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 Posttraumatic stress disorder is a debilitating disorder that can affect individuals who have either experienced or witnessed a life threatening trauma usually involving death or severe injury (1). The National Comorbidity Survey estimates that the lifetime prevalence of PTSD is 8% in the general population and 24% in trauma victims. There is also a sex-ratio bias of 2:1 between women and men (2). PTSD is an anxiety disorder marked by sustained and dysfunctional emotional reactions to a traumatic experience. It haunts its victims with terrifying memories, flashbacks, nightmares, night terrors, and panic attacks (3). Although some symptoms such as anxiety or insomnia are to some extent treatable, pharmacologic agents specifically targeting PTSD remain unavailable. This is owing to the fact that the precise neurobiological mechanism of PTSD has yet to be determined. Many recent neuroimaging studies investigated the structural and functional changes of the brains in patients with PTSD and obtained some significant findings (4–6). Bremner performed the first neuroimaging study of PTSD. He measured hippocampal volume using MRI (7). His research showed that PTSD correlates with decreased hippocampal volume. In another review, Hull describes 30 published reports on PTSD that used neuroimaging methods. Of these, 12 reports focused on brain structure and 18 reports focused on brain function. Additionally, 2 of these studies combined the imaging methods (8). Significant evidence from these studies supports the involvement of the hippocampus in patients suffering from PTSD. For instance, smaller right or left bilateral hippocampal volumes were found with structural MRI in patients suffering from chronic PTSD, such as war veterans or individuals who suffered childhood sexual abuse (5,7–12). The reduction in hippocampal neuronal density in patients with chronic PTSD was also noted in research reports that used proton MRS (13–16). MRS can provide information about alterations in NAA and Cho-containing compounds in the human brain without exposing it to radiation; hence, NAA is considered a putative neuronal marker (17). For example, Schuff and others used both MRI and 1H-MRS to measure hippocampal volume and changes in NAA (18). An 18% reduction in right hippocampal NAA, compared with a 6% reduction in left hippocampal volume, implied that NAA is a more sensitive measure of neuronal loss than volume changes. Considering the results of both MRI and MRS studies in chronic PTSD, we hypothesize that there may be a structural and neuronal integrity deficit of the hippocampus in patients with chronic PTSD (6). This conclusion has interesting implications about studies of cognitive processing in patients with PTSD. The effects of hippocampal damage on declarative memory systems in humans are well documented, with some neuropsychological evidence of short-term explicit verbal memory dysfunction in patients with PTSD (19–21). Two neuroimaging studies of the hippocampal functioning of patients with PTSD reported hippocampal dysfunctions focused mainly on patients’ declarative memory (22,23). These findings on hippocampal deficits focused mainly on samples from adult populations suffering from chronic PTSD, such as veterans and victims of child abuse. There were, however, no consistent findings in studies of child and adult patients with recent-onset PTSD. Of MRI studies, 2 studies found no hippocampal reduction in patients with recent-onset PTSD (24,25), and 2 studies failed to obtain the results of a decrease in hippocampal volume in patients whose PTSD was related to pediatric maltreatment (26,27). In contrast, other study evidence suggested a bilateral hippocampal volume reduction in a sample of individuals with PTSD related to recent burn trauma (28). After controlling for effects of whole brain volume and age, other studies on patients with recent-onset PTSD related to accidents found that the right-side hippocampal volume was significantly smaller than that in nontraumatized control subjects (29). These inconsistent findings indicate that the reduction of hippocampal volume in individuals with recent-onset PTSD should be investigated and validated by further studies. It is possible that hippocampal pathology is relatively subtle and that standard morphometric MRI procedures do not always detect it in patients with recent-onset PTSD. Thus we should employ more exact methods to measure hippocampal pathology in patients with recent-onset PTSD. The VBM analysis is not biased toward one particular structure and gives an even and comprehensive assessment of anatomical differences throughout the brain (30,31). Different from previous studies, volumetric analyses of the hippocampus VBM can assess anatomical differences everywhere in the brain without operational bias toward those brain structures with easily identifiable boundaries. This method may help us to explore subtle hippocampal pathologies in patients with recent-onset PTSD. Conversely, MRS studies can reveal neuron changes (17), which means that the combination of VBM and MRS could provide more accurate information on hippocampal structural pathology. To our knowledge, the combination of VBM and MRS has not been used in previous studies of PTSD. It is a new approach to studying recent-onset PTSD. The main goal of our study was to use a combination of VBM and MRS to explore hippocampal structural abnormalities in patients with recent-onset PTSD. We hypothesized that there may be hippocampal structural abnormalities in patients with recent-onset PTSD. MethodsParticipants There were 24 participants in our study. All the participants were right-handed individuals who were victims of a disastrous fire that occurred in November 2003 in the Hunan province of China. A team of psychiatrists from the Mental Health Institute of Central South University went to investigate the influence of fire on victims 5 months after the fire. To estimate whether victims had symptoms of PTSD, the investigators used the DEQ as a screening tool (32). When an individual reported significant symptoms of PTSD, he or she was interviewed by 2 psychiatrists who made a diagnosis according to structured clinical interview and the DSM-IV (33). Of the 87 fire victims, 19 individuals met the diagnostic criteria for PTSD. From this group, we recruited 12 individuals with recent-onset PTSD into the PTSD group of our neuroimaging study, according the informed consent principle. We also recruited 12 individuals who were interviewed by psychiatrists and not diagnosed as having PTSD to the group without PTSD. Each group consisted of 8 women and 4 men. The symptoms of the individuals in the PTSD group were directly related to the fire. The severity of the symptoms was assessed using the DEQ (32). Only 2 participants in the PTSD group met the current comorbid diagnostic criteria for major depression. No one in the PTSD group met diagnostic criteria for other psychiatric disorders such as panic disorder or specific phobia. None of the participants in the group without PTSD met criteria for any current psychiatric disorders. None of the 24 participants who were examined by physicians at the Second Xiangya Hospital, Central South University had neurological or major medical conditions. Participants also had no history of alcohol or other substance abuse within 1 year prior to the study. They were enrolled into the study in parallel. Participants in the PTSD group had never taken psychotropic drugs to treat PTSD. The 2 groups did not differ significantly in age (mean 34.56 years, SD 4.91, for individuals with PTSD and mean 33.25 years, SD 5.27, for individuals without PTSD; t = 0.49, P = 0.68). Individuals with PTSD had higher scores on the DEQ than those without PTSD (mean 43.12, SD 5.61, compared with mean 12.58, SD 4.92, respectively; t = 4.46, P = 0.001. Prior to the study, we obtained informed consent from each participant. The study protocol conformed to the ethical guidelines as stipulated in the 1975 Declaration of Helsinki. After the neuroimaging examination, participants with PTSD were given systemic pharmacological treatment by psychiatrists in the Mental Health Institute of Central South University. Data Acquisition Participants underwent quantitative MRI and 1H-MRS of the brain at the Second Xiangya Hospital. Spectroscopic and imaging experiments were performed using a 1.5-tesla whole-body scanner with a standard head coil and software (General Electric Medical Systems Signa, Milwaukee, WI). Anatomic images were acquired using a high-resolution 3-D SPGR sequence (that is, SPGR, 1 mm contiguous slices, TR = 25 msec, TE = 6 msec, flip angle = 258, matrix = 256 × 128, FOV 24 × 24 cm). 1H-MRS was used to examine 15.3 × 20.3 × 40 mm voxel in both hippocampi with PROBE-P (TE = 144 ms, TR = 1000 ms, 248 acquisitions), General Electric Medical System version of automated point-resolved spectroscopy. The hippocampus was identified from the T1-weighted images in the coronal plane. The anterior border of the voxel was located in the most anterior slice that showed hippocampus but not the amygdala. The peaks of spectra were identified according to resonance positions determined by previous studies (14–17). A radiographer who was blind to the participant diagnoses analyzed the MRS results and identified the peaks from NAA, Cr, and Cho, using Functool 2 (Advantage Windows 4.0 software by General Electric Medical Systems). We then analyzed the results of the VBM, so the analysis was not blind. Data Analyses Structural MRI. To assess the anatomical differences between individuals with PTSD and those without PTSD across the entire structural spectrum of the brain without operational bias, we used automated VBM (29). VBM was recently used in structural MRI studies of various neuropsychiatric disorders (30,34). This method was also used in another PTSD study (35). According to the VBM analyses, the difference of gray or white matter density between individuals with PTSD and those without PTSD can be detected using 2-tailed t test statistics, with significance levels set at P < 0.001 (corrected). Magnetic Resonance Spectroscopy. We performed the analysis of MRS data using SPSS version 10.0 software for Windows. The comparisons of NAA/Cr and NAA/Cho between participants with PTSD and participants without PTSD were implemented with 2-tailed t tests, with significance levels set at P < 0.05. ResultsMagnetic Resonance Spectroscopy Compared with individuals without PTSD, a decrease of the ratio of NAA to Cr in the left hippocampus was found in individuals with PTSD (P = 0.006) (Figure 1). No difference was found in the ratio of NAA to Cr in the right hippocampus or in the ratio of NAA to Cho in the bilateral hippocampi. The lower NAA/Cr ratio in participants with PTSD suggests that the left hippocampal neuronal metabolism may be impaired in individuals with recent-onset PTSD.
 Structural MRI Participants with PTSD and participants without PTSD also differed in grey matter density of the left hippocampus (Talairach peak coordinate, x = –30, y = –15, z = –14; t score = 3.79), left anterior cingulate cortex (Brodmann area 32) (Talairach peak coordinate, x = –2, y = 40, z = 17, t score = 5.05) and bilateral insulars (Brodmann area 13) (left insular, Talairach peak coordinate, x = 6, y = 2, z = 0; t score = 4.64; right insular, peak coordinate, Talairach, x = 34, y = 4, z = 6; t score = 4.44) (Figure 2). There were no other significant differences between the groups in other gray matter regions or in any of the white matter regions. These results indicate that the left hippocampus, the left anterior cingulate cortex, and the bilateral insulars volumes have been significantly reduced in individuals with PTSD, compared with individuals without PTSD.
 DiscussionFire victims with recent-onset PTSD exhibited significantly lower grey matter density and a lower ratio of NAA/Cr in the left hippocampus than did victims of the same accident who did not suffer from PTSD. This may indicate that there were structural deficits of the left hippocampi of patients with recent-onset PTSD. It also provides evidence that hippocampal structural damage may occur in individuals who have been exposed to recent trauma and who also meet the diagnostic criteria for PTSD. This finding is similar to those of prior MRI and MRS studies of patients with chronic PTSD (6,7,17, 28,29). Results of the current study support the hypothesis that acute, not only chronic, traumatic stress may also correlate to hippocampal structural changes. The hippocampus is a brain structure involved in learning and memory, especially declarative memory (21). Using neuroimaging, we can understand how the hippocampus participates in the processes of declarative memory such as encoding and retrieving tasks (36–42). Several studies have examined hippocampal function in human declarative memory. Dolan and Fletcher’s study using fMRI supported the finding that the left anterior hippocampal response is sensitive to encoding demands and that the posterior parahippocampal response is sensitive to retrieval demands (36). Gron also reported the observation of left-sided anterior hippocampal activity during conditions of initial learning as well as maximum recall (37). In Kirwan’s study, the left hippocampus was activated during encoding tasks (38). Three recent neuroimaging studies also provide supportive evidence for hippocampal response to declarative memory in the human brain (39–41). Alkire reported hippocampal activity at encoding correlates with long-term free recall of nonemotional information (42). Alkire’s study used PET scanning, and there was a striking correlation (r = 0.91, P < 0.001) between activity of the left hippocampus and word recall. These findings provide evidence for hippocampal involvement in declarative memory encoding. Symptoms of PTSD show that there are 2 significant deficits of memory. One is a deficit of declarative memory such as diminished encoding or impaired retrieval abilities. The other is a deficit of nondeclarative memory such as intrusive memory or hyper activation of emotional memory (3,43). Many clinical and psychological studies indicate that the hippocampus is the key brain structure for the observed deficit in declarative memory in patients with PTSD (43–45). Owing to its glucocorticoid receptor sites, the hippocampus is the primary source of feedback for glucocorticoid regulation, which keeps cortisol levels within normal physiological range. This makes the hippocampus particularly sensitive to stress (46,47). Considered along with previous studies, the results of our study imply that hippocampal impairment provides an explanation for the declarative memory deficits of individuals with PTSD. In our study, deficits of the left hippocampus were found and in some neuroimaging studies, the left hippocampus as also found to correlate to declarative memory (36–38,42). Although results of previous neuroimaging studies and the current research show evidence of hippocampal structural changes in patients with PTSD, there is no clear causal relation between the hippocampus and PTSD. Remarkably, even when exposed to a similarly significant and stressful trauma (that is, a threat to the individual’s life or the life of his or her loved ones accompanied by intense fear, horror, or distress), only a small proportion of individuals develop symptoms of PTSD (2). Although the evidence is not significant enough to identify the cause, whether psychological (for example, ineffective coping style or inability to cope with stress) or biological (for example, gene disfigurement), of an individual’s vulnerability to PTSD following a traumatic stressor, some clinical and neuroimaging researchers have argued that it is possible that the hippocampal abnormality is a biological diathesis phenomenon of PTSD. For example, a neuroimaging study of monozygotic twins found that unexposed cotwins of veterans with PTSD had smaller hippocampal volumes, compared with the unexposed cotwins of veterans without PTSD (10). This study also mentioned that smaller hippocampal volume may predict pathologic vulnerability to psychological trauma. In addition to the evidence collected thus far, however, we also need to further investigate the possibility that these changes in hippocampal structure in individuals with PTSD may be the result of traumatic stressors, no matter how chronic they are or how recent their onset. First, animal studies have provided ample support for the hypothesis that the hippocampus may be impaired owing to high levels of glucocorticoid and that stress induces these high levels of glucocorticoid in the hippocampus (46,47). Second, a study on long-term treatment with paroxetine for patients with PTSD reported that hippocampal volume increased following the improvement of verbal declarative memory and PTSD symptoms (48). Third, the VBM results of our study demonstrate a reduction of hippocampal grey matter density in patients with PTSD. Interestingly, one study reported that training could induce grey matter changes (49). This implies that the hippocampal deficit in individuals with PTSD may be reversible. To account for the etiology of the hippocampus in PTSD, studies using long-term and medical treatment may be necessary. We are mindful of the fact that most neuroimaging studies, including our research, are cross-sectional in design and therefore unable to determine the origins or causal factors for hippocampal abnormality. Nonetheless, in the current study, 3 participants with PTSD have finished a 3-month treatment course, and their declarative memory performance, as well as the ratio of NAA/Cr in their left hippocampi, increased as their PTSD symptoms improved. Indeed, more cases are needed for future studies of this most interesting phenomenon. The present study has several limitations. The relatively small number of participants (n = 12 in each group) did not allow us to perform a random-effects analysis. Additionally, neuroimaging techniques remain central to our further understanding of the pathophysiology of PTSD and they are as yet far from direct clinical application. Only when a marker of brain structure or function definitely correlates to PTSD is it possible for neuroimaging to identify individuals at high risk or to confirm the diagnosis of this disorder. However, a design of new targets for therapeutic intervention with neuroimaging using fMRI, PET, or SPECT may offer the hope of clinical application. Studies using larger sample sizes and therapeutic intervention designs are a logical progression for future studies. In conclusion, using a combination of MRI and MRS, we found that fire victims with PTSD exhibited structural abnormalities in the left hippocampus. Future research should set out to investigate the causal relation between hippocampal changes and PTSD and to determine whether the hippocampus, together with other brain structures, is responsible for PTSD pathologies. Funding and SupportThis work was supported by a grant (30470621) from the National Natural Science Foundation of China, a grant (2006CB5000808) from the National 973 Program of China, and a grant (20030533022) from the National Ministry of Education of China. References1. Breslau N. Epidemiological studies of trauma, posttraumatic stress disorder, and other psychiatric disorders. Can J Psychiatry 2002;47: 923–9. 2. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52:1048–60. 3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Association; 1994. 4. Yehuda R. 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Why stress is bad for your brain. Science 1996;273:749–50. 48. Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 2003;54:693–702. 49. Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn V, May A. Change of grey matter induced by training. Nature 2004;427:311–2. Author(s)Manuscript received October 2005, revised, and accepted March 2006. 1. Professor, Mental Health Institute, The Second Xiangya Hospital, Central South University Changsha, Hunan, China. 2. Assistant Professor, Department of Radiation, The Second Xiangya Hospital, Central South University Changsha, Hunan, China. 3. Professor, Department of Clinical Psychology, The Seventh Hospital of Hang Zhou, Hangzhou, Zhejiang, China. 4. Professor, Key Laboratory of Animal Models and Human Disease Mechanisms and Laboratory of Learning and Memory, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, Yunan, China. Address for correspondence: Dr S Chen, Department of Clinical Psychology, The Seventh Hospital of Hangzhou, Hangzhou, Zhejiang 310013, PR China e-mail: shulinchen1990@yahoo.com.cn
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