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ScienceDirect Comprehensive Psychiatry 55 (2014) 1688 – 1695 www.elsevier.com/locate/comppsych

Altered spontaneous neuronal activity of visual cortex and medial anterior cingulate cortex in treatment-naïve posttraumatic stress disorder Hongru Zhu a, b, 1 , Junran Zhang c, 1 , Wang Zhan d , Changjian Qiu a , Ruizhi Wu a , Yajing Meng a, b , Haofei Cui a , Xiaoqi Huang e , Tao Li a, b , Qiyong Gong e,⁎⁎, Wei Zhang a,⁎ a

Mental Health Center, West China Hospital of Sichuan University, Chengdu 610041, China State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China c School of Electrical Engineering and Information, Sichuan University, Chengdu 610065, Sichuan Province, China d Neuroimaging Center, University of Maryland, College Park 20740, MD, USA e Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu 610041, China b

Abstract Background: Although no more traumatic stimuli exists, a variety of symptoms are persisting in chronic Posttraumatic Stress Disorder (PTSD) patients. It is therefore necessary to explore the spontaneous brain activity of treatment-naïve PTSD patients during resting-state. Method: Seventeen treatment-naïve PTSD patients and twenty traumatized controls were recruited and underwent a resting functional magnetic resonance imaging (Rs-fMRI) scan. The differences of regional brain spontaneous activity between the participants with and without PTSD were measured by Amplitude of Low-frequency fluctuation (ALFF). The relationship between the altered brain measurements and the symptoms of PTSD were analyzed. Result: Compared to traumatized controls, the PTSD group showed significantly altered ALFF in many emotion-related brain regions, such as the medial anterior cingulate cortex (MACC), dorsolateral prefrontal cortex (DLPFC), insular (IC), middle temporal gyrus (MTG), and ventral posterior cingulate cortex (VPCC). Interestingly this is the first report of a hyperactive visual cortex (V1/V2) during resting-state in treatment-naïve PTSD patients. There were significant positive correlations between ALFF values in the bilateral visual cortex and re-experiencing or avoidance in PTSD. Negative correlation was observed between ALFF values in MACC and avoidance. Conclusion: This study suggested that the visual cortex and the MACC may be involved in the characteristic symptoms of chronic PTSD, such as re-experiencing and avoidance. Future studies that focus on these areas of the brain are required, as alteration of these areas may act as a biomarker and could be targeted in future treatments for PTSD. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Posttraumatic Stress Disorder (PTSD) is a debilitating psychiatric disorder that can develop in individuals exposed to traumatic events, such as the threat of death or serious injury, whereby the individual typically reacts with intense fear, helplessness or horror. PTSD can be clinically

⁎ Correspondence to: W. Zhang, Mental Health Center, West China Hospital of Sichuan University, Chengdu 610041, China. Tel.: +86 28 85422005. ⁎⁎ Correspondence to: Q. Gong, Department of Radiology, Huaxi MR Research Center (HMRRC), West China Hospital of Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041 China. E-mail addresses: [email protected] (W. Zhang), qiyonggong@hmrrc. org.cn (Q. Gong). 1 Hongru Zhu and Junran Zhang contributed equally to this study. http://dx.doi.org/10.1016/j.comppsych.2014.06.009 0010-440X/© 2014 Elsevier Inc. All rights reserved.

characterized by symptoms of re-experiencing, emotional numbing and avoidance, and hyperarousal [1]. These symptoms can seriously limit the patients' work and everyday life, and may increase the risk of hypertension, coronary heart disease, peptic ulcer and even suicide [2]. The neurophysiological mechanism of PTSD can be explained from specific regional brain alterations [3] to altered neurocircuitry between regions [4] and even instabilities in the brain network [5]. The explicit neuronal mechanisms behind the PTSD pathophysiology however, are yet to be elucidated [6]. Previous functional neuroimaging studies have suggested that PTSD may exist in parallel with neurological changes in several corticolimbic regions, including the amygdala [7–9], the hippocampus [10–14], the insular [15–20] and the prefrontal cortex [21–23]. Such neurological alterations are viewed as being connected with

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the physiological and psychological abnormalities associated with PTSD including: impaired emotion; memory; visual recognition and regulation of fear responses; enhanced attention to threat-related stimuli and biased memory for adverse events [24–28]. In addition, the involvement of the occipital cortex in PTSD related physiological and psychological abnormalities has been reported, however the specific mechanistic role of the occipital cortex in PTSD pathology remains largely unknown. Morris et al. [29] suggested that the effect of emotional stimuli on visual cortex (in the occipital lobe) activation corresponds to the ventral amygdala’s response in healthy volunteers. It has been reported that the parallel changes in the subregional amygdala and the sensory cortex responses are observed during acquisition of an implicit association between a visual conditioned stimulus and an auditory unconditioned stimulus [29]. It is well known that visual imagery is mediated by the topographically organized visual cortex [30].Re-experiencing traumatic phenomena as a specific visual mental image, requires activation of the visual cortex along with activation or deactivation of various other brain regions. Rauch et al. suggested that the visual cortex response of PTSD patients to novel, aversive stimuli, may be related to some visual components of the re-experiencing phenomenon [31]. The study by Hendler et al. [7] on male veterans with PTSD found that the lateral occipital complex (LOC), a brain region critical for object perception, had no reduction in activity as a result of repeated presentations of trauma-related stimuli indicating diminished habituation in PTSD patients. In addition to functional studies, there are a small number of reports suggesting reduced gray matter volume in the occipital lobe in PTSD patients [32–34], however these findings are yet to be validated. Resting-state functional magnetic resonance imaging (Rs-fMRI) analysis [35] has been increasingly used to investigate the networks of the intrinsic brain signaling fluctuations in the absence of task load [36]. The results of the majority of current Rs-fMRI studies support the notion that PTSD is a disorder associated with dysfunctions in the integrated brain-signaling network, such as the mPFCamygdala circuit, the corticothalamic [37] and the default mode network (DMN) [38]. In general, however, it is important to note that the reported Rs-fMRI studies were limited to poorly defined patient groups. For instance, it is well recognized that treatment is a significant compounding factor to the resting-state of the brain [39]. In the majority of these PTSD neuroimaging studies, however, no treatmentnaïve criteria was applied in, thus those patients that had received treatment to reduce the symptoms were still included in the patient group. Therefore, it is difficult to ascertain if the detected neurological alterations reported in these studies were indeed caused by the disease alone. In the present study, treatment-naïve patients with chronic PTSD as a result of the 8.0-magnitude Wenchuan earthquake [40] were investigated. The regional amplitude of low-frequency fluctuations (ALFFs) [41] in Rs-fMRI was analyzed to

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characterize regional spontaneous neuronal activity [42] in patients with chronic PTSD. It was hypothesized that the treatment-naïve PTSD patients would present with abnormalities for regional cerebral function, particularly in the frontolimbic, the DMN and the occipital cortex, brain regions known to be important for emotion, memory and recognition. Moreover, these alterations in resting-state brain function may be associated with PTSD symptom severity.

2. Material and methods 2.1. Participants Seventeen right-handed PTSD patients who survived the Wenchuan 8.0-magnitude earthquake (5 males and 12 females with a mean age of 44.41 ± 8.44 years) were compared to twenty healthy controls that experienced the same earthquake (9 males and 11 females with a mean age of 40.35 ± 9.43 years). All subjects were between 21 and 61 years of age. All subjects were recruited from the disaster areas of the Wenchuan earthquake 2 years after the earthquake (2010–2011). To avoid treatment-elicited changes in patient mental function, only treatment-naïve (neither psychotherapy nor pharmacotherapy) PTSD patients were recruited into the study. The exclusion criteria for both groups included: 1) history of neurological disorders; 2) present or past Axis-I psychiatric disorders other than PTSD; 3) head injury or loss of consciousness (N1 h); 4) drug or alcohol abuse⁄dependence within the 6 months prior to the study; 5) contraindications to MRI; 6) learning or developmental disorders or 7) a family history of mental disorders. All subjects were assessed by DSM-IV Structured Clinical Interview (SCID), the Clinician Administered Posttraumatic Stress Disorder Scale (CAPS), the Hamilton Rating Scale for Depression (HRSD), and the Hamilton Rating Scale for Anxiety (HRSA), and all patients underwent brain scans at the Huaxi MR Research Center of West China Hospital. This study was approved by the Medical Ethics Committee of West China Hospital, Sichuan University, and all participants provided written informed consent. 2.2. Data acquisition The brain scans of all subjects were obtained using a 3 T MR imaging system (GE EXCITE, Milwaukee, USA) with an 8-channel phased array head coil. During the MRI examination, subjects were instructed to relax with eyes closed, but not to fall asleep, which was later confirmed via a survey containing the following questions: (1) Did you fall asleep during the scanning? (2) Did you keep your eyes closed during the scanning? and (3) What were you thinking during the scanning? Subjects were fitted with soft earplugs and positioned carefully in the coil with a comfortable support. The MR images were sensitized to changes in blood-oxygen-level dependent (BOLD) signal levels (repetition time (TR)/echo time (TE) = 2,000/30 ms; flip

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angle = 90°) were obtained by a gradient-echo-planar imaging (EPI) sequence. There were 5 dummy scans collected prior to the actual MRI scans and the first 5 volumes of MRI time series discarded for magnetization stabilization. The slice thickness was 5 mm (no slice gap) with a matrix size of 64 × 64 and a field of view of 240 × 240 mm 2, resulting in a voxel size of 3.75 × 3.75 × 5 mm 3. Each brain volume comprised of 30 axial slices and each functional run contained 200 image volumes. 2.3. Data preprocessing Functional image preprocessing and statistical analyses were performed using Statistical Parametric Mapping (SPM8, http://www.fil.ion.ucl.ac.uk/spm). For each participant, EPI images were slice-time-corrected, realigned to the first image and unwrapped to correct for susceptibility-bymovement interaction. Briefly, the images were corrected for intravolume acquisition time differences between slices using the sinc interpolation and images were then corrected for the intervolume geometric displacement as a result of head movement, using a six-parameter (rigid-body) spatial transformation as previously described [43]. Data of three male patients in the PTSD group were discarded due to head movements greater than 1.5 mm of translation or 1.5 degrees of rotation in any direction. After correction for this, all of the realigned images were spatially normalized to the Montreal Neurological Institute (MNI) template, and each voxel was resampled to 3 × 3 × 3 mm 3 without spatial filtering. Finally, Images were smoothed using a 4 mm fullwidth half-maximum (FWHM) isotropic Gaussian filter.

connectivity criterion of 5rmm yielding an AlphaSim correction threshold of p b 0.05 (http://afni.nimh.nih.gov/ pub/dist/doc/manual/AlphaSim.pdf). Confounding factors of age and gender were removed from the data through general linear models. Once a significant between-group difference was observed in the ALFF results, seven abnormal areas are defined as ROI, and the mean ALFF values across all voxels in the abnormal areas in PTSD were calculated by REST. Then, the relationship between the ALFF values of the abnormal areas and the subscale scores of the CAPS in the PTSD group were analyzed by linear correlation analyses with age and gender now treated as unnecessary confounding factors (SPSS V17.0, Chicago, Illinois, USA).

3. Results 3.1. Subjects demographics Data from 17 earthquake survivors with PTSD and 20 trauma-exposed non-PTSD controls was utilized in the current study. There were no significant differences between the two groups in terms of age, sex or years of education (p N 0.05; Table 1). The CAPS (total scores and subscales), HRSD and HRSA had significant differences between PTSD group and controls (p b 0.001; Table 1). There was a significant correlation between the HRSD and HRSA scores in PTSD patients (p = 0.001, r = 0.71). No significant correlation was found between the HRSD/HRSA scores and the total CAPS scores in PTSD group (p N 0.05).

2.4. ALFF calculation

3.2. ALFF findings

Following the preprocessing, resulting data were further temporally band-pass filtered (0.01–0.08 Hz) to reduce the effects of low-frequency drift and high-frequency physiological noise. In addition, linear-trend removal was performed, and the time series was transformed to the frequency domain using fast Fourier transform (FFT) (parameters: taper percent = 0; FFT length = shortest) to obtain the power spectrum. The power spectrum was square-rooted and averaged across 0.01–0.08 Hz at each voxel to calculate the ALFF. The ALFF of each voxel was then divided by the global mean of ALFF values for standardization. The ALFF values were calculated using the Resting-state fMRI data analysis toolkit (REST V1.8, State Key Laboratory of Cognitive Neuroscience and Learning in Beijing Normal University; http://www.restfmri.net/forum/REST_V1.8) [44].

The differences between the ALFF findings of PTSD patient group and the control group are presented in Fig. 1. The PTSD group showed significantly decreased ALFF in the left insular cortex (IC, BA 13), the dorsolateral prefrontal cortex (DLPFC, BA 9/44), the ventral posterior cingulate cortex (VPCC, BA 23), the medial anterior cingulate cortex (MACC, BA 32) and the right middle temporal gyrus (MTG, BA 21), compared with the control group. Increased ALFF

2.5. Statistical analysis The ALFF maps in the PTSD and control groups were compared on a voxel-wise basis via a 2-sample Student’s t-test using the statistical SPM8 package. A threshold adjustment method based on the Monte-Carlo simulations correction was used for an exploratory whole-brain analysis with a voxel-wise p value of p b 0.001, a cluster size N10 (270 mm 3) and cluster

Table 1 Demographic information and psychological variables.

Female to male ratio Ages Educational years CAPS(total) Re-experiencing Avoidance Hyperarousal HRSD (mean ± SD) HRSA (mean ± SD)

Controls (n = 20)

PTSD (n = 17)

p Value

11:9 40.35 ± 9.43 8.65 ± 3.39 11.35 ± 8.32 3.75 ± 3.35 1.95 ± 2.11 5.65 ± 4.65 4.00 ± 3.49 3.95 ± 4.20

12:5 44.41 ± 8.44 7.00 ± 3.76 60.88 ± 14.29 19.71 ± 6.57 21.59 ± 6.52 19.76 ± 5.83 13.65 ± 5.45 13.47 ± 4.30

0.50 0.18 0.16 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001

CAPS, Clinician Administered Posttraumatic Stress Disorder Scale; HRSD, Hamilton Rating Scale for Depression; HRSA, Hamilton Rating Scale for Anxiety.

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Fig. 1. Regions showing changed ALFF in PTSD compared with controls (p b0.05, AlphaSim corrected).Scatter plots show significant correlations between regional ALFF (the structures in the blue circles) and the subscale CAPS scores in the PTSD group (p b 0.05). IC, Insular cortex; DLPFC, left dorsolateral prefrontal cortex; MTG, middle temporal gyrus; VPCC, ventral posterior cingulate cortex; MACC, medial anterior cingulate cortex; V1/V2, primary visual cortex and secondary visual cortex; V2, secondary visual cortex; CAPS, Clinician Administered Posttraumatic Stress Disorder Scale; ALFF, amplitude of lowfrequency fluctuation.

was observed only in the bilateral visual cortex (BA 17/18) of PTSD patients (Table 2, Fig. 1B). The relationship between ALFF values in abnormal areas and CAPS scales (total CAPS, the defined subscale scores) are presented in Table 3. In PTSD patients, a significant positive correlation was observed between ALFF values in the bilateral visual cortex and the CAPS scales (total CAPS, re-experiencing and avoidance subscale scores). As shown in Fig. 1A, there was a positive correlation between ALFF values in the V1/V2.L and the avoidance subscale (p = 0.04, r = 0.51). In addition, there was a positive correlation between ALFF values in the V1.R and the re-experiencing subscale (p = 0.03, r = 0.54). All brain regions with increased ALFF values in PTSD patients, namely the V1/V2.L and V1.R regions, were found to be related to the severity of PTSD symptoms, particularly in subscales corresponding to avoidance and re-experiencing scores, respectively.

Negative correlations between decreased ALFF values in MACC and CAPS scales (total CAPS and the avoidance subscale) were observed (p = 0.02; r = −0.54) (Fig. 1A and Table 3). There was no significant correlation between CAPS scores and ALFF values in other altered regions of the brain (Table 3).

4. Discussion The findings of the present study indicate altered spontaneous brain activities in treatment-naïve PTSD patients. In accordance with the findings of several past fMRI studies of PSTD patients, the results of the present study indicate that, without medication, there is reduced activity in the MACC and the DLPFC in the brains of

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Table 2 Abnormal brain regions in PTSD patients by ALFF analysis. Seed region

Brodmann area

PTSD b controls IC.L 13 DLPFC.L 44/9 MTG.R 21 VPCC.L 23 MACC.L 32 PTSD N controls V1/V2.L 17/18 V1.R 17

Cluster size

T score (peak value)

Peak coordinates (MNI) x

y

z

11 19 15 18 14

−5.12 −4.74 −4.73 −4.79 −3.96

−39 −48 63 −9 −3

15 6 −15 −12 24

9 30 −9 30 36

23 11

4.79 4.71

−15 15

−75 −96

3 −6

IC.L, left insular cortex; DLPFC.L, left dorsolateral prefrontal cortex; MTG. R, right middle temporal gyrus; VPCC.L, left ventral posterior cingulate cortex; MACC.L, left medial anterior cingulate cortex; V1/V2.L, left primary visual cortex and secondary visual cortex; V2.R, right secondary visual cortex; (p b 0.05, AlphaSim corrected).

treatment- naïve PTSD patients, relative to traumatized nonPTSD controls. The IC, VPCC and MTG regions of the brain in treatment- naïve PTSD also showed decreased ALFF in the current study. Interestingly, in the present study, a hyperactive visual cortex was observed during the restingstate in the treatment-naïve PTSD patients, a finding never before reported in Rs-fMRI studies of PTSD. In the current study, the bilateral visual cortex (in the occipital cortex) of PTSD patients had increased spontaneous activity compared with the bilateral visual cortex of the traumatized control group. These spontaneous activity magnitudes in the PTSD group of patients were positively correlated with the re-experiencing or avoidance subscale scores in the PTSD group. To the best of the authors’ knowledge, there are no previous reports indicating a positive correlation between hyperfunction of bilateral visual cortex in PTSD patients using the Rs-fMRI. Consequently, the findings of the current study indicate an important role of the visual cortex in the pathophysiological mechanism of chronic PTSD, particularly in resting-state. A previous resting single photon emission computed tomography (SPECT) study of 11 PTSD patients and 17 trauma survivors revealed the left occipital gyrus (BA 18; 19) regional cerebral blood flow were positively correlated with CAPS scores [45]. In addition, Yang et al. suggested that adolescents with earthquake-related PTSD group demonstrated activation in the bilateral visual cortex (BA 17/18/19) during earthquake imagery [46]. Moreover, Hendler et al. reported that the LOC, a region of the brain that responds preferentially to objects, was not habituated in PTSD patients following repeated presentations of trauma-related stimuli [7]. The findings of these additional studies [47] indicate that regional LOC hyperactivity, observed following repeated presentations of trauma-related stimuli in PTSD patients [7], may be related to impairments of the brain information processing, particularly, the brain inhibitory network, in PTSD patients [47]. In a

structural imaging study, Chao et al., reported a reduced volume of left occipital gray matter in PTSD patients relative to traumatized controls [48]. This involvement of the visual cortex in the manifestation of PTSD symptoms is supported by findings of anatomical studies that indicate that the amygdala projects to all visually related areas of the temporal and occipital cortex and can modulate sensory processing at very early stages in the cortical hierarchy [49]. It has been reported that the function of the visual cortex can be modulated by the emotional content of visual stimuli [29] and that the visual cortex is also involved in visual imagery. In the present study, the left visual cortex was related to the avoidance tendencies of PTSD patients, whilst the right visual cortex was associated with the re-experiencing tendencies of PTSD patients. Thus, the results of the current study indicate that abnormal spontaneous hyperactivity of the visual cortex in PTSD patients, during a state of rest, is associated with emotional dysregulation and disrupted visual imagery or re-experiencing. The specific interactions between the left and right visual cortical regions remain unclear, indicating a need for future studies focusing specifically on the differences between the left and right visual cortical regions in PTSD patients. In the present study, in the PTSD patient group, the MACC had decreased ALFF values in addition to an inverse correlation with avoidance scores. Previous studies have reported such an inadequate top-down control by ACC/MPFC results in a permanent state of amygdala hyperresponsiveness along with a failure to suppress attention to trauma-related stimuli [50]. The decreased relationship between MACC activity and PSTD symptoms, as revealed in the present study, are in correlation with findings of a previous fMRI study of PTSD patients whereby abnormalities of the MACC existed in the resting-state and were related to the severity of avoidance by PTSD patients of traumatic-related events [16]. The decreased spontaneous IC brain activity observed in the current study is consistent with an independent Rs-fMRI study investigating a different cohort of PTSD patients that experienced the same earthquake [51]. In this previous study, subjects were recruited from 9 to 15 months post-earthquake and presented with relative acute PTSD. Furthermore, the decreased spontaneous IC brain activity observed in the current study is in accordance with reports of reduced greymatter volume in the bilateral IC in PTSD patients [18]. In addition, a previous psychological study has reported that the IC was related to declarative memory and pressing intrusive thoughts [52]. Consequently it may be, speculated that decreased spontaneous activity in the IC may contribute to declarative memory dysfunction and more frequent flashbacks of a traumatic events in PTSD patients. Further investigations are required to provide a better understanding of the relationship between the IC and declarative memory dysfunction. Findings from previous neuroimaging studies [53,54] indicate that the DLPFC may be pivotal in the conscious regulation of emotion and in addition, that increased DLPFC activity is critical in the reduction of fear responses [27]. Such studies indicate a unique role of the DLPFC in the

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Table 3 The relationship between the ALFF values and the CAPS scales. Decreased regions IC_L CAPS Re-experiencing Avoidance Hyperarousal

r p r p r p r p

−0.06 0.83 −0.04 0.87 −0.01 0.73 0.01 0.96

DLPFC_L −0.23 0.38 −0.12 0.65 −0.28 0.28 −0.11 0.68

Increased regions

VPCC_L

MACC_L

−0.10 0.69 −0.35 0.17 −0.03 0.90 0.18 0.50

−0.55⁎ 0.02 −0.35 0.17 −0.54⁎ 0.02 −0.35 0.17

MTG_R

V1/V2_L

V1_R

0.05 0.86 −0.11 0.68 0.11 0.67 0.11 0.68

0.49⁎ 0.05 0.40 0.11 0.51⁎ 0.04 0.18 0.49

0.50⁎ 0.04 0.54⁎ 0.03 0.16 0.53 0.44 0.08

CAPS, Clinician Administered Posttraumatic Stress Disorder Scale; IC.L, left insular cortex; DLPFC.L, left dorsolateral prefrontal cortex; MTG.R, right middle temporal gyrus; VPCC.L, left ventral posterior cingulate cortex; MACC.L, left medial anterior cingulate cortex; V1/V2.L, left primary visual cortex and secondary visual cortex; V2.R, right secondary visual cortex; ⁎ Correlation is significant at the 0.05 level (2-tailed).

recovery of PTSD patients. The altered structure and function of the DLFPC has consistently been reported in various PTSD groups [55–58]. Moreover, it has been reported that lesions of the DLPFC are associated with substantially higher levels of depression and/or increased severity of PTSD symptoms [59,60]. It has also been reported that the DLPFC are associated with the fear extinction [61], an ability to manage negative emotions and a positive increase in vocabulary memory [62]. Recently, the findings of a study conducted by Lyoo et al. revealed that increased DLPFC thickness was positively correlated with an increased reduction in PTSD symptoms and improved recovery for PTSD patients [63]. These findings are in accordance with the results of the present study, whereby, in the current study, the regional cerebral function in the left DLPFC was deceased in PTSD patients even in the resting-state. Consequently, it may be speculated that, as the function of the DLPFC is tightly related to the disturbances in fear and verbal memory experienced by PTSD patients, exploration of the function of the DLPFC is a potential biomarker for the prognosis of PTSD. In addition to decreased DLPFC activity, it is possible that decreased activity of the VPCC and MTG areas of the brain may be associated with increased severity of PTSD symptoms. Whilst both the VPCC and MTG are considered parts of the DMN [64,65], it has been reported that the VPCC is activated in response to self-referential thinking [66] whereas the MTG is activated in relation to memory retrieval [65]. Therefore, decreased activities in these regions of the brain may result in abnormal self-referential processing and memory retrieval in PTSD patients [67,68]. The findings of the correlation analysis using the CAPS subscales in the present study indicate that abnormal ALFF values in particular brain regions may be associated with specific sub-categories of PTSD symptoms. For instance, the results of the present study revealed that alterations in the bilateral visual cortex and the MACC affected the severity of PTSD symptoms by directly negatively impacting the reexperiences or avoidance symptoms rather than the total severity of symptoms during the resting-state. These results

indicate that the use of subscales may assist in better understanding the pathophysiological mechanisms of PTSD, thereby aiding in the development of improved therapeutic targets. The findings of the current study are inconsistent with those of another resting-state study in PTSD that reported increased ALFF values in BA 10 and BA 32 [69]. The possible reason for this inconsistency is that whilst traumatized controls were recruited in the present study, the previous study included health controls. Technically, the differences between PTSD patients and health controls representative a mixed effect from trauma and disease. And it is more effective to discriminate the abnormities of the disease itself by comparing the PTSD patients and the same traumatized controls. In addition, the traumatic event were different from theirs. Instead of different motor vehicle accidents, participants in this study suffered same natural disaster at the same time, which provided a more homogeneous sample. The current study consisted of several limitations. Firstly, there was a greater number of female PTSD patients included in the patient group, most likely because it has been well documented that females have a higher prevalence of PTSD [70] and are more likely to make known their mental dysfunction. In addition, 3 male PTSD patients were removed from the study due to excessive head motion beyond the Rs-fMRI criterion of the present study, thus further decreasing the number of male PTSD participants. An attempt was made to manage this gender effect by removing variances from all analyses using general linear models. Even so, the authors acknowledge that in order to truly test for between-gender differences in “resting-state” brain function, future studies designed to recruit equal numbers of males and females are required. A second limitation of the current study was the small sample size. This was primarily due to the exclusion of patients with comorbid psychiatric disorders and those that had received any previous standard therapy. Furthermore, because of the limited sample size, the linear correlation analyses in this study may not survive strict multiple comparison correction.

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The statistical significances of correlations would be more valuable after multiple comparison correction. This could be solve by increasing the number of subjects and limiting the number of comparisons. Future studies could include a larger group of subjects and focus on a few specific regions of interest and subscales. Finally, this was a cross-sectional study, therefore it remains unclear if the functional abnormalities observed during the brain’s resting-state are indeed risk factor for the development of PTSD following psychological trauma. Twin studies and longitudinal studies are required to resolve this issue. 5. Conclusion The visual cortex (V1/V2) and the MACC may be involved in the characteristic symptoms of chronic PTSD, such as re-experiencing and avoidance. Spontaneous activity of the visual cortex and the MACC may play an important role in the pathophysiological mechanism of chronic PTSD. Future studies that focus on these areas of the brain are required, as alteration of these areas may act as a biomarker and could be targeted in future treatments for PTSD. Acknowledgment This study was supported by National Natural Science Foundation (Grant Nos. 81371484, 81000605), National Key Technologies R&D Program (Program No: 2012BAI01B03) of China, the Support Plan of Sichuan (Grant No. 2011SZ0292) and Natural Science Foundation of Guangdong (Grant No. S20120200-10867). Dr. Qiyong Gong acknowledges the support from his American CMB Distinguished Professorship Award (Award No. F510000/G16916411) administered by the Institute of International Education, USA. References [1] American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. 4th ed. Washington, DC: American Psychiatric Press; 2000 [Text revision]. [2] Pickering TG. Mental stress as a causal factor in the development of hypertension and cardiovascular disease. Curr Hypertens Rep 2001;3:249-54. [3] Shin LM, Lasko NB, Macklin ML, Karpf RD, Milad MR, Orr SP, et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch Gen Psychiatry 2009;66:1099-107. [4] Sripada RK, King AP, Garfinkel SN, Wang X, Sripada CS, Welsh RC, et al. Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder. J Psychiatry Neurosci 2012;37:241-9. [5] Bluhm RL, Williamson PC, Osuch EA, Frewen PA, Stevens TK, Boksman K, et al. Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma. J Psychiatry Neurosci 2009;34:187-94. [6] Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 2010;35:169-91. [7] Hendler T, Rotshtein P, Yeshurun Y, Weizmann T, Kahn I, Ben-Bashat D, et al. Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage 2003;19:587-600.

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