Background
Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a special kind of clinical entity that characteristically affects the bones, joints, and skin [
1]. Inflammatory osteitis with hyperostosis is the main feature of this disease and may occur without skin lesions. SAHPO syndrome is a rare disease and its prevalence is generally considered less than 1/10,000, although sufficient data on it is unavailable [
2]. So far, the etiology, pathophysiological mechanisms, treatment and long-term prognosis of SAPHO syndrome have not been fully understood. Most of researchers only focus on dermatological and osteoarticular changes of SAPHO patients. Furthermore, there is no related literature concerning about depressive symptoms in SAPHO syndrome.
Resting state functional magnetic resonance imaging (rs-fMRI) can reveal intrinsic functional architecture of the brain by measuring the spontaneous fluctuations in blood oxygenation level dependent (BOLD) signals in brain during resting state [
3]. Amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) are two common rs-fMRI data analysis methods. The ALFF reflects the extent of spontaneous neuronal activity [
4], while the FC reveals the tendency of cortical networks to be co-activated [
5]. Both methods have been applied effectively to detect the mechanisms of pathophysiology of major depressive disorder (MDD)[
6‐
12] and other mental disorders, such as autism spectrum disorders[
13], schizophrenia[
14], obsessive-compulsive disorders[
15] and so on. One of the most widely studied resting state networks is the default mode network (DMN), which plays an important role in self-referential, emotional processes, episodic memory and perceptual processing [
16]. A great variety of abnormal regions have been revealed in MDD, mainly including the prefrontal cortex, anterior cingulate cortex, cerebellum, amygdala and so on [
17,
18].
Spondyloarthritis (SpA), a family member of immune-mediated inflammatory disorders which includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, and undifferentiated SpA, is considered to be associated with depression [
19], and SAPHO syndrome may be one subtype of SpA. Baysal et al. [
20] reported that the depression had interaction with disease activity and quality of life in AS patients. A recent population-based study revealed that MDD increased the risk of developing PsA among psoriasis patients. Therefore, it is important to identify depression in SAPHO patients as it may have similar effect on AS/psoriatic patients. Our research team is involved in the largest cohort study of SAPHO syndrome in the world [
21]. When assessing the clinical, laboratory and radiological features of SAPHO syndrome, we also tried to explore the episode of depressive symptoms in SAPHO patients and revealed neurobiological basis of depression symptoms in these patients using rs-fMRI.
Methods
Subjects
Twenty-eight SAPHO patients (aged 16–65, mean 44.6 years, 15 females) were consecutively admitted from inpatient clinics in Peking Union Medical College Hospital from July 25, 2015 to October 20, 2015. All of the SAPHO patients met the diagnostic criteria proposed by Kahn and Khan [
1] and had typical anterior chest wall and dermatological manifestations, detailed data shown in Additional file
1: Table S1. There are no uniform scoring criteria to evaluate the severity of SAPHO syndrome, and both SAPHO syndrome and ankylosing spondylitis (AS) are considered to belong to SpA. Therefore, we use the scoring criteria of AS to describe the severity of SAPHO syndrome, including Visual Analogue Scale (VAS) [
22], Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [
23] and Bath Ankylosing Spondylitis Functional Index (BASFI) [
24]. The drugs that SAPHO patients were using during our study included nonsteroidal anti-inflammatory drugs (NSAIDs), bisphosphonates, and disease-modifying antirheumatic drugs (DMARDs), detailed clinical data of which were shown in Additional file
1: Table S2. Fifteen age- and gender- matched normal controls (NC) (aged 25–65, mean 44.5, 8 females) were enrolled from the local community and they were drug-naïve.
The investigation of depression diagnose was tested by an experienced psychiatrist (Dr.Duan) using the Mini-International Neuropsychiatric Interview (M.I.N.I) [
25], and severity of depressive symptoms was tested by the 17-item Hamilton Depression Rating Scale (HDRS) [
26]. The group of the depressed SAPHO (D-SAPHO) patients should meet MDD criteria using M.I.N.I. intervention, and HDRS scores should be more than 7. The remaining patients were non-depressed SAPHO (ND-SAPHO) patients. At the same day of psychiatric evaluation, all participants went through MRI scans. The detailed clinical data of all subjects were shown in Table
1.
Table 1
Clinical and demographic characteristics
Ages (years) | 49.3 ± 8.7 | 40.6 ± 13.7 | 44.5 ± 10.9 | 0.1642a
|
Gender (M/F) | 5/8 | 8/7 | 7/8 | 0.669b
|
Disease duration (months) | 37.3 ± 45.1 | 27.8 ± 42.8 | NA | 0.5860c
|
HDRS score | 18.1 ± 5.3 | 5.8 ± 2.7 | 3.1 ± 2.3 | <0.0001a
|
VAS | 4.0 ± 1.2 | 4.1 ± 3.4 | NA | 0.8974c
|
BASDAI | 3.6 ± 1.5 | 2.7 ± 2.3 | NA | 0.2359c
|
BASFI | 2.6 ± 2.4 | 2.3 ± 2.9 | NA | 0.9466c
|
Our study was approved by the local ethic committee of Peking Union Medical College Hospital. The written informed consents before psychometric and neurologic evaluations were signed by all of the subjects.
MRI Data Acquisition
All subjects were scanned with a 3-Tesla MRI scanner (MAGNETOM Skyra System, Siemens, Erlangen, Germany). Foam pads and the earplugs were used to minimize head motion and acoustic noise. The subjects were asked to stay still with their eyes closed and not think anything particular during the resting state scan. Functional images were collected using an echo-planar imaging sequence (repetition time [TR] =2510 ms, echo time [TE] =30 ms, flip angle = 90°, field of view [FOV] =240 mm × 240 mm, in-plane matrix = 80 × 80, slice thickness/gap = 3/0 mm). Additionally, subjects underwent structural imaging using a T1-weighted magnetization-prepared rapidly acquired gradient-echo sequence (176 slices, TR = 2300 ms, TE = 3.17 ms, TI = 900 ms, flip angle = 8°, FOV = 256 mm × 256 mm, in-plane matrix = 256 × 256, slice thickness/gap = 1/0 mm).
Rs-fMRI date analysis
The image preprocessing was performed using Data Processing Assistant for Resting-State fMRI (DPARSF) (
http://www.restfmri.net) [
27], which was based on Statistical Parametric Mapping (
http://www.fil.ion.ucl.ac.uk/spm) and Resting-State fMRI Data Analysis Toolkit 1.8 (REST) (
http://www.restfmri.net) [
28]. The first 10 volumes of the functional images were discarded to allow the magnetization to reach for a steady-state. Slice timing correction, head motion correction and nuisance covariate removal were performed. If the subjects’ head motion was more than 2.5 mm in the X, Y, Z-axis or rotation exceeding 2.5°, the subjects would be excluded. No subject was removed due to head motion in this study. Then functional images were normalized into the space of Montreal Neurological Institute template, using unified segmentation on T1 image, and were resampled to a voxel size of 3 × 3 × 3 mm
3. Spatial smoothing was used with a 6 mm full-width at half maximum Gaussian smoothing kernel. The data were further processed with the linear detrending and temporally band-pass filtering (0.01–0.08 Hz).
ALFF analysis
The ALFF analysis was also conducted by using the DPARSF software. The time series of each voxel was first transformed into a frequency domain through using fast Fourier transform and the square root of the power spectrum was obtained. ALFF was calculated as the average over a predefined frequency interval (0.01 Hz to 0.08 Hz), performed on a voxel-by-voxel basis. To reduce the global effects of variability, the ALFF of each voxel was divided by the global mean ALFF value.
Statistics and ALFF-depression correlation analysis
An analysis of variance (ANOVA) was performed on the ALFF to identify brain areas with significant differences among D-SAPHO patients, ND-SAPHO patients and NC (voxel-level
P < 0.01, cluster size > 1080 mm
3/40 voxels, corresponding to a corrected
P < 0.05 as determined by AlphaSim correction). Then these clusters were extracted as a mask. Two sample t-tests were conducted to compare the ALFF differences among the three groups within the mask (voxel-level
P < 0.001, cluster size >108 mm
3 /4 voxels, corresponding to a corrected
P < 0.05 as determined by AlphaSim correction). The correction thresholds were determined by the Monte Carlo simulations based on the AlphaSim in Analysis of Functional Neuroimage [
29], which were implemented on the REST software. To explore the correlation between depression and regional resting state activity, a post-hoc correlation analysis was performed between the HDRS scores and ALFF values which were extracted in regions where significant differences between D-SAPHO patients and ND-SAPHO patients were observed.
FC analysis
FC analysis was performed to explore the changes of DMN in SAPHO patients. To identify the DMN map, a seed region of interests (ROIs) was placed in the posterior cingulate cortex (PCC; 0X,-53Y, 26Z; seed size of 10 mm × 10 mm × 10 mm). For each subject, the average BOLD time course of voxels within ROIs was plotted. Subsequently, we computed the correlation coefficient between that the BOLD time course of voxels within ROIs and the time course of all the other voxels in the brain. Then, the r-scored maps were converted to z-scores by using Fisher’s r-to-z transformation.
Statistics and FC-depression correlation analysis
The FC differences among groups were performed by using two sample t-tests (voxel-level P < 0.001, cluster size > 432 mm3/16 voxels, corresponding to a corrected P < 0.05 as determined by AlphaSim correction) after the ANOVA analysis. The FC values of these regions showing significant differences in DMN between D-SAPHO patients and ND-SAPHO patients were calculated separately. Subsequently, the correlation of the FC values and HDRS scores were analyzed.
Discussion
To the best of our knowledge, this is the first study to reveal depressive symptoms in SAPHO syndrome. Our research team previously reported the largest cohort study of SAPHO syndrome in the world, including one hundred and sixty-four patients [
21].In this study, psychiatric evaluation and MRI scans were performed on twenty-eight patients of these SAPHO patients, and fourteen SAPHO patients were diagnosed with depression. Therefore, we inferred that the prevalence of depression in SAPHO patients was at least 7.9% (13/164), and much higher than that in Chinese adults (6.40‰) [
30]. A study using multivariate logistic regression analysis revealed that severity of disease (BASDAI), quality of life, and educational level were factors associated with the risk of depression in SpA [
31]. Thus, we speculated that these factors might also contribute to the episode of depression in patients with SAPHO syndrome.
This study not only confirmed the existence of depression in SAPHO patients by psychiatric tests, but also revealed the abnormal brain activities of D-SAPHO patients by rs-fMRI. We found that D-SAPHO patients showed decreased ALFF in the bilateral VLPFC and right DLPFC, and disrupted FC in DMN.
In our current study, we found decreased local spontaneous activity in the bilateral VLPFC and right DLPFC in D-SAPHO patients compared with both ND-SAPHO patents and NC. As is known, the VLPFC is considered to be negatively correlated with negative affect [
32] and inhibitive controls of negative emotions and cognitions, such as reappraisal [
33]. Meanwhile, a recent research showed that depression patients had decreased activation of left VLPFC compared to normal controls when processing negative information such as loss [
34]. Furthermore, decreased ALFF values in the left VLPFC were negatively correlated to the HDRS score of D-SAPHO patients in our study, which suggested that ALFF measurement in left VLPFC would be a good marker to detect and evaluate the severity of depression in SAPHO patients. The DLPFC has primarily been correlated with cognitive and executive functions and it plays an important role in MDD [
35]. Previous studies on MDD patients showed changes of metabolite concentrations in DLPFC [
36,
37]. Moreover, a previous study demonstrated that the gray matter density (GMD) of right DLPFC decreased in the MDD patients compared with controls and the GMD values of right DLPFC were negatively correlated with the HDRS scores[
38]. In contrast to decreased activity in the bilateral prefrontal cortex, increased ALFF in the bilateral middle temporal gyrus was observed in D-SAPHO patients compared to ND-SAPHO patients. In addition to language comprehension, the temporal lobe also contributes to social cognition and emotional processing [
39]. Two previous studies using regional homogeneity (ReHo) analysis [
40] and morphometric MRI [
41] identified local activity and structure abnormalities in MDD, which were consistent with the pattern of our present findings. Wu et al. [
40] demonstrated high ReHo in the right middle temporal gyrus in MDD patients and Ramezani et al. [
41] revealed the abnormal structure of medial temporal regions in MDD patients.
Compared to the NC group, decreased ALFFs in the ventromedial prefrontal cortex (VMPFC) were demonstrated in D-SAPHO patients and ND-SAPHO patients separately, nevertheless there was no significant difference in spontaneous activity of VMPFC between D-SAPHO patients and ND-SAPHO patients. As is known, the VMPFC, which is anatomically synonymous with the orbitofrontal cortex, is considered to be involved with the control of emotional, cognitive and social behavior [
42]. Firstly, we speculated that rs-fMRI could reveal the abnormal brain activity related to depression of SAPHO patients prior to clinical criteria. In other word, ND-SAPHO patients had the potential to merge depressive symptoms which could be detected by the decreased ALFF in the VMPFC. Secondly, we hypothesized that decreased ALFF in the VMPFC in SAPHO patients could be a SAPHO-specific marker rather than a depression-specific marker.
Further procession by the method of FC in our study, one kind of network level analysis, demonstrated disrupted DMN in SAPHO patients. Moreover, D-SAPHO patients had more FC impairment than ND-SAPHO patients compared to NC. The FC study disclosed that D-SAPHO patients had an increased DMN FC in anterior portions (the bilateral inferior frontal cortex, anterior cingulate cortex and insula cortex), and a decreased DMN FC in posterior areas (left middle occipital cortex), when compared to ND-SAPHO patients. Specially, the FC values between PCC and all of the regions showing significant differences in FC between D-SAPHO patients and ND-SAPHO patients were significantly correlated with the HDRS scores of all SAPHO patients (including D-SAPHO patients and ND-SAPHO patients) in our study, and the FC values between the PCC and left middle occipital cortex was negatively correlated with the HDRS scores of D-SAPHO patients. Our finding indicates that abnormal FCs in DMN are involved in the symptomatology of depression in SAPHO patients. Although we lacked studies exploring the neural mechanisms underlying the functional impairment of DMN in D-SAPHO patients, there are a number of studies in MDD corroborating our results. Similar to our results, Coutinho et al. [
43] also described that the FCs of the anterior areas of DMN were positively correlated with depression scores, whereas posterior portions of DMN were negatively correlated with depression scores. These results could be interpreted as dissociation between anterior and posterior FCs in DMN, in which anterior regions could be involved in self-referential and emotional processes and posterior potions could be involved in episodic memory and perceptual processing [
16]. A previous review found that patients with MDD exhibited changed connectivity between the anterior DMN and posterior DMN [
44], in consistent to our understanding that disrupted DMN was involved in depression in SAPHO patients.
We recognize some limitations in this study. Firstly, our study was limited by the relatively small SAPHO samples, whereas SAHPO syndrome is a rare disease and previous reports about it usually involved dozens of patients. Secondly, SAPHO patients in our study were not drug-naive, which might lead to a potential confusion on rs-fMRI. It is also worthwhile to mention that differences in drug therapies are not distinguishable between D-SAPHO patients and ND-SAPHO patients in this study.
Acknowledgements
Not applicable.