Altered functional connectivity of the dorsolateral prefrontal cortex in first-episode patients with major depressive disorder

European Journal of Radiology 81 (2012) 4035–4040

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Altered functional connectivity of the dorsolateral prefrontal cortex in first-episode patients with major depressive disorder Ting Ye a,b,1,2 , Jing Peng c,1,3 , Binbin Nie a,4 , Juan Gao a,b,5 , Jiangtao Liu c,6 , Yang Li d,7 , Gang Wang d,8 , Xin Ma d,9 , Kuncheng Li c,10 , Baoci Shan a,∗ a

Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics, Chinese Academy of Sciences, PO Box 918, Yu-Quan St, Shijingshan District, Beijing 100049, China Graduate School of Chinese Academy of Sciences, PO Box 918, Yu-Quan St, Shijingshan District, Beijing 100049, China c Department of Radiology, Xuanwu Hospital of Capital Medical University, No. 45, Chang-Chun St, Xuanwu District, Beijing 100053, China d Department of Psychiatry, Anding Hospital of Capital Medical University, No. 5, An Kang Hutong, Deshengmen wai, Xicheng District, Beijing 100088, China b

a r t i c l e

i n f o

Article history: Received 23 February 2011 Accepted 21 April 2011 Keywords: Major depressive disorder Functional connectivity Dorsolateral prefrontal cortex Voxel-based morphometry

a b s t r a c t Background: The aim of this study was to investigate resting-state functional connectivity alteration of the right dorsolateral prefrontal cortex (DLPFC) in patients with first-episode major depressive disorder (MDD). Methods: Twenty-two first-episode MDD patients and thirty age-, gender- and education-matched healthy control subjects were enrolled. Rest state functional magnetic resonance images and structure magnetic resonance images were scanned. The functional connectivity analysis was done based on the result of voxel-based morphometry (VBM). And the right DLPFC was chosen as the seed region of interests (ROI), as its gray matter density (GMD) decreased in the MDD patients compared with controls and its GMD values were negative correlation with the Hamilton Depression Rating Scale (HDRS) scores. Results: Compared to healthy controls, the MDD patients showed increased functional connectivity with right the DLPFC in the left dorsal anterior cingulate cortex (ACC), left parahippocampal gyrus (PHG), thalamus and precentral gyrus. In contrast, there were decreased functional connectivity between the right DLPFC and right parietal lobe. Conclusions: By applying the VBM results to the functional connectivity analysis, the study suggested that abnormality of GMD in right DLPFC might be related to the functional connectivity alteration in the pathophysiology of MDD, which might be useful in further characterizing structure–function relations in this disorder. © 2012 Published by Elsevier Ireland Ltd.

1. Introduction Major depressive disorder (MDD) is characterized by the recurrence of discrete depressive episodes usually featuring symptoms such as low mood, anhedonia, poor motivation,

∗ Corresponding author. Tel.: +86 10 88233185. E-mail addresses: [email protected] (T. Ye), [email protected] (J. Peng), [email protected] (B. Nie), [email protected] (J. Gao), [email protected] (J. Liu), [email protected] (Y. Li), [email protected] (G. Wang), [email protected] (X. Ma), [email protected] (B. Shan). 1 These two authors contributed equally to this work. 2 Tel: +86 10 88236364. 3 Tel: +86 10 83198376; fax: +86 10 83198376. 4 Tel: +86 10 88236364. 5 Tel: +86 10 88236364. 6 Tel: +86 10 83198376; fax: +86 10 83198376. 7 Tel: +86 10 58303189. 8 Tel: +86 10 58303189. 9 Tel: +86 10 58303035. 10 Tel: +86 10 83198376; fax: +86 10 83198376. 0720-048X/$ – see front matter © 2012 Published by Elsevier Ireland Ltd. doi:10.1016/j.ejrad.2011.04.058

impaired psychomotor activity, reduced sleep, appetite, energy and libido [1]. MDD is ranked by the World Health Organization as the first leading cause of years lived with disability. The etiology and pathophysiology of MDD is still under investigation. Brain-imaging techniques such as magnetic resonance imaging (MRI) have been widely used in MDD studies, and achieved many valuable results. The voxel-based morphometry (VBM) studies revealed that reduced gray matter concentration (GMC) in left inferior temporal cortex, the right dorsolateral prefrontal cortex (DLPFC) and reduced gray matter volume (GMV) in the left hippocampal gyrus, the cingulate gyrus and the thalamus was associated with both depressive psychopathology and worse executive performance [2]. Diffusion tensor imaging (DTI), which measures white matter (WM) microstructure, demonstrated lower fractional anisotropy (FA) in the WM tract connecting subgenual ACC to amygdala in the right hemisphere [3]. Functional connectivity analysis showed significantly increased functional connectivity between the subgenual cingulate, thalamus, orbitofrontal cortex, and precuneus in MDD [1].

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Resting-state functional connectivity analysis, a measure of the temporal synchrony or correlations of the blood oxygen leveldependent (BOLD) contrast MRI signals between a reference seed region of interest (ROI) and other brain regions, was used to identify a set of plausible functional connectivity alterations for the reference ROI in neuropsychiatric disorders [4]. Previous functional connection investigations have reported several functionally aberrant brain areas within limbic-cortical circuits and offered a series of meaningful information about the psychopathology of MDD. Kenny et al. used the left and right heads of caudate nuclei (hCN) as the seed regions and found greater connectivity in frontal (precentral, subgyral, middle frontal, and paracentral lobule), sublobar (thalamus and insula), limbic (cingulate), parietal (postcentral gyrus, precuneus, inferior parietal lobule, and supramarginal gyrus), and temporal (superior temporal gyrus) in MDD [5]. Resting-state corticolimbic connectivity study of MDD with seed regions in the pregenual ACC, dorsomedial thalamus, pallidostriatum and amygdala indicated decreased pregenual ACC connectivity to the left and right dorsomedial thalamus, the left and right amygdala as well as the left pallidostriatum [6]. Aizenstein’s study assessed the functional connectivity by correlating the fMRI time-series between the dLPFC and dACC, the result showed diminished functional connectivity between these two regions [7]. However, the seed regions used in these studies were anatomic integrated regions predefined subjectively by toolkit such as wfupickallas, which were considered play a critical role in MDD. These results may lead one to believe that MDD is related to these integrated ROIS, but numerous studies revealed that functional alteration was shown only in part of an anatomic region. For example, ACC has been subdivided into a dorsal cognitive (BA 24) [8] and rostral affective (BA 32) [9] division. Based on such evidence, it is reasonable to speculate that the cause of MDD might not be an anatomic integrated region, but rather a part of the region showing some structural abnormality. In contrast to previous connectivity studies that have been based on a priori defined seed ROI, the present study employed the voxelbased morphometry (VBM) results as the seed ROIs to analyze the functional connectivity, which combined the gray matter density (GMD) alteration with the functional abnormalities.

stroke, Parkinson’s disease, seizure disorder, and multiple sclerosis. Five patients were taking antidepressants at the time of enrollment, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and/or other hypnotics. Healthy control subjects had no personal history of psychiatric illness or any family history of major psychiatric diseases in their first-degree relatives. They also met the exclusion criteria above. 2.2. MRI data acquisition Subjects were scanned by using a 3.0 Tesla MRI scanner (Trio + tim; Siemens, Erlangen, Germany). Participants lay supine with eyes closed, head tightly fixed by belt and foam pads to minimize head movement. The resting-state functional images were acquired by using an echo-planar imaging sequence with the following parameters: 28 axial slices, thickness/skip = 4/1 mm, repetition time (TR) = 2000 ms, echo time (TE) = 40 ms, flip angle (FA) = 90◦ , field of view (FOV) = 256 mm × 256 mm. In addition, a T1-weighted sagittal whole brain image was acquired with three-dimensional spoiled gradient-recalled sequence (a threedimensional magnetization-prepared rapidgradient echo (3DMPRAGE) sequence) [176 slices, TR = 2000 ms, TE = 2.19 ms, slice thickness = 1.0 mm, skip = 0 mm, FA = 9◦ , FOV = 256 mm × 224 mm]. 2.3. Data preprocessing At first, the original resting data were converted to Analyze format using MRIcro (Chris Rorden, http://www.cabiatl. com/mricro/mricro/mricro.html). Then all slices of each subject were corrected for the acquisition time delay between slices and realigned to the first image for head motion correction using a statistical parametric mapping software package (SPM2, Wellcome Department of Imaging Neuroscience, London, UK). The realigned images were normalized to the MNI space with the standard echo planar imaging (EPI) template in SPM2, and resampled to 3 mm × 3 mm × 3 mm. The normalized images were smoothed with a Gaussian kernel of 8 mm full-width at half maximum (FWHM). The smoothed images were used to analyzing the functional connectivity among different cerebral areas. 2.4. VBM analysis

2. Materials and methods 2.1. Subjects Twenty-two patients with MDD were recruited from an outpatient clinic located at the Department of Psychiatry in Anding Hospital, Capital Medical University, China. 30 healthy controls were enrolled by means of advertisements from the local community. The two groups were matched by age, gender and education. All participants were right-handed. The relevant Human Research Ethics Review Committees approved the study protocol, and the participants gave written informed consent after a complete description of the study. All patients were interviewed with the Structured Clinical Interview for DSM-IV. They met the following inclusion criteria: (1) based on DSM-IV criteria; (2) in their first depressive episode, and age ranging from 18 to 59; (3) 17-item Hamilton Depression Rating Scale (HDRS) scores were higher than 7. Exclusion criteria were: (1) there were history of head trauma with loss of consciousness; (2) having serious medical or surgical illness; (3) there were brain abnormalities/incidental findings detected on the T2-weighted images; (4) contraindications to magnetic resonance (MR) scanning; (5) there were any other major psychiatric illness, including substance abuse or dependence within the last 6 months; (6) suffering from primary neurological illness, such as dementia,

The T1-weighted sagittal whole brain images were firstly converted to Analyze format using MRIcro software. The converted images were analyzed using an optimized VBM protocol (VBM2, dbm.neuro.uni-jena.de/vbm) and the statistical parametric mapping (SPM2) software (Wellcome Department of Imaging Science; www.fil.ion.ucl.ac.uk/spm/) [10]. Brain regions with significant GM changes in patients were yielded based on a voxel-level height threshold of p < 0.001 (uncorrected) and a cluster-exent threshold of 20 voxel. A Pearson partial correlation analysis was performed to evaluate the correlation between the gray matter loss in the regions with GMD group difference between MDD patients and healthy controls and the Hamilton Depression Rating Scale (HDRS) score using SPSS 10.0 software (SPSS, Chicago, IL). Age was included as nuisance covariates, and two-tailed levels of significance (p < 0.05) were used in the analysis. 2.5. Functional connectivity analysis Functional connectivity map was then obtained using the REST toolkit (REST, http://resting-fmri.sourceforge.net), which is an extension toolbox of the SPM2. The linear trend was removed and an ideal band-pass filter (0.01 < f < 0.08 Hz) was applied to reduce the low-frequency drifts and high-frequency

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Fig. 1. Overview of the seed region for functional connectivity analysis: one active region of the right DLPFC showing significant structural GMD reduction in MDD patients in VBM study.

physiological noise. A correlation map was produced by computing the correlation coefficients between the seed region of interest (ROI) and all other brain voxels. As Fig. 1 shows, the seed ROI located in the right DLPFC was generated from the result of VBM study. In all brain areas with GMD abnormal, a negative correlation between GMD values and the HDRS scores was found only in the right DLPFC [10]. In addition, there is an emerging consensus that DLPFC is an important component of the neural network involved in MDD and participates in attention to emotion and the anticipation of negative emotion [11,12]. Resting-state studies using PET revealed hypermetabolism in the right DLPFC in acute MDD [13,14]. MRI studies during emotional stimulation associated altered neuronal activity in right DLPFC in MDD specifically with anticipation or attention to emotional judgment [15–17]. Therefore, the

resting-state functional correlation between right DLPFC and other brain regions reflects functional alterations that make sense for MDD. Correlation coefficients were converted to the Z values using Fisher Z-score transformation to improve the normality [18]. Functional connectivity maps were then analyzed with SPM2 based on the framework of the general linear model [19]. Twosample t-test [20] was used to identify the significant difference of correlation coefficients between the patients with depression and the healthy controls. Brain regions with significant changes of correlation coefficients were yielded at the voxel-level with a height threshold of p < 0.005 (uncorrected) and a cluster-extent threshold of 20 voxels. Moreover, the original correlation coefficients of brain regions with significant changes were extracted and saved from each participant using our in-house developed software.

Table 1 Demographic and clinical characteristics of MDD patients and healthy controls. Characteristic

Age (years) Gender (male/female) Education (years) Duration of illness (months) HDRS scores

MDD patients (n = 22)

Healthy controls (n = 30)

Analysis

Mean

SD

Mean

SD

p-Value

46.7 8/14 11.2 8.6 18.5

8.9 – 3.4 6.5 6.3

45.9 11/19 12.5 – 2.6

9.0 – 3.0 – 1.5

0.74*

MDD: major depressive disorder; HDRS: Hamilton Depression Rating Scale. * p-Value was obtained by an independent-sample two-tailed t-test.

0.15* <0.05*

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Table 2 Regions of statistically significant functional connectivity alteration in MDD patients compared to healthy controls. Anatomical regions

Connectivity increase Precentral gyrus Anterior cingulate cortex Parahippocampal gyrus Thalamus Connectivity decrease Parietal lobe

Side

BA

Cluster size (mm3 )

p value

T value

MNI coordinates x

y

z

L L L L

4 24 34 –

54 23 30 45

<0.001 <0.001 <0.001 0.001

4.06 3.94 3.63 3.32

-15 -6 −21 −6

-36 -6 0 −6

75 45 12 18

R

40

63

<0.001

3.51

45

−54

39

Note: L = left hemisphere; R = right hemisphere; BA = Brodmann’s area; the T sore is the highest value in the cluster which it belongs; the threshold was set at p < 0.005 uncorrected, the cluster size is more than 20 mm3 .

3. Results As shown in Table 1, no significant differences in age, gender distribution and years of education were observed between MDD patients and healthy controls. Compared to healthy controls, the MDD patients showed increased functional connectivity with the seed ROI the right dorsolateral prefrontal cortex (Brodmann’s Area [BA] 46) in the left anterior cingulate cortex (BA 24), left parahippocampal gyrus (BA 34), thalamus and precentral gyrus (BA 4). In contrast, the regions that showed decreased functional connectivity were in the right parietal lobe (BA 40) (Table 2, Figs. 2 and 3). 4. Discussion In the popular functional connectivity analysis, an anatomic integrated region was predefined subjectively and chose as the seed ROI. However, this manner of choosing seed ROI is not very logical. In general, a structurally abnormal area is not an integrated anatomic region. Functional abnormalities are based on the anatomic abnormalities, so we chose a structural abnormal area but not an integrated anatomic region as the seed ROI. This new approach of functional connectivity analysis may have advantages over currently popular protocols and provided more reasonable and persuasive results for the investigation. The functional connectivity between the right DLPFC and the right parietal lobe showed significant decreased, as indicated in Fig. 2. In anatomical, there is neural connection between DLPFC and parietal lobe. Parietal lobe and the DLPFC were demonstrated more positively correlated to share reciprocal neural pathways [21,22]. Moreover, decreased functional connectivity pattern was identified In DLPFC-parietal network in MDD which was consistent with our result [23]. A general role of the right parietal lobe was emphasized in the regulation of negative emotional arousal. Lesions centered on the right parietal cortex were found to impair emotional experience and arousal [24,25] and recognition of facial expressions for fear and sadness [26]. PET studies reported that inferior parietal (BA 40) deactivations were accompanied with sadness [27], memorydriven anxiety provocations and memory-driven anger [28–30]. In

current work, uncoupling between the DLPFC and the parietal lobe is seen in MDD patients. We guess the uncoupling might be the cause of negative emotional processing bias and their lack of energy for self-related interest of MDD. Enhanced functional connectivity of the right in the DLPFC was observed in the left dorsal anterior cingulate cortex (ACC), left parahippocampal gyrus (PHG), thalamus and precentral gyrus. The functional connectivity enhancement between right DLPFC and contralateral dorsal ACC as well as thalamus was found in previous studies [22,31]. However, the functional connectivity enhancement between right DLPFC and contralateral PHG dorsal has not been reported, as we known. ACC could be subdivided into a dorsal cognitive (BA 24) [8] and rostral affective (BA 32) [32] division. The cognitive subdivision is interconnected with the DLPFC, parietal cortex, premotor, and supplementary motor areas [33]. Strong evidence points towards close anatomical and functional interplay between dorsal ACC and the DLPFC [34–36]. It has been reported that the ACC monitors for conflict or error in response pathways during initial task performance, which contributes to the implementation of cognitive control in DLPFC when selecting between alternative responses is difficult [37]. Depression is a serious and mostly incapacitating disorder which is characterized by a range of symptoms affecting both emotional and cognitive domains. From a neurobiological point of view, we speculate that the observed increased connectivity between the DLPFC and the dorsal ACC may represent a higher neural response to negative stimuli, in line with the confirmation of disrupted error monitoring and executive control in the fronto-cingulate network in the pathophysiology of MDD [31]. PHG is associated with memory-driven anxiety. This structure, particularly on the left, appears to be active in the processing of negative emotional stimuli, including those related to trauma [38,39]. Almeida et al. proposed a simple forward connection model from the PHG to subgenual cingulate gyrus (sgCG) and from sgCG to DLPFC by the dynamic causal modeling. The increased connectivity in this network suggests a dysfunctional ventromedial neural system implicated in early stimulus appraisal, encoding and automatic regulation of emotion that might represent a pathophysiological functional neural mechanism for mood dysregulation in BD [40].

Fig. 2. A sequence of axial slices illustrating deceased functional connectivity in the right parietal lobe in MDD patients compared with healthy controls.

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Fig. 3. A sequence of axial slices illustrating increased functional connectivity in MDD patients compared with healthy controls. Notable regions of higher connection are in the left dorsal anterior cingulate cortex, left parahippocampal gyrus, thalamus and precentral gyrus.

Increased negative functional connectivity was shown between the right PHG and bilateral lateral prefrontal cortices [41]. Our finding provides supportive evidence that the functional over-coupling in PHG-DLPFC network may be associated with the emotional dysfunction in MDD patients. Correlations between brain regions do not imply specific causal interactions [42]. A correlation between PHG and DLPFC may arise because the sgCG influences both PHG and DLPFC. The thalamus has recently been subjected to intense scrutiny in depression. Studies have found histological and functional abnormalities in the thalamus of patients with depression [6,33]. Recent resting-state connectivity analysis has shown reduced connectivity between the medial thalamus and the putatively cognitive dorsal ACC in depressed subjects compared to controls [1,43]. Enhanced connection between dorsal ACC and DLPFC has also been found in this result. DLPFC has been proved to be an important component of the neural network involved in MDD and participates in attention to emotion and the anticipation of negative emotion [11,44,12]. In light of these findings, we guessed that the correlation between thalamus and DLPFC may increase because the dorsal ACC influences both thalamus and DLPFC in depressed subjects.

5. Conclusion By applying the VBM results to the functional connectivity analysis, the study suggested that abnormality of GMD in right DLPFC might be related to the functional connectivity alteration in the pathophysiology of MDD, which might be useful in further characterizing structure–function relations in this disorder.

Acknowledgments This work was supported by grants from the Major State Basic Research Development Program of China (973 Program) (2007CB512303), the National Natural Science Foundation of China (30970768).

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