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Disrupted white matter integrity in first-episode, drug-naive, late-onset depression
Journal of Affective Disorders 163 (2014) 70–75
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Research report
Disrupted white matter integrity in first-episode, drug-naive, late-onset depression Wenbin Guo a,b,1, Feng Liu c,1, Guanglei Xun d,1, Maorong Hu e,1, Xiaofeng Guo a, Changqing Xiao b, Huafu Chen c, Jindong Chen a,nn, Jingping Zhao a,n a Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan 410011, China b Mental Health Center, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China c Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China d Shandong Mental Health Center, Jinan, Shandong 250014, China e Mental Hospital of Nanchang University & Mental Health Center of Jiangxi Province, Nanchang, Jiangxi 330029, China
art ic l e i nf o
a b s t r a c t
Article history: Received 10 October 2013 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 1 April 2014
Background: Abnormalities of white matter integrity in frontal and limbic regions have been postulated to play a key role in the pathophysiology of geriatric depression. However, there is no diffusion tensor imaging (DTI) study in patients with first-episode, drug-naive, late-onset depression (LOD). The aim of this study was to investigate whole-brain fractional anisotropy (FA) difference between patients with LOD and healthy controls without a previously determined region of interest. Methods: The sample included 15 patients with first-episode, drug-naive LOD and 15 age-, sex-, and education-matched healthy controls. The tract-based spatial statistics (TBSS) method was employed to analyze the DTI data. Results: Lower FA in the white matter of bilateral parahippocampal gyrus was observed in patients with LOD relative to healthy controls by voxel-wise statistics with the TBSS method. Patients did not have higher FA values in any brain regions compared to healthy controls. There was no correlation between the abnormal FA value in bilateral parahippocampal gyrus and depression severity or related factors. Limitations: The present study should be considered preliminary due to relatively small sample size. Conclusions: Our findings suggest that loss of white matter integrity in parahippocampal gyrus may be associated with the pathophysiology of LOD, and thus highlight the limbic contribution to the pathophysiology of LOD. & 2014 Elsevier B.V. All rights reserved.
Keywords: Late-onset depression Diffusion tensor imaging Tract-based spatial statistics White matter
1. Introduction Late-onset depression (LOD) is often defined as depression with first onset over the age of 60, a commonly used cut-off age point to divide LOD from early-onset depression (EOD) (Brodaty et al., 2005, 2001). The individuals with LOD have clinical pictures distinctive from those of the elders with EOD. For instance, patients with LOD may experience less guilt but more generalized anxiety, hypochondriasis and apathy (Brodaty et al., 2005). LOD is also related to high rate of relapse (Luijendijk et al., 2008),
n
Corresponding author. Tel.: +86 73185360921. Corresponding author. E-mail addresses: [email protected] (J. Chen), [email protected], [email protected] (J. Zhao). 1 These authors contributed equally to this work. nn
http://dx.doi.org/10.1016/j.jad.2014.03.044 0165-0327/& 2014 Elsevier B.V. All rights reserved.
disability and cognitive impairment (Alexopoulos, 2005). At the neural level, patients with LOD have been recently found to have reversal pattern of neural activities in the frontal, temporal and limbic regions compared to patients with EOD by our group (Chen et al., 2012; Guo et al., 2013b). However, it is unclear why these patients begin their first depressive episode so late, and the pathophysiology of LOD remains equivocal. Since its emergence two decades ago, diffusion tensor imaging (DTI) has become a promising approach for characterizing alterations of white matter fibers even in normally appearing white matter. In central nervous system, the motion of water molecules is hindered by myelin sheaths of neuronal axons, and the movement is faster parallel to the axons than perpendicular to them. Such anisotropic diffusion can be measured by fractional anisotropy (FA), one of the most common parameters of DTI to assess the white matter integrity. FA is extracted as the directionality and
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the extent of diffusion from the tensor model, which quantifies the directionality of local tract structure. FA is thought to reflect fiber density, axonal diameter, and myelination in white matter, and high FA is a general characteristic of healthy white matter. Evidence of DTI alterations has been documented in geriatric depression by using the region-of-interest (ROI) or voxel-based analysis (VBA) methods. Taylor et al. (2004) observed white matter changes of the right superior frontal cortex in geriatric depression. Abnormal FA in widespread regions of frontal and temporal gyri has been reported in geriatric depression (Nobuhara et al., 2006), and these changes remained significant even when the patients achieved remission (Yuan et al., 2007). Charlton et al. (2013) reported lower white-matter integrity in bilateral cingulum and right uncinate fasciculus in depressed elders. Lower FA in several fronto-limbic areas (i.e., dorsolateral, medial frontal regions, and posterior cingulate) has been found in geriatric depression (Alexopoulos et al., 2009). These findings suggest that disconnection between frontal and limbic areas plays a key role in the pathophysiology of geriatric depression. Although ROI- and VBA-based methods have provided useful information, both have weaknesses. First, it is difficult to delineate ROI boundaries and time-consuming for the ROI method (Smith et al., 2006). Moreover, the ROI-based method can detect changes only in the pre-selected regions and lack the whole-brain white matter information. To the VBA method, a number of smoothing and alignment problems may bias the final results (Smith et al., 2006). Based on the VBA method, tract-based spatial statistics (TBSS) has been proposed to alleviate the alignment problem (Smith et al., 2006). Independent of perfect nonlinear registration, it projects the individual FA values onto a given FA skeleton. Spatial smoothing is not necessary. Thus, the TBSS method improves objectivity and simplicity in the interpretation of DTI results by minimizing the effects of misalignment (Smith et al., 2006). The TBSS method has been well conducted to analyze white matter abnormalities in geriatric depression with inconsistent results. White matter abnormalities in the uncinate and cingulate white matter are noticed in depressed elders (Alves et al., 2012; Mettenburg et al., 2012). In contrast, two recent studies reported no white matter change in depressed elders (Bezerra et al., 2012; Colloby et al., 2011). Multiple factors may account for the inconsistency. One of the most predominant factors is that patients enrolled in the previous studies are individuals who have EOD but are now older. Long illness duration and medication use may impact neuronal networks and reflect an increased risk due to multiple mechanisms for damage. Hence, it is meaningful to recruit patients with first-episode, drug-naive LOD when conducting studies in depressed elders. Here, we undertook a DTI study by recruiting patients only with first-episode, drug-naive LOD. According to the previous DTI studies (Alves et al., 2012; Mettenburg et al., 2012), we hypothesized that specific, regional white matter alterations in FA would be detected in LOD relative to healthy controls, especially in the frontal and limbic areas. We also hypothesized that there were some correlations between the altered FA and clinical characteristics.
2. Materials and methods 2.1. Subjects Fifteen patients with first-episode, drug-naive LOD, aged from 60 to 79 years old, were consecutively recruited from Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South
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University, China. Major depressive episode was diagnosed with the Structured Clinical Interview for DSM-IV (SCID), Clinician Version (First et al., 1997). The age of first depressive episode was after 60 years for the patients. Depression severity was rated using a 17-item Hamilton Rating Scale for Depression (HRSD), and patients should have scores higher than 18. In addition, patients should score higher than 24 in Mini-Mental State Examination (MMSE) as a screen for risk of dementia. Exclusion criteria were other psychiatric disorders besides depression, primary medical illness or neurological illness, such as cardiovascular illness, dementia or organic brain disorders. Individuals with complaint of decline in memory by patients, family members, or physicians were also excluded for the possible diagnosis of mild cognitive impairment. In addition, T2-weighted MRI of all subjects did not have any gray matter atrophy, which was visually inspected by an experienced radiologist. Fifteen healthy controls were recruited from the community. They were interviewed by using SCID, nonpatient edition (First et al., 1997). None of them had a history of serious medical or neuropsychiatric illness or a family history of major psychiatric or neurological illness in their first-degree relatives. No gray matter atrophy was found in them by using T2-weighted MRI. They were matched with the patients in age, sex and education level. The study was approved by the local Ethics Committee of the Second Xiangya Hospital, Central South University. All subjects were informed about procedures and gave written consent. The study was also in accordance with recommendations laid down in the current version of the Declaration of Helsinki. 2.2. Scan acquisition Scanning was performed on a 1.5 T GE scanner (General Electric, Fairfield, Connecticut, USA). Participants were required to lie motionless and keep their eyes closed. The following DTI parameters were used: repetition time¼ 12,000 ms; echo time¼ 105 ms; acquisition matrix¼128 128; field of view¼ 240 240 mm2; slice thickness¼ 4 mm, no gap; 30 contiguous axial slices. The diffusion sensitizing gradients were applied along 13 non-collinear directions (b¼ 1000 s/mm2) with an acquisition without diffusion weighting (b¼ 0). 2.3. Scan processing Images were processed by using the FMRIB software library (FSL, version 4.1.8; http://www.fmrib.ox.ac.uk/fsl). Head motion and eddy current distortions were corrected by using an affine transformation of each diffusion weighted image to the reference volume of the nondiffusion weighted (b ¼0) image. Then, a binary mask was generated from the nondiffusion weighted image. After these steps, diffusion tensor models were fitted independently for each voxel within the binary brain mask. Thus images of FA were generated for each subject. By using an FMRIB58_FA template, FA images were non-linearly aligned into 1 1 1 mm3 MNI standard space, and resulted in a standard space version of each subject's FA image. From these new images, a mean FA image was calculated and thinned to create a mean FA skeleton using an FA threshold value of 0.2. Finally, each subject's aligned FA data were projected onto the skeleton by assigning each voxel to the maximum FA value detected in a direction surrounding the tract. 2.4. Statistical analysis When appropriate, demographic and clinical data were compared using two-sample t-test and Chi-square test. Voxel-wise
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cross-subject statistics of two-sample t-tests were carried out by FSL Randomize tool (version 2.1) using 10,000 permutations. Age and years of education were used as covariates to minimize the potential effect of the two variables, although they did not exhibit significant difference between groups. The results were corrected for multiple comparisons with the threshold-free cluster enhancement (TFCE) method. Statistical maps were set at P o0.05 (twosided, corrected). Linear correlation was conducted to examine correlations between the mean FA in brain regions with abnormal FA and depression severity, and related factors. The threshold of Po0.05 was considered to be significant.
3. Results 3.1. Subjects Demographic data and disease severity of patients and healthy controls are presented in Table 1. The two groups do not differ in age, sex ratio and education level. As expected, the patients have significantly lower level of MMSE scores compared to healthy controls. 3.2. Differences in FA values between groups As shown in Table 2 and Fig. 1, lower FA in white matter of bilateral parahippocampal gyrus was observed in patients relative to healthy controls. No significantly higher FA value in any brain regions was found in patients with LOD compared to healthy controls. 3.3. Correlations between FA values, depression severity, and related factors Linear correlation analyses showed no correlation between lower FA values of bilateral parahippocampal gyrus and HRSD scores or MMSE scores in the patient group. There was also no correlation between lower FA values of bilateral parahippocampal gyrus and age, education level, or illness duration in the patient group.
Table 1 Demographic and clinical information of patients with LOD and healthy controls. Variables (Mean7 SD)
LOD
Healthy controls
P values
Sex (M/F) Age (years) Education (years) MMSE score Illness duration (months) HRSD score
6/9 67.53 7 6.12 9.93 7 3.90 25.40 7 1.45 5.93 7 3.41 21.60 7 2.16
6/9 64.877 3.70 10.53 7 4.10 28.067 1.71
– 0.160a 0.685a o 0.001a
LOD, late-onset depression; MMSE, Mini-Mental State Exam; HRSD, Hamilton Rating Scale for Depression. a
The P values were obtained by two sample t-tests.
Table 2 Areas of lower FA in patients with LOD compared with healthy controls. Areas of lower FA patients vs. controls X White matter of left parahippocampal gyrus White matter of right parahippocampal gyrus
Y
Z
P value Voxels size
25 27 23 0.023
15
25 15 31 0.015
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4. Discussion The main finding of the present study is that patients with LOD have lower FA in white matter of bilateral parahippocampal gyrus than that of healthy controls. Since our patients are individuals with first-episode, drug-naive, short-illness-duration (o 1 year) LOD (age of onset 460 years), the effect from confounding factors, such as medication, heterogeneity, and white matter changes by enduring long time of the disease, can be greatly reduced. Independent of segmentation schemes or a prior selection, TBSS offers a robust voxel-wise analysis to detect white matter abnormalities of the whole brain in a comprehensive way. Moreover, TBSS applies a strategy which confines the comparison to an FA skeleton and diminishes volume averaging effect. Therefore, TBSS adopted here is informative. A number of studies have adopted TBSS to analyze white matter alterations in depressed elders. Widespread structural abnormalities of white matter were detected in depressed elders, especially in the uncinate and cingulate white matter, which demonstrate significant correlations with diminished performance on neuropsychological testing (Mettenburg et al., 2012). Alves et al. (2012) reported reduced FA in the right posterior cingulate cluster in patients with geriatric depression, which showed a positive correlation with performance in a verbal naming task. In contrast, two recent studies revealed no white matter change in depressed elders (Bezerra et al., 2012; Colloby et al., 2011). Although the inconsistency may be due to some confounding factors, such as the sample size, medication, the cut-off age point to separate patients with geriatric depression from individuals with non-geriatric depression, and different pathological processes underlying white matter changes (such as demyelination, small vessel ischemic disease and perivascular dilatation), it has been indicated that patients with geriatric depression who begin their first depression onset before the age of 60 (EOD) are completely different from those who become depressed after the age of 60 (LOD) in both clinical symptoms (Brodaty et al., 2005) and neural activity (Guo et al., 2013b). Long illness duration and medication may bias the findings from patients with early-onset, geriatric depression, especially to the neuroimaging findings. Therefore, the present results of lower FA in white matter of bilateral parahippocampal gyrus are meaningful relative to those from older patients with EOD in previous studies. In addition to its contribution to learning and memory, the limbic system plays a key role in anxiety and depressive state (Fountoulakis et al., 2004). The limbic system fibers receive projections from the nearby cingulate gyrus, extending to the middle temporal lobe and hippocampus (Oishi et al., 2011). Lower FA was observed in the limbic system, such as anterior cingulate and posterior cingulate, in depressed elders (Bae et al., 2006), suggesting its involvement in the pathophysiology of geriatric depression. Located around the hippocampus, the parahippocampal gyrus, an important component of the limbic system, acts as a key role in memory and emotional regulation (Disner et al., 2011; Liu et al., 2013; Manns et al., 2003). The parahippocampal gyrus also has intimate communications with high-order brain regions (i.e. the entorhinal cortex, the anterior cingulate cortex) (Zhang et al., 2009). Abnormalities of cortical-limbic circuits have been implicated in mechanisms of emotional dysfunction (Drevets, 2000; Guo et al., 2013a; Liu et al., 2012b; Tekin and Cummings, 2002). Lower FA in the parahippocampal gyrus, which leads to disrupted fronto-limbic connectivity resulting in the loss of prefrontal lobe control over limbic areas, is regarded as the root of the pathophysiology of emotional, cognitive and behavior alterations in major depression (Liu et al., 2012a; Savitz and Drevets, 2009). Moreover, parahippocampal gyrus showed reduced glucose metabolism in geriatric depression (Smith et al., 2011a), which could be
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Fig. 1. White matter showing significantly lower FA in first-episode, drug-naive, late-onset depression (P o0.05, corrected). FA maps show sagittal, coronal, and axial views. The background image is the standard MNI152 brain template. Green voxels represent the FA white matter skeleton. Red-yellow voxels represent regions with lower FA in patients compared with healthy controls. FA ¼ fractional anisotropy; MNI ¼Montreal Neurological Institute. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
normalized by antidepressants (Smith et al., 2011b). In addition, significant gray matter volume reduction in right parahippocampal gyrus was observed in geriatric depression (Bell-McGinty et al., 2002). Furthermore, decreased white matter integrity in the right parahippocampal gyrus was reported in adults with first-episode, drug-naive major depressive disorder (Zhu et al., 2011). In line with these studies, lower FA in the white matter of bilateral parahippocampal gyrus in the present study may disrupt communications between the parahippocampal gyrus and high-order brain regions accounting for disconnection of cortical-limbic circuits (i.e., frontolimbic circuits) (Alexopoulos et al., 2000; Charlton et al., 2013). Indeed, depression can accelerate the loss of white matter integrity (Shimony et al., 2009) and increasing white matter changes are associated with limbic and dorsal cortical communication in geriatric depression (Rogers et al., 2004). Therefore, our results extend the previous evidence that the loss of white matter integrity in the limbic regions may contribute to the pathophysiology of LOD. White matter alterations in frontal regions have been usually reported in geriatric depression (Nobuhara et al., 2006; Taylor et al., 2004; Yuan et al., 2007) and young depression (Guo et al., 2012a, 2012b; Ma et al., 2007). Hence, the present findings without any FA alterations in the frontal lobe are somehow unexpected. The inconsistency may result from some possible factors including sample size, depression severity, analysis method, heterogeneity of subjects and medication. For instance, Yuan's and Ma's studies found lower FA in frontal regions in first-episode remitted geriatric depression (Yuan et al., 2007) and first-episode, drug-naive young depression (Ma et al., 2007) by the VBA method.
Their uncorrected P might amplify their false positive findings in addition to other confounding factors, such as depression severity and analysis methods (VBA vs. TBSS). In contrast, our results from a corrected P by the TBSS method may minimize the presence of false positive findings. There are at least two possible explanations for the present results of the absence of FA changes in the frontal lobe. First, the present results may suggest that white matter abnormality in the frontal regions may not necessarily contribute to the pathophysiology of LOD. This notion is supported by several studies. For example, no significant difference in DTI parameters in the frontal regions in depressed elders was found in an early investigation (Taylor et al., 2001). A recent study using the TBSS method indicated white matter changes in the bilateral frontal, right temporal and midbrain in depressed elders. However, their results are only suggestive since their corrected FA results are not statistically significant (Colloby et al., 2011). Another study even observed no white matter change in geriatric depression using the TBSS method (Bezerra et al., 2012). The present findings are also consistent with a TBSS study without white matter abnormality in frontal regions in middle-aged depression, which reported a trend for lower FA values in the left sagittal striatum and right cingulate cortex (Kieseppa et al., 2010). An alternative interpretation to the absence of FA changes in the frontal lobe is that brain circuits are dynamic, and disruption of multimodal areas may lead to various clinical presentations. Different parts of the frontal lobe have afferent and efferent links with other cortical, limbic and subcortical areas (Zhang et al., 2009). Frontal impairment may be potentially associated with a multitude of nonfrontal disrupted links.
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Since clinical characteristics such as the depression severity and the illness duration are reported to have correlations with lower FA values in certain regions in geriatric depression (Alves et al., 2012; Mettenburg et al., 2012), we hypothesized that patients with a higher depression severity and/or a longer illness duration would have a higher reduction in FA values in the parahippocampal gyrus. Therefore, the result of no correlation between these factors is somewhat unexpected. Although the result could be confounded by the relative small sample size, it is also possible that the abnormality may be a trait change for patients with LOD independent of depression severity and illness duration. Another possibility for no correlation is the concentration of clinical characteristics in the current study, such as illness duration around 6 months and HRSD total score around 21. Furthermore, the present findings of no correlation are supported by a large amount of studies, which also observed no association between anisotropy parameters and clinical characteristics in depressed elders (Bezerra et al., 2012) and young adults with depression (Ma et al., 2007; Madden et al., 2004). The relationship between white matter integrity and depression severity, illness duration, or cognitive function has not been clearly established. The present study has several limitations. First, the sample size was relatively small. Hence, the present findings should be considered preliminary and need to be replicated with a larger sample size. Second, we recruited merely first-episode, drugnaive patients with LOD to exclude the possible influence of the heterogeneity of illness. It is helpful to clarify the pathophysiology of LOD by the inclusion criterion. Since geriatric depression is a complex psychiatric syndrome, findings from LOD may not be generalized to other clinical subtypes of geriatric depression. Hence, this inclusion criterion might in turn limit the generalizability of our results. Third, brain white matter hyperintensity (WMH) is an index associated with demyelination resulting in white matter lesions. The fact that patients were not excluded based on the presence of WMH might have biased the present results. However, we did not exclude healthy controls with WMH, and partly balanced the influence of WMH. Furthermore, the criterion of not excluding participants based on the presence of WMH was adopted by most DTI studies in geriatric depression for the reason that WMH is common in older adults (Alexopoulos et al., 2009; Charlton et al., 2013; Yuan et al., 2007). Fourth, neuropsychological measurements (e.g., executive function, attention, memory, verbal skills, etc.) were not conducted in the present study, which might have hampered any firm conviction about the cognitive status of depressed patients. We were also unable to know correlations between lower FA in bilateral parahippocampal gyrus and neuropsychological measurements. Finally, DTI was performed on a 1.5 T scanner, resulting in relatively low signal-to-noise ratio compared to the images from a 3.0 T scanner. In summary, our findings first suggest that loss of white matter integrity in parahippocampal gyrus may be involved in the pathophysiology of LOD, and thus highlight the limbic contribution to the pathophysiology of LOD.
Role of funding source The study was supported by Grants from the Natural Science Foundation of China (Grant nos. 81260210, 30900483, and 81360211), the Natural Science Foundation of Guangxi (Grant no. 2013GXNSFAA019107), and the special funding by the Ministry of Health of the Peoples’ Republic of China (Grant no. 201002003).
Conflict of interest No conflict of interest declared.
Acknowledgments The authors thank all individuals who served as the research participants. The authors also appreciate anonymous reviewers for their suggestions and comments.
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Research report
Disrupted white matter integrity in first-episode, drug-naive, late-onset depression Wenbin Guo a,b,1, Feng Liu c,1, Guanglei Xun d,1, Maorong Hu e,1, Xiaofeng Guo a, Changqing Xiao b, Huafu Chen c, Jindong Chen a,nn, Jingping Zhao a,n a Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan 410011, China b Mental Health Center, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China c Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China d Shandong Mental Health Center, Jinan, Shandong 250014, China e Mental Hospital of Nanchang University & Mental Health Center of Jiangxi Province, Nanchang, Jiangxi 330029, China
art ic l e i nf o
a b s t r a c t
Article history: Received 10 October 2013 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 1 April 2014
Background: Abnormalities of white matter integrity in frontal and limbic regions have been postulated to play a key role in the pathophysiology of geriatric depression. However, there is no diffusion tensor imaging (DTI) study in patients with first-episode, drug-naive, late-onset depression (LOD). The aim of this study was to investigate whole-brain fractional anisotropy (FA) difference between patients with LOD and healthy controls without a previously determined region of interest. Methods: The sample included 15 patients with first-episode, drug-naive LOD and 15 age-, sex-, and education-matched healthy controls. The tract-based spatial statistics (TBSS) method was employed to analyze the DTI data. Results: Lower FA in the white matter of bilateral parahippocampal gyrus was observed in patients with LOD relative to healthy controls by voxel-wise statistics with the TBSS method. Patients did not have higher FA values in any brain regions compared to healthy controls. There was no correlation between the abnormal FA value in bilateral parahippocampal gyrus and depression severity or related factors. Limitations: The present study should be considered preliminary due to relatively small sample size. Conclusions: Our findings suggest that loss of white matter integrity in parahippocampal gyrus may be associated with the pathophysiology of LOD, and thus highlight the limbic contribution to the pathophysiology of LOD. & 2014 Elsevier B.V. All rights reserved.
Keywords: Late-onset depression Diffusion tensor imaging Tract-based spatial statistics White matter
1. Introduction Late-onset depression (LOD) is often defined as depression with first onset over the age of 60, a commonly used cut-off age point to divide LOD from early-onset depression (EOD) (Brodaty et al., 2005, 2001). The individuals with LOD have clinical pictures distinctive from those of the elders with EOD. For instance, patients with LOD may experience less guilt but more generalized anxiety, hypochondriasis and apathy (Brodaty et al., 2005). LOD is also related to high rate of relapse (Luijendijk et al., 2008),
n
Corresponding author. Tel.: +86 73185360921. Corresponding author. E-mail addresses: [email protected] (J. Chen), [email protected], [email protected] (J. Zhao). 1 These authors contributed equally to this work. nn
http://dx.doi.org/10.1016/j.jad.2014.03.044 0165-0327/& 2014 Elsevier B.V. All rights reserved.
disability and cognitive impairment (Alexopoulos, 2005). At the neural level, patients with LOD have been recently found to have reversal pattern of neural activities in the frontal, temporal and limbic regions compared to patients with EOD by our group (Chen et al., 2012; Guo et al., 2013b). However, it is unclear why these patients begin their first depressive episode so late, and the pathophysiology of LOD remains equivocal. Since its emergence two decades ago, diffusion tensor imaging (DTI) has become a promising approach for characterizing alterations of white matter fibers even in normally appearing white matter. In central nervous system, the motion of water molecules is hindered by myelin sheaths of neuronal axons, and the movement is faster parallel to the axons than perpendicular to them. Such anisotropic diffusion can be measured by fractional anisotropy (FA), one of the most common parameters of DTI to assess the white matter integrity. FA is extracted as the directionality and
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the extent of diffusion from the tensor model, which quantifies the directionality of local tract structure. FA is thought to reflect fiber density, axonal diameter, and myelination in white matter, and high FA is a general characteristic of healthy white matter. Evidence of DTI alterations has been documented in geriatric depression by using the region-of-interest (ROI) or voxel-based analysis (VBA) methods. Taylor et al. (2004) observed white matter changes of the right superior frontal cortex in geriatric depression. Abnormal FA in widespread regions of frontal and temporal gyri has been reported in geriatric depression (Nobuhara et al., 2006), and these changes remained significant even when the patients achieved remission (Yuan et al., 2007). Charlton et al. (2013) reported lower white-matter integrity in bilateral cingulum and right uncinate fasciculus in depressed elders. Lower FA in several fronto-limbic areas (i.e., dorsolateral, medial frontal regions, and posterior cingulate) has been found in geriatric depression (Alexopoulos et al., 2009). These findings suggest that disconnection between frontal and limbic areas plays a key role in the pathophysiology of geriatric depression. Although ROI- and VBA-based methods have provided useful information, both have weaknesses. First, it is difficult to delineate ROI boundaries and time-consuming for the ROI method (Smith et al., 2006). Moreover, the ROI-based method can detect changes only in the pre-selected regions and lack the whole-brain white matter information. To the VBA method, a number of smoothing and alignment problems may bias the final results (Smith et al., 2006). Based on the VBA method, tract-based spatial statistics (TBSS) has been proposed to alleviate the alignment problem (Smith et al., 2006). Independent of perfect nonlinear registration, it projects the individual FA values onto a given FA skeleton. Spatial smoothing is not necessary. Thus, the TBSS method improves objectivity and simplicity in the interpretation of DTI results by minimizing the effects of misalignment (Smith et al., 2006). The TBSS method has been well conducted to analyze white matter abnormalities in geriatric depression with inconsistent results. White matter abnormalities in the uncinate and cingulate white matter are noticed in depressed elders (Alves et al., 2012; Mettenburg et al., 2012). In contrast, two recent studies reported no white matter change in depressed elders (Bezerra et al., 2012; Colloby et al., 2011). Multiple factors may account for the inconsistency. One of the most predominant factors is that patients enrolled in the previous studies are individuals who have EOD but are now older. Long illness duration and medication use may impact neuronal networks and reflect an increased risk due to multiple mechanisms for damage. Hence, it is meaningful to recruit patients with first-episode, drug-naive LOD when conducting studies in depressed elders. Here, we undertook a DTI study by recruiting patients only with first-episode, drug-naive LOD. According to the previous DTI studies (Alves et al., 2012; Mettenburg et al., 2012), we hypothesized that specific, regional white matter alterations in FA would be detected in LOD relative to healthy controls, especially in the frontal and limbic areas. We also hypothesized that there were some correlations between the altered FA and clinical characteristics.
2. Materials and methods 2.1. Subjects Fifteen patients with first-episode, drug-naive LOD, aged from 60 to 79 years old, were consecutively recruited from Mental Health Institute of the Second Xiangya Hospital, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South
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University, China. Major depressive episode was diagnosed with the Structured Clinical Interview for DSM-IV (SCID), Clinician Version (First et al., 1997). The age of first depressive episode was after 60 years for the patients. Depression severity was rated using a 17-item Hamilton Rating Scale for Depression (HRSD), and patients should have scores higher than 18. In addition, patients should score higher than 24 in Mini-Mental State Examination (MMSE) as a screen for risk of dementia. Exclusion criteria were other psychiatric disorders besides depression, primary medical illness or neurological illness, such as cardiovascular illness, dementia or organic brain disorders. Individuals with complaint of decline in memory by patients, family members, or physicians were also excluded for the possible diagnosis of mild cognitive impairment. In addition, T2-weighted MRI of all subjects did not have any gray matter atrophy, which was visually inspected by an experienced radiologist. Fifteen healthy controls were recruited from the community. They were interviewed by using SCID, nonpatient edition (First et al., 1997). None of them had a history of serious medical or neuropsychiatric illness or a family history of major psychiatric or neurological illness in their first-degree relatives. No gray matter atrophy was found in them by using T2-weighted MRI. They were matched with the patients in age, sex and education level. The study was approved by the local Ethics Committee of the Second Xiangya Hospital, Central South University. All subjects were informed about procedures and gave written consent. The study was also in accordance with recommendations laid down in the current version of the Declaration of Helsinki. 2.2. Scan acquisition Scanning was performed on a 1.5 T GE scanner (General Electric, Fairfield, Connecticut, USA). Participants were required to lie motionless and keep their eyes closed. The following DTI parameters were used: repetition time¼ 12,000 ms; echo time¼ 105 ms; acquisition matrix¼128 128; field of view¼ 240 240 mm2; slice thickness¼ 4 mm, no gap; 30 contiguous axial slices. The diffusion sensitizing gradients were applied along 13 non-collinear directions (b¼ 1000 s/mm2) with an acquisition without diffusion weighting (b¼ 0). 2.3. Scan processing Images were processed by using the FMRIB software library (FSL, version 4.1.8; http://www.fmrib.ox.ac.uk/fsl). Head motion and eddy current distortions were corrected by using an affine transformation of each diffusion weighted image to the reference volume of the nondiffusion weighted (b ¼0) image. Then, a binary mask was generated from the nondiffusion weighted image. After these steps, diffusion tensor models were fitted independently for each voxel within the binary brain mask. Thus images of FA were generated for each subject. By using an FMRIB58_FA template, FA images were non-linearly aligned into 1 1 1 mm3 MNI standard space, and resulted in a standard space version of each subject's FA image. From these new images, a mean FA image was calculated and thinned to create a mean FA skeleton using an FA threshold value of 0.2. Finally, each subject's aligned FA data were projected onto the skeleton by assigning each voxel to the maximum FA value detected in a direction surrounding the tract. 2.4. Statistical analysis When appropriate, demographic and clinical data were compared using two-sample t-test and Chi-square test. Voxel-wise
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cross-subject statistics of two-sample t-tests were carried out by FSL Randomize tool (version 2.1) using 10,000 permutations. Age and years of education were used as covariates to minimize the potential effect of the two variables, although they did not exhibit significant difference between groups. The results were corrected for multiple comparisons with the threshold-free cluster enhancement (TFCE) method. Statistical maps were set at P o0.05 (twosided, corrected). Linear correlation was conducted to examine correlations between the mean FA in brain regions with abnormal FA and depression severity, and related factors. The threshold of Po0.05 was considered to be significant.
3. Results 3.1. Subjects Demographic data and disease severity of patients and healthy controls are presented in Table 1. The two groups do not differ in age, sex ratio and education level. As expected, the patients have significantly lower level of MMSE scores compared to healthy controls. 3.2. Differences in FA values between groups As shown in Table 2 and Fig. 1, lower FA in white matter of bilateral parahippocampal gyrus was observed in patients relative to healthy controls. No significantly higher FA value in any brain regions was found in patients with LOD compared to healthy controls. 3.3. Correlations between FA values, depression severity, and related factors Linear correlation analyses showed no correlation between lower FA values of bilateral parahippocampal gyrus and HRSD scores or MMSE scores in the patient group. There was also no correlation between lower FA values of bilateral parahippocampal gyrus and age, education level, or illness duration in the patient group.
Table 1 Demographic and clinical information of patients with LOD and healthy controls. Variables (Mean7 SD)
LOD
Healthy controls
P values
Sex (M/F) Age (years) Education (years) MMSE score Illness duration (months) HRSD score
6/9 67.53 7 6.12 9.93 7 3.90 25.40 7 1.45 5.93 7 3.41 21.60 7 2.16
6/9 64.877 3.70 10.53 7 4.10 28.067 1.71
– 0.160a 0.685a o 0.001a
LOD, late-onset depression; MMSE, Mini-Mental State Exam; HRSD, Hamilton Rating Scale for Depression. a
The P values were obtained by two sample t-tests.
Table 2 Areas of lower FA in patients with LOD compared with healthy controls. Areas of lower FA patients vs. controls X White matter of left parahippocampal gyrus White matter of right parahippocampal gyrus
Y
Z
P value Voxels size
25 27 23 0.023
15
25 15 31 0.015
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4. Discussion The main finding of the present study is that patients with LOD have lower FA in white matter of bilateral parahippocampal gyrus than that of healthy controls. Since our patients are individuals with first-episode, drug-naive, short-illness-duration (o 1 year) LOD (age of onset 460 years), the effect from confounding factors, such as medication, heterogeneity, and white matter changes by enduring long time of the disease, can be greatly reduced. Independent of segmentation schemes or a prior selection, TBSS offers a robust voxel-wise analysis to detect white matter abnormalities of the whole brain in a comprehensive way. Moreover, TBSS applies a strategy which confines the comparison to an FA skeleton and diminishes volume averaging effect. Therefore, TBSS adopted here is informative. A number of studies have adopted TBSS to analyze white matter alterations in depressed elders. Widespread structural abnormalities of white matter were detected in depressed elders, especially in the uncinate and cingulate white matter, which demonstrate significant correlations with diminished performance on neuropsychological testing (Mettenburg et al., 2012). Alves et al. (2012) reported reduced FA in the right posterior cingulate cluster in patients with geriatric depression, which showed a positive correlation with performance in a verbal naming task. In contrast, two recent studies revealed no white matter change in depressed elders (Bezerra et al., 2012; Colloby et al., 2011). Although the inconsistency may be due to some confounding factors, such as the sample size, medication, the cut-off age point to separate patients with geriatric depression from individuals with non-geriatric depression, and different pathological processes underlying white matter changes (such as demyelination, small vessel ischemic disease and perivascular dilatation), it has been indicated that patients with geriatric depression who begin their first depression onset before the age of 60 (EOD) are completely different from those who become depressed after the age of 60 (LOD) in both clinical symptoms (Brodaty et al., 2005) and neural activity (Guo et al., 2013b). Long illness duration and medication may bias the findings from patients with early-onset, geriatric depression, especially to the neuroimaging findings. Therefore, the present results of lower FA in white matter of bilateral parahippocampal gyrus are meaningful relative to those from older patients with EOD in previous studies. In addition to its contribution to learning and memory, the limbic system plays a key role in anxiety and depressive state (Fountoulakis et al., 2004). The limbic system fibers receive projections from the nearby cingulate gyrus, extending to the middle temporal lobe and hippocampus (Oishi et al., 2011). Lower FA was observed in the limbic system, such as anterior cingulate and posterior cingulate, in depressed elders (Bae et al., 2006), suggesting its involvement in the pathophysiology of geriatric depression. Located around the hippocampus, the parahippocampal gyrus, an important component of the limbic system, acts as a key role in memory and emotional regulation (Disner et al., 2011; Liu et al., 2013; Manns et al., 2003). The parahippocampal gyrus also has intimate communications with high-order brain regions (i.e. the entorhinal cortex, the anterior cingulate cortex) (Zhang et al., 2009). Abnormalities of cortical-limbic circuits have been implicated in mechanisms of emotional dysfunction (Drevets, 2000; Guo et al., 2013a; Liu et al., 2012b; Tekin and Cummings, 2002). Lower FA in the parahippocampal gyrus, which leads to disrupted fronto-limbic connectivity resulting in the loss of prefrontal lobe control over limbic areas, is regarded as the root of the pathophysiology of emotional, cognitive and behavior alterations in major depression (Liu et al., 2012a; Savitz and Drevets, 2009). Moreover, parahippocampal gyrus showed reduced glucose metabolism in geriatric depression (Smith et al., 2011a), which could be
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Fig. 1. White matter showing significantly lower FA in first-episode, drug-naive, late-onset depression (P o0.05, corrected). FA maps show sagittal, coronal, and axial views. The background image is the standard MNI152 brain template. Green voxels represent the FA white matter skeleton. Red-yellow voxels represent regions with lower FA in patients compared with healthy controls. FA ¼ fractional anisotropy; MNI ¼Montreal Neurological Institute. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
normalized by antidepressants (Smith et al., 2011b). In addition, significant gray matter volume reduction in right parahippocampal gyrus was observed in geriatric depression (Bell-McGinty et al., 2002). Furthermore, decreased white matter integrity in the right parahippocampal gyrus was reported in adults with first-episode, drug-naive major depressive disorder (Zhu et al., 2011). In line with these studies, lower FA in the white matter of bilateral parahippocampal gyrus in the present study may disrupt communications between the parahippocampal gyrus and high-order brain regions accounting for disconnection of cortical-limbic circuits (i.e., frontolimbic circuits) (Alexopoulos et al., 2000; Charlton et al., 2013). Indeed, depression can accelerate the loss of white matter integrity (Shimony et al., 2009) and increasing white matter changes are associated with limbic and dorsal cortical communication in geriatric depression (Rogers et al., 2004). Therefore, our results extend the previous evidence that the loss of white matter integrity in the limbic regions may contribute to the pathophysiology of LOD. White matter alterations in frontal regions have been usually reported in geriatric depression (Nobuhara et al., 2006; Taylor et al., 2004; Yuan et al., 2007) and young depression (Guo et al., 2012a, 2012b; Ma et al., 2007). Hence, the present findings without any FA alterations in the frontal lobe are somehow unexpected. The inconsistency may result from some possible factors including sample size, depression severity, analysis method, heterogeneity of subjects and medication. For instance, Yuan's and Ma's studies found lower FA in frontal regions in first-episode remitted geriatric depression (Yuan et al., 2007) and first-episode, drug-naive young depression (Ma et al., 2007) by the VBA method.
Their uncorrected P might amplify their false positive findings in addition to other confounding factors, such as depression severity and analysis methods (VBA vs. TBSS). In contrast, our results from a corrected P by the TBSS method may minimize the presence of false positive findings. There are at least two possible explanations for the present results of the absence of FA changes in the frontal lobe. First, the present results may suggest that white matter abnormality in the frontal regions may not necessarily contribute to the pathophysiology of LOD. This notion is supported by several studies. For example, no significant difference in DTI parameters in the frontal regions in depressed elders was found in an early investigation (Taylor et al., 2001). A recent study using the TBSS method indicated white matter changes in the bilateral frontal, right temporal and midbrain in depressed elders. However, their results are only suggestive since their corrected FA results are not statistically significant (Colloby et al., 2011). Another study even observed no white matter change in geriatric depression using the TBSS method (Bezerra et al., 2012). The present findings are also consistent with a TBSS study without white matter abnormality in frontal regions in middle-aged depression, which reported a trend for lower FA values in the left sagittal striatum and right cingulate cortex (Kieseppa et al., 2010). An alternative interpretation to the absence of FA changes in the frontal lobe is that brain circuits are dynamic, and disruption of multimodal areas may lead to various clinical presentations. Different parts of the frontal lobe have afferent and efferent links with other cortical, limbic and subcortical areas (Zhang et al., 2009). Frontal impairment may be potentially associated with a multitude of nonfrontal disrupted links.
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Since clinical characteristics such as the depression severity and the illness duration are reported to have correlations with lower FA values in certain regions in geriatric depression (Alves et al., 2012; Mettenburg et al., 2012), we hypothesized that patients with a higher depression severity and/or a longer illness duration would have a higher reduction in FA values in the parahippocampal gyrus. Therefore, the result of no correlation between these factors is somewhat unexpected. Although the result could be confounded by the relative small sample size, it is also possible that the abnormality may be a trait change for patients with LOD independent of depression severity and illness duration. Another possibility for no correlation is the concentration of clinical characteristics in the current study, such as illness duration around 6 months and HRSD total score around 21. Furthermore, the present findings of no correlation are supported by a large amount of studies, which also observed no association between anisotropy parameters and clinical characteristics in depressed elders (Bezerra et al., 2012) and young adults with depression (Ma et al., 2007; Madden et al., 2004). The relationship between white matter integrity and depression severity, illness duration, or cognitive function has not been clearly established. The present study has several limitations. First, the sample size was relatively small. Hence, the present findings should be considered preliminary and need to be replicated with a larger sample size. Second, we recruited merely first-episode, drugnaive patients with LOD to exclude the possible influence of the heterogeneity of illness. It is helpful to clarify the pathophysiology of LOD by the inclusion criterion. Since geriatric depression is a complex psychiatric syndrome, findings from LOD may not be generalized to other clinical subtypes of geriatric depression. Hence, this inclusion criterion might in turn limit the generalizability of our results. Third, brain white matter hyperintensity (WMH) is an index associated with demyelination resulting in white matter lesions. The fact that patients were not excluded based on the presence of WMH might have biased the present results. However, we did not exclude healthy controls with WMH, and partly balanced the influence of WMH. Furthermore, the criterion of not excluding participants based on the presence of WMH was adopted by most DTI studies in geriatric depression for the reason that WMH is common in older adults (Alexopoulos et al., 2009; Charlton et al., 2013; Yuan et al., 2007). Fourth, neuropsychological measurements (e.g., executive function, attention, memory, verbal skills, etc.) were not conducted in the present study, which might have hampered any firm conviction about the cognitive status of depressed patients. We were also unable to know correlations between lower FA in bilateral parahippocampal gyrus and neuropsychological measurements. Finally, DTI was performed on a 1.5 T scanner, resulting in relatively low signal-to-noise ratio compared to the images from a 3.0 T scanner. In summary, our findings first suggest that loss of white matter integrity in parahippocampal gyrus may be involved in the pathophysiology of LOD, and thus highlight the limbic contribution to the pathophysiology of LOD.
Role of funding source The study was supported by Grants from the Natural Science Foundation of China (Grant nos. 81260210, 30900483, and 81360211), the Natural Science Foundation of Guangxi (Grant no. 2013GXNSFAA019107), and the special funding by the Ministry of Health of the Peoples’ Republic of China (Grant no. 201002003).
Conflict of interest No conflict of interest declared.
Acknowledgments The authors thank all individuals who served as the research participants. The authors also appreciate anonymous reviewers for their suggestions and comments.
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