Edited by: Gianluca Serafini, Ospedale San Martino (IRCCS), Italy
Reviewed by: Seishu Nakagawa, Tohoku University, Japan; Tim Varkevisser, University Medical Center Utrecht, Netherlands
This article was submitted to Mood and Anxiety Disorders, a section of the journal Frontiers in Psychiatry
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After an exposure to traumatic events, most individuals will experience flashbacks, avoidance of trauma-related cues, sleep disorders, or other symptoms. Normally, these symptoms lessen or disappear within a few weeks, but some trauma-exposed individuals may experience a slow recovery and develop post-traumatic stress disorder (PTSD) (
Numerous neuroimaging studies have confirmed that functional and structural abnormalities are present in multiple brain areas of PTSD patients (
Partially consistent with this neural circuit model, many PTSD fMRI studies, performed during the task- or resting-state, found decreased functional connectivity between the amygdala and the mPFC (
We aimed to use resting-state fMRI and Granger causality analysis to observe the change in the effective connectivity of the amygdala in PTSD patients, and to correlate that with the severity of PTSD symptoms. Compared to other modeling methods for effective connectivity (SEM or a dynamic causality model, for example), the Granger causality analysis does not require researchers to pre-select the interaction areas, and this advantage makes it popular for analyzing the effective connectivity of many diseases, including depression, mild cognitive impairment, and chronic tinnitus, among others (
On July 18, 2014, Typhoon Rammasun, a category 5 super typhoon struck Wenchang city on the island province of China. People residing in this area were heavily affected by this typhoon, which caused at least 14 deaths. Particularly, in Luodou farm of Wenchang city, more than 1000 people were trapped and almost drowned by the storm tide induced by this destructive typhoon. We recruited 70 typhoon-exposed subjects from this area, 36 with PTSD (nine males and 27 females) and 34 without PTSD (trauma exposed controls [TEC], seven males and 27 females), who were all screened with the PTSD Checklist-Civilian Version (PCL-C) (
General exclusion criteria included age <18 years or >65 years, left-handedness, a history of head injury or loss of consciousness, significant medical and neurological conditions, comorbid lifetime or current psychiatric disorders other than depression and anxiety, alcohol or drug abuse/dependence, use of anti-depressants or any form of psychotherapy, and contraindications to MRI, such as claustrophobia, pregnancy, and ferromagnetic implants. In the PTSD group, completed imaging data were not available for three female subjects, and six were removed for denture-related artifacts (one female, one male), brain infarction revealed by conventional MRI (one female), pregnancy (one female), and excessive movement during MRI scanning (translation >1.5 mm or rotation >1.5° in any direction, one male and one female). In addition, we excluded one female TEC for excessive movement and two male HCs for brain infarction. Thus, 27 PTSD patients, 33 TECs, and 30 HCs were ultimately included in the statistical analysis. The study was conducted in accordance with the declaration of Helsinki and was approved by the ethics committee of Hainan General Hospital and the Second Xiangya Hospital of Central South University. All participants provided written, informed consent after a detailed description of this study.
A 3.0 Tesla whole-body MRI scanner (Magnetom Tim Skyra, Siemens Medical Solutions, Erlangen, Germany) with a 32-channel phased array head coil was used for image acquisition. Subjects' heads were immobilized using a foam pad and a Plexiglas head cradle. High-resolution, T1-weighted, 3D anatomical images were also acquired with a sagittal magnetization-prepared rapid gradient echo sequence for later co-registration and normalization (TR/TE = 2300/1.97 ms, flip angle = 9°, FOV = 256 × 256 mm, matrix = 256 × 256, 176 slices, slice thickness = 1 mm, the total time points = 353 s). BOLD fMRI was prescribed parallel to the anterior commissure-posterior commissure line, which was acquired using a gradient-echo planar imaging (EPI) sequence with an interleaved slice excitation order and a 2 mm isotropic spatial resolution (FOV = 230 × 230 mm, matrix = 64 × 64, TR/TE = 2,000 ms/30 ms, flip angle = 90°, 35 slices, slice thickness = 3.6 mm, no intersection gap, total volume number = 250, the total time points = 508 s). During the functional scanning, subjects were instructed to lie quietly, keep their eyes closed, and let their mind wander without falling asleep.
The imaging data were preprocessed using Statistical Parametric Mapping software (SPM8,
In this study, the SPM8 Anatomy toolbox was used to select the bilateral amygdala (two parts, including the basolateral amygdala and central medial amygdala) as a region of interest (ROI) using 3 × 3 × 3 mm3 resampling normalization. The bilateral amygdala was set as a seed region using the WFU_PickAtlas software (
The chi-squared test was used to analyze gender distribution, and a one-way analysis of variance (ANOVA) was performed for all continuous variables except for PCL scores, for which an independent
We used SPM8 to analyze the GCA maps of the three groups. Within each group, a random effect, one-sample
To investigate the association between PTSD symptom severity and brain measures, mean GCA (
The demographic and clinical characteristics are summarized in Table
Demographic and clinical data of traumatized individuals and healthy controls.
Gender (males/females) | 7/20 | 7/26 | 7/23 | 0.912 |
Age (year) | 48.4 ± 10.3 | 48.5 ± 7.5 | 49.9 ± 6.1 | 0.729 |
Education (year) | 6.4 ± 3.4 | 7.0 ± 3.4 | 9.7 ± 3.3 | < 0.001 |
Days after the disaster to exam | 105.5 ± 9.5 | 118.0 ± 10.0 | 125.8 ± 1.0 | < 0.001 |
SAS score | 65.8 ± 13.3 | 41.3 ± 8.1 | 36.0 ± 5.5 | < 0.001 |
SDS score | 69.6 ± 13.2 | 41.3 ± 9.1 | 33.5 ± 7.2 | < 0.001 |
PCL score | 53.7 ± 8.5 | 28.9 ± 5.4 | < 0.001 |
|
CAPS total score | 78.2 ± 19.3 |
A significant difference in effective connectivity between the left amygdala and the left supplementary motor area (SMA) was observed in the PTSD vs. the TEC group (Table
Comparison of effective connectivity from the amygdala.
Left SMA/paracentral lobule | −3, −9, 72 | 66 | 3.17 |
Bilateral vmPFC | −3, 69, 3 | 79 | 3.16 |
Right ITG/MTG | 63, −24, −24 | 99 | 4.04 |
Bilateral vmPFC | −3, 66, 3 | 448 | 4.57 |
Left SFG | −18, 6, 51 | 149 | −3.99 |
Right SFG | 42, 0, 60 | 97 | −3.96 |
Left MFG | −42, 15, 24 | 65 | −4.13 |
Comparison of the effective connectivity between the amygdala and different brain areas in the different groups. The influence of the left amygdala on the whole brain
Effective connectivity between the amygdala and between the amygdala and the mPFC and between the amygdala and the SMA in the different groups.
Comparison of effective connectivity between the amygdala and the bilateral superior temporal gyrus and between the amygdala and the middle temporal gyrus.
Comparison of effective connectivity between the amygdala and the superior temporal gyrus and between the amygdala and the precuneus.
As for the effective connectivity from the right amygdala, no significant difference was identified between the PTSD and the TEC groups. However, significant differences in effective connectivity between the right amygdala and the left precuneus/posterior cingulate gyrus (PCC) and between the right amygdala and the superior parietal lobule (SPL) were observed in the PTSD group vs. the HC group (Table
Comparison of the effective connectivity from the right amygdala.
Left precuneus/PCC | −6, −48, 21 | 116 | −3.64 |
Left SPL | −24, −51, 72 | 73 | −3.87 |
Right ITG | 57, −57, −18 | 68 | −3.60 |
A significant difference in effective connectivity between the bilateral SMA and the left amygdala was observed in the PTSD group vs. the TEC group (Table
Comparison of the effective connectivity to the left amygdala.
Bilateral SMA/paracentral lobule | −6, −24, 72 | 133 | −3.73 |
Left SPL/MOG | −24, −69, 42 | 76 | 4.01 |
Right SPL/IPL | 33, −48, 39 | 82 | 3.69 |
Left SFG | −24, −3, 48 | 66 | 3.90 |
Right MFG | 36, 15, 27 | 165 | 4.77 |
Bilateral vmPFC | −9, 51, 0 | 526 | −4.02 |
Left SFG | −18, 9, 48 | 131 | 3.77 |
Right SFG | 27, 3, 60 | 65 | 3.64 |
Left SPL/MOG | −24, −66, 45 | 89 | 4.01 |
There were significant differences in effective connectivity between the bilateral SMA and the right amygdala, between the left precuneus/PCC and the right amygdala in the PTSD group vs. the TEC group (Table
Comparison of effective connectivity to the right amygdala.
Left precuneus/PCC | −3, −51, 33 | 88 | 3.15 |
Bilateral SMA/paracentral lobule | 3, −12, 69 | 179 | −3.94 |
Left precuneus/PCC | −3, −51, 21 | 85 | 3.32 |
Right MFG | 39, 12, 27 | 70 | 4.16 |
Left STG/postcentral gyrus | −57, −21, 6 | 176 | −3.44 |
Right STG/postcentral gyrus | 63, −6, 15 | 156 | −4.17 |
Left MFG | −30, 39, 24 | 62 | −3.37 |
Right MFG | 30, 51, 3 | 70 | −3.69 |
Bilateral vmPFC | 12, 54, −15 | 76 | −3.82 |
Left STG/postcentral gyrus | −57, −12, 15 | 110 | −3.75 |
Left OFC | −27, 42, −15 | 93 | −3.85 |
Right OFC | 18, 54, −12 | 63 | −4.73 |
Left cuneus/precuneus | −9, −75, 33 | 77 | −3.87 |
Significant differences in effective connectivity between the left precuneus/PCC and the right amygdala, between the bilateral MFG and the amygdala, and between the bilateral STG and the right amygdala were observed in the PTSD group vs. the HC group (Table
Pearson correlation analysis showed that the strength of effective connectivity (average
Based on previous functional connectivity research, this study used fMRI and Granger causality analysis to compare the effective connectivity of the amygdala between healthy volunteers and those who had experienced a typhoon. The results showed that PTSD patients and TECs had altered effective connectivity between the amygdala and the mPFC, between the amygdala and the SMA, between the amygdala and the dlPFC, between the amygdala and the STG, and between the amygdala and the precuneus/PCC, indicating that PTSD and trauma may cause abnormal integration of functions between the amygdala and other multiple brain regions.
In recent years, many studies have reported altered functional connectivity between the amygdala and the mPFC in patients with PTSD. Researchers believe that this may reflect abnormal regulation of the amygdala by the mPFC in PTSD (
Interestingly, when compared to the healthy controls, PTSD patients and the TECs in our study showed decreased inhibition of the mPFC by the amygdala or even activation of the mPFC. This indicates that trauma might cause an enhanced ascending drive of the mPFC by the amygdala. Stein et al. analyzed the effective connectivity of the amygdala in healthy volunteers using a fearful face fMRI paradigm and found that the amygdala activated the mPFC in a bottom-up manner (
In addition, our study found that the PTSD and the TEC groups showed greater inhibition of the amygdala by the STG compared to that in the healthy controls. These results indicate that abnormal functional and effective connectivity between the amygdala and the STG is a trauma-associated brain function change. Structural MRI studies of PTSD found that, compared to healthy controls, patients exposed to trauma had increased gray matter volume or decreased cortical thickness in their STG (
The precuneus/PCC are key brain areas for the default network, and they play important roles in visual spatial imagination, self-referential processing, and autobiographical memory (
This study also has some limitations. First, we chose only the bilateral amygdala as the ROI and did not analyze the effective connectivity of the sub-areas of the amygdala; thus, future work should further explore the changes in effective connectivity in the sub-areas of the amygdala. Second, the low time resolution of fMRI and the delayed hemodynamic response may have affected the results of the Granger causality analysis. Since the Granger causality is not equivalent to the interaction between neurons, the combination of brain structural studies at either the cellular or molecular levels would help to further clarify the neural mechanism of PTSD. Finally, although the simultaneous inclusion of trauma and healthy controls helped to elucidate whether changes in brain functions were PTSD- or trauma-associated, the cross-sectional study design made it difficult for us to distinguish whether PTSD-related abnormal effective connectivity of the amygdala is a risk factor for disease or an acquired change.
In conclusion, based on the Granger causality analysis, this study found that both PTSD and trauma caused changes in effective connectivity between the amygdala and many brain regions, including the mPFC, the dlPFC, the SMA, the STG, and the precuneus/PCC. Trauma could lead to increased ascending activation of the mPFC by the amygdala, and decreased regulation of the amygdala by the dlPFC. The greater inhibition of the amygdala by the mPFC may serve as a protective factor for PTSD, and altered amygdala-SMA and amygdala-STG effective connectivity may reflect compensatory mechanisms of brain function. These data raise the possibility that insufficient inhibition of the amygdala by the mPFC might lead to PTSD in those who have been exposed to traumatic incidents, and may inform future therapeutic interventions.
FC and JK collected the data, performed the analysis and wrote the manuscript. RQ contributed to the design of the study. TL collected the MRI data. QX contributed to the design of the study. YZ contributed to the discussion and manuscript revision. JL revised the manuscript for intellectual content. GL and LZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors reviewed the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.