EE Regional Cerebral Blood Flow in the Amygdala and Medial Prefrontal Cortex During Traumatic Imagery in Male and Female Vietnam Veterans With PTSD Lisa M. Shin, PhD; Scott P. Orr, PRD; Margaret A. Carson, PAD, RN; Scott L. Rauch, MD; Michael L. Macklin, BA; Natasha B. Lasko, PhD; Patricia Marzol Peters, BA; Linda J Metzger, PhD; Darin D. Dougherty, MD; Paul A. Cannistraro, MD; Nathaniel M. Alpert, PhD; Alan J. Fischman, MD, PhD; Roger K. Pitman, MD Context: Theoretical neuroanatomie models of pos traumatic stress disorder (PTSD) and the results of pre vious neuroimaging studies of PTSD highlight the po- tential importance of the amygdala and medial prefrontal regions in this disorder. However, the functional rela- Lionship between these brain regions in PTSD has not been directly examined, Objective: To examine the relationship between the amygdala and medial prefrontal regions during symp- tom provocation in male combat veterans (MCVs) and female nurse veterans (PNVs) with PTSD. Design: Case-control study. Setting: Academic medical center. Participants: Volunteer sample of 17 (7 men and 10 women) Vietnam veterans with PTSD (PTSD group) and 19 (® men and 10 women) Vietnam veterans without PTSD (control group). Main Outcome Measures: We used positron emis. sion tomography and the seript-driven imagery para- digm to study regional cerebral blood flow (rCBF) dur- ing the recollection of personal traumatic and neutral events. Psychophystologic and emotional sel-report data also were oblained to confirm the intended effects of script-driven imagery Results: The PTSD group exhibited rCBF decreases in ‘medial frontal gyrus in the traumatic vs neutral com- parison. When this comparison was conducted sepa- rately by subgroup, MCVs and FNVs with PTSD exhib- lied these medial frontal gyrus decreases. Only MCV exhibited rCBF increases in the left amygdala. How- ever, for both subgroups with PTSD, rCBF changes in me- dial frontal gyrus were inversely correlated with tCBP changes in the left amygdala and the right amygdala/ periamygdaloid cortex. Furthermore, in the traumatic con- dition, for both subgroups with PTSD, symptom sever- ity was positively related to rCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus, Conelusions: These results suggest « reciprocal rela- Uonship between medial prefrontal cortex and amyg- ila function in PTSD and opposing associations be- tween activity in these regions and symptom severity consistent with current functional neuroanatomie mod- els ofthis disorder. Arch Gen Psychiatry. 200%;61:168-176 [EVERAL RECENT FUNCTIONAL neuroimaging studies have in- vestigated brain activation during exposure to trauma- related stimuli in posttrau- tivation in anterior cingulate gyrus," me- dial frontal gyrus,* and subcallosal gyrus.” Recent functional magnetic resonance maging studies using cognitive activation paradigmshave urtherdemonstrated theim- Author afitions ae given at the endo the article matic stress disorder (PTSD). For ex- ample, the presentation of combat sights and sounds to male combat veterans (MCVs) with PTSD has been associated with relatively increased activation in the amygdala" and cerebellum” and rela- tively decreased activation in subsallosal gy- rus. The recollection of personal trat- matic events (via the script-driven imagery paradigm) in PTSD has been associated with activation in the amygdala,’ orbitofrontal cortex, anterior temporopolar cortex.*" and insular cortex” and relatively decreased ac- portanceof theamygdalaand medial prelron- tal regions in PTSD. Rauch et al!” demon- strated hyperresponsivity oftheamysdalato masked fearful facial expressions in MCVs with PTSD. Shin etal" reported diminished recruitment of anterior cingulate cortex during the emotional counting Stroop task faMCVswith PTSD. Medial prefrontal strac- ralabnormalitiesalso have been reported in PTSD, including decreased volumesof pre- genual anterior cingulatecortex and subeal- losal cortex"? and diminished neuronal {integrity in anterior cingulate cortex.” (©2004 American Medical Association, All ights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016Table 1. Demographic and Clinical Data PTSD aroup arabe = (a=10) (o=9) oe 51562) S181) 027) S15(18) Euston 14820) sao) 163 (18) wai, CAPS tol sore 903 (252) 605 (165) 48063) 416) SCLODA depression subscale sore 14109) 19 (10) 04(08) oat) Abbreviaons: CAPS, Clician Administered PTSD Seal Pe, feral nurse veterans; OV, male combat veteran; PTSD, postaumat arse ded ‘L308, Symptom Chocks. 00-Ravsed ‘Data are gvn as mean (50) The results of these neuroimaging studies are broadly ‘consistent with the hypotheses that, in PTSD, the amyg- dala is hyperresponsive and medial prefrontal regions are hyporesponsive, and that these regions are reciprocally re- lated." Although researchers have hypothesized such a reciprocal relationship between the amygdala and medial prefrontal regions in PTSD, no previous studies in the it- ‘erature have provided correlational data in support of this hypothesis. The most relevant evidence to date comes from Semple etal, who reported higher regional cerebral blood ow (rCBF) in the amygdala and lower fCBF in anterior ‘ingulate/medial frontal gyrus in patients with PTSD and, substance abuse. However, correlations between rCBF ‘changes in the amygdala and medial frontal regions were not reported, Most of the neuroimaging studies of PTSD to date have included either MCVs of women with histories of physical or sextal abuse. In contrast o male Vietnam vel- terans, women who served as nurses in Vietnatn have fe ceived relatively litte research attention.!"* Female nurse veterans (PNVs) were exposed to horrific war-related in- juries, mutilated bodies, death, and threats to personal safety and thus were also at risk of developing many nega- tive outcomes, including PTSD." In the present research, we studied rCBF in 36 male and female Vietnam veterans using positron emission (o- mography (PET) and a script-driven imagery para- ddigm.*”* In separate conditions, participants recalled and, imagined personal traumatic (war-related) and neutral ‘events, During traumatic imagery, compared with ne tral imagery, we predicted that veterans with PTSD would ‘exhibit (1) greater activation in the amygdala, orbito- frontal cortex, temporopolar cortex, and insular cortex and (2) diminished activation in medial prefrontal re _glons (including medial frontal gyrus, rostral anterior cin- ‘gulate gyrus, and subcallosal gyrus) compared with vet- ‘erans without PTSD. We also performed parallel analyses in MCVs and PNVs separately to determine whether pat- terns of brain activation in our regions of interest dif- fered in these subgroups. Given the lack of neuroimag- ing data on ENVs, we had no a priori hypotheses regarding the direction of such subgroup differences. In addition, we conducted correlational analyses to determine (1) the functional relationship between the amygdala and me- dial prefrontal regions and (2) the relationship between PTSD symptom severity and rCBF in the amygdala and medial prefrontal regions during the traumatic imagery (©2004 American Med condition, To demonstrate that participants achieved an emotional state during scanning, we also analyzed their subjective ratings and psychophystologie data (es PARTICIPANTS Parilpants were 36 right-handed Vietnam veterans without a history of head injury, neurologic disorders or other major tnedical conditions, Seventeen paticpants (7 men and 10 wom Gn) met DSM-IV diagnostic cera for curren PTSD (PTSD group) and 19 patcipans (9 men and 10 women) never ad PTSD (control group) according to the Clinician- Administered PTSD Scale (CAPS), 4 structured clini in terviewAllof the male participants had served in coma, nd allof the female participants had served as nurses in Vietnam, Urine drugscreen results were negative forall paripants. No artcipant was taking peychottopc or cardiovascular medi Gione athe ume of he study. Demographic and clinical data are given in Yale ¥. Age education and CAPS scores were analyzed using separate 2G gnosis PISD vscontol) % 2 auhgroup MCV ts FNV') analy fev vtiance Forte sake of brevity we lit only the sais cally signficanlfecs. Aman elect of ubgroup was observed for education (F,,.=12 3; Pu 002). Female mse veterans had 4 greater mean numberof yeas of education than MCVs,re- Aecing ENV nursing sng Table 1) signin main elec of diaghosis was observed for CAPS scores (F=2051;P001) ana for mean depression subselescores onthe Symptom Check- iis-o@-Revied" (Fyor217-4 P01) The PSD group had higher core on these measures than the control group. ‘The presence of other Axis I mental disorders was as- sessed sng the Structured Clinical teri fr DSM-IV.» Pat- tipants inthe PISD group met diagnostic crtera forthe fol lowing curentcomorbul diagnoses: major depression (OMCVS and 5 ENVs),paniedisorder(@ McVeand I ENV), socal pho= bia ( MCV and 1 FNV), specific phobia (2 ENV) binge ing dsorder( ENV), and romatoform disorder (X ENV). Par Ucipant inthe control group met diagnostic criteria for dysthymia (2 MCV) specie phobla (1 FNV), and somato- form disorder (1 MCY), “This std was approved by the institutional evew boards ofthe Massachusetts General Hospital, Boston, andthe Veter ‘ns Alles Medical Center, Manchester Write informed con fen was obtained frm each parttpan SCRIPTS The design and procedures of the script-driven imagery task were identical to those reported elsewhere” Before the PET 1 Association, All rights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016i ae Sey ly mpd ge ener it hcg Shen Sed mason cmon eg Be sa sm soap leant eprint ‘Rovio ule ete ‘epee ittaytaidblsoge le iste eyes tect sitet acm ee SULIT, PERLE a at PSYCHOPHYSIOLOGIC RESPONSES Participants heart ate, skin conductance, and lft ater ron- tli ceettomyographic (ENG) responses were measured via {moda insrament systems (Coufbourn instrument, lle town, Pa nthe PET laboratory (Masachusets General Hos pital, Boston) according to established procedres =" aychophysologic measurements vere recorded for 30 sc- nds helore each PET scan (sling), for 60 seconds daring ich PET sean (Gmagery, and for 39 seonds medina ter each PET sean (recover). Within the rsline and ag ry periods (for each scan), readings were averaged. For each Sch the mean value during the baseline period was sub tracted rom the mean vale during the imagery period, yild- ing response” (change) scores SUBJECTIVE RATINGS Immediately after each scan, participants rated the intensity of| several emotions using separate visual analog scales (0=ab- sent and 12=maximal) "The rated emotions included hap- piness, sadness, anger, far, disgust, surprise, and guilt. Par- ticipants also rated their arousal level, vividness of imagery, awareness of present surroundings, and degree to which they Felt that the visualized event was happening again, POSITRON EMISSION TOMOGRAPHY Procedures “The PET equipment and procedures have been described in pre- ‘ous sties "Briefly, PET data were gathered using #15- tlie, whole-body tomogiaph (Scandtronix PC4096, General Electric Medical Systems, Mibwauke, Wis) The camera pro- dluced contiguous slices 6.5 mm apart, with axial resolution at ‘0mm full half manimurn (axa fel 97°3 mum), ln ages were reconstructed using « measured atenuaton corec- (©2004 American Med tion and a Hanning-weighted reconstruction iter set to allow for 8mm in-plane spatial resolution (full-width half maximum). Aer entering the scanner, each participant was fitted with athermoplasticcustom-molded face mask, an overlying face mask attached to a vacuum, and nasal cannula, which delivered the oxygen-15-labeled carbon dioxide. The concentration of oxygen- 15-Labeled carbon dioxide was 80 mCV/ (2960 MBL) the flow ratewas 2 Lin. Each participants head was aligned in the scan- net felative to the canthomeatal line, and transmission measure ‘ments were made using an orbiting pin source. Data Analysis Statistical parametric mapping analysisof the PET data was on dicted using a computer software package (SPMO: Well: ome Departinent of Cogntive Neurology, London, England)” Within SPM09, al images were corrected for imerscan move- tent using sinc inlerpoation and then were transformed into 4 standard stereotactic space using bilinear interpolation In ages were then smoothed sing a -dimensional Gaussian ict with a wih of L0-mm fullwidc half maximum. At cach voxel, the PET daia were normalized wing the global mean and ft toa linear stastcal model wsng the method oat squares Hypotheses were tested as contasis in which linear com- pounds of the model parameters were evaluated using stats {is which were ther transformed to 2 scores. ‘We ssceeed our predicions with (1) separate voxewise traumatic ws neural contrast each diagnostic group and (2) 2 voxcivie test ofthe condition X diagnose interaction, Sepa Tate parallel statistical parametric mapping analyses were con- dicted foreach subgroup, We chose to conduct the traumatic ‘neutral contrasts within a ined-effecte model because this Drocediremininizes ype error Although fxed-fects analy Ecslimit our ally to generalize fom the study sample tothe larger population of patents with PISD, the present findings inthe amygdala and medial prefrontal corex (se the "Re sulls"cectlon) ate stir to those of previous studies" us ing fixed effects models: Furthermore, random-lects analy ses ofthe present dataset revealed similar findings inthe Amygdala and medal prefrontal cortex Fro determine whether the rCBF changes in medal pre- frontal regions were related to rCBF changes inthe amyglala in PTSD, we (1) defined a functional region of interest (diam Cte 4 mm) around the deactivation in medial ronal gyi in the traumatic v= neural contrast tn the PTSD group (Mon- toeal Neurological Institue [MINI] coordinates, 10, #32, +2), (@) exacted tCBF values per condition pe patcipant from that region of interest, (9) Calculated the taumati = nett {CBF change core per patcpant and (4 determined whether those changescores were associated with rCBF changesin other brain areas in the raumatie vs neutral comparison (asin i dividual participant “con” images) via a voxelwise corel tional analysts. Finally, within SPMO9, voxelwise “covariates only” analyses were conducted to determine the relationship Between PTSD symptom severity (CAPS) scores and FCBF in the amygdala and medial prefrontal regions forthe traumatic condition. All ofthese correlational procedures were per formed on the entire PTSD group and separately forthe MCV and FNV subgroups with PSD. Forthe sake of brevity. we fo cused specifically on the amygdala and medial prefrontal re- sions inthe corelational analyses. STATISTICAL ANALYSIS ‘The statistical parametric maps resulting from the analyses de- scribed herein were inspected for activations in oura priori e- {gions of interest. Given our strong, directional hypotheses, we used significance threshold of P< 001, uncorrected (23.09) 1 Association, All rights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016‘Table 2. Psychophysiologle Responses to Traumatic and Neutral Imagery Seripts* arabe =) @=9) Traumatic endion Heart rata response, betsnin 4549) 4749 14028) 2812) ‘kn conductance reponse, ps 02003) 05 (08) 005 05) -02(05) ettomyorapic response i 19108) 34028) 03,08) 4408) Nour cancion Heart rata response, betsnin 1320) 04.24) 01 (48) 02115) ‘kn conductance reponse, ps 01 (01) 0102) 03 (08) 2104) ctomyonrapic response yi 0104) 03 (08) emo) 04 (03) ‘Abbreviation: Ae, femal ure veterans; Me, mala combat eran, PTSD, postraumal rss dora, *Datare gv as mean (50), for activations in these a prot! regions. Most ofthe key acti- vations occurring in the amygdala and medial prefrontal cor- tex would remain significant even if we used an extremely com- servative Bonferroni volume-corrected P=.002 (2=2.88, 24 voxels of 6% 6% 6mm) forthe amygdalasnd P0007 (2=3.19, 75 voxels) for medial prefrontal cortex. Because the proce” dure of correcting P values based on region size is biased to- ‘ward finding statistical significance in small structures, we used the previously stated constant significance threshold. For re- sions about which we had no. prior prediction, we used amore ‘conservative constant significance threshold of P= O0001,1n- corrected (2427) The statistical analyses ofthe psychophysiologic and sub- jective rating data were conducted not to present these results as findings in their own right (which has already been done in ‘humerous publications with essentially the same results) but rather to demonstrate that the predicted emotional stivations and associated group and condition dilferences, on which the validity of the neuroimaging findings depends, had been achieved, For this reason, corrections for multiple compari- Sons were not performed for the results of these snalyses. —_ I iinm—_dy__ PSYCHOPHYSIOLOGIC RESPONSES Heart rate, skin conductance, and EMG responses to trau- matic and neutral imagery scripts were averaged across scans in each condition and were analyzed using sepa- rate 2 (diagnosis: PTSD vs control) X 2 (subgroup: MCVs vs FNVs) X2 (condition: neutral vs traumatic) analyses of variance (Table 2) Regarding heart rate responses, the only signifi- ‘cant effect was a main effect of condition (F,,.=22.75 P<.001). Heart rate responses were greater in the trau- matic condition than in the neutral condition across both ‘groups (Table 2). Regarding skin conductance responses, there were sig- nificant main effects of diagnosis (F, condition (F, .=19.2;P<001). The condition X diagnosis Interaction was also significant (F, ,,=7.7; P=.01). In- ‘ereases inskin conductance responses from the neutral © the traumatic condition were greater in the PTSD group vs the control group (Table 2). Also significant was the condition X diagnosis X subgroup interaction (F,.4.=10.7s P=.003). Examination of the means indicated that the dif ference in skin conductance response changes between (©2004 American Med PTSD and control participants was greater in PNVs than in MCVs. Finally, regarding EMG responses, significant main effects of diagnosis (P, ,.=14-0; P<001), subgroup (F243; P=.05), and condition (P, .=30.3; P<.001) were observed. The condition X diagnosis interaction was also significant (F,,.=11.5; P=.002). The EMG re- sponse increases [rom the neutral to the traumatic con- dition were greater in the PTSD group than in the con- trol group (Table 2). A significant condition X subgroup interaction was also found (F, .=43; P=.05). Inspec- on of the means demonstrated that EMG response in- creases from the neutral to the traumatic condition were greater in FNVs than in MCV, SUBJECTIVE RATINGS Ratings were averaged across scans in each condition and were submitted to separate 2 (diagnosis: PTSD vs con- trol) X2 (subgroup: MCVs vs FNVs) X2 (condition: neu- tral vs traumatic) analyses of variance. Significant main elfects of condition were observed for happiness, sad- ness, anger, fear, disgust, surprise, guilt, arousal, and viv- ldness of imagery (For all: F, ,=20.4; P<.001). Com- pared with the neutral condition, the traumatic condition was associated with lower ratings of happiness and higher ratings on all the other scales. Significant main effects of condition also were observed for ratings of awareness of present surroundings and the degree to which par pants felt that the visualized event was happening again (orall:F, =7-7; P=.01). All participants reported leel- ing less aware of their surroundings and more like the visualized event was happening again during the trau- ‘matic condition relative to the neutral condition, Furthermore, significant main elfects of diagnosis were found for fear, arousal, disgust, and guile (Lor all: F s,244; P=S.05). Ratings on these scales were higher in the PTSD group compared with the control group. Sig- nificant condition X diagnosis interactions were ob- served for fear, arousal, guilt, and surprise (for all: F, .=4.6; P=.05). The PTSD group had greater in- creases on these scales than the control group. A signili- cant condition X diagnosis X subgroup interaction was ob- served for ratings of surprise (F, ,.=4.9; P2.04). The smerease in surprise ratings between conditions was stron- 1 Association, All rights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016Figure 1. Reional aera aod ow dares in modal ont rus (22470; Montel Neulopal Institut coordinates, +10, +5, -2) nthe ‘taumati vs neta comparison inal paricpants wih postraumatc sess ‘dearer (=?) Reon etal lod da ae Spermposad on Standard T! template (SPMOO; Waleone Depart of Cagritne Heurlogy Londen England and pj scaring to urge Tioaalaep IPTDGicp 1a Tet Tate canon Figure 2. Moralzd rina carer led Now BF values in medal 70; Mente Nauologal nut coors, «10 +52 atc and nual eondtons nthe pstwauate sts ore Ero bas present {ger for MCVs with PTSD than for FNVs with PTSD. Pi. nally, a significant condition X diagnosis interaction was observed for the degree to which participants felt that the Visualized event was happening again (F,4)=5.6; P=.03); the PTSD group had greater increases on this scale com- pared with the control group. PET RESULTS Traumatic vs Neutral Comparison: PTSD and Control Groups In the PTSD group (n=17), the traumatic ys neutral com- parison yielded no statistically significant rCBF in- creases, Significant CBP decreases occurred in medial fron- tal gyrus (z=4.70; MNI coordinates, +10, +52, +2) (Figure 1 and Figure 2). Nonpredicted regions with sig- nificant rCBF decreases included superior frontal gyrus (=4.35; MNI coordinates, -28, +62, +2), middle tempo- ral gyrus (2=4.61; MNI coordinates, -52, -10, 16: and 22440; MNI coordinates, +58, ~4, -26), inferior parietal cortex (2=5.00; MNI coordinates, ~42, ~50, +40), and oc- cipital cortex (2=5.20; MNI coordinates, ~34, -90, +2 ©2004 American Medical Assoc ‘Dovmlosded From: itp Jarchpsye jamanetsvork coma by a Universidade de Sio Paulo User om ral com- In the control group, the traumatic vs ne parison yielded no statistically significant rCBF in- creases or decreases. For completeness, we note that a nonsignificant rCBF increase occurred in me gyrus (2=2,60; MNI coordinates, +16, +58, +20) al frontal The diagnosis X condition interaction revealed no regions with greater rCBF increases in the PTSD group or greater decreases in the control group. Regions with greater increases in the control group oF greater de- creases in the PTSD group included medial frontal g rus (2=3.50; MNI coordinates, +6, +58, +2) and occip tal cortex (2=4.79; MNI coordinates, -34, -88, +4) Traumatic vs Neutral Comparison: ‘Subgroup Analyses Table 3 gives regions of rCBF increases in MCVs and FNVs with PTSD, Increases in rCBF in the amygdala were observed in MCVs with PTSD only. Table 4 gives re- gions of rCBF increases in MCVs and NVs without PTSD. Finally, diagnosis X condition interactions in the MCV and PNV subgroups demonstrated that amygdala ac vation in the traumatic vs neutral comparison was greater in MCVs with PTSD than in MCVs without PTSD (lable dala was observed in the analogous interaction among, FNVs. ). No such differential activation in the amy Medial Frontal/Amygdala Correlations Inallof the PTSD participants, rCBF changes in medial fron- tal gyrus (MNI coordinates, +10, +52, +2) were negatively correlated with rCBF changes in the left amygdala (2=3.23: MINI coordinates, -26. +214) and the right amygdala’ periamygdaloid cortex (2=3.48; MNI coordinates, +18, +6, )-Inother words, smaller rCBF responses in medial fron- tal gyrus were associated with larger tCBF responses in the amygdala and periamygdaloid cortex. These correlations remained when participants with current major depres- sion were removed from the analyses. In addition, this relationship was observed in each, PTSD subgroup separately. In MCVs with PTSD, rCBF changes in medial frontal gyrus were negatively corr lated with rCBF changes in the left amygdala (2=3.51 MNI coordinates, -16, +2, -12) and right periamygd” loid cortex (2=2.88; MNI coordinates, +22, +0, -26). In FNVs with PTSD, ¢CBF changes in medial frontal gyrus were negatively correlated with rCBF changes in the let amygdala (2=3.54; MNI coordinates, -28, +4, -18) and the right amygdala/periamygdaloid cortex (2=3.38; MNI coordinates, +16, +4, -18) To assess the specifict relationship between medial frontal gyrus and amyg- dala, analogous correlational analyses were performed us- ing FCBF change data in another prefrontal region that demonstrated rCBF decreases in the traumatic vs net- tral comparison in the PTSD group; rCBF changes in su- perior frontal gyrus were not correlated with rCBF changes fn the amygdala. In addition, no other regions wer Uistically significantly correlated with rCBF changes in ‘medial frontal gyrus except in MCVs with PTSD. tn that subgroup, we also observed positive correlations with the of this inverse functional on, Al rights reserved, 0372472016‘Table 3, Traumatle vs Neutral Comparison: PSD Group” ‘ale Combat veorane Female Mugs Veterans Region z8care Aesion score Coortnates anygdala sar None a Na 2a esa ott gyrus a2 +10, 492,42 moa wont gyus 323 10, +30, 42 Inarior temporal gyrus Sor 154-624 Occipital eorex 45 “22-002 Occipital eon 20 722-86, 14 ‘Abbreviations: Mi Morzeal Neurological lsu NA, nt aplale; PTSD, pstraumatc toss dsrder. CF, regina cerebral lod tow ‘Apri eins of inerest ar shown bol 47 Scoteis bow the tatstal signcancetrsho for a pri elon buts listed for completeness. ‘Table 4. Taumatle vs Neutral Comparison: Control Group ‘ale Combat veers ree Veorane Region 82019 Coosa (3) Region zoe coortnas 4,93) esa ota gyrus 200 10, $0,480 Mota ota gras ast 2.80, 20 None Supaiortmporal gyrus 453 56 -20, «16 Oetptal cortox 46 128, 02,24 ‘Abbreviations: Mi, Marvel Neurological lsu CB rgional cerebral Hood fow “Apri eins of interest are shown in bol 42 Scr is bow the sttsteal shncancetreshol for apr regjons buts sted for completeness. ‘Table 5. Diagnosis x Condition Interactions ‘ale Combat veers Female Norge Veterans esion cara ____cooainats (2) egion :8c0r9 ___coeainates (6.3) ‘reer creases in the PTSD Group or Goalr Decreases in Contos ‘anygeata 343 “20,0,-20 None 20 4-22 ‘relerDecease In he PTSD Group oF Greater erases Im Contos esa ott gyrus 3.00 98,842 Moa wont gyrus 22 0.7218 22th 2,900.8 ‘Anterior cingulate gyrus 3st 10,0, 42 Ungal grin a 76-8 Occitan a5 “34-00, Abbreviations: Mil. Morzeal Neurological lsu PSD, postraumatie sess sore ‘Apri eins of inerest ar shown bol 47 Scoteis bow the tatstal signcancetrsho for a pri elon buts listed for completeness. left hippocampus (2=4.37; MNI coordinates, -28,-12, _ intherrightamyge £83; MNI coordinates, +28, +4 =12) and fustform gyrus (24.28; MNI coordinates, +38, 4) (although centered on the anterior/lateral margin, —46, -8) and negative correlations with the cerebellum of the amygdala, this activation extended posteriorly and (z=4.68; MNI coordinates, +20, -30, -16) and orbito- medially to include the entire right amygdala and the an- frontal cortex (2=4.42; MNI coordinates, +26,+42,-14). terior right hippocampus [2=4.01; MNI coordinates, 0, -16)). In MCVs with PTSD, CAPS scores were posi- Symptom Severity Correlations Lively associated with rCBF in the traumatic condition tn the right amy 93; MNI coordinates, +24, +4 In the PTSD group (n=17), CAPS scores were posi: =16) extending posteriorly to the right hippocampus tively associated with rCBF in the traumatic condition (2=3.07; MNI coordinates, 20, -12, -16) and were neg: jon, All rights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016lively associated with rCBF in medial frontal gyrus (z=3.29; MNI coordinates, -2, +52, +6) and anterior cin- agulate gyrus (2=3.40; MNI coordinates, ~4, +20, +28) In FNVs with PTSD, CAPS scores were also positively associated with the right amygdala/hippocampus (2=2.63; MNI coordinates, +24, -6, -14) and negatively assocl- ated with medial frontal gyrus (z=4.40; MNI coordi- nates, +10, +70, -6). These relationships remained even after controlling for depression severity scores, —1kIi::m_—_@__ During the recollection and imagery of traumatic vs net tral personal events, MCVs and FNVs with PTSD exhib- ited FCBF decreases in medial frontal gyrus. Only MCV's showed rCBF increases in the left amygdala. However, for both subgroups with PTSD, rCBF changes in medial frontal gyrus were inversely correlated with #CBF changes in the left amygdala and the right amygdala/ periamygdaloid cortex Furthermore, inthe traumatic com dition, for both subgroups with PTSD, symptom sever- ity was positively related to FCBF in the right amygdala and negatively related to rCBF in medial frontal gyrus ‘Our finding of decreased activation of medial rom- tal gyrus during the symptomati state in PTSD is con- sistent with the results of previous research" and with tmodels of PTSD that hypothesize abnormal function of redial prefrontal structures, Howe reported such decreased activation of medial prefrontal regions in PTSD. For example, using single-photon emis- sion computed tomography. Zubietaet al” reported rela- Lively increased medial prefrontal cortex blood flo in a ‘combat sounds condition relative toa white noise con- dition, The reason for such a disparate result is unclear ‘but may be auributed othe different neuroimaging tech niques (single-photon emission computed tomogea- phy) implemented in that study. Lanius et al™ found that hinctional magnetic resonance imaging signal changes inmedial frontal gyrus and anterior cingulate gyrus may vary depending on the dissociative state of parueipants; specifically, patients with PTSD who dissoctated during scanning showed increased activation in these regions, ‘whereas those who did not dissociate showed less acti vation in these regions. Thus, perhaps discrepant find- Ings in the literature regarding medial prefrontal re- zblons can be explained by variability in the dissociative sate of partieipants across (and within) studies, 1m participants with PTSD, blood flow changes in redial frontal gyrus were inversely correlated with blood flow changes in the amygdala This finding resonates with those ofa previous study" reporting decreased blood flow inanterior cingulate gyrus/medial frontal gyrus and in- ‘creased blood flow inthe amygdala in patients with PTSD. Although the direction of causality anno be snferred froma correlational analyses, the relationship between theamyg- dala and medial prefrontal cortex is likely tobe reeipro- ‘al, Medial prefrontal regions send projections to the amygdala in primates," and they may play an impor- tant role in the process of extinction of fear condition ing." Conversely, in rodents, prefrontal nurons show decreases in spontaneous aetvity inthe presence of acon ditioned aversive tone asa function of amygdala activ- er,notall studies have (©2004 American Med lty, suggesting that the amygdala may modulate prefron- tal neuronal activity." Longitudinal and wvin studies of PTSD may help elucidate the precise functional relation- ship between these structures and determine whether the more primary abnormality involves medial prefrontal re- gions or the amygdala, In the PTSD group, PTSD symptom severity was posi- Lively correlated with fCBP in the right amygdala and negatively correlated with rCBF in medial frontal gyrus during traumatic imagery. Positive correlations be- Loven subjective ratings of distress and right amygdala activity have been reported previously in PTSD* and in social anxiety." The present results supplement these pre- vious findings. In the present study, left amygdala activation in the Luaumatic vs neutral comparison was found among MCV with PTSD but not among PNVs with PTSD. This dif- ference between PTSD subgroups may be driven by dif ferences in trauma type (eg, directly experiencing dan- ager vs witnessing frightening situations) or sex or may have reflected a type Il error in FNVs with PTSD. How- ever, regarding rCBF findings in our a priori regions of Interest, these 2 subgroups exhibited more commonali- lies than differences, In contrast to the results of previous research, we found no evidence of rCBF increases in orbitofrontal cor- tex, temporopolar cortex, or insular cortex during trau- ‘matic imagery in the PTSD group. An explanation for this remains elusive, especially given that the methods imple- mented in this study were similar to those of previous studies."” In addition, previous studies have reported in- creased activation in medial frontal regions in conteol par- ticipants without PTSD." In the present study, PNVS without PTSD exhibited significant activation in medial frontal gyrus (Table 4), but similar activations in MCV without PTSD, and in the control group asa whole, fll below our significance threshold. The reason for sub- threshold medial frontal activation in the control group fs unclear. This study cannot (and was never intended to) di- rectly assess sex differences in neural responses to (rat ‘matic imagery because the men and women in this study experienced different types of trauma. Thus, any rCBF differences between MCVs and FNVs may be attribut- able to sex, trauma type, ora combination of the two. In addition, although the number of participants in our PTSD group was relatively large by functional neuroimaging, standards (n=17), analyzing data in MCVs and FNVs separately resulted in a relative loss of power and an in- creased risk of type Il error for the subgroup analyses. However, despite the small numbers per subgroup, the FCBP results in a priori regions of interest were strik- ingly similar in MCVs and FNVs with PTSD. The pres- ent study is limited by the presence of comorbidity in the PTSD group, and future neuroimaging studies of PTSD should use psychiatric control groups. It should be noted, however, that the key results from the present study r mained even after controlling for depression. Finally, the present design did not include a low-level baseline con- dition asa secondary comparison condition, which could have helped determine the patterns of activation associ- ated with the neutral and traumatic conditions sepa- 1 Association, All rights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016rately and might have further clarified activation differ- ‘ences between groups: In summary, velerans with PTSD exhibited rCBF de- ‘ereases in medial frontal gyrus during traumatic vs new tral script-driven imagery. These rCBF changes were in- versely correlated with rCBF changes in the lelt amygdala and the right amygdala/periamygdaloid cortex. Purther- more, in the traumatic condition, symptom severity was positively related to rCBF in the right amygdala and nega- lively related to CBF in medial frontal gyrus. These re- sults are consistent with functional neuroanatomic mod- cls of PTSD that posit a reciprocal relationship between, medial prefrontal cortex and amygdala in PTSD. ‘Submitted for publication March 27, 2003; final revision re ceived July 2, 2005; accepted July 10, 2003. From the Department of Psychology, Tufts Univer sity, Medford, Mass (Dr Shin); the Department of Psyehia- try, Massachusetts General Hospital and Harvard Medical School, Boston (Drs Shin, Orr, Rauch, Lasko, Metzger Dougherty, Cannistraro, and Pitman and Ms Peters): VA Research Service, Manchester, NH(D1s Orr, Carson, Lasko, ‘and Metzger and Mr Macklin); Continuing Nursing Edu ‘ation, StAnselm College, Manchester (Dr Carson); the De- partment of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston (Drs Rauch, Dougherty, Alpert, and Fischman); and Adult Oncology, Dana Farber Cancer Center, Boston (Ms Peters) This study was supported by merit review grants from the Veterans Affairs Medical Rescarch Service (Drs Pit- man, Carson, and Orr); a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression, Great Neck, NY (Dr Shin); and grant MH- 60219 from the National Institute of Mental Health, Bethesda, ‘Md (Dr Rauch). We thank: Paul Whalen, PRD, Cary Savage, PhD, Chris Lopher Chabris, PhD, and Christopher Wright, MD, PhD, {for their comments on this manuscript; the individuals who ‘served as research participants; and Sandra Barrow, BS, Avis Loring, RTN, and Steve Weise, BS, for their technical as- Corresponding author: Lisa M. Shin, PhD, Depart ment of Psychology, Tufts University, 490 Boston Ave, Med- ford, MA 02155 (e-mail: lisa shin@tufts.edu). Es} 1. Liteon Tar Ad Jung TD, ChanbrinK, Minasina5, Koepe| A FigLL rain acéatonin PTS in spose to waunsalaud stim Bol ajay. 108651726 2. Pita Fran O, ead von Korn Fir Fediean Ne refuresonal aos of ostraunat tes dare PET sya prove ‘aon study. ur rch Psychiatry in Newrasa 200225268. 4 Bempe 40S LH, lope , Sout SU, Sour Charney OSM. 1 cores of exposure owaunate pes ad sound in etna combst ‘trans with nc wa postraunate sess sede a psivon emission twonoyay sy. Bi Pech 1005 806-86 4 Faraner Fst A Fans, or Kring, Fhe Fdson Mb rin ‘neon napa with tru rete post aumate sess dora before ‘adore exnet posite emission nappy proven sy, esos Let: 20:20701-108 Oauchh Besan Gr M, Pode, Herzach P,MeCann UO, Pst agonal cereal be to aaa with fasta ens pe ath pestraunate sess dor. al Psych. 2001 5020625, 20 2 2 Es En 8 6 a 28 20 0 au SL van de Kok BA Filer RE. Aor HM, Or SP, Saag CR Fischman ‘Alenka Pinan Asymptomprovocson sy postu sess ioe sng poston emision tography and siptciven imagery. Ach Sen Pseniay 10065 8037 Shin LM Met, oss SM Thompson, AauhSL Apr Meer 1 Lasko Gr S, Pinan K. Rein eel ood Now curing sre ‘vimana in cldood sn abuts PTSD FET mssgaton Am 4 Pacha, 100 88575 584 nie Wianzon P, Dears M, okemanK, Gaps MA, Natl tJ, Manon RS ural corel of aumate omar npostaumae sas srdafunconal MRI mesg, Am Jy. 200,158 1920- ime rar J, Narayan M, Sab LH, Southwick SM, Mein T Chany DS. Nal contest mere hich ena ae vee iat ut pstraumatc svess sore. 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Inthe original article tle “Elficacy of Olanzapine and Olanza- pine-Fluoxetine Combination in the Treatment of bipolar | Depression,” pub lished inthe November issue ofthe ARCHIVES (2003;60:1079-1088). the key in Figure 3 was incorrect. Inthe corrected key, the top lines forthe olansapine- {uoxetine combination group, and the middle line is forthe olanzapine mono- therapy group. Figure 3 is reprinted correctly here. Time Reps, o Figure 3. Kaplan esliates ol tie to response Response i dated 2354 decrease in Montgomar-Asterg Depression Rating Sele tal scare of 50%: ermre ar at at £ woes of etmant Medan time to reponse {orth olanzapine group (85 days) was sigan eater compared wth ‘tho placebo group (30 cas). Median time to response othe. tlatapae tose combaatin graup (21 des} was sigan ar ‘han forth lrzapine ard last grtps. (©2004 American Medical Association, All ights reserved. ‘Downloaded From: itp:Jlrchpsye jamanetirork com/by a Universidade de Sio Paulo User on.03/24/2016