7.76
L
−5.41
R
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
regions where the ALFF and GMV were reduced. Finally, as mentioned above, there are significant correlations between the HAMD scores and the mean VBM and ALFF values, suggesting that the severity of depressive illness may play an important role in the brain structures and functional abnormality in depression. As predicted, we found reduced GMV and ALFF values in the resting-state brain circuits. The GMV reductions were found in the parietal-temporal regions (bilateral inferior temporal gyrus, the left inferior frontal gyrus, the left precuneus, and right midcingulate) and visual components (the right fusiform gyrus and right cuneus). Decreased functional activity was mainly found in the frontal-parietal regions (the right middle frontal gyrus, the right superior frontal gyrus and the left posterior cingulate) and the right lingual gyrus. After the treatment, we found GM reduction mainly in the frontal regions (left inferior and middle frontal gyrus), left parahippocampal and right fusiform, and ALFF deficits in the right precuneus. Our results suggest that brain function and structure may alter independently and play a different role in the neurobiology of MDD. Gray matter volume abnormalities measured by VBM may represent a more stable and long time change results, but the functional deficits measured by ALFF may be more present in the disease status. These alterations of GMV and ALFF in posttreatment MDDs may be trait markers of MDD. The cingulated cortex is part of the cingulated system, which is involved in emotion formation and processing and cognitive function, such as learning and memory.21 Previous diffusion tensor imaging results showed that in the cingulum bundle part, there are changes in the structure of belt buckle connectivity. It also
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FIGURE 3. Statistical maps showing ALFF differences between MDD and HC. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 3 can be viewed online in color at www.jcat.org.
has an effect on relieving depression.22 Our data suggest a decreased GMV in the right mid-cingulate and reduced ALFF in the left posterior cingulate. This is also reported in the previous studies.14,23 In the MDD patients in this study, these structural abnormalities also included reduced GMV in the frontal cortex, right temporal fusiform gyrus, and right cuneus. Smaller GMV was observed in the bilateral inferior temporal, which was also observed in the first-episode MDD15 and in the drug-naive MDD patients.24 The superior frontal, middle frontal, and precuneus are recognized as the key regions related to the frontal-parietal network, which is associated with attention, cognitive control, and decision-making
processes.15,25 Previous studies suggested that abnormal function exist in these regions.26 We also found reduced ALFF values in the right superior frontal and right middle frontal of the brains. The lingual gyrus of occipital lobe is part of the visual recognition network, which is thought to play a role in the perception of facial emotion and is crucial for social functioning and individual emotion.27,28 In our results, the MDD patients had reduced ALFF values in the right lingual gyrus compared to HC. The deficits of ALFF values are also found in some other studies,20,29 suggesting that the lingual gyrus activity and short-term change in symptom severity may have a positive correlation. Reduced ALFF values in the fusiform have been found in this study.9 Temporal lobe and fusiform gyrus ALFF anomalies may indicate the presence of interference in the social function and emotional loop circuit. The fusiform cortex is a part of the visual loop and is thought to TABLE 4. Brain Regions Showing ALFF Values and GMV Abnormalities in Treated MDDs, Compared With Pretreatment
Areas VBM Rectus Putamen Lingual gyrus Medial frontal gyrus Supper parietal gyrus Precentral ALFF Fusiform FIGURE 4. Statistical maps showing ALFF differences between treated MDD and HC. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 4 can be viewed online in color at www.jcat.org.
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Cluster Size 359 420 1009 1241
MNI Coordinates x
y
z
−1.5 48 −22.5 −18 18 −10.5 9 −57 3 −1.5 −16.5 54
T BA Values R/L −30.26 18.33 42.62 6 50.37
L L R L
11
355
−13.5
−72
57
7
66.05
L
364
−36
3
33
9
17.28
L
41
−36
−33
−18
36
9.68
L
Brain regions with underlines survived the cluster level threshold P < 0.05 (corrected) for the whole brain. x, y, z coordinates of primary peak locations in the MNI space.
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FIGURE 5. Statistical maps showing gray matter volume differences between pre- and posttreatment MDDs. Blue denotes decreased gray matter volume, and the color bar indicates the T values from paired-sample t tests. Figure 5 can be viewed online in color at www.jcat.org.
be involved in visual emotional facial stimulation neural circuits. Facial emotion stimuli-responsive change is considered as a possible indicator for early diagnosis of MDDs. After 8 weeks of antidepressant treatment, we found a decreased GMV in the left inferior frontal gyrus, left middle frontal gyrus, left parahippocampal, and right fusiform as well as reduced ALFF in the right precuneus compared to HC. The MDD patients with severely impaired hippocampal function and structure, existence of lateralization (left predominant). After short-term antidepressant treatment and clinical recovery, this damage was not effectively reversed.30,31 Precuneus is part of the DMN. It
has been found to have reduced functional in first-episode and treatment-naive MDD patients.32 Other studies also found decreased functional connectivity of precuneus.33 The deficits of ALFF suggest the function abnormalities of precuneus in MDD patients. Based on these results, we conclude that some functional and anatomical abnormalities regions in MDD became normal. However, there are still some regions with VBM and ALFF deficits, and these regions do not overlap. In addition, after antidepressant treatment, we also found increased VBM in the right superior temporal gyrus, right postcentral gyrus, and left cuneus as well as increased ALFF in the left middle
FIGURE 6. Statistical maps showing ALFF differences between pre- and posttreatment MDDs. Blue denotes decreased ALFF, and the color bar indicates the T values from 2-sample t tests. Figure 6 can be viewed online in color at www.jcat.org. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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temporal gyrus. The higher ALFF and GMV regions in cured MDD patients may be considered to be a compensatory reallocation, which evokes patients with MDD to function in a relatively effective way. Further studies are needed to clarify how the compensation influences patients with MDD.
TABLE 6. Correlation Between the Mean VBM of the Right Fusiform Gyrus and HAMD Scores in the Patient Group
Study Limitations Several limitations affect the interpretation of our findings. First, although our findings are notable, the relatively small sample size may limit the translational value of our results. More studies with a larger sample size are needed. Second, changes in the brain regions after treatment may be due to different methods used for treatment because we did not restrict the type of treatment. Therefore, in the future, we will study the changes in brain regions with different treatment methods and compare the changes to find deference between them. Finally, the VBM and ALFF methods used in the current study have their own limitations. The ALFF method is used to identify the resting-state functional alterations of GM, and the VBM method is used to investigate the anatomical deficits of GM, they study different aspects of GM in MDDs. Therefore, combined application of different methods is necessary to find the structure and functional abnormalities of depression, the relationship between them, and how they contribute to depression.
CONCLUSIONS To the best of our knowledge, this is the first to investigate anatomical and functional alterations in the same sample. There exists a separation pattern of brain regions with anatomical and functional alterations in pre- and posttreatment depression patients. In summary, our findings support the notion that brain functional and anatomical deficits may contribute independently to the neurobiology of MDD. The functional and morphological abnormalities in the cured MDD patients may be related with
TABLE 5. Correlation Between the Mean ALFF of the Left Fusiform Gyrus and HAMD Scores in the Patient Group
the recurrence of depression. Future studies with combination of functional and morphological MRI methods will clarify the reasons of functional and morphological abnormalities and the separation phenomenon, which will provide new insights into understanding the neurobiology of MDD.
ACKNOWLEDGMENTS The authors thank the Binzhou Medical University and Yantai Affiliated Hospital of Binzhou Medical University.
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