Psychological Medicine (2014), 44, 1927–1936. © Cambridge University Press 2013 doi:10.1017/S003329171300250X
OR I G I N A L A R T I C L E
Abnormalities in whole-brain functional connectivity observed in treatment-naive post-traumatic stress disorder patients following an earthquake C. Jin1†, R. Qi2†, Y. Yin1,3, X. Hu1, L. Duan1, Q. Xu2, Z. Zhang2, Y. Zhong2, B. Feng4, H. Xiang5, Q. Gong6, Y. Liu7, G. Lu2* and L. Li1* 1
Mental Health Institute, The Second Xiangya Hospital of Central South University, Hunan, People’s Republic of China Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing. People’s Republic of China 3 The Seventh People’s Hospital of Hangzhou, Hangzhou, Zhejiang, People’s Republic of China 4 Mianzhu Psychiatric Hospital, Erhuan Road and Mianzun Road, Deyang, Sichuan, People’s Republic of China 5 Mental Health Center of Sichuan Province, Mianyang, Sichuan, People’s Republic of China 6 Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China 7 Department of Psychiatry, University of Florida, Gainesville, FL, USA 2
Background. Convergent studies have highlighted the dysfunction of the amygdala, prefrontal cortex and hippocampus in post-traumatic stress disorder (PTSD). However, only a few studies have investigated the functional connectivity between brain regions in PTSD patients during the resting state, which may improve our understanding of the neuropathophysiology of PTSD. The aim of this study was to investigate patterns of whole-brain functional connectivity in treatment-naive PTSD patients without co-morbid conditions who experienced the 8.0-magnitude earthquake in the Sichuan province of China. Method. A total of 72 PTSD patients and 86 trauma-exposed non-PTSD controls participated in the resting-state functional magnetic resonance imaging study. All these subjects were recruited from the disaster zone of the 2008 Sichuan earthquake. Functional connectivities between 90 paired brain regions in PTSD patients were compared with those in trauma-exposed non-PTSD controls. Furthermore, Pearson correlation analysis was performed between significantly abnormal connectivities in PTSD patients and their clinician-administered PTSD scale (CAPS) scores. Results. Compared with non-PTSD controls, PTSD patients showed weaker positive connectivities between the middle prefrontal cortex (mPFC) and the amygdala, hippocampus, parahippocampal gyrus and rectus, as well as between the inferior orbitofrontal cortex and the hippocampus. In addition, PTSD patients showed stronger negative connectivity between the posterior cingulate cortex (PCC) and the insula. The CAPS scores in PTSD patients correlated negatively with the connectivity between the amygdala and the mPFC. Conclusions. PTSD patients showed abnormalities in whole-brain functional connectivity, primarily affecting the connectivities between the mPFC and limbic system, and connectivity between the PCC and insula. Received 20 December 2012; Revised 5 September 2013; Accepted 10 September 2013; First published online 29 October 2013 Key words: Functional connectivity, post-traumatic stress disorder, resting-state functional magnetic resonance imaging.
Introduction Post-traumatic stress disorder (PTSD) is an anxiety disorder that can follow exposure to extreme stressful experiences, e.g. combat, earthquake and violent crime (Hughes & Shin, 2011). It is characterized by
* Address for correspondence: L. Li, M.D., Mental Health Institute, The Second Xiangya Hospital of Central South University, 139# Renmin Zhong Road, Changsha 410011, Hunan, People’s Republic of China. (Email: [email protected]) [L. Li.] (Email: [email protected]) [G. Lu] † These authors contributed equally to this work.
three hallmark symptoms: re-experiencing of the traumatic event, withdrawal or avoidance behavior, and hyperarousal or increased startle responses (Hughes & Shin, 2011). Imaging plays an important role in uncovering the brain abnormalities of PTSD. Accumulating evidence from neuroimaging studies (Liberzon & Phan, 2003; Bremner, 2007; Hughes & Shin, 2011) has presented a neurocircuitry model of PTSD that emphasizes the role of the amygdala, as well as its interactions with the medial prefrontal cortex and hippocampus. Within this model of PTSD (Liberzon & Phan, 2003; Hughes & Shin, 2011), the amygdala is hyperresponsive, mediates symptoms of hyperarousal and
1928 C. Jin et al. explains the indelible quality of the emotional memory for the traumatic event; and the prefrontal cortex is hyporesponsive, leading to deficits of fear extinction. In addition, the abnormal hippocampal function may underlie declarative memory impairments and deficits in identifying safe contexts. Some other regions including the insula (Rabinak et al. 2011; Garrett et al. 2012) and areas within the brain default mode network (DMN) (Bluhm et al. 2009; Lanius et al. 2010; Sripada et al. 2012b) also exhibited functional abnormalities in PTSD in previous neuroimaging studies. Recently, resting-state functional magnetic resonance imaging (rs-fMRI), which attracts increased attention, has indicated that the pathophysiology of many brain diseases including PTSD may be associated with the changes in spontaneous low-frequency fluctuations measured during the resting state (Yin et al. 2011a, b; Sripada et al. 2012a). These blood oxygenation level-dependent signals are thought to be associated with spontaneous neuronal activity (Fox & Raichle, 2007). In a recent rs-fMRI study, PTSD patients exhibited abnormal low-frequency fluctuations in many cortices and areas of the limbic system, i.e. the frontal and occipital gyri, lingual gyrus and the insula (Yin et al. 2011b). However, many brain regions are functionally related and interconnected (Damoiseaux et al. 2006; Mantini et al. 2007), and the changes in functional interaction between brain regions in PTSD remain unclear up to now. In rs-fMRI, the functional connectivity analysis algorithm measures the temporal synchrony or correlation between spatially separate regions (Lowe et al. 2000). Studies using this method have reported abnormal functional connectivity in many neuropsychiatric diseases, such as Alzheimer’s disease (Greicius et al. 2004) and schizophrenia (Woodward et al. 2012), contributing to the understanding of neuropathophysiological mechanisms of these diseases. To our knowledge, there have been very limited previous functional connectivity studies in the resting-state focused on PTSD, and the published findings have been varied and even contradictory (Bluhm et al. 2009; Rabinak et al. 2011; Sripada et al. 2012a). One study used the amygdala as the seed region and found reduced correlation between the amygdala and anterior cingulate cortex in PTSD patients, suggesting the disturbed coupling between the amygdala and frontal cortex (Sripada et al. 2012a). However, Rabinak et al. (2011), also using region of interest (ROI) analysis, failed to detect abnormal connectivity between the amygdala and frontal cortex. Using independent component analysis, Bluhm et al. (2009) found that in PTSD patients the posterior cingulate cortex (PCC)/precuneus within the brain DMN exhibited weaker connectivity with the amygdala and hippocampus. Different methodology,
variance in co-morbidities and medication exposure may account for the inconsistencies among these studies. In addition, the seed-based or single networkbased methods in previous functional connectivity studies restrain the obtained information to the selected regions of interest and make it difficult to examine the functional connectivity patterns on a whole-brain scale. In the present study, we performed the rs-fMRI technique on a whole-brain scale to explore the abnormalities of functional connectivity in treatment-naive PTSD patients following an earthquake without co-morbid conditions. We hypothesized that wholebrain functional connectivity would be disrupted in patients with a single diagnosis of PTSD, especially between the frontal cortex and the limbic system (e.g. amygdala).
Method Subjects This study was approved by the local medical research ethics committee, and written informed consent was obtained from all participants. We performed a large-scale PTSD survey of post-earthquake survivors in Sichuan Province, China, which was hit by an 8.0-magnitude earthquake on 12 May 2008. Investigation was carried out in the two most devastated regions 8 months after the earthquake. In Hanwang town, 3100 survivors were interviewed and screened with the PTSD Checklist (PCL; Blanchard et al. 1996). Survivors scoring 535 points were then screened with the clinician-administered PTSD scale (CAPS; Blake et al. 1995) to confirm the PTSD diagnosis. In Beichuan County, the other severely affected region, a total of 1100 survivors were also interviewed and screened with the PCL and CAPS. After these procedures, all 415 subjects fulfilling the PTSD diagnosis were scheduled for the following fMRI study. In addition, 109 trauma-exposed non-PTSD subjects with PCL scores below 30 points were selected as a control group in this fMRI study. To further confirm the PTSD diagnosis and rule out psychiatric co-morbidities, all subjects were screened with the Chinese version of the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (First et al. 2002) as revised by Professor Lipeng Fei from Beijing Hui Long Guan Hospital, China. The exclusion criteria of the PTSD subjects in this fMRI study included the any psychiatric co-morbidities or other psychiatric disorder (n = 134), any history of or current brain injury (n = 12), as well as any other significant medical or neurological conditions (n = 58), any MRI contraindication (n = 81),
Whole-brain functional connectivity in PTSD patients
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of 200 brain volumes were collected, resulting in a total scan time of 400 s. Data pre-processing Pre-processing of functional images was carried out using the SPM8 software package (http://www.fil.ion. ucl.ac.uk/spm). First, slice-timing adjustment and realignment for head-motion correction were performed. A total of 15 PTSD patients and nine non-PTSD controls were excluded from further analysis because of excessive movement (translation exceeded 1.5 mm or rotation exceeded 1.5°). Consequently, 57 PTSD and 77 controls remained. We also evaluated the group differences in translation and rotation of head motion according to the following formula (Liao et al. 2010): Head motion/rotation = L 1 |xi − xi−1 |2 + |yi − yi−1 |2 + |zi − zi−1 |2 , L − 1 i=2
Fig. 1. Flow chart of the participants enrolled in the study. MRI, Magnetic resonance imaging; CAPS, clinician-administered traumatic stress disorder scale; fMRI, functional MRI.
left-handed (n = 16), and unavailable data (n = 16). In addition, after the MR scanning, we also excluded the patients aged 560 years (n = 10) and CAPS scores 0.05). Differences in connectivity between groups In all, nine connectivities of every two ROIs were significantly different between PTSD patients and non-PTSD controls (Fig. 2), including seven decreased positive connectivities and two increased negative connectivities. Additionally, at a lenient significant level of p < 0.001 (uncorrected), we found 19 abnormal connectivities in PTSD patients, including 16 decreased
Table 1. Demographics and clinical data of PTSD patients and controls
Protocols Gender, n Male Female Mean age, years (S.D.) Mean length of education, years (S.D.) Handedness, n Right-handers Non-right-handers Mean CAPS score (S.D.) Co-morbid diagnoses, n
PTSD (n = 57)
Controls (n = 77)
14 43 41.32 (9.07) 7.77 (2.98)
24 53 41.73 (8.46) 7.55 (2.81)
57 0 66.18 (12.19) 0
77 0 – 0
p 0.40a
0.79b 0.65b
1a
PTSD, Post-traumatic stress disorder; S.D., standard deviation; CAPS, clinician-administered PTSD scale for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition; –, unavailable data. a The p values for gender distribution and handedness in the two groups were obtained by the χ2 test. b The p values for age and education difference between the two groups were obtained by the two-sample t test.
positive connectivities and three increased negative connectivities (Fig. 3). All of the abnormal connectivities were visualized with the BrainNet Viewer (http://www.nitrc.org/projects/bnv/). Abnormal positive connectivities Compared with non-PTSD controls, all seven positive connectivities were weaker in PTSD patients (Fig. 2a and Table 2). In detail, these were connectivities between the right amygdala and left middle prefrontal cortex (mPFC), between the left mPFC and bilateral hippocampus, between the left mPFC and bilateral parahippocampal gyri, between the left mPFC and right rectus, and between the left inferior orbitofrontal cortex (OFC) and right hippocampus. No increased positive connectivity was found in PTSD patients. In addition, at p < 0.001 (uncorrected), we found 16 weaker positive connectivities, also mainly between the frontal cortex and limbic system. There were also other weaker positive connectivities between the parietal and temporal cortices and the limbic system (for more details of these 16 decreased connectivities, see Fig. 3a and Table 2). Abnormal negative connectivities Only two negative connectivities were stronger in PTSD patients than in non-PTSD controls: between the left PCC and bilateral insula (Fig. 2b and
Whole-brain functional connectivity in PTSD patients
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(a)
(b)
Fig. 2. Differences in the whole-brain functional network between post-traumatic stress disorder (PTSD) and control groups (corrected for multiple comparisons). (a) Compared with non-PTSD controls, PTSD patients showed seven weaker positive connections: between the right amygdala (AMY) and left middle prefrontal cortex (mPFC), between the left mPFC and left/ right hippocampus (HIP), between the left mPFC and left/right parahippocampal gyri (PHG), between the left mPFC and right rectus, and between the left inferior orbitofrontal cortex (Inf_OFC) and right hippocampus. (b) In addition, two negative connections were stronger in PTSD patients than in non-PTSD controls: connectivities between the left posterior cingulate cortex (PCC) and left/right insula (INS). L, Left; R, right.
(a)
(b)
Fig. 3. Differences in the whole-brain functional network between post-traumatic stress disorder (PTSD) and control groups at p < 0.001(uncorrected). (a) Compared with non-PTSD controls, PTSD patients show 16 weaker positive connections: between the left middle prefrontal cortex (mPFC) and right amygdala (AMY), bilateral hippocampal/parahippocampal gyri (PHG), bilateral rectus (Rec) and right Calcarine fissure (Cal), between the left inferior orbitofrontal cortex (Inf_OFC) and right PHG, between the triangular part of the left inferior frontal gyrus (IFGtriang) and the right PHG and right AMY, between the left superior frontal gyrus (SFG) and right hippocampus (HIP), between the left inferior parietal lobe (IPL) and right AMY, and between the left inferior temporal gyrus (ITG) and right HIP. (b) In addition, three negative connectivities are stronger in PTSD patients than in non-PTSD controls: connectivities between the left posterior cingulate cortex (PCC) and left/right insula (INS), and between the right PCC and left INS. L, Left; R, right.
1932 C. Jin et al. Table 2. Decrease in positive functional connectivity in PTSD patients compared with controls
Region 1
Region 2
Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left inferior OFC Left inferior OFC Left IFGtriang Left IFGtriang Left IFGtriang Left SFG Left IPL Left ITG
Right amygdala Left hippocampus Right hippocampus Left PHG Right PHG Right rectus Left rectus Right Cal Right hippocampus Right PHG Right hippocampus Right PHG Right amygdala Right hippocampus Right amygdala Right hippocampus
ta −4.53 −4.08 −4.80 −3.87 −4.52 −3.96 −3.47 −3.45 −4.26 −3.63 −3.69 −3.67 −3.41 −3.48 −3.45 −3.59
p
Effect size: Pearson’s r
Effect size: Cohen’s d
0.000 013b 0.000 078b 0.000 004b 0.000 171b 0.000 014b 0.000 125b 0.000 704 0.000 766 0.000 039b 0.000 402 0.000 328 0.000 355 0.000 857 0.000 687 0.000 762 0.000 473
0.37 0.33 0.38 0.32 0.37 0.32 0.29 0.29 0.35 0.30 0.30 0.30 0.28 0.29 0.29 0.30
0.79 0.71 0.83 0.67 0.78 0.69 0.60 0.60 0.74 0.63 0.64 0.64 0.59 0.60 0.60 0.62
PTSD, Post-traumatic stress disorder; mPFC = middle prefrontal cortex; PHG, parahippocampal gyrus; Cal, Calcarine fissure; OFC, orbitofrontal cortex; left IFGtriang, triangular part of the left inferior frontal gyrus; SFG, superior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus. a A negative t value represents a decrease. b Type 1 error corrected by using false-positive adjustment (p < 1/4005 = 0.000 249). All other functional connectivities are present at p < 0.001 (uncorrected).
Table 3. Increase in negative functional connectivity in PTSD patients compared with controls
Region 1
Region 2
Left PCC Left PCC Right PCC
Left insula Right insula Left insula
ta +3.79 +4.03 +3.38
p
Effect size: Pearson’s r
Effect size: Cohen’s d
0.000 232b 0.000 093b 0.000 959
0.31 0.33 0.28
0.66 0.70 0.59
PTSD, Post-traumatic stress disorder; PCC, posterior cingulate cortex. A positive t value represents an increase. b Type 1 error corrected by using false-positive adjustment (p < 1/4005 = 0.000 249). All other functional connectivities are present at p < 0.001 (uncorrected). a
Table 3). No decreased negative connectivity was exhibited in PTSD patients. At p < 0.001 (uncorrected), the right PCC and left insula also showed increased negative connectivity in PTSD patients (for more details, see Fig. 3b and Table 3). Validation of the functional connectivity findings To provide some validation for the whole-brain-based analytical approach used in this study, we performed seed-based functional connectivity analysis (Fox et al. 2005; Fox & Greicius, 2010). We selected four areas
as seed regions. These were the left mPFC, the left PCC and the bilateral amygdala. The left mPFC was selected because it showed the most abnormal connections in this study; the left PCC and bilateral amygdala were chosen because they showed abnormal functional connectivities both in our findings and several previous neuroimaging studies (Bluhm et al. 2009; Sripada et al. 2012a). The results of comparing each seed’s functional connectivity network between PTSD patients and controls also supported our wholebrain functional connectivity findings (see the online Supplementary material).
Whole-brain functional connectivity in PTSD patients
Fig. 4. Correlation results between abnormal connectivities and clinician-administered post-traumatic stress disorder scale (CAPS) scores in post-traumatic stress disorder (PTSD) patients (p < 0.05, uncorrected). Among all the different connectivities, only the connectivity between the right amygdala (R-AMY) and the left middle frontal cortex (L-mPFC) inversely correlated with the CAPS scores of PTSD patients. FC, Functional connectivity.
Correlation results Among all the nine significantly different connectivities, only the connectivity between the right amygdala and the left mPFC negatively correlated with the CAPS scores of patients (Fig. 4). No correlation was found between any other abnormal interregional connectivity and the CAPS performances of patients.
Discussion The present rs-fMRI study indicated that PTSD patients following an earthquake suffered from disrupted whole-brain functional connectivity, primarily located between the frontal cortex and limbic system regions. All these findings provide further evidence of cortico-limbic circuitry dysfunction in patients with a single diagnosis of PTSD. Decreased functional connectivity in PTSD patients The prefrontal–limbic system plays an important role in learning, memory and affective processing (Braun, 2011). Abnormal brain activity in the prefrontal–limbic system in PTSD patients has been previously reported in several fMRI (Garrett et al. 2012; Sripada et al. 2012b) and positron emission tomography/single-photon emission computed tomography (PET/SPECT) studies (Shin et al. 2004; Chung et al. 2006). Weaker functional connectivity between the mPFC and the limbic system observed in the present study is complementary to previous studies and provides important insight into understanding the coupling between the frontal cortex and the limbic system in PTSD patients. Taken together, the abnormal prefrontal–limbic system in
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these studies may partially explain some defects in PTSD, such as the disturbed emotional processing and memory regulation abilities. The PFC and amygdala are two key components of the cortico–limbic circuit involved in emotional processing and have wide interconnections with each other (Ghashghaei et al. 2007; Pessoa, 2008). Decreased PFC activity accompanied by increased amygdala activity in PTSD patients has been reported in many studies with traumatic-related stimuli (Etkin & Wager, 2007), traumatic-unrelated emotional tasks (Shin et al. 2005; Williams et al. 2006), and of the resting state (Sripada et al. 2012a). One recent fMRI study used the amygdala as the seed region of functional connectivity and also found decreased connectivity between the amygdala and PFC (Sripada et al. 2012a). The PFC is a region of central importance in the processes of body regulation, fear modulation and working memory (Braun, 2011). The amygdala has a critical role in emotion and in fear conditioning (Braun, 2011; Sripada et al. 2012a). Decreased mPFC–amygdala connectivity, as reported in the present study, may indicate impaired coupling between them or diminished PFC regulation of the amygdala. We also found decreased frontal cortex–hippocampus/parahippocampal gyrus connectivity in this study. The hippocampus is essential for memory functions, especially memorizing facts and events, and memory consolidation (Braun, 2011). Damage to the hippocampus can cause the inability to form new memories (Braun, 2011). The frontal cortex has strong connections to the hippocampus (Tamminga & Buchsbaum, 2004); a connectivity disturbance between them indicates disturbed frontal regulation over the hippocampus which may result in the failure to inhibit negative memory (Tamminga & Buchsbaum, 2004). It should be noted that there are inconsistent findings regarding the hippocampal responsivity in PTSD patients in different task-related neuroimaging studies, both with hypoactivity and hyperactivity (Hughes & Shin, 2011). It seems that the direction of hippocampal functional abnormalities depends in part on the type of tasks and analysis employed (Bremner, 2007; Hughes & Shin, 2011). rs-fMRI used here has the advantages of easy application and no impact of task performance difference among subjects (Fox & Greicius, 2010; Lee et al. 2012), and thus could overcome the limitations of previous studies with task-driven paradigms. One previous rs-fMRI study found decreased functional connectivity within the DMN including the hippocampus and the PFC in PTSD patients (Bluhm et al. 2009). That study was based on a hypothesis-driven method to extract one single network (DMN), whereas the present study is based on a data-driven algorithm. Our findings in the whole-brain scale provide another
1934 C. Jin et al. important insight into understanding the abnormal interaction between the hippocampus and PFC in PTSD patients.
Supplementary material For supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S003329171300250X.
Increased functional connectivity in PTSD patients The PCC is a core component of the brain DMN, mainly involved in memory encoding, consolidation and environmental monitoring (Raichle et al. 2001). The insula controls evaluative, experiential and expressive aspects of internal emotional states via visceral and somatic changes evoked during presentations of aversive stimuli (Braun, 2011). The increased connectivity between the PCC and insula observed in this study may potentially reflect a tight functional link between visceral perception and memory, and suggests that there might be a threat-sensitive circuitry in PTSD (Sripada et al. 2012b). In a recently published study, Sripada et al. (2012b) also found increased functional connectivities between the insula and DMN regions. Taken together, these studies provide important insight into understanding the neuropathology of PTSD. This study has some limitations. First, we used a relatively low sampling rate (repetition time = 2 s); some physiological noise, such as cardiac and respiratory rates, was not collected during the scans. Although the bandpass filtering in the range 0.01–0.08 Hz was used to reduce these physiological noises, the impact of them on functional connectivity remains to be determined. Second, as our study only included subjects who experienced the natural disaster of an earthquake, we urge caution when generalizing these results to other traumatic events. Third, the cross-sectional nature of our measurements did not allow us to ascertain whether the functional connectivity abnormalities in PTSD were present before the traumatic experience or acquired signs that occur after its appearance. Finally, in this study, the male and female subjects in the patient and control groups were not balanced; the gender difference may have potential effects on the vulnerability, tolerance and response to PTSD, which needs to be clarified in further studies.
Conclusions In summary, the present study examined whole-brain functional connectivity in treatment-naive PTSD patients following an earthquake without co-morbid conditions using rs-fMRI. We found decreased connectivity between the prefrontal cortex and limbic system and increased connectivity between the PCC and insula. Whole-brain functional connectivity may be a non-invasive modality to investigate the neuropathology of PTSD.
Acknowledgements This work was supported by the National Natural Science Foundation of China (30830046-81171286 and 91232714 to L.L.; 81201077 to Y.Z.), the National 973 Program of China (2009CB918303 to L.L.) and a Chinese Key Grant to G.L. (BWS11J063 and 10z026).
Declaration of Interest None.
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OR I G I N A L A R T I C L E
Abnormalities in whole-brain functional connectivity observed in treatment-naive post-traumatic stress disorder patients following an earthquake C. Jin1†, R. Qi2†, Y. Yin1,3, X. Hu1, L. Duan1, Q. Xu2, Z. Zhang2, Y. Zhong2, B. Feng4, H. Xiang5, Q. Gong6, Y. Liu7, G. Lu2* and L. Li1* 1
Mental Health Institute, The Second Xiangya Hospital of Central South University, Hunan, People’s Republic of China Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing. People’s Republic of China 3 The Seventh People’s Hospital of Hangzhou, Hangzhou, Zhejiang, People’s Republic of China 4 Mianzhu Psychiatric Hospital, Erhuan Road and Mianzun Road, Deyang, Sichuan, People’s Republic of China 5 Mental Health Center of Sichuan Province, Mianyang, Sichuan, People’s Republic of China 6 Huaxi MR Research Center, Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China 7 Department of Psychiatry, University of Florida, Gainesville, FL, USA 2
Background. Convergent studies have highlighted the dysfunction of the amygdala, prefrontal cortex and hippocampus in post-traumatic stress disorder (PTSD). However, only a few studies have investigated the functional connectivity between brain regions in PTSD patients during the resting state, which may improve our understanding of the neuropathophysiology of PTSD. The aim of this study was to investigate patterns of whole-brain functional connectivity in treatment-naive PTSD patients without co-morbid conditions who experienced the 8.0-magnitude earthquake in the Sichuan province of China. Method. A total of 72 PTSD patients and 86 trauma-exposed non-PTSD controls participated in the resting-state functional magnetic resonance imaging study. All these subjects were recruited from the disaster zone of the 2008 Sichuan earthquake. Functional connectivities between 90 paired brain regions in PTSD patients were compared with those in trauma-exposed non-PTSD controls. Furthermore, Pearson correlation analysis was performed between significantly abnormal connectivities in PTSD patients and their clinician-administered PTSD scale (CAPS) scores. Results. Compared with non-PTSD controls, PTSD patients showed weaker positive connectivities between the middle prefrontal cortex (mPFC) and the amygdala, hippocampus, parahippocampal gyrus and rectus, as well as between the inferior orbitofrontal cortex and the hippocampus. In addition, PTSD patients showed stronger negative connectivity between the posterior cingulate cortex (PCC) and the insula. The CAPS scores in PTSD patients correlated negatively with the connectivity between the amygdala and the mPFC. Conclusions. PTSD patients showed abnormalities in whole-brain functional connectivity, primarily affecting the connectivities between the mPFC and limbic system, and connectivity between the PCC and insula. Received 20 December 2012; Revised 5 September 2013; Accepted 10 September 2013; First published online 29 October 2013 Key words: Functional connectivity, post-traumatic stress disorder, resting-state functional magnetic resonance imaging.
Introduction Post-traumatic stress disorder (PTSD) is an anxiety disorder that can follow exposure to extreme stressful experiences, e.g. combat, earthquake and violent crime (Hughes & Shin, 2011). It is characterized by
* Address for correspondence: L. Li, M.D., Mental Health Institute, The Second Xiangya Hospital of Central South University, 139# Renmin Zhong Road, Changsha 410011, Hunan, People’s Republic of China. (Email: [email protected]) [L. Li.] (Email: [email protected]) [G. Lu] † These authors contributed equally to this work.
three hallmark symptoms: re-experiencing of the traumatic event, withdrawal or avoidance behavior, and hyperarousal or increased startle responses (Hughes & Shin, 2011). Imaging plays an important role in uncovering the brain abnormalities of PTSD. Accumulating evidence from neuroimaging studies (Liberzon & Phan, 2003; Bremner, 2007; Hughes & Shin, 2011) has presented a neurocircuitry model of PTSD that emphasizes the role of the amygdala, as well as its interactions with the medial prefrontal cortex and hippocampus. Within this model of PTSD (Liberzon & Phan, 2003; Hughes & Shin, 2011), the amygdala is hyperresponsive, mediates symptoms of hyperarousal and
1928 C. Jin et al. explains the indelible quality of the emotional memory for the traumatic event; and the prefrontal cortex is hyporesponsive, leading to deficits of fear extinction. In addition, the abnormal hippocampal function may underlie declarative memory impairments and deficits in identifying safe contexts. Some other regions including the insula (Rabinak et al. 2011; Garrett et al. 2012) and areas within the brain default mode network (DMN) (Bluhm et al. 2009; Lanius et al. 2010; Sripada et al. 2012b) also exhibited functional abnormalities in PTSD in previous neuroimaging studies. Recently, resting-state functional magnetic resonance imaging (rs-fMRI), which attracts increased attention, has indicated that the pathophysiology of many brain diseases including PTSD may be associated with the changes in spontaneous low-frequency fluctuations measured during the resting state (Yin et al. 2011a, b; Sripada et al. 2012a). These blood oxygenation level-dependent signals are thought to be associated with spontaneous neuronal activity (Fox & Raichle, 2007). In a recent rs-fMRI study, PTSD patients exhibited abnormal low-frequency fluctuations in many cortices and areas of the limbic system, i.e. the frontal and occipital gyri, lingual gyrus and the insula (Yin et al. 2011b). However, many brain regions are functionally related and interconnected (Damoiseaux et al. 2006; Mantini et al. 2007), and the changes in functional interaction between brain regions in PTSD remain unclear up to now. In rs-fMRI, the functional connectivity analysis algorithm measures the temporal synchrony or correlation between spatially separate regions (Lowe et al. 2000). Studies using this method have reported abnormal functional connectivity in many neuropsychiatric diseases, such as Alzheimer’s disease (Greicius et al. 2004) and schizophrenia (Woodward et al. 2012), contributing to the understanding of neuropathophysiological mechanisms of these diseases. To our knowledge, there have been very limited previous functional connectivity studies in the resting-state focused on PTSD, and the published findings have been varied and even contradictory (Bluhm et al. 2009; Rabinak et al. 2011; Sripada et al. 2012a). One study used the amygdala as the seed region and found reduced correlation between the amygdala and anterior cingulate cortex in PTSD patients, suggesting the disturbed coupling between the amygdala and frontal cortex (Sripada et al. 2012a). However, Rabinak et al. (2011), also using region of interest (ROI) analysis, failed to detect abnormal connectivity between the amygdala and frontal cortex. Using independent component analysis, Bluhm et al. (2009) found that in PTSD patients the posterior cingulate cortex (PCC)/precuneus within the brain DMN exhibited weaker connectivity with the amygdala and hippocampus. Different methodology,
variance in co-morbidities and medication exposure may account for the inconsistencies among these studies. In addition, the seed-based or single networkbased methods in previous functional connectivity studies restrain the obtained information to the selected regions of interest and make it difficult to examine the functional connectivity patterns on a whole-brain scale. In the present study, we performed the rs-fMRI technique on a whole-brain scale to explore the abnormalities of functional connectivity in treatment-naive PTSD patients following an earthquake without co-morbid conditions. We hypothesized that wholebrain functional connectivity would be disrupted in patients with a single diagnosis of PTSD, especially between the frontal cortex and the limbic system (e.g. amygdala).
Method Subjects This study was approved by the local medical research ethics committee, and written informed consent was obtained from all participants. We performed a large-scale PTSD survey of post-earthquake survivors in Sichuan Province, China, which was hit by an 8.0-magnitude earthquake on 12 May 2008. Investigation was carried out in the two most devastated regions 8 months after the earthquake. In Hanwang town, 3100 survivors were interviewed and screened with the PTSD Checklist (PCL; Blanchard et al. 1996). Survivors scoring 535 points were then screened with the clinician-administered PTSD scale (CAPS; Blake et al. 1995) to confirm the PTSD diagnosis. In Beichuan County, the other severely affected region, a total of 1100 survivors were also interviewed and screened with the PCL and CAPS. After these procedures, all 415 subjects fulfilling the PTSD diagnosis were scheduled for the following fMRI study. In addition, 109 trauma-exposed non-PTSD subjects with PCL scores below 30 points were selected as a control group in this fMRI study. To further confirm the PTSD diagnosis and rule out psychiatric co-morbidities, all subjects were screened with the Chinese version of the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (First et al. 2002) as revised by Professor Lipeng Fei from Beijing Hui Long Guan Hospital, China. The exclusion criteria of the PTSD subjects in this fMRI study included the any psychiatric co-morbidities or other psychiatric disorder (n = 134), any history of or current brain injury (n = 12), as well as any other significant medical or neurological conditions (n = 58), any MRI contraindication (n = 81),
Whole-brain functional connectivity in PTSD patients
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of 200 brain volumes were collected, resulting in a total scan time of 400 s. Data pre-processing Pre-processing of functional images was carried out using the SPM8 software package (http://www.fil.ion. ucl.ac.uk/spm). First, slice-timing adjustment and realignment for head-motion correction were performed. A total of 15 PTSD patients and nine non-PTSD controls were excluded from further analysis because of excessive movement (translation exceeded 1.5 mm or rotation exceeded 1.5°). Consequently, 57 PTSD and 77 controls remained. We also evaluated the group differences in translation and rotation of head motion according to the following formula (Liao et al. 2010): Head motion/rotation = L 1 |xi − xi−1 |2 + |yi − yi−1 |2 + |zi − zi−1 |2 , L − 1 i=2
Fig. 1. Flow chart of the participants enrolled in the study. MRI, Magnetic resonance imaging; CAPS, clinician-administered traumatic stress disorder scale; fMRI, functional MRI.
left-handed (n = 16), and unavailable data (n = 16). In addition, after the MR scanning, we also excluded the patients aged 560 years (n = 10) and CAPS scores 0.05). Differences in connectivity between groups In all, nine connectivities of every two ROIs were significantly different between PTSD patients and non-PTSD controls (Fig. 2), including seven decreased positive connectivities and two increased negative connectivities. Additionally, at a lenient significant level of p < 0.001 (uncorrected), we found 19 abnormal connectivities in PTSD patients, including 16 decreased
Table 1. Demographics and clinical data of PTSD patients and controls
Protocols Gender, n Male Female Mean age, years (S.D.) Mean length of education, years (S.D.) Handedness, n Right-handers Non-right-handers Mean CAPS score (S.D.) Co-morbid diagnoses, n
PTSD (n = 57)
Controls (n = 77)
14 43 41.32 (9.07) 7.77 (2.98)
24 53 41.73 (8.46) 7.55 (2.81)
57 0 66.18 (12.19) 0
77 0 – 0
p 0.40a
0.79b 0.65b
1a
PTSD, Post-traumatic stress disorder; S.D., standard deviation; CAPS, clinician-administered PTSD scale for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition; –, unavailable data. a The p values for gender distribution and handedness in the two groups were obtained by the χ2 test. b The p values for age and education difference between the two groups were obtained by the two-sample t test.
positive connectivities and three increased negative connectivities (Fig. 3). All of the abnormal connectivities were visualized with the BrainNet Viewer (http://www.nitrc.org/projects/bnv/). Abnormal positive connectivities Compared with non-PTSD controls, all seven positive connectivities were weaker in PTSD patients (Fig. 2a and Table 2). In detail, these were connectivities between the right amygdala and left middle prefrontal cortex (mPFC), between the left mPFC and bilateral hippocampus, between the left mPFC and bilateral parahippocampal gyri, between the left mPFC and right rectus, and between the left inferior orbitofrontal cortex (OFC) and right hippocampus. No increased positive connectivity was found in PTSD patients. In addition, at p < 0.001 (uncorrected), we found 16 weaker positive connectivities, also mainly between the frontal cortex and limbic system. There were also other weaker positive connectivities between the parietal and temporal cortices and the limbic system (for more details of these 16 decreased connectivities, see Fig. 3a and Table 2). Abnormal negative connectivities Only two negative connectivities were stronger in PTSD patients than in non-PTSD controls: between the left PCC and bilateral insula (Fig. 2b and
Whole-brain functional connectivity in PTSD patients
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(a)
(b)
Fig. 2. Differences in the whole-brain functional network between post-traumatic stress disorder (PTSD) and control groups (corrected for multiple comparisons). (a) Compared with non-PTSD controls, PTSD patients showed seven weaker positive connections: between the right amygdala (AMY) and left middle prefrontal cortex (mPFC), between the left mPFC and left/ right hippocampus (HIP), between the left mPFC and left/right parahippocampal gyri (PHG), between the left mPFC and right rectus, and between the left inferior orbitofrontal cortex (Inf_OFC) and right hippocampus. (b) In addition, two negative connections were stronger in PTSD patients than in non-PTSD controls: connectivities between the left posterior cingulate cortex (PCC) and left/right insula (INS). L, Left; R, right.
(a)
(b)
Fig. 3. Differences in the whole-brain functional network between post-traumatic stress disorder (PTSD) and control groups at p < 0.001(uncorrected). (a) Compared with non-PTSD controls, PTSD patients show 16 weaker positive connections: between the left middle prefrontal cortex (mPFC) and right amygdala (AMY), bilateral hippocampal/parahippocampal gyri (PHG), bilateral rectus (Rec) and right Calcarine fissure (Cal), between the left inferior orbitofrontal cortex (Inf_OFC) and right PHG, between the triangular part of the left inferior frontal gyrus (IFGtriang) and the right PHG and right AMY, between the left superior frontal gyrus (SFG) and right hippocampus (HIP), between the left inferior parietal lobe (IPL) and right AMY, and between the left inferior temporal gyrus (ITG) and right HIP. (b) In addition, three negative connectivities are stronger in PTSD patients than in non-PTSD controls: connectivities between the left posterior cingulate cortex (PCC) and left/right insula (INS), and between the right PCC and left INS. L, Left; R, right.
1932 C. Jin et al. Table 2. Decrease in positive functional connectivity in PTSD patients compared with controls
Region 1
Region 2
Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left mPFC Left inferior OFC Left inferior OFC Left IFGtriang Left IFGtriang Left IFGtriang Left SFG Left IPL Left ITG
Right amygdala Left hippocampus Right hippocampus Left PHG Right PHG Right rectus Left rectus Right Cal Right hippocampus Right PHG Right hippocampus Right PHG Right amygdala Right hippocampus Right amygdala Right hippocampus
ta −4.53 −4.08 −4.80 −3.87 −4.52 −3.96 −3.47 −3.45 −4.26 −3.63 −3.69 −3.67 −3.41 −3.48 −3.45 −3.59
p
Effect size: Pearson’s r
Effect size: Cohen’s d
0.000 013b 0.000 078b 0.000 004b 0.000 171b 0.000 014b 0.000 125b 0.000 704 0.000 766 0.000 039b 0.000 402 0.000 328 0.000 355 0.000 857 0.000 687 0.000 762 0.000 473
0.37 0.33 0.38 0.32 0.37 0.32 0.29 0.29 0.35 0.30 0.30 0.30 0.28 0.29 0.29 0.30
0.79 0.71 0.83 0.67 0.78 0.69 0.60 0.60 0.74 0.63 0.64 0.64 0.59 0.60 0.60 0.62
PTSD, Post-traumatic stress disorder; mPFC = middle prefrontal cortex; PHG, parahippocampal gyrus; Cal, Calcarine fissure; OFC, orbitofrontal cortex; left IFGtriang, triangular part of the left inferior frontal gyrus; SFG, superior frontal gyrus; IPL, inferior parietal lobe; ITG, inferior temporal gyrus. a A negative t value represents a decrease. b Type 1 error corrected by using false-positive adjustment (p < 1/4005 = 0.000 249). All other functional connectivities are present at p < 0.001 (uncorrected).
Table 3. Increase in negative functional connectivity in PTSD patients compared with controls
Region 1
Region 2
Left PCC Left PCC Right PCC
Left insula Right insula Left insula
ta +3.79 +4.03 +3.38
p
Effect size: Pearson’s r
Effect size: Cohen’s d
0.000 232b 0.000 093b 0.000 959
0.31 0.33 0.28
0.66 0.70 0.59
PTSD, Post-traumatic stress disorder; PCC, posterior cingulate cortex. A positive t value represents an increase. b Type 1 error corrected by using false-positive adjustment (p < 1/4005 = 0.000 249). All other functional connectivities are present at p < 0.001 (uncorrected). a
Table 3). No decreased negative connectivity was exhibited in PTSD patients. At p < 0.001 (uncorrected), the right PCC and left insula also showed increased negative connectivity in PTSD patients (for more details, see Fig. 3b and Table 3). Validation of the functional connectivity findings To provide some validation for the whole-brain-based analytical approach used in this study, we performed seed-based functional connectivity analysis (Fox et al. 2005; Fox & Greicius, 2010). We selected four areas
as seed regions. These were the left mPFC, the left PCC and the bilateral amygdala. The left mPFC was selected because it showed the most abnormal connections in this study; the left PCC and bilateral amygdala were chosen because they showed abnormal functional connectivities both in our findings and several previous neuroimaging studies (Bluhm et al. 2009; Sripada et al. 2012a). The results of comparing each seed’s functional connectivity network between PTSD patients and controls also supported our wholebrain functional connectivity findings (see the online Supplementary material).
Whole-brain functional connectivity in PTSD patients
Fig. 4. Correlation results between abnormal connectivities and clinician-administered post-traumatic stress disorder scale (CAPS) scores in post-traumatic stress disorder (PTSD) patients (p < 0.05, uncorrected). Among all the different connectivities, only the connectivity between the right amygdala (R-AMY) and the left middle frontal cortex (L-mPFC) inversely correlated with the CAPS scores of PTSD patients. FC, Functional connectivity.
Correlation results Among all the nine significantly different connectivities, only the connectivity between the right amygdala and the left mPFC negatively correlated with the CAPS scores of patients (Fig. 4). No correlation was found between any other abnormal interregional connectivity and the CAPS performances of patients.
Discussion The present rs-fMRI study indicated that PTSD patients following an earthquake suffered from disrupted whole-brain functional connectivity, primarily located between the frontal cortex and limbic system regions. All these findings provide further evidence of cortico-limbic circuitry dysfunction in patients with a single diagnosis of PTSD. Decreased functional connectivity in PTSD patients The prefrontal–limbic system plays an important role in learning, memory and affective processing (Braun, 2011). Abnormal brain activity in the prefrontal–limbic system in PTSD patients has been previously reported in several fMRI (Garrett et al. 2012; Sripada et al. 2012b) and positron emission tomography/single-photon emission computed tomography (PET/SPECT) studies (Shin et al. 2004; Chung et al. 2006). Weaker functional connectivity between the mPFC and the limbic system observed in the present study is complementary to previous studies and provides important insight into understanding the coupling between the frontal cortex and the limbic system in PTSD patients. Taken together, the abnormal prefrontal–limbic system in
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these studies may partially explain some defects in PTSD, such as the disturbed emotional processing and memory regulation abilities. The PFC and amygdala are two key components of the cortico–limbic circuit involved in emotional processing and have wide interconnections with each other (Ghashghaei et al. 2007; Pessoa, 2008). Decreased PFC activity accompanied by increased amygdala activity in PTSD patients has been reported in many studies with traumatic-related stimuli (Etkin & Wager, 2007), traumatic-unrelated emotional tasks (Shin et al. 2005; Williams et al. 2006), and of the resting state (Sripada et al. 2012a). One recent fMRI study used the amygdala as the seed region of functional connectivity and also found decreased connectivity between the amygdala and PFC (Sripada et al. 2012a). The PFC is a region of central importance in the processes of body regulation, fear modulation and working memory (Braun, 2011). The amygdala has a critical role in emotion and in fear conditioning (Braun, 2011; Sripada et al. 2012a). Decreased mPFC–amygdala connectivity, as reported in the present study, may indicate impaired coupling between them or diminished PFC regulation of the amygdala. We also found decreased frontal cortex–hippocampus/parahippocampal gyrus connectivity in this study. The hippocampus is essential for memory functions, especially memorizing facts and events, and memory consolidation (Braun, 2011). Damage to the hippocampus can cause the inability to form new memories (Braun, 2011). The frontal cortex has strong connections to the hippocampus (Tamminga & Buchsbaum, 2004); a connectivity disturbance between them indicates disturbed frontal regulation over the hippocampus which may result in the failure to inhibit negative memory (Tamminga & Buchsbaum, 2004). It should be noted that there are inconsistent findings regarding the hippocampal responsivity in PTSD patients in different task-related neuroimaging studies, both with hypoactivity and hyperactivity (Hughes & Shin, 2011). It seems that the direction of hippocampal functional abnormalities depends in part on the type of tasks and analysis employed (Bremner, 2007; Hughes & Shin, 2011). rs-fMRI used here has the advantages of easy application and no impact of task performance difference among subjects (Fox & Greicius, 2010; Lee et al. 2012), and thus could overcome the limitations of previous studies with task-driven paradigms. One previous rs-fMRI study found decreased functional connectivity within the DMN including the hippocampus and the PFC in PTSD patients (Bluhm et al. 2009). That study was based on a hypothesis-driven method to extract one single network (DMN), whereas the present study is based on a data-driven algorithm. Our findings in the whole-brain scale provide another
1934 C. Jin et al. important insight into understanding the abnormal interaction between the hippocampus and PFC in PTSD patients.
Supplementary material For supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S003329171300250X.
Increased functional connectivity in PTSD patients The PCC is a core component of the brain DMN, mainly involved in memory encoding, consolidation and environmental monitoring (Raichle et al. 2001). The insula controls evaluative, experiential and expressive aspects of internal emotional states via visceral and somatic changes evoked during presentations of aversive stimuli (Braun, 2011). The increased connectivity between the PCC and insula observed in this study may potentially reflect a tight functional link between visceral perception and memory, and suggests that there might be a threat-sensitive circuitry in PTSD (Sripada et al. 2012b). In a recently published study, Sripada et al. (2012b) also found increased functional connectivities between the insula and DMN regions. Taken together, these studies provide important insight into understanding the neuropathology of PTSD. This study has some limitations. First, we used a relatively low sampling rate (repetition time = 2 s); some physiological noise, such as cardiac and respiratory rates, was not collected during the scans. Although the bandpass filtering in the range 0.01–0.08 Hz was used to reduce these physiological noises, the impact of them on functional connectivity remains to be determined. Second, as our study only included subjects who experienced the natural disaster of an earthquake, we urge caution when generalizing these results to other traumatic events. Third, the cross-sectional nature of our measurements did not allow us to ascertain whether the functional connectivity abnormalities in PTSD were present before the traumatic experience or acquired signs that occur after its appearance. Finally, in this study, the male and female subjects in the patient and control groups were not balanced; the gender difference may have potential effects on the vulnerability, tolerance and response to PTSD, which needs to be clarified in further studies.
Conclusions In summary, the present study examined whole-brain functional connectivity in treatment-naive PTSD patients following an earthquake without co-morbid conditions using rs-fMRI. We found decreased connectivity between the prefrontal cortex and limbic system and increased connectivity between the PCC and insula. Whole-brain functional connectivity may be a non-invasive modality to investigate the neuropathology of PTSD.
Acknowledgements This work was supported by the National Natural Science Foundation of China (30830046-81171286 and 91232714 to L.L.; 81201077 to Y.Z.), the National 973 Program of China (2009CB918303 to L.L.) and a Chinese Key Grant to G.L. (BWS11J063 and 10z026).
Declaration of Interest None.
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