Neural Dysregulation in Posttraumatic Stress Disorder: Evidence for DisruptedEquilibrium Between Salience and Default Mode Brain NetworksREBECCA K. SRIPADA, MS, ANTHONY P. KING, PHD, ROBERT C. WELSH, PHD, SARAH N. GARFINKEL, PHD, XIN WANG, MD,CHANDRA S. SRIPADA, MD, AND ISRAEL LIBERZON, MD

Objective: Convergent research demonstrates disrupted attention and heightened threat sensitivity in posttraumatic stress disorder(PTSD). This might be linked to aberrations in large-scale networks subserving the detection of salient stimuli (i.e., the saliencenetwork [SN]) and stimulus-independent, internally focused thought (i.e., the default mode network [DMN]).Methods: Resting-statebrain activity was measured in returning veterans with and without PTSD (n = 15 in each group) and in healthy community controls (n =15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions and all other voxels ofthe brain. Results: Compared with control groups, participants with PTSD showed reduced functional connectivity within the DMN(between DMN seeds and other DMN regions) including the rostral anterior cingulate cortex/ventromedial prefrontal cortex (z = 3.31; p =.005, corrected) and increased connectivity within the SN (between insula seeds and other SN regions) including the amygdala (z =3.03; p = .01, corrected). Participants with PTSD also demonstrated increased cross-network connectivity. DMN seeds exhibitedelevated connectivity with SN regions including the insula (z = 3.06; p = .03, corrected), and SN seeds exhibited elevated connectivitywith DMN regions including the hippocampus (z = 3.10; p = .048, corrected). Conclusions: During resting-state scanning, partici-pants with PTSD showed reduced coupling within the DMN, greater coupling within the SN, and increased coupling between the DMNand the SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-free conditions. Disequi-librium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSDpathophysiology. Key words: PTSD, default mode network, salience network, functional connectivity, resting state, fMRI.

PTSD = posttraumatic stress disorder; vmPFC = ventromedialprefrontal cortex; ICN = intrinsic connectivity networks; DMN =default mode network; PCC = posterior cingulate cortex; CEN =central executive network; SN = salience network; OEF = OperationEnduring Freedom; OIF = Operation Iraqi Freedom; CAPS =Clinician-Administered PTSD Scale; fMRI = functional magneticresonance imaging; ACC = anterior cingulate cortex; SVC = smallvolume correction; ROI = region of interest.

INTRODUCTION

Posttraumatic stress disorder (PTSD) is a debilitating psy-chiatric disorder characterized by reexperiencing, avoid-

ance, and hyperarousal symptoms (1). These symptoms havebeen linked to deficits in attentional control (2Y4), threat sen-sitivity (5Y7), episodic memory (8Y10), and fear extinction(11,12), functions subserved by corticosubcortical circuits in-volving the amygdala, insula, ventromedial prefrontal cortex(vmPFC), and hippocampus (13,14). Although the activation

patterns of these regions have been examined extensively in thepast, identifying dysregulated patterns of connectivity betweenthese regions could shed important and unique light on thebrain basis of PTSD (15,16) and on previously unexplainedmechanisms of PTSD symptom development.

Regions implicated in PTSD (e.g., insula, amygdala, vmPFC,and hippocampus) are key nodes in several major intrinsicconnectivity networks (ICNs). ICNs are large-scale networksidentified by connectivity methods that are associated withcharacteristic functions (17,18), are stable across tasks (19,20)and over time (21,22), correspond to anatomical white mattertracts (23), and demonstrate direct behavioral correlates (24Y26).The insula and amygdala, which have been found to be hyper-active in PTSD (15,16), are involved in the salience network(SN), an ICN responsible for detecting and orienting to salientstimuli (27Y30). A second important ICN, the default modenetwork (DMN), is associated with stimulus-independent, inter-nally focused thought and autobiographical memory (31Y33).The vmPFC and hippocampus, regions reported to be hypoactivein PTSD during specific tasks (16), along with the posteriorcingulate cortex (PCC), are core components of this network(17,28). A third ICN, the central executive network (CEN),encompasses the dorsolateral prefrontal cortex and lateral parietalregions. This network is associated with goal-directed behaviorand high-level cognitive functions including planning, decisionmaking, and working memory (27,30). It has been suggested thatthe SN ‘‘arbitrates’’ between the DMN and the CEN (34). SNregions assess the significance or salience of stimuli the organismencounters and help to maintain an adaptive balance betweeninternal mentation and externally oriented focus and taskexecution.

Recently, functional connectivity analyses have begun tobe used to probe network-level function in PTSD. Duringtask-based studies, patients with PTSD show exaggeratedconnectivity within DMN regions and reduced connectivitywithin SN and CEN regions (35). These relationships might

904 Psychosomatic Medicine 74:904Y911 (2012)0033-3174/12/7409Y0904Copyright * 2012 by the American Psychosomatic Society

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

From the Departments of Psychology (R.K.S., I.L.), Psychiatry (R.K.S.,A.P.K., R.C.W., X.W., C.S.S., I.L.), Radiology (R.C.W.), University of Michigan,Ann Arbor, Michigan; Ann Arbor VA Medical Center (I.L.), Ann Arbor,Michigan; and Brighton and Sussex Medical School (S.N.G.), Brighton, UK.

Address correspondence and reprint requests to Rebecca K. Sripada, MS,4250 Plymouth Rd, 2702 Rachel Upjohn Bldg, Ann Arbor, MI 48109. E-mail:rekaufma@umich.edu

The research reported in this article was supported by grants from the Na-tional Institute of Mental Health (R24 MH075999; to I.L.), from the Tele-medicine and Advanced Technology Research Center (W81XWH-08-2-0208;to I.L. and A.K.), from the Michigan Institute for Clinical and Health Research(U028028; to S.G.), and from the University of Michigan Center for Compu-tational Medicine and Bioinformatics Pilot Grant Program (to A.K.).

Supplemental digital content is available for this article. Direct URL citationsappear in the printed text and are provided in the HTML and PDF versionsofthis article on the journal’s Web site (www.psychosomaticmedicine.org).

Financial disclosures: All authors report no biomedical financial interests orpotential conflicts of interest.

Received for publication May 9, 2012; revision received August 29, 2012.DOI: 10.1097/PSY.0b013e318273bf33

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

potentially be better assessed, however, through connectivityanalyses at rest, without the confounds of tasks that may bebiased to elicit amygdala activity or provoke PTSD symp-toms. Resting-state connectivity offers a powerful way toassess intrinsic connections between brain networks (17,36,37),which, in turn, have been linked to important functions such asprocessing speed (26) and cognitive flexibility (38) in health andin disease. During rest, disrupted connectivity within the DMNand SN has been reported in PTSD (39Y44) and acute stressdisorder (45,46). However, no research to date has used the ICNframework to investigate the relationship between the DMN, theSN, and the CEN at rest in PTSD. Identifying abnormal inter-relationships between these networks could illuminate the dis-ruptions in attention regulation and balance of internal/externalsensitivity characteristically found in PTSD, including abnor-malities underlying symptoms of hyperarousal.

Given the findings that patients with PTSD show alterationsin functions linked to the DMN and SN, we hypothesizeddisruptions in the balance between these networks in task-freeresting-state, when the DMN is typically active and the SN andCEN are quiescent. Given the aberrations in episodic memoryin PTSD, we hypothesized a reduced connectivity within theDMN. Given the heightened threat sensitivity, impaired atten-tional control, and hyperarousal in PTSD, functions associatedwith SN connectivity (27,47,48), we hypothesized increasedconnectivity within the SN and reduced segregation (i.e., in-creased cross-network connectivity) between DMN regions andSN regions.

METHODS AND MATERIALSParticipantsWe recruited study participants from among veterans returning from de-

ployments to Afghanistan (Operation Enduring Freedom, or OEF) and Iraq(Operation Iraqi Freedom, or OIF) with a current PTSD diagnosis and seekingtreatment for PTSD at the Veterans Affairs (VA) Ann Arbor Healthcare System(n = 15), along with veterans without PTSD (combat-exposed controls; n = 15)and 15 healthy controls from the community. All procedures took place betweenAugust 2008 and July 2010. Healthy controls and combat controls (veterans ofOEF and OIF without PTSD) were recruited from the community via adver-tisement. All participants received comprehensive psychiatric assessment withthe Mini-International Neuropsychiatric Interview (49), which contains a PTSDmodule and self-report instruments. Combat veterans also received the Clinician-Administered PTSD Scale (CAPS) (50). Clinical interviews were performed byexperienced masters- or doctoral-level clinicians with extensive training in theCAPS, at a subspecialty clinic specializing in PTSD. Participants with PTSDwereprovided with the opportunity to participate in research at the time of their initial

VA visit, and all interested eligible participants were included in the study. Allparticipants in the PTSD group met the Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition criteria for current (past month) PTSD. Allcombat exposure (including index trauma for participants with PTSD) tookplace within the past 5 years. Exclusion criteria were as follows: a) psychosis,b) history of traumatic brain injury, c) alcohol or substance abuse or dependencein the past 3 months, d) any psychoactive medication other than sleep aids,e) left-handedness, f) presence of ferrous-containing metals within the body, andg) claustrophobia. Control groups included only participants without Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition psychiatric diag-noses, and the healthy community control group included only participants whohad not experienced a traumatic event. The demographic and clinical character-istics of the participants are shown in Table 1. All participants were right-handedmen between 21 and 37 years old. Seven participants in the PTSD group also metthe diagnostic criteria for comorbid depression, and 1 had comorbid panic disor-der; however, in no case could comorbid diagnosis be considered primary, that is,preceding PTSD. Two participants with PTSDwere using low-dose trazodone as asleep aid; no other psychiatric medications were permitted. After a completedescription of the study was provided to the participants, written informed consentwas obtained. The study was approved by the institutional review boards of theUniversity of Michigan Medical School and the Ann Arbor VA Healthcare System.

Resting-State ParadigmThe participants underwent structural magnetic resonance imaging (MRI)

and functional MRI (fMRI) scanning that included resting-state procedures andemotion regulation and conditioning tasks. Reports on emotion regulation andconditioning tasks are forthcoming; a report of amygdala-seed resting-statefunctional connectivity has been previously published (43). Resting-state scansalways occurred before tasks. A black fixation cross on a white background wasdisplayed at the center of the screen for 10 minutes. The participants wereinstructed to relax and keep their eyes open and fixed on the cross. To controlfor physiological variation, multiple regression analysis was used to remove theeffects of cardiac and respiratory signals (51).

Data AnalysisScans were collected on a 3.0-T General Electric Signa Excite scanner

(Milwaukee, WI). Further details are provided in Supplemental Digital Content1 (SDC1; http://links.lww.com/PSYMED/A51). Default mode regions of in-terest (ROIs) (PCC and vmPFC) were 10-mm-radius spheres centered at(0,j56,20) for PCC and (j2,48,j4) for vmPFC. These seed regions wereadopted from previous studies of the DMN in participants with PTSD (40,45)and schizophrenia (52) and healthy controls (17). SN ROIs (bilateral anteriorinsula) were partitioned from a whole insula mask using a linear interpolationbased on the location of the middle insular gyrus, following Aupperle and col-leagues (53). We extracted spatially averaged time series from each ROI for eachparticipant. Average blood-oxygen-level-dependent (BOLD) time series fromparticipant-specific structural MRI-derived white matter and cerebrospinal fluidmasks were added to the model as nuisance covariates to control for nonspecificglobal sources of noise associatedwithBOLD fMRI scanning.We did not performglobal-signal regression because it had been suggested that this may producespurious anticorrelationwith orthogonal networks that increase in proportion to thesize of those networks (54). Resting-state functional connectivity measures low-frequency spontaneous BOLD oscillations (0.01- to 0.10-Hz band) (17); thus,the time course for each voxel was band-pass filtered in this range. Pearson

TABLE 1. Demographic and Clinical Characteristics of Participants

Characteristic PTSD (n = 15) CC (n = 15) HC (n = 15) F/W2 p

Age, M (SD) 27.3 (4.5) 26.6 (3.3) 26 (5.9) 0.26 .77

Race 12W, 1A, 1AA, 1H 13W, 1AA, 1H 12W, 1A, 1AA, 1H 4.05 .85

Marital status (Married/Single) 10/5 6/9 4/11 5.04 .08

CAPS, M (SD) 75.9 (17.2) 10.9 (7.7) N/A 12.9 G.001

PTSD = posttraumatic stress disorder; CC = combat-exposed control; HC = healthy community control; F = analysis of variance F test; W2, chi-square test; M = mean;SD = standard deviation; W = white; A = Asian; AA = African American; H = Hispanic; CAPS = Clinician-Administered PTSD Scale; N/A = not applicable.

DISRUPTED INTRINSIC CONNECTIVITY NETWORKS IN PTSD

Psychosomatic Medicine 74:904Y911 (2012) 905

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

product-moment correlation coefficients were calculated between average timecourses in the seed ROIs and all other voxels of the brain, resulting in a three-dimensional correlation coefficient image (r-image). Both positive correlationsand anticorrelations were computed. These r-images were then transformed to zscores using a Fisher r-to-z transformation (55).

z-Score images from the individual functional connectivity analyses wereentered into second-level random-effects analyses (one-sample and two-samplet tests) implemented in SPM5. Second-level maps were thresholded at p G .001,uncorrected (extent threshold, k = 10). In addition, ROI analysis with smallvolume correction (SVC) was conducted. A priori ROIs including the amygdala(k = 93), hippocampus (k = 252), anterior cingulate cortex (ACC; k = 838), andinsula (k = 499) were used as masks because these regions are of interestin PTSD (15,16). Images were thresholded using a voxel-wise threshold ofp G .005, uncorrected with a minimum cluster size of 3 connected voxels (foramygdala clusters), 4 connected voxels (for hippocampus clusters), 6 connectedvoxels (for insula clusters), and 12 connected voxels (for ACC clusters). Thesecombinations of activation threshold and cluster size were determined usingAlphaSim (56) to correspond to a false-positive rate of p G .05, corrected formultiple comparisons within ROIs. Using the thresholds and cluster sizes de-fined earlier, the corrected voxel-wise probabilities are as follows: amygdala,p G .0016; hippocampus, p G .00098; insula, p G .00045; and ACC, p G .00072.Only the activations within the ROIs that survived the voxel correction criteriawere extracted and used for further analysis. Connectivity foci were labeled bycomparison with the neuroanatomical atlas by Talairach and Tournoux (57).Reported voxel coordinates correspond to standardized Montreal NeurologicInstitute space. To assess for correlations with symptom severity, CAPS scoreswere added as regressors in a separate whole-brain analysis of connectivitybetween seed regions and ROIs, corrected for multiple comparisons across fourseed regions. Finally, we conducted an exploratory conjunction analysis (58) todetermine whether regions of group difference with one ICN seed region showedoverlap with the other ICN (e.g., regions of differential group connectivity withDMN seed regions falling within SN, and vice versa).

Motion parameters (maximum displacement, mean displacement, maximumangle, mean angle) were compared via independent-samples Kruskal-Wallis tests.

RESULTSParticipantsAlthough levels of combat exposure were not different in the

returning veterans with and without PTSD, PTSD symptoms(CAPS scores) in the healthy combat-exposed control groupwere low and significantly lower than those in the PTSD group.Groups did not differ by age or race; however, there was a trendfor marital status such that participants with PTSD were morelikely to be married than healthy community or combat controls(p = .08; see Table 1).

MotionThere were no movements greater than 3 mm and no motion

differences between groups (in all cases, p 9 .2).

fMRI FindingsIn the following paragraphs, we focus on comparisons be-

tween the PTSD group and the combat-exposed controls andhealthy community controls combined (‘‘controls’’). Of note,single-group results and two-group comparisons between thePTSD group and individual control groups are presented inSDC1, Tables S1 through S5.

PTSD Versus ControlsPosterior Cingulate Cortex

In comparison with controls, participants with PTSD showedgreater functional connectivity between the PCC seed and the

right putamen ([24,j9,3]; k = 30; z = 4.13; p G .001) and rightinsula ( [39,15, j3], k = 6, z = 3.06, p = .03, SVC). Comparedwith participants with PTSD, the controls showed greater con-nectivity between the PCC seed and the left hippocampusat trend level ([j27,j15,j18], k = 5, z = 2.58, p = .005; seeFigs. 1 and 2; Table 2).

Ventromedial Prefrontal Cortex

Compared with controls, participants with PTSD showedgreater functional connectivity between the vmPFC seed andthe precentral sulcus/supplementary motor area ([15,j15,72],k = 26, z = 4.08, p G .001), right precentral gyrus ([54,j12,27],k = 12, z = 3.7, p G .001), and bilateral superior temporal sulcus([j51,j66,12], k = 12, z = 3.51; [48,j57,12], k = 13, z = 4.15;p G .001). Compared with participants with PTSD, the controlsshowed greater connectivity between the vmPFC seed and therostral ACC ([j12,27,27], k = 20, z = 3.31, p = .005, SVC; seeFig. 2; Table 2).

Left Anterior Insula

Compared with controls, participants with PTSD showedgreater functional connectivity between the left anterior in-sula seed and the left peri-insula/superior temporal gyrus([j48,j33,21], k = 11, z = 3.54, p G .001), right hippocampus([36,j12,j15], k = 12, z = 3.10, p = .048, SVC), and rightamygdala ([24,6,j18], k = 5, z = 3.03, p = .01, SVC; see Fig. 2;

Figure 1. Functional connectivity analysis. Statistical significance (color-codedt score) of resting-state functional connectivity patterns for default mode net-work (PCC seed and vmPFC seed) and salience network (left anterior insulaseed and right anterior insula seed) for 15 participants with PTSD and 30controls (15 combat-exposed controls and 15 healthy community controls).PCC = posterior cingulate cortex; vmPFC = ventromedial prefrontal cortex;PTSD = posttraumatic stress disorder; L insula = left insula; R insula = rightinsula. To view image in color, please visit: www.psychosomaticmedicine.org.

R. K. SRIPADA et al.

906 Psychosomatic Medicine 74:904Y911 (2012)

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

Table 2). For the left anterior insula, the controls did not showsignificantly greater functional connectivity than did partici-pants with PTSD in any regions.

Right Anterior Insula

There were no significant group differences in the rightanterior insula connectivity between the PTSD group and thecombined control group. Please see SDC1 for comparisonswith individual control groups.

Correlations With Symptom SeverityPosterior Cingulate Cortex

Within the PTSD group, functional connectivity between thePCC seed and the precentral sulcus was positively correlatedwith symptom severity as measured by the CAPS ([j9,j6,72],k = 7, z = 3.79, r = 0.88, p G .001; corrected for comparisons atmultiple seed regions) and CAPS subscales (intrusive subscale:r = 0.72, p = .009; avoidance subscale: r = 0.64, p = .03;hyperarousal subscale: r = 0.69, p = .01).

Ventromedial Prefrontal Cortex

Within the PTSD group, functional connectivity between thevmPFC seed and the left hippocampus was negatively corre-lated with total CAPS score ([j33,j21,j12], k = 12, z = 3.9,r = j0.89, p G .001; corrected for multiple comparisons) andCAPS subscales (Intrusive subscale: r = j0.71, p = .004;

avoidance subscale: r = j0.68, p = .007; hyperarousal sub-scale: r = j0.75, p = .002).

Left Anterior Insula

There were no significant correlations between left anteriorinsula connectivity and total CAPS score in the PTSD group.

Right Anterior Insula

Within the PTSD group, functional connectivity between theright anterior insula seed and the right peri-insula/rolandicoperculum was positively correlated with symptom severity asmeasured by the CAPS ([57,j6,18], k = 6, z = 4.47, r = 0.67,p G .001; corrected for multiple comparisons) and CAPS sub-scales (intrusive subscale: r = .6, p = 0.02; avoidance subscale:r = 0.56, p = .04).

Conjunction AnalysisA conjunction analysis was performed comparing the map

of functional connectivity with a PCC seed, participants withPTSD 9 controls, and control group connectivity with an anteriorinsula seed. Results showed an overlap in the right putamen([27,j6,3], k = 30) and right thalamus ([9,j21,6], k = 18).

Functional connectivity with a vmPFC seed, participantswith PTSD 9 controls, was compared with a map of controlgroup connectivity with an anterior insula seed. Results showedan overlap in the precentral sulcus ([18,j12,72], k = 8), right

Figure 2. Group comparison. A, Compared with controls, participants with PTSD showed greater connectivity between the posterior cingulate cortex (PCC; seedregion shown in panel A) and the right putamen (column 2; y =j4) and right insula (column 3; z = 2) and a trend for less connectivity between the PCC seed and theleft hippocampus (column 4; x =j27). B, Compared with controls, participants with PTSD showed greater connectivity between the ventromedial prefrontal cortex(vmPFC; seed region shown in panel B) and the supplementary motor area (column 2; x = 5) and bilateral superior temporal sulcus (column 3; z = 11) and lessconnectivity between the vmPFC seed and the rostral anterior cingulate cortex (column 4; x = j10). C, Compared with controls, participants with PTSD showedgreater connectivity between the left anterior insula (= seed region shown in panel C) and the right amygdala (column 2; y = 8), the left peri-insula (column 3; z = 21)and the right hippocampus (column 4; x = 37). PTSD = posttraumatic stress disorder; PCC = posterior cingulate cortex; vmPFC = ventromedial prefrontal cortex;L insula = left insula. To view image in color, please visit: www.psychosomaticmedicine.org.

DISRUPTED INTRINSIC CONNECTIVITY NETWORKS IN PTSD

Psychosomatic Medicine 74:904Y911 (2012) 907

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

superior temporal sulcus ([51,j54,9], k = 7), and left superiortemporal sulcus ([j51,j60,9], k = 8).

DISCUSSIONIn this study, we investigated patterns of resting-state DMN

and SN functional connectivity, comparing military combatveterans deployed to Iraq or Afghanistan (OEF/OIF) withPTSD versus OEF/OIF combat-exposed healthy veterans andhealthy community controls. To our knowledge, this is the firststudy to systematically examine the relationship between theSN and DMN ICNs in PTSD during rest and the first to ex-amine resting-state DMN functional connectivity in combatveterans. Overall, we found reduced connectivity within theDMN, increased connectivity within the SN, and increasedconnectivity between DMN regions and SN regions in partici-

pants with PTSD. The results suggest a possible brain basis forexaggerated attention to external stimuli, potentially contributingto hypervigilance and hyperarousal symptoms of PTSD.

Our within-group findings (presented in SDC1) are highlyconsistent with existing models of DMN and SN functionalconnectivity (17,31,32,37). We found strong functional con-nectivity in healthy control groups (i.e., combat controls andcommunity controls) between PCC and vmPFC seeds and otherDMN regions including the angular gyrus, lateral temporallobe, and hippocampus. The DMN is associated with stimulus-independent thought, including spontaneous cognition, autobio-graphical memory, and mind wandering (59); thus, this networkis active during nonstructured tasks. DMN seed regions alsoshowed expected anticorrelation with regions of the SN (in-cluding the insula, inferior frontal gyrus, and supplementarymotor area) (27). Our analysis also revealed high functionalconnectivity between SN seeds (bilateral anterior insula) andother SN regions including the dorsal ACC/supplementary motorarea, amygdala, and striatum, along with anticorrelation betweenSN seeds and DMN regions including PCC, vmPFC, and hip-pocampus. The SN is associated with attention to external stim-uli, and although the SN is coactive with DMN during certaintasks (60), it typically anticorrelates with DMN during rest(17,61,62). Our results thus confirm existing models that suggestthat rest and other nonstructured activities require deactivationof attentional and executive processes reflected by anticorrela-tion between the DMN and the SN.

Compared with control groups, participants with PTSDshowed reduced functional connectivity between DMN seedsand other DMN regions including the rostral ACC/vmPFC andhippocampus, consistent with a previous study in PTSD (40)and another study in obsessive-compulsive disorder (63). Theseregions are also hypoactive in PTSD during tasks (16) includ-ing script-driven imagery and trauma-relevant and trauma-irrelevant negative stimuli (15). Thus, our results suggest thatregions underactive in PTSD in a variety of task-based contextsalso fail to incorporate into resting-state networks, potentiallyindicating more general disruptions in self-referential thoughtin PTSD. Our findings add to a growing body of evidencesuggesting that in PTSD, there is weakened DMN functionalintegration during resting state (40,41,46) and alterations inDMN function more generally (35,39). Although the implica-tions of this dysfunction remain to be further investigated, itmay suggest that default mode functioning is hampered byhyperarousal and avoidance or that abnormal interconnected-ness between DMN and SN contributes to these symptoms.Indeed, within our PTSD sample, less DMN connectivity tohippocampus was associated with higher CAPS score (totalscore, as well as reexperiencing, avoidance, and hyperarousalsubscales). Thus, reduced cohesiveness of the DMN may beassociated with greater symptom severity in PTSD.

Participants with PTSD also demonstrated greater functionalconnectivity between SN seeds and other SN regions includingthe insula, peri-insula, and amygdala. The SN is associated withhomeostatic regulation and interoceptive, autonomic, and rewardprocessing (27,28,34,64), functions known to be dysregulated in

TABLE 2. Connectivity Results From Two-Sample t Test Comparisonof PTSD (n = 15) Versus Both Combat-Exposed Controls (n = 15)

and Healthy Community Controls (n = 15)

Contrast Map and Brain RegionClusterSize

MNICoordinates

(x,y,z)Analysis

(z)

PCC PTSD 9 controls

Right putamen 30 24,j9,3 4.13

Right insulaa 7 33,3,6 3.41

PCC controls 9 PTSD

Left hippocampusb 5 j27,j15,j18 2.58

vmPFC PTSD 9 controls

Right superior temporal sulcus 13 48,j57,12 4.15

Precentral sulcus/supplementarymotor area

26 15,j15,72 4.08

Right precentral gyrus 12 54,j12,27 3.7

Left superior temporal sulcus 12 j51,j66,12 3.51

vmPFC controls 9 PTSD

Rostral anterior cingulatecortex/vmPFC

20 j12,27,27 3.31

Left anterior insula PTSD 9 controls

Left peri-insula/superiortemporal gyrus

11 j48,j33,21 3.54

Right hippocampus 12 36,j12,j15 3.10

Right amygdala 5 24,6,j18 3.03

Left anterior insula controls 9 PTSD

No clusters greater than 10 voxels

Right anterior insula PTSD 9 controls

No clusters greater than 10 voxels

Right anterior insula controls 9 PTSD

No clusters greater than 10 voxels

PTSD = posttraumatic stress disorder; MNI = Montreal Neurologic Institute;PCC = posterior cingulate cortex; vmPFC = ventromedial prefrontal cortex.A priori regions of interest (ROIs) in bold.a Significant at p G .05, corrected for multiple voxel-wise comparisons acrossthe ROIs. All other activations are presented at p G .001 (uncorrected) with acluster extent threshold of at least 10 contiguous voxels.b p = .005.

R. K. SRIPADA et al.

908 Psychosomatic Medicine 74:904Y911 (2012)

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

anxiety disorders (65,66). Greater within-SN connectivity mayreflect exaggerated sustained attention to extraneous stimuli. Inactivation studies, co-occurring increases in insula and amygdalaactivity are greater in PTSD than in control groups during traumareminders (67) and fear acquisition (68), and a recent meta-analysis confirms patterns of disrupted DMN and SN in PTSDduring structured tasks (69). Recently, we have reported thatindividuals with PTSD show greater intrinsic connectivity be-tween the amygdala and the insula at rest (43), potentiallyreflecting a tighter functional link between visceral perceptionand emotional response. Our findings complement those ofDaniels and colleagues (35), who report ICN alterations in PTSDduring a working memory task. However, although Danielset al. reported decreased within-network SN connectivity andincreased within-network DMN connectivity during task, wefound increased within-network SN connectivity and decreasedwithin-network DMN connectivity during rest. This discrepancymight reflect differences in the balance between ICNs duringcognitively demanding tasks (where CEN and SN are predomi-nant) versus rest (where DMN is predominant). Thus, the studyof Daniels and colleagues and our own both suggest aberrantICN activity in PTSD. In our analysis, greater functional con-nectivity between SN seed regions and the peri-insula/operculumwas associated with higher CAPS score, further supporting thehypothesis that pervasive SN activity during task-free states maybe involved in PTSD psychopathology.

In addition to weakened within-network DMN connectivityand exaggerated within-network SN connectivity, participantswith PTSD also demonstrated increased cross-network con-nectivity between DMN regions and SN regions. In PTSD, ascompared with controls, SN seed regions showed increasedconnectivity to the left hippocampus, part of the DMN. In turn,DMN seed regions showed increased connectivity to SN regionsof the insula, putamen, and supplementary motor area, as well asposterior superior temporal sulcus. The superior temporal sulcus,although not previously implicated in the SN, is an associativearea that shows strong resting-state functional connectivity withSN regions including the supplementary motor area, insula, andstriatum (70); thus, it may contribute to SN function. A con-junction analysis confirmed that regions showing exaggeratedconnectivity with DMN in PTSD were constituents of the SNin the control groups. Enhanced cross-network connectivity inPTSD between the DMN and regions of the SN has also beenshown in prior studies. For example, elevated connectivity inPTSD has been observed between the thalamus (a key SN node)and the DMN (71). In addition, enhanced connectivity betweenthe DMN and the amygdala predicted the development of PTSDsymptoms in acutely traumatized individuals (45), and enhancedconnectivity between the DMN and the insula was associatedwith higher self-report anxiety (72).

The SN supports monitoring of salient cognitive, homeo-static, or emotional events and is typically anticorrelated withDMN during rest (27,73). Thus, our results indicate a disrup-tion of equilibrium between these networks, or diminishednetwork segregation. In particular, the coactivation of the SNwith DMN might reflect sustained and likely inappropriate

activation of SN during periods of rest, when this network istypically quiescent. This finding may reflect or help to explainsustained hypervigilance and hyperarousal in patients withPTSD. Indeed, in our sample, greater functional connectivitybetween DMN seeds and supplementary motor area, an im-portant node in the SN network, was correlated with enhancedhyperarousal symptoms (and total PTSD symptoms). Our re-sults are thus consistent with previous findings of disruptedcorticosubcortical connectivity in PTSD (45,71,72) and extendthese findings by revealing an underlying dysfunction in thebalance between ICNs.

The functional impact of disrupted resting-state connectivityhas been debated. Disrupted ICN segregation could be relatedto the development of other symptoms or physiological ab-normalities in PTSD. For instance, greater intrinsic connectivityin the SN is associated with higher self-report anxiety (27) andgreater HPA axis responsivity to aversive stimuli (47). Dis-ruptions in the equilibrium between ICNs may affect regulatoryefficiency, particularly alterations in the SN, which plays a rolein switching between other large-scale networks (34). Finally,weaker anticorrelation between the DMN and its anticorrelatednetworks (both at task and at rest) is associated with diminishedperformance in a cognitive interference task (26) and a psycho-motor vigilance task (48). Taken together, these findings suggestthat disequilibrium between ICNs is a pervasive phenomenonthat may affect patients with PTSD across a variety of contexts.

This study has several limitations. First, our sample size wassmall; thus, our results should be considered preliminary.Second, seed voxelYbased resting-state connectivity providesan important method to assess connectivity within specific net-works, but it is essentially correlational and thus does not allowfor inferences about causal relationships. Activation differencesand connectivity differences cannot be disentangled using seed-based connectivity measures. Because we did not collect mea-sures of mental activity during the resting-state scan, we cannotdiscern whether differential engagement in various cognitiveprocesses could be driving the observed group differences. Third,because only male veterans with combat exposure were includedin this study, generalizations to women or to non-combatYrelatedPTSD should be made with caution. Fourth, our PTSD sampleincluded participants with comorbid major depression. Althoughdepression commonly co-occurs with PTSD in veteran popula-tions (up to 80% by some estimates (74)), inclusion of depressedparticipants may render some of the variance attributable to thepresence of depression. However, our results were not affectedby the removal of participants with current comorbid depression(see Supplemental Results in SDC1). Therefore, we retaineddepressed participants in our final analysis.

In conclusion, this study found reduced coupling within theDMN, increased coupling within the SN, and increased cou-pling between the DMN and the SN in participants with PTSDduring resting state. These findings may reflect a dominanceof threat-sensitive circuitry in PTSD, even in task-free condi-tions. Our results suggest that disequilibrium between large-scalenetworks subserving salience detection versus internally focusedthought may be associated with PTSD pathophysiology.

DISRUPTED INTRINSIC CONNECTIVITY NETWORKS IN PTSD

Psychosomatic Medicine 74:904Y911 (2012) 909

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

REFERENCES1. APA. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,

Text Revision. Washington, DC: American Psychiatric Press; 2000.2. Marx BP, Brailey K, Proctor SP, Macdonald HZ, Graefe AC, Amoroso P,

Heeren T, Vasterling JJ. Association of time since deployment, combatintensity, and posttraumatic stress symptoms with neuropsychological out-comes following Iraq war deployment. Arch Gen Psychiatry 2009;66:996Y1004.

3. Bardeen JR, Orcutt HK. Attentional control as a moderator of the rela-tionship between posttraumatic stress symptoms and attentional threat bias.J Anxiety Disord 2011;25:1008Y18.

4. Banich MT, Mackiewicz KL, Depue BE, Whitmer AJ, Miller GA, Heller W.Cognitive control mechanisms, emotion and memory: a neural perspectivewith implications for psychopathology. Neurosci Biobehav Rev 2009;33:613Y30.

5. Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M. In-creased anxiety during anticipation of unpredictable aversive stimuli inposttraumatic stress disorder but not in generalized anxiety disorder. BiolPsychiatry 2009;66:47Y53.

6. Cisler JM, Wolitzky-Taylor KB, Adams TG Jr, Babson KA, Badour CL,Willems JL. The emotional Stroop task and posttraumatic stress disorder: ameta-analysis. Clin Psychol Rev 2011;31:817Y28.

7. Pineles SL, Shipherd JC, Mostoufi SM, Abramovitz SM, Yovel I. Atten-tional biases in PTSD: more evidence for interference. Behav Res Ther2009;47:1050Y7.

8. Isaac CL, Cushway D, Jones GV. Is posttraumatic stress disorder associatedwith specific deficits in episodic memory? Clin Psychol Rev 2006;26:939Y55.

9. Dere E, Pause BM, Pietrowsky R. Emotion and episodic memory inneuropsychiatric disorders. Behav Brain Res 2010;215:162Y71.

10. Guez J, Naveh-Benjamin M, Yankovsky Y, Cohen J, Shiber A, Shalev H.Traumatic stress is linked to a deficit in associative episodic memory. JTrauma Stress 2011;24:260Y7.

11. Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB, ZeidanMA, Handwerger K, Orr SP, Rauch SL. Neurobiological basis of failure torecall extinction memory in posttraumatic stress disorder. Biol Psychiatry2009;66:1075Y82.

12. Milad MR, Orr SP, Lasko NB, Chang Y, Rauch SL, Pitman RK. Presenceand acquired origin of reduced recall for fear extinction in PTSD: resultsof a twin study. J Psychiatr Res 2008;42:515Y20.

13. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and re-trieval. Neuropsychopharmacology 2008;33:56Y72.

14. Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB.Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women withintimate-partner violence posttraumatic stress disorder. Biol Psychia-try 2010;68:433Y41.

15. Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety dis-orders. Neuropsychopharmacology 2010;35:169Y91.

16. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysisof emotional processing in PTSD, social anxiety disorder, and specificphobia. Am J Psychiatry 2007;164:1476Y88.

17. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME.The human brain is intrinsically organized into dynamic, anticorrelatedfunctional networks. Proc Natl Acad Sci U S A 2005;102:9673Y8.

18. Corbetta M, Patel G, Shulman GL. The reorienting system of the humanbrain: from environment to theory of mind. Neuron 2008;58:306Y24.

19. Smith SM, Fox PT, Miller KL, Glahn DC, Fox PM, Mackay CE, FilippiniN, Watkins KE, Toro R, Laird AR, Beckmann CF. Correspondence of thebrain’s functional architecture during activation and rest. Proc Natl AcadSci U S A 2009;106:13040Y5.

20. Laird AR, Fox PM, Eickhoff SB, Turner JA, Ray KL, McKay DR, GlahnDC, Beckmann CF, Smith SM, Fox PT. Behavioral interpretations of in-trinsic connectivity networks. J Cogn Neurosci 2011;23:4022Y37.

21. Shehzad Z, Kelly AM, Reiss PT, Gee DG, Gotimer K, Uddin LQ, Lee SH,Margulies DS, Roy AK, Biswal BB, Petkova E, Castellanos FX, MilhamMP. The resting brain: unconstrained yet reliable. Cereb Cortex 2009;19:2209Y29.

22. Zuo XN, Kelly C, Adelstein JS, Klein DF, Castellanos FX, Milham MP.Reliable intrinsic connectivity networks: test-retest evaluation using ICAand dual regression approach. Neuroimage 2010;49:2163Y77.

23. van den Heuvel MP, Mandl RC, Kahn RS, Hulshoff Pol HE. Functionally

linked resting-state networks reflect the underlying structural connectivityarchitecture of the human brain. Hum Brain Mapp 2009;30:3127Y41.

24. Fox MD, Snyder AZ, Vincent JL, Raichle ME. Intrinsic fluctuations withincortical systems account for intertrial variability in human behavior. Neuron2007;56:171Y84.

25. Hamilton JP, Furman DJ, Chang C, Thomason ME, Dennis E, Gotlib IH.Default-mode and task-positive network activity in major depressive dis-order: implications for adaptive and maladaptive rumination. Biol Psy-chiatry 2011;70:327Y33.

26. Kelly AM, Uddin LQ, Biswal BB, Castellanos FX, Milham MP. Compe-tition between functional brain networks mediates behavioral variability.Neuroimage 2008;39:527Y37.

27. SeeleyWW,Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, ReissAL, Greicius MD. Dissociable intrinsic connectivity networks for salienceprocessing and executive control. J Neurosci 2007;27:2349Y56.

28. Dosenbach NU, Fair DA, Miezin FM, Cohen AL, Wenger KK, DosenbachRA, FoxMD, Snyder AZ, Vincent JL, Raichle ME, Schlaggar BL, PetersenSE. Distinct brain networks for adaptive and stable task control in humans.Proc Natl Acad Sci U S A 2007;104:11073Y8.

29. Cauda F, D’Agata F, Sacco K, Duca S, Geminiani G, Vercelli A. Functionalconnectivity of the insula in the resting brain. Neuroimage 2011;55:8Y23.

30. Sridharan D, Levitin DJ, Menon V. A critical role for the right fronto-insular cortex in switching between central-executive and default-modenetworks. Proc Natl Acad Sci U S A 2008;105:12569Y74.

31. Spreng RN, Mar RA, Kim AS. The common neural basis of autobio-graphical memory, prospection, navigation, theory of mind, and the defaultmode: a quantitative meta-analysis. J Cogn Neurosci 2009;21:489Y510.

32. Toro R, Fox PT, Paus T. Functional coactivation map of the human brain.Cereb Cortex 2008;18:2553Y9.

33. Qin P, Northoff G. How is our self related to midline regions and thedefault-mode network? Neuroimage 2011;57:1221Y33.

34. Menon V. Large-scale brain networks and psychopathology: a unifyingtriple network model. Trends Cogn Sci 2011;15:483Y506.

35. Daniels JK, McFarlane AC, Bluhm RL, Moores KA, Clark CR, Shaw ME,Williamson PC, Densmore M, Lanius RA. Switching between executiveand default mode networks in posttraumatic stress disorder: alterations infunctional connectivity. J Psychiatry Neurosci 2010;35:258Y66.

36. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA,Shulman GL. A default mode of brain function. Proc Natl Acad Sci U S A2001;98:676Y82.

37. Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observedwith functional magnetic resonance imaging. Nat Rev Neurosci 2007;8:700Y11.

38. Wig GS, Buckner RL, Schacter DL. Repetition priming influences distinctbrain systems: evidence from task-evoked data and resting-state correla-tions. J Neurophysiol 2009;101:2632Y48.

39. Wu RZ, Zhang JR, Qiu CJ, Meng YJ, Zhu HR, Gong QY, Huang XQ,Zhang W. Study on resting-state default mode network in patients withposttraumatic stress disorder after the earthquake. Sichuan Da Xue XueBao Yi Xue Ban 2011;42:397Y400.

40. Bluhm RL, Williamson PC, Osuch EA, Frewen PA, Stevens TK, BoksmanK, Neufeld RW, Theberge J, Lanius RA. Alterations in default networkconnectivity in posttraumatic stress disorder related to early-life trauma. JPsychiatry Neurosci 2009;34:187Y94.

41. Daniels JK, Frewen P, McKinnon MC, Lanius RA. Default mode altera-tions in posttraumatic stress disorder related to early-life trauma: a devel-opmental perspective. J Psychiatry Neurosci 2011;36:56Y9.

42. Shin LM, Lasko NB, Macklin ML, Karpf RD, Milad MR, Orr SP, Goetz JM,Fischman AJ, Rauch SL, Pitman RK. Resting metabolic activity in thecingulate cortex and vulnerability to posttraumatic stress disorder. ArchGen Psychiatry 2009;66:1099Y107.

43. Sripada RK, King AP, Garfinkel SN, Wang X, Sripada CS, Welsh RC,Liberzon I. Altered resting-state amygdala functional connectivity in menwith posttraumatic stress disorder. J Psychiatry Neurosci 2012;37:241Y9.

44. Rabinak CA, Angstadt M, Welsh RC, Kenndy AE, Lyubkin M, Martis B,Phan KL. Altered amygdala resting-state functional connectivity in post-traumatic stress disorder. Front Psychiatry 2011;2:62.

45. Lanius RA, Bluhm RL, Coupland NJ, Hegadoren KM, Rowe B, ThebergeJ, Neufeld RW, Williamson PC, Brimson M. Default mode network con-nectivity as a predictor of post-traumatic stress disorder symptom severityin acutely traumatized subjects. Acta Psychiatr Scand 2010;121:33Y40.

46. Lui S, Huang X, Chen L, Tang H, Zhang T, Li X, Li D, KuangW, Chan RC,Mechelli A, Sweeney JA, Gong Q. High-field MRI reveals an acute impact

R. K. SRIPADA et al.

910 Psychosomatic Medicine 74:904Y911 (2012)

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

on brain function in survivors of the magnitude 8.0 earthquake in China.Proc Natl Acad Sci U S A 2009;106:15412Y7.

47. Hermans EJ, van Marle HJ, Ossewaarde L, Henckens MJ, Qin S, vanKesteren MT, Schoots VC, Cousijn H, RijpkemaM, Oostenveld R, FernandezG. Stress-related noradrenergic activity prompts large-scale neural net-work reconfiguration. Science 2011;334:1151Y3.

48. Thompson GJ, Magnuson ME, Merritt MD, Schwarb H, Pan WJ,McKinley A, Tripp LD, Schumacher EH, Keilholz SD. Short-time win-dows of correlation between large-scale functional brain networkspredict vigilance intraindividually and interindividually. Hum Brain Mapp.In press.

49. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E,Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychi-atric Interview (M.I.N.I.): the development and validation of a structureddiagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychi-atry 1998;59(Suppl 20):22Y33;quiz 4Y57.

50. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, CharneyDS, Keane TM. The development of a Clinician-Administered PTSDScale. J Trauma Stress 1995;8:75Y90.

51. Glover GH, Li TQ, Ress D. Image-based method for retrospective cor-rection of physiological motion effects in fMRI: RETROICOR. MagnReson Med 2000;44:162Y7.

52. Bluhm RL, Miller J, Lanius RA, Osuch EA, Boksman K, Neufeld RW,Theberge J, Schaefer B, Williamson P. Spontaneous low-frequency fluc-tuations in the BOLD signal in schizophrenic patients: anomalies in thedefault network. Schizophr Bull 2007;33:1004Y12.

53. Aupperle RL, Ravindran L, Tankersley D, Flagan T, Stein NR, SimmonsAN, Stein MB, Paulus MP. Pregabalin influences insula and amygdalaactivation during anticipation of emotional images. Neuropsychopharma-cology 2011;36:1466Y77.

54. Anderson JS, Druzgal TJ, Lopez-Larson M, Jeong EK, Desai K, Yurgelun-Todd D. Network anticorrelations, global regression, and phase-shifted softtissue correction. Hum Brain Mapp 2011;32:919Y34.

55. Fisher RA. Frequency distribution of the values of the correlation coeffi-cient in samples of an indefinitely large population. Biometrika 1915;10:507Y21.

56. Ward B. Simultaneous inference for fMRI data, 2000. Availale at:http://afni.nimh.nih.gov/pub/dist/doc/manual/AlphaSim.pdf. AccessedMay 9, 2012.

57. Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain.New York: Thieme; 1988.

58. Price CJ, Friston KJ. Cognitive conjunction: a new approach to brain ac-tivation experiments. Neuroimage 1997;5:261Y70.

59. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain’s default net-work: anatomy, function, and relevance to disease. Ann N Y Acad Sci2008;1124:1Y38.

60. GaoW, LinW. Frontal parietal control network regulates the anti-correlateddefault and dorsal attention networks. Hum Brain Mapp 2012;33:192Y202.

61. Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity inthe resting brain: a network analysis of the default mode hypothesis. ProcNatl Acad Sci U S A 2003;100:253Y8.

62. Fransson P. Spontaneous low-frequency BOLD signal fluctuations: anfMRI investigation of the resting-state default mode of brain functionhypothesis. Hum Brain Mapp 2005;26:15Y29.

63. Jang JH, Kim JH, Jung WH, Choi JS, Jung MH, Lee JM, Choi CH, KangDH, Kwon JS. Functional connectivity in fronto-subcortical circuitryduring the resting state in obsessive-compulsive disorder. Neurosci Lett2010;474:158Y62.

64. Menon V, Uddin LQ. Saliency, switching, attention and control: a networkmodel of insula function. Brain Struct Funct 2010;214:655Y67.

65. Paulus MP, Stein MB. Interoception in anxiety and depression. Brain StructFunct 2010;214:451Y63.

66. Paulus MP. Decision-making dysfunctions in psychiatryValtered homeo-static processing? Science 2007;318:602Y6.

67. Vermetten E, Schmahl C, Southwick SM, Bremner JD. Positron tomo-graphic emission study of olfactory induced emotional recall in veteranswith and without combat-related posttraumatic stress disorder. Psycho-pharmacol Bull 2007;40:8Y30.

68. Bremner JD, Vermetten E, Schmahl C, Vaccarino V, Vythilingam M, AfzalN, Grillon C, Charney DS. Positron emission tomographic imaging ofneural correlates of a fear acquisition and extinction paradigm in womenwith childhood sexual-abuse-related post-traumatic stress disorder. Psy-chol Med 2005;35:791Y806.

69. Patel R, Spreng RN, Shin LM, Girard TA. Neurocircuitry models ofposttraumatic stress disorder and beyond: a meta-analysis of functionalneuroimaging studies. Neurosci Biobehav Rev. 2012;36:2130Y42.

70. Habas C, Guillevin R, Abanou A. Functional connectivity of the superiorhuman temporal sulcus in the brain resting state at 3T. Neuroradiology2011;53:129Y40.

71. Yin Y, Jin C, Hu X, Duan L, Li Z, Song M, Chen H, Feng B, Jiang T, Jin H,Wong C, Gong Q, Li L. Altered resting-state functional connectivity ofthalamus in earthquake-induced posttraumatic stress disorder: a functionalmagnetic resonance imaging study. Brain Res 2011;1411:98Y107.

72. Dennis EL, Gotlib IH, Thompson PM, Thomason ME. Anxiety modulatesinsula recruitment in resting-state functional magnetic resonance imagingin youth and adults. Brain Connectivity 2011;1:245Y54.

73. Krebs RM, Boehler CN, Roberts KC, Song AW, Woldorff MG. The in-volvement of the dopaminergic midbrain and cortico-striatal-thalamiccircuits in the integration of reward prospect and attentional task demands.Cereb Cortex 2012;22:607Y15.

74. Hankin CS, Spiro A 3rd, Miller DR, Kazis L. Mental disorders and mentalhealth treatment among U.S. Department of Veterans Affairs outpatients:the Veterans Health Study. Am J Psychiatry 1999;156:1924Y30.

DISRUPTED INTRINSIC CONNECTIVITY NETWORKS IN PTSD

Psychosomatic Medicine 74:904Y911 (2012) 911

SPECIAL SERIES ON NEUROSCIENCEIN HEALTH AND DISEASE

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.