Research paperA resting-state fMRI study in borderline personality disorder combining amplitude of low frequency fluctuation, regional homogeneity and seed based functional connectivity
Introduction
Borderline personality disorder (BPD), a severe axis II mental disorder, is a long-term abnormal behavior pattern characterized by instability in emotion regulation, interpersonal relationships, impulse control, and self-identification, resulting in social disability, self-injury, and suicide (Leichsenring et al., 2011). Since the application of magnetic resonance imaging (MRI) technology in neuroscience, tremendous progress has been made in the pathomechanism of BPD, especially the abnormal alterations in brain structure and function.
In structural MRI, abundant voxel-based morphometric (VBM) studies have confirmed decreased gray matter volume (GMV) in several brain regions in BPD (Soloff et al., 2008), including the orbitofrontal cortex (Chanen et al., 2008, Tebartz van Elst et al., 2003) and the hippocampus-amygdala complex (Driessen et al., 2000, Schmahl et al., 2003, Silbersweig et al., 2007, Vermetten et al., 2006), and increased GMV in precuneus (Irle et al., 2007) and posterior cingulate cortex (PCC, Yang et al., 2016). In one previous VBM study, we also found that increased GMV in bilateral middle cingulate cortex (MCC), PCC and precuneus in BPD (Jin et al., 2016). Meanwhile, a growing body of task-related functional MRI studies have discovered close correlations between abnormal brain activities and psychological processing or core symptoms of BPD (Siegle, 2007, Xu et al., 2016), such as fronto-limbic activation associated with emotional dysfunction (Silvers et al., 2016), aberrant insula and amygdala activity associated with interpersonal and social-cognitive deficits (King-Casas et al., 2008, Mier et al., 2013), a greater activity in the dorsolateral prefrontal cortex (DLPFC) associated with impulsivity and aggressive behaviors (Silbersweig et al., 2007), disturbed amygdala activity and decreased functional connectivity with superior frontal gyrus associated with self-injury behaviors and reduced pain sensitivity (Kraus et al., 2009, Reitz et al., 2015).
In the last decade, more and more researchers have realized that the human brain also keeps highly activity in task free state (i.e. resting state). About 60–80% of overall brain energy consumption is devoted to brain spontaneous neuronal activity in resting state, whereas the task-evoked energy consumption is remarkably small, often less than 5% (Raichle and Mintun, 2006), which implies that intrinsic activity comprises important and nonnegligible functions (Raichle, 2010). To detect the resting state blood oxygen level dependent (BOLD) signals, part researchers tried the amplitude of low frequency fluctuation (ALFF) (Yang et al., 2007) and the regional homogeneity (ReHo) (Zang et al., 2004), which are two data-driven approaches of resting-state fMRI (rs-fMRI), with the former reflecting the neural spontaneous activity in a single voxel level and the later reflecting synchronization activities between a voxel with its nearest neighbors, respectively. And ALFF mirrors the brain functional segregation, while ReHo mirrors the brain functional integration. Commonly, ALFF and ReHo under the average level of the whole brain indicate lower spontaneous activity in specific brain areas (Du et al., 2016) and decreased synchronization of regional neural activity (Philip et al., 2013), respectively. These two methods have been widely used in various diseases (such as schizophrenia, depression, attention deficit hyperactivity disorder, etc) to examine abnormal functional alterations in a special brain region or alterations of brain function before and after treatment with medication or psychotherapy (Iwabuchi et al., 2015, Li et al., 2016, Lui et al., 2010, Shang et al., 2016). Until now, only one study used ALFF to evaluate BPD related brain functional alteration, and found decreased neural spontaneous activity in the posterior occipital lobes, the right precuneus and the dorsal PCC (Salvador et al., 2016). Given that the importance of resting state brain function and the lack of rs-fMRI studies in BPD, it is worth exploring the alterations of brain function in BPD patients by combining these two methods (ALFF and ReHo) to get a more comprehensive understanding of the related brain abnormalities in resting state in BPD.
Abundant previous studies suggested that psychological process and various symptoms of BPD involved in a consequence of alterations within discrete brain networks and disturbed functional connectivity rather than isolated brain regions (Doll et al., 2013, O'Neill et al., 2015, Wolf et al., 2011). O'Neill et al. found that increased connectivity between precuneus and frontal regions during resting state might be related to extensive processing of internal thoughts and self-referential information in BPD (O'Neill et al., 2015). Wolf et al. also reported increased functional connectivity between the left frontopolar cortex (FPC) and the left insula, whereas decreased connectivity between the FPC and the left cuneus in BPD. Meanwhile, they found that impulsivity scores were positively correlated with connectivity density of the left FPC, dissociative tension scores were positively correlated with connectivity of the left insula and negatively correlated with connectivity of the cuneus in BPD patients (Wolf et al., 2011). Additionally, Doll's study found that aberrant functional connectivity was shown in central executive network (CEN), salience network (SN), and default mode network (DMN) in BPD (Doll et al., 2013). In all, functional connectivity (FC) is also an effective method to study brain function integration in BPD.
Therefore, using a multiple-algorithm analysis in combination of ALFF, ReHo and FC, we conducted a data-driven empirical study to explore the spontaneous brain activity, synchronization activity and functional connectivity in BPD comprehensively. AFLL and ReHo were calculated and then the abnormal brain regions were selected as seeds to calculate seed-based FC. Firstly, we hypothesized BPD patients would show altered neural spontaneous activity, non-synchronous activity and disturbed functional connectivity in resting state, compared with control subjects. Secondly, our previous VBM study found increased GMV in bilateral PCC and precuneus in BPD (Jin et al., 2016), we hypothesized that these two brain regions might also exist functional alteration in BPD. Thirdly, given that altered brain structure in BPD were mainly distributed in frontotemporal and limbic areas as previous literature reviewed, we hypothesized that brain regions with abnormal function would locate in these areas as well.
Section snippets
Sample
A group of 40 right-handed un-medicated young BPD patients with a mean age of 25.23 years (standard deviation 3.17) and a group of 35 age- and education-matched control subjects with a mean age of 24.77 years (standard deviation 1.19) participated in this study.
BPD patients were recruited from outpatient clinics affiliated with the Second Xiangya Hospital of Central South University, Changsha, Hunan, China. The diagnosis of BPD was made by two qualified psychiatrists based on the structured
ALFF and ReHo analysis
To explore the difference of brain spontaneous activity and regional homogeneity between BPD group and control group, two-sample t-tests were operated in a voxel-wised manner in the Resting-State fMRI Data Analysis Toolkit (REST, http://restfmri.net/forum/REST_V1.8) software (Song et al., 2011), with age, gender, and education as covariates. The results were corrected for multiple comparisons to a significant level of p<0.05 by REST AlphaSim program with 10,000 iterations combining individual
Demographic and clinical characteristics of participants
The demographic and clinical characteristics of all participants were summarized in Table 1. The BPD group and control group were well matched, with no significant differences in age, gender and education. Compared with the control group, the BPD group had significantly higher scores on depression, trait anxiety, insecure attachment, negative affectivity, impulsivity, and childhood trauma, except for the state anxiety scores.
Amplitude of low frequency fluctuation and regional homogeneity
Compared with the control group, the BPD group showed decreased ALFF
Discussion
To our best knowledge, this is the first study to focus on brain function in resting state in BPD by a data-driven multiple-algorithm analysis combining ALFF, ReHo with seed-based FC. Compared with control subjects, BPD patients showed significant alterations in the right PCC and adjacent precuneus, with decreased neural spontaneous activity and non-synchronous activity, as well as disturbed functional connectivity with other brain regions in resting state. Combining with our previous Voxel
Conclusions
Based on this data-driven analysis, we discovered that the right PCC and precuneus were altered in resting state in BPD. Combining with our previous VBM study which has found increased GMV in the right PCC and precuneus, we confirmed that these two areas were core brain regions altered both in structure and function in BPD. Given that the PCC along with adjacent precuneus was core areas of the DMN, altered neural spontaneous activity, synchronization activity and disturbed functional
Acknowledgements
This study was supported by Grant from the National Natural Science Foundation of China (Grant no. 81370034).
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These two authors Contributed equally.