Study Of Treatment Na(?)ve Posttraumatic Stress Disorder After Earthquake By Using Resting-state Functional MRI

Posttraumatic stress disorder(PTSD)is a common psychological disorder after severe mental stress or life event,which belongs to stress disorder.PTSD is the only one whose risk factor is obvious among all kinds of psychological diseases.In the year of 1980,Diagnostic and Statistical Manual of Mental Disorders(DSM-?)made PTSD as an official name for this stress disorder.According to DSM-?released in 2013,the main clusters of symptom of PTSD were hyperarousal,persistent re-experiencing of the trauma,avoidance of trauma-related stimuli,and negative alterations in cognitions and mood,with one more symptom cluster(the fourth one)than described in DSM-IV.PTSD has been a heavy burden for the society and economy.The exact etiology of PTSD is not clear to date.In the past decades,neuropsychological,endocrine,genetic,and molecular methods as well as structural and functional neuro-imaging methodologies had played pivotal role in uncovering the neurophysiological mechanism,deepened our understanding of PTSD from organ to cell and molecular level.However,one fundamental problem is still kept unsolved.That is why some people suffered PTSD after traumatic event while the others survived the same event was spared?One current answer is that PTSD is a result of genetic variation and environmental risk factors.The possible neuropathological mechanism are fear conditioning,the inhibition of fear memory extinction and fear memory consolidation.Neuroimaging methodology is playing an increasingly important role in seeking into neuropathological mechanism of PTSD,and providing powerful tools for the diagnosis,etiology research,and prognosis.Especially,in recent years,blood oxygen level dependent(BOLD)functional magnetic resonance imaging(fMRI)studies have been widely used in PTSD.BOLD signals are derived from intravenous magnetic sensitive contrast agent-deoxyhemoglobin.In the past 20 years,BOLD fMRI has been widely used in cognitive neuroscience and clinical applications:pre-surgical planning,evaluation of therapy,and diagnosis.BOLD fMRI studied mainly include two methods:task-related and resting-state.Task-related BOLD fMRI is widely used,however,this method is performed when a specific task or stimulus is fulfilled by a subject.In the year 1995,Biswal found spontaneous brain activity during resting state without a task or stimulus,which presented as a low frequence fluctuation(lower than 0.1 Hz).From then on,that study became a milestone of the blooming of BOLD fMRI-related research.Many advances of resting-state fMRI studies are:no need for task design,good compliance of the subject,and long-time acquisition of MR signals for sustained brain activity research.The two basic organization of human brain are segregation and integration.Methods depict segregation are:regional homogeneity(ReHo)and amplitude of low frequency fluctuation(ALFF)or fraction amplitude of low frequency fluctuation(fALFF).While methods describe integration are:functional connectivity(FC),effective connectivity(EC),and network analysis based on graph theory.Functional connectivity is the temporal correlation between different brain regions spatially apart without direction while the EC with a direction for causal relationship.The main methods to study FC include:? classical seed-based region of interest(ROI)analysis with prior hypothesis;?Independent Component Analysis(ICA)which is a data-driven method without a prior hypothesis.The commonly used method for EC is Granger causality analysis.Large-range network analysis based on graph theory could view from a whole brain aspect to detect the pathological and physiological mechanism of signal processing.The widely and intensely usage of BOLD fMRI methods,especially resting-state fMRI,deepen our understanding of the neuro-circuit of amygdale-prefrontal cortex-hippocampus.In the further,by puring the study subjects,applying more subtle templates,more rigorous study design and meta analysis we can get more valid and reliable results and information about the PTST etiology.Recently,there is no clinically used and widely accepted method for the diagnosis of PTSD.The method commonly used for research is a diagnosis based on symptom severity and clinical experience.This diagnosis dramatically relies on the subjective neuropsychological tests and the experience of the doctor.Although researchers have always seeking for an objective and reliable biomarker for the diagnosis of PTSD,this aim is still unreached.Neuroimaging research can apply many objective neuroimging biomarker for PTSD,nevertheless,by summarizing sums of existing studies,we find that a single method or a single biomarker might be not adequate for the diagnosis.Based on the notion that brain disease is caused by abnormal brain FC,we design a series of studies by using resting-state BOLD fMRI FC to seek for a group of subject neuroimaging biomarkers for the diagnosis of PTSD.The design includes three part as follows:Part One.The FCD Analysis of Treatment Naive PTSD afterEarthquakeObjective:To study the FCD alteration of treatment naive PTSD after the earthquakeMaterials and methods:All the participants were victims suffered from the 8.0 magnitude earthquake in Wenchuan,China on May 12,2008.All of them were informed about the study and all the informed consents were received.This study got approval from ethics committee.By using the Clinician-Administered PTSD Scale(CAPS)the symptom severity was scored.By using Structured Clinical Interview for DSM-IV axis I Disorders(SCID-?),the diagnosis of PTSD was established.Totally,72 cases of PTSD(male 19,female 53)participated the routine and resting-state MR scan by using GE Signa EXCITE 3.0T MR scanner.Resting-state fMRI data was preprocessed and calculated to generate FCD maps.By using SPM8(http://www.fil.ion.ucl.ac.uk/spm)software,we compared the FCD alteration between PTSD and traumatic group.By using SPSS 20.0 version(IBM Inc.Armonk,NY)software,we analyzed the correlation between FCD and PTSD symptomatic scores.The diagnosis efficacy was analyzed by using receiver operator characteristic curve(ROC).Results:Compared with non-PTSD,the PTSD group showed increased global and long-range FCD in bilateral middle cingulate cortex,and decreased global and long-range FCD in middle temporal gyrus and fusiform.In addition,increased long-range FCD in the left insular and inferior parietal lobule can also be found in PTSD group.PTSD patients showed increased short-range FCD in left hemisphere and right insular(anterior part)and inferior frontal gyrus,while the decreased short-range FCD mainly located in bilateral temporal gyri and occipital gyri and right posterior insular.We also found short-range FCD in the left superior and middle occipital gyri showed moderate diagnostic efficacy with an area under the curve(AUC)equaled to 0.71(95%CI=0.62-0.80).The long-range FCD in right superior and middle temporal gyri correlate negatively with intrusion and arousal symptoms.The short-range FCD in the left middle/inferior temporal gyrus and lingual gyrus correlated negatively to arousal and avoidance symptoms respectively.The short-range FCD in the calcarine correlated positively with arousal.Conclusion:This study used a graph theory-based,bias-free FC method to compare the alteration of FCD in PTSD after the earthquake and non-PTSD and found many alteration of global FCD,long-and short-range FCD in various brain regions.And many of them correlated with PTSD symptom scores.The decrease of long-range FCD in right superior/middle temporal gyri and short-range FCD in left inferior/middle temporal gyri and right lingual gyrus might underlie PTSD etiology.In addition,the short-range FCD in the left superior and middle occipital gyri showed moderate diagnostic efficacy.Part Two.Altered Connectivity-Amplitude in Treatment Naive PTSD after EarthquakeObjective:To explore alterations of coupling between amplitude of low frequency fluctuation(ALFF)and functional connectivity density(FCD)in treatment naive posttraumatic stress disorder(PTSD)by using resting-state functional MR imaging(rs-fMRI).Materials and methods:This study was approved by the institutional ethical review board,and all participants signed written informed consent.Sixty two PTSD patients and 62 matched traumatic controls underwent rs-fMRI scanning.The correlation analysis between FCD and ALFF was conducted to assess the imaging coupling.The combination of FCD and ALFF was generated to investigate its potential to improve the diagnostic accuracy of detecting PTSD patients.Pearson correlation analysis was performed to correlate imaging variables to neuropsychological data in PTSD patients.Results:Combination of FCD and ALFF could generate synergetic effect on diagnosing and investigating PTSD.Compared with Non-PTSD,FCD increased in dACC(dorsal anterior cingulate cortex)and ALFF decreased.Both FCD and ALFF were decreased in the right fusiform and right MTG(middle temporal gyrus).FCD-ALFF in dACC(AUC=0.73,P<0.01,95%CI=0.64-0.82)increased the image contrast and diagnostic efficiency,which was higher than solely used FCD or ALFF.FCD+ALFF in the right fusiform(AUC=0.70,P<0.01,95%CI=0.62-0.79)and right MTG(AUC=0.72,P<0.01,95%CI=0.63-0.81)increased diagnostic efficiency than solely used FCD or ALFF.The coupling strength between FCD and ALFF was decreased in dACC in PTSD patients.Negative correlation was found between FCD,ALFF and FCD+ALFF values in the right MTG and arousal score.Positive correlation was found between ALFF in dACC and intrusion score.Conclusion:Combining application of FCD and ALFF exerted synergetic effect on investigating PTSD with better diagnostic efficiency and more comprehensiveunderstanding of the neurophysiological mechanism of PTSD.Part Three.Altered Default Mode Network Configuration in Treatment Naive PTSD after EarthquakeObjective:The aim of this study was to assess the topological reconfiguration of the brain default mode network(DMN)in patients with treatment naive posttraumatic stress disorder(PTSD)using resting-state functional magnetic resonance imaging(rs-fMRI).Materials and methods:With approval by our ethics committee,rs-fMRI was performed in 62 PTSD patients and 62 age,gender,and education level matched traumatic controls who had suffered the same earthquake in the year 2008 without PTSD.The DMN was constructed according to the seeds released by the FIND laboratory.FC across all pairs of DMN seeds was calculated as the DMN network edges.All the seeds and edges constructed a weighted DMN which was further analyzed by using graph theoretical approaches.Pearson correlation was performed between abnormal DMN inter-seeds FC strength and network metrics and neuropsychological scores in PTSD patients.Results:Compared to non-PTSD,patients with PTSD showed decreased DMN functional connectivity(FC)between the right superior frontal gyrus and left inferior parietal lobule(IPL)(BA39),and showed increased FC between the right IPL(BA40)and precuneus(BA31)and left posterior cingulate cortex.It was also found that decreased nodal efficiency located in the right superior frontal gyrus and precuneus(dorsal part of BA7),while the increased nodal strength in the right hippocampus and parahippocampus.In addition,the functional connectivity strength between the right IPL(BA40)and precuneus(BA31)correlated negatively to the avoid scores(r=-0.26,P=0.04).Conclusion:Compared to non-PTSD,DMN inter-seeds FC strength and nodal topological characters were altered in PTSD patients.The increased functional connectivity strength between the right IPL(BA40)and precuneus(BA31)might be part of the mechanism underlying avoid syndrome of PTSD.