The authors have declared that no competing interests exist.
Conceived and designed the experiments: YZ ZW JX JW. Performed the experiments: LQ YS SS WD. Analyzed the data: YZ LQ YS WD SS. Contributed reagents/materials/analysis tools: YZ LQ YS. Wrote the paper: YZ ZW LQ.
The goal of this study was to investigate the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in 15 people who developed PTSD following recent trauma. Fifteen participants who experienced acute traumatic events underwent a 7.3-min resting functional magnetic resonance imaging scan within 2 days post-event. All the patients were diagnosed with PTSD within 1 to 6 months after trauma. Brain areas in which activity was correlated with that of the posterior cingulate cortex (PCC) were assessed. To assess the relationship between the severity of PTSD symptoms and PCC connectivity, contrast images representing areas positively correlated with the PCC were correlated with the subject’s Clinician-Administered PTSD Scale scores (CAPS) when they were diagnosed. Furthermore, the PCC, medial prefrontal cortex and bilateral amygdala were selected to assess the correlation of the strength of functional connectivity with the CAPS. Resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later. These results suggest that early altered resting-state functional connectivity of the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease and may be a major risk factor that predisposes patients to develop PTSD.
Post-traumatic stress disorder (PTSD) is an anxiety disorder that can develop following exposure to a traumatic event, such as military combat, traffic accidents, rape, assault, or natural disasters. It is a complex syndrome that involves re-experiencing of symptoms (e.g., nightmares and flash-backs), hyperarousal symptoms (e.g., insomnia), numbing symptoms (e.g., restricted affect and anhedonia), and avoidance symptoms (e.g., avoiding trauma-related stimuli), in addition to cognitive impairment, such as poor concentration and difficulty in explicitly recalling aspects of the traumatic event
Over the past decade, neuroimaging techniques have been critical in the process of identifying important brain systems in the pathophysiology of PTSD. Specifically, findings from functional neuroimaging studies indicated abnormalities in amygdale and amygdala-linked circuitry involving the medial prefrontal cortex (mPFC), insula, anterior cingulate cortex (ACC), and hippocampus
Resting-state functional connectivity has been widely used in the study of PTSD
The current study included 15 car accident victims randomly recruited from the Emergency Department of Renji Hospital. Most of them witnessed actual or threatened death or serious injury to others, and some of them had mild concussive neurotrauma and bruises. In order to guarantee scanning quality, to avoid major head movements during data acquisition, and to eliminate the potential effect of lesions in the brain on the analysis of resting state functional connectivity, we excluded the patients with significant head injury. All subjects underwent baseline evaluation within 2 days (2d). The tests included the Mini-International Neuropsychiatric Interview (MINI)
The exclusion criteria were as follows: (1) younger than 18 or older than 60 years, with an education <9 years; (2) ASDI <3; (3) significant head injury (i.e., abnormalities on conventional MRI, neurological abnormalities during emergency department evaluation, and loss of consciousness longer than several seconds during the accident); (4) a history of neurological disorders; (5) current axis I disorders at the time of the accident, as assessed using the MINI
The current study was approved by the Research Ethics Committee of Renji Hospital. All subjects gave their informed written consent. All procedures were in accordance with institutional guidelines.
MRI was performed on a 3T magnetic resonance scanner (GE Signa HDxt 3T, USA). A standard head coil with foam padding was used to restrict head motion. During resting-state fMRI, the subjects were instructed to keep their eyes closed, remain motionless, and not to think of anything in particular. A gradient-echo echo-planar sequence was used to acquire functional images (repetition time [TR] = 2000 ms, echo time [TE] = 30 ms, field of view [FOV] = 230 mm2×230 mm2, matrix = 64×64, thickness = 4 mm, and gap = 0). Each fMRI scan lasted 440 s. Other sequences were also acquired, including: (1) sagittal T1-weighted 3D-magnetization prepared rapid acquisition gradient echo sequences (TR = 9.4 ms, TE = 4.6 ms, flip angle = 15°, slice thickness = 1 mm, gap = 0 mm, FOV = 256 mm×256 mm, matrix = 256×256, and slices = 155); (2) axial T1-weighted fast field echo sequences (TR = 331 ms, TE = 4.6 ms, FOV = 256 mm ×256 mm, slice thickness = 4 mm, gap = 0, slices = 34, and matrix = 512×512); and (3) axial T2-weighted turbo spin-echo sequences (TR = 3013 ms, TE = 80 ms, FOV = 256 mm×256 mm, slice thickness = 4 mm, gap = 0, slices = 34, and matrix = 512×512).
Brain MR imagings (T1-weighted and T2-weighted images) were evaluated by two experienced neuroradiologists. No gross abnormalities were observed in the participants. Functional MRI preprocessing was carried out using Data Processing Assistant for Resting-State fMRI (DPARSF V 2.0, by YAN Chao-Gan,
Each voxel’s time-series was detrended to correct for lineral drift over time. Nine nuisance covariates (time-series predictors for global signal, white matter, cerebrospinal fluid, and the six movement parameters, including the first derivative, obtained during realignment to account for motion-related effects in blood oxygenated level-dependent) were sequentially regressed from the time-series
The PCC template, which consisted of Brodmann’s areas 29, 30, 23, and 31, was selected as the region of interest (ROI) using WFU-Pick Atlas software
For each subject and seed region, a correlation map was produced by computing the correlation coefficients between the reference time series and the time series from all the other brain voxels. Correlation coefficients were then converted to
To examine whether the strength of functional connectivity in the PCC varies with the severity of disease in PTSD patients, Pearson’s correlative analysis was performed to examine relationships between the z-values and CAPS in PTSD patients at the time that patients were diagnosed using a threshold of p<0.05 as corrected by AlphaSim. Left and right amygdala templates were selected as ROIs using WFU-Pick Atlas software
The mean age of PTSD patients (4 females, 11 males) was 41.52±12.56 years, and the mean duration of education was 12.02±2.56 years. All subjects underwent baseline evaluation within 2 d post-accident. No patient met diagnostic criteria for current axis I disorders as assessed using the MINI, and the mean ASDI was 15.42±6.01. Follow-up evaluation for PTSD diagnosis was conducted at 1 month and 6 months post-accident. Eleven and 4 patients were diagnosed 1 month and 6 months post-accident, respectively, and the mean time from accident to PTSD diagnosis was 2.33±2.28 months. The mean CAPS when the patients were diagnosed was 44.53±15.76.
Connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampal gyrus/right amygdala (see
Note: The right part of the figure represents the patient’s left side. PTSD = post-traumatic stress disorder.
Peak MNI coordinate region | Peak MNI coordinates | Number of cluster voxels | |||
x | y | z | |||
1 | left superior temporal gyrus | −42 | 3 | −24 | 44 |
2 | Right hippocampal gyrus/right amygdala | 36 | −24 | −24 | 61 |
(p<0.05, AlphaSim-corrected) |
Note: PTSD = post-traumatic stress disorder; PCC = posterior cingulated cortex;
CAPS = the Clinician-Administered PTSD Scale.
Four regions were selected, including the PCC, mPFC and bilateral amygdala. Correlation analysis of the strength of functional connectivity within each pair of seed regions and CAPS was performed. The strengths of functional connectivity of the PCC-right amygdala (r = −0.57, p = 0.03), PCC-left amygdala (r = −0.53, p = 0.04) and right amygdala-left amygdala (r = −0.54, p = 0.04) were negatively correlated with CAPS scores in the PTSD patients at the time of diagnosis. (See
PCC-mPFC | PCC-L-amygdala | PCC-R-amygdala | mPFC-L-amygdala | mPFC-R-amygdala | L-amygdala-R-amygdala | |
r | −0.03 | −0.53 | −0.57 | 0.28 | 0.26 | −0.54 |
p | 0.90 |
|
|
0.30 | 0.36 |
|
Note: PCC = posterior cingulate cortex; mPFC = medial prefrontal cortex; CAPS = the Clinician-administered PTSD Scale; PTSD = Post-traumatic Stress Disorder; R-amygdala = right amygdala; L-amygdala = left amygdala.
To the best of our knowledge, this is the first study to examine the relationships between default network connectivity and prospective PTSD symptoms soon after trauma. This study demonstrated that resting state connectivity with the PCC was negatively correlated with CAPS scores in the left superior temporal gyrus and right hippocampus/amygdala. Furthermore, the strength of connectivity between the PCC and bilateral amygdala, and even between the bilateral amygdala could predict the severity of PTSD symptoms later.
These results are partly consistent with previous studies
Amygdala activity plays a causal role in the experience of negative effects, such as fear, anxiety, and distress. In healthy brains, amygdala activity is thought to be dampened via top-down inhibition by the mPFC, yielding a reduction in subjective distress. However, in PTSD, a defect in mPFC function impairs inhibition of the amygdala, resulting in abnormal amygdala activity and pathological distress
We did not observe any significant differences in PCC connectivity to the mPFC or anterior cingulate cortex in PTSD patients at rest. This is a notable negative finding and requires replication; however, we acknowledge that it could have resulted from the following: (1) a small sample size may have led to false negative results and/or more subtle connectivity abnormalities; and (2) the resting-state task may be insensitive to detecting early and mild PCC-prefrontal and amygdala-mPFC connectivity abnormalities, which may require engagement by an overt task. Koenigs et al.
The current study has several limitations. First, the sample size was relatively small. Second, the seed-point method as the mode of analysis may have been biased by the particular seed region chosen, focusing on long-distance patterns of connectivity. However, we applied all of the ROIs mentioned in previous studies. Third, we did not obtain the patient’s fMRI again when they were diagnosed. Fourth, these connectivity differences could be resolved by other factors unrelated to the traumatic event. Fifth, we excluded the patients with significant head injury (i.e., abnormalities on conventional MRI, neurological abnormalities during emergency department evaluation, and loss of consciousness longer than several seconds during the accident). PTSD can commonly result from concussive injury resulting in loss of consciousness; thus, this criterion for exclusion severely limits generalizability. Follow-up studies should be conducted in the future to verify the present findings.
This paper describes a preliminary study investigating the relationship between resting-state functional connectivity and the severity of post-traumatic stress disorder (PTSD) symptoms in people who developed PTSD following recent trauma. Early altered functional connectivity in the PCC with the left superior temporal gyrus, right hippocampus and amygdala could predict the severity of the disease, and may be a major risk factor that predisposes patients to develop PTSD.
The authors thank Dr. Yong Zhang and Dr. He Wang from GE Healthcare for technical support.