Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with...

Changes in RelativeGlucose Metabolic RateFollowing CortisolAdministration in AgingVeterans withPosttraumatic StressDisorder: An FDG-PETNeuroimaging Study

Rachel Yehuda, Ph.D.Philip D. Harvey, Ph.D.Julia A. Golier, M.D.Randall E. Newmark, B.A.Christopher R. Bowie, Ph.D.Janelle J. Wohltmann, B.A.Robert A. Grossman, M.D.James Schmeidler, Ph.D.Erin A. Hazlett, Ph.D.Monte S. Buchsbaum, M.D.

The authors aimed to examine central glucocorti-coids effects by measuring relative glucose meta-bolic rate (rGMR) in the hippocampus, amyg-dala, and anterior cingulate cortex (ACC) andthe relationship between amygdala and ACCactivity. The participants were male combat vet-erans with and without PTSD, 52 to 81 yearsold. The authors utilized randomized, double-blind, placebo-controlled examinations of therGMR response to 17.5 mg hydrocortisone(HCORT) using 2-Deoxy-2-[18F]fluorodeoxy-glucose (FDG) Positron Emission Tomography(PET) neuroimaging. Group differences in hemi-spheric laterality of rGMR were observed follow-ing placebo administration, reflecting lowerrGMR in the right hippocampus and ventralamygdala, and higher rGMR in the left ventral

amygdala in the PTSD� group compared to thePTSD� group. HCORT reduced these groupdifferences in laterality. The net effect of HCORTwas to restore a normal inverse associationbetween the ACC and amygdala in the PTSD�group, but disrupt this neural network in thePTSD� group. The magnitude of improvementin working memory correlated with greater hemi-spheric laterality in the dorsal amygdala follow-ing HCORT in both groups. The restorativeeffects of HCORT on metabolism and workingmemory provide a rationale for examining thetherapeutic benefits of glucocorticoid manipula-tion in aging PTSD patients.

(The Journal of Neuropsychiatry and ClinicalNeurosciences 2009; 21:132–143)

132132 http://neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 21:2, Spring 2009

REGULAR ARTICLES

Most studies of glucocorticoid responsiveness haveused measures that reflect glucocorticoid actions

in the periphery or challenge strategies that fail to dis-tinguish peripheral from central effects.1 Central glu-cocorticoid effects in posttraumatic stress disorder(PTSD) are suggested by the efficacy of cortisol admin-istration in PTSD prophylaxis and treatment,2–4 whichmay relate to alterations in cortisol, catecholamine, andcorticotrophin releasing factor level in PTSD.5–7 We re-cently reported that an intravenous bolus of 17.5 mghydrocortisone sodium succinate (HCORT) in PTSDpreferentially affected memory performance in combatveterans with PTSD, with different effects in youngerversus older PTSD cohorts,8–9 which may reflect age-related changes in brain glucocorticoid responsive-ness.10–12

The aim of our present study was to examine centraleffects of glucocorticoids on relative glucose metabolicrate (rGMR) in the hippocampus, dorsal amygdala,ventral amygdala, and anterior cingulate cortex (ACC).These regions have been implicated in PTSD patho-physiology13–16 and are known to be regulated by glu-cocorticoids.17–19 Studies examining activity of these re-gions of interest in response to presentation of traumaticor emotional stimuli have demonstrated alterations inmetabolic activity of these structures as well as in theirinterconnections.20–35 In particular, amygdala activationhas most often been demonstrated to be increased inPTSD, while ACC activity is diminished.20–24,36 Howeverthese differences vary by psychological task, with ACCactivation in PTSD greater than in comparison subjectsduring trauma script tasks.37 Because the ACC nor-mally inhibits amygdala activity in response to stress,the neuroimaging findings support an impaired regu-lation of the neural circuitry connecting the amygdalato the ACC, possibly observed even under baseline con-ditions.

The amygdala projections leading to the ACC origi-nate in the dorsal region of the amygdala, whereas theventral amygdala, comprised of the basolateral com-plex, projects to orbitofrontal regions.34 The basolateralcomplex has been specifically implicated in glucocorti-coid enhancement of memory,19 as shown on fMRIstudies,30,34 justifying the separate examination of thedorsal and ventral regions in PTSD.

In this study, brain metabolism was examined in re-sponse to placebo and an intravenous bolus of HCORT,administered in a randomized, double-blind manner,and quantified using [18F]fluorodeoxyglucose (FDG)positron emission tomography (PET) neuroimaging.We hypothesized a greater response to the effects ofHCORT in the PTSD� group, consistent with enhancedresponsiveness to glucocorticoids. In view of findingsimplicating laterality differences in PTSD, including re-ports of either greater group differences by hemisphere,or difference confined to one hemisphere,20,22–24 we fur-ther hypothesized that placebo rGMR might differ ac-cording to hemisphere based on group, and to the ex-tent that this would be true, the effects of HCORT mightalso differ by hemisphere.

METHODS

ParticipantsThe sample consisted of 32 male veterans 52 to 81 yearsold (16 with chronic PTSD, 16 without PTSD) and rep-resent a slightly larger sample than that for whom wepreviously reported an enhanced ACTH response38 andimproved performance on working memory followingHCORT administration.9 This lower age limit was im-posed to compare the current findings with the onlyother report of the effects of HCORT on brain glucosemetabolism, which was done in an aging population.39

Furthermore, this age range is of interest because glu-cocorticoid-dependent memory deficits have beenfound to be particularly prominent in older personswith PTSD and appear to become more marked withage.40 The study was approved by the institutional re-view boards at both the Mount Sinai School of Medicineand the U.S. Department of Veterans Affairs (VA). Allparticipants provided written, informed consent priorto their participation.

Exclusion criteria were current or lifetime history ofbipolar disorder, psychotic illness, organic mental dis-order, current alcohol or drug abuse or dependence,

Received November 14, 2007; revised January 9, 2008; accepted Jan-uary 17, 2008. Drs. Yehuda, Golier, Bowie, Grossman, Schmeidler,and Ms. Wohltmann are affiliated with The Traumatic Stress StudiesProgram, Department of Psychiatry, at The Mount Sinai School ofMedicine in New York; Drs. Yehuda, Golier, Bowie, and Ms. Wohlt-mann are also affiliated with The PTSD Program at the James J. PetersBronx Veterans Affairs Medical Center in Bronx, NY; Dr. Harvey isaffiliated with the Department of Psychiatry and Behavioral Sciencesat Emory University School of Medicine in Atlanta; Mr. Newmark,Dr. Hazlett, and Dr. Buchsbaum are affiliated with The NeurosciencePET Laboratory, Department of Psychiatry, at The Mount SinaiSchool of Medicine in New York. Address correspondence to RachelYehuda, Ph.D., Bronx VA OOMH, 130 West Kingsbridge Rd., Bronx,NY 10468; [email protected] (e-mail).

Copyright © 2009 American Psychiatric Publishing, Inc.

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133J Neuropsychiatry Clin Neurosci 21:2, Spring 2009 http://neuro.psychiatryonline.org 133

neurological illness including cerebrovascular accident,head injury with loss of consciousness lasting greaterthan 10 minutes, or laboratory data indicating signifi-cant medical illness. Participants were abstinent fromalcohol abuse for a minimum of 6 months and alcoholdependence for a minimum of 2 years, an adequateinterval for recovery from the nonpermanent, neuro-toxic effects of alcohol,41–42 and were not taking psychi-atric medications or steroids. The period of abstinencefrom alcohol abuse and dependence ranged from 2.5 to43 years.

Clinical AssessmentsAxis I diagnoses were made by trained psychologistraters according to the DSM-IV criteria using the Struc-tured Clinical Interview for DSM-IV43 and the ClinicianAdministered PTSD Scale (CAPS),44 confirmed at a con-sensus conference.

PET Imaging After HCORT Versus Placebo Administra-tion Participants were instructed to report to the lab-oratory at 8 a.m. on two separate occasions, 1–2 weeksapart. A 20 gauge angiocath was placed in the antecu-bital region for blood sampling and delivery of either17.5 mg HCORT or placebo (normal saline) and 18FDG.A baseline blood sample was collected 10 minutes be-fore the injection of saline or HCORT and at severalintervals postinjection for ACTH and cortisol determi-nation (data presented elsewhere38). The dose ofHCORT yielded circulating plasma cortisol levelswithin a high, but physiological range (mean � stan-dard error � 41.35�1.83 �g/dl).38 To control for ordereffects, the occurrence of drug and placebo was ran-domly assigned in each of the two groups on the firstsession and was then counterbalanced in each groupseparately by alternating between placebo and cortisolday. Neither the rater nor the subject knew whetherdrug or placebo was injected.

FDG was administered intravenously 5 minutes aftersaline or HCORT. Positron emission tomography scanswere carried out following a 35-minute uptake period,as described elsewhere,45 on a General Electric MedicalSystems scanner (model 2048) with in-plane resolution,4.5 mm full width at half maximum (FWHM) 6.5 mmaxially, in the Mount Sinai School of Medicine Neuro-science PET Lab. Twenty axial slices were obtained at6.5 mm intervals. An individually molded thermoplas-tic face mask was used for each participant to help himremain stationary during image acquisition. Following

the scan a series of neuropsychological tests were ad-ministered (results reported elsewhere9).

MRI MRI data were obtained on a 3T Siemens Allegrasystem. High-resolution structural images with goodgray/white matter contrast were obtained using a T1-weighted Magnetization Prepared Rapid Gradient Echosequence. A total of 208 slices were collected with isotro-pic resolution of 0.82 mm3, matrix size�256�256�208,field of view�21 cm, repetition time�2500 ms, echotime�4.38 ms, interval time�1100 ms and a 8° flip anglefast low angle shot acquisition giving a total imagingtime of about 10 minutes. The magnetic resonance im-ages had the skull removed with the Brain ExtractionTool and were then resectioned to standard Talairachcoordinates using a rigid body 6 parameter transforma-tion with FLIRT (Functional-Magnetic-Resonance-Im-aging-Brain Linear Image Registration Tool v5).46 Brainedges were visually traced on all MRI axial slices.

The procedure for tracing the hippocampus andamygdala are described in detail elsewhere.47–48 Briefly,outlining of the amygdala begins at its largest extent(approximately the center in the anteroposterior dimen-sion) where clear boundaries between gray matter andsurrounding white matter are visible. We utilized anedge contrast enhancing technique (gradient filter) inorder to better visualize the dentate gyrus of the hip-pocampus and boundaries between the hippocampusand the amygdala. The anterior boundary of the hip-pocampus at the junction with the amygdala is definedby the presence of the temporal horn of the lateralventricle (lateral and superior to the genu of the hip-pocampus), and the posterior boundary is tracedthroughout its entire extent, past the level of the pul-vinar, until it is no longer visible. Intertracer reliabilityfor this study was assessed by counting the number ofpixels common to two tracers’ regions of interest out-lines divided by the average number of pixels in eachtraced region of interest. For 10 subjects, this was 86%for the amygdala and 88.3% for the hippocampus.

Identification of the ACC Cortical Brodmann’s areameasurements were used to identify the ACC (Brodma-nn’s areas 24, 25, 32 combined), based on the Perrycoronal atlas of the brain,49 as described in detail else-where.50–52 This procedure used a digitized version of adetailed postmortem histologically based atlas that in-cluded 33 coronal slices of the whole brain, less thetemporal lobe, and 28 coronal sections through the tem-

RELATIVE GLUCOSE METABOLIC RATE IN PTSD


poral lobe (14 in each hemisphere). Image segmentationinto gray and white pixels was performed using cutoffvalues determined by visual examination of each sub-ject’s axial within-brain-edge histogram. Relative glu-cose metabolic rate was measured from each subject’scoregistered PET and was calculated by dividing themean FDG uptake values for the gray matter in eachBrodmann area by the whole brain mean FDG uptakevalue. These methods provide standard and knownbrain atlas locations for replication.

StatisticsThe overall analytic strategy was to examine group dif-ferences in response to placebo and HCORT adminis-tration (HCORT-placebo) in the hippocampus, ventralamygdala, dorsal amygdala, and ACC as the main re-gions of interest, using univariate and multivariateanalysis of covariance (MANCOVA) followed by pair-wise comparisons for significant interactions. All re-gions were divided by hemisphere. Additional subdi-visions in the ACC were by gray versus white matterand the three Brodmann’s areas comprising it. An ad-ditional analysis compared the effects of HCORT in thefour regions of interest traced on the right and leftamygdala and hippocampus.

Age was used as a covariate since it was significantlyassociated with the placebo rGMR (r��0.36, df�31,p�0.045) and change in rGMR (r�0.41, df�31,

p�0.020) in the dorsal amygdala. There was no signif-icant association of hippocampal volume with hip-pocampal rGMR, of ventral and dorsal amygdala vol-ume with ventral and dorsal rGMR respectively, andwhole brain volume with the rGMR of the ACC. Ac-cordingly, volumetric measures were not used as co-variates. Presence or absence of comorbid depressivedisorder was significantly associated only with hip-pocampal rGMR after controlling for age (r�0.36,df�29, p�0.046), and was used as an additional covari-ate.

Correlational analyses of rGMR, exploratory analysisof observed changes in laterality in the four regions,and previously reported improvement in workingmemory resulting from HCORT administration9 wereperformed in each group separately.

RESULTS

Demographics, clinical characteristics, and volumetricmeasurements of the sample are summarized in Table1. There were no significant group differences in demo-graphic characteristics or in the total volumes of thehippocampus, amygdala, or the whole brain. ThePTSD� group had higher rates of current and pastdepressive disorder and a trend toward higher rates ofpast alcohol dependence. The period of abstinence from

TABLE 1. Demographics, Clinical Characteristics, and Volumetric Measurements in Veterans With and Without PTSD

PTSD� (n�16) PTSD� (n�16) Group ComparisonsMean (SD) or % (n) Mean (SD) or % (n) (df�30)

DemographicsAge (years) 65.13 (9.92) 60.06 (6.92) t�1.67, df�30, p�0.11Race �2�3.26, df�3, p�0.35

White 81.3% (n�13) 56.3% (n�9)Black 12.5% (n�2) 18.8% (n�3)Asian 0 12.5% (n�2)Hispanic 6.2% (n�1) 12.5% (n�2)

Education (years) 14.9 (3.51) 14.2 (2.23) t�0.72, df�30, p�0.047Clinical Characteristics

Age of focal (worst) trauma 30.2 (17.53) 26.7 (13.76) t�0.63, df�30, p�0.54Current major depression 0 25.0% (n�4) �2�4.57, df�1, p�0.03Past major depression 6.3% (n�1) 81.3% (n�13) �2�18.29, df�1, p�0.0005Past alcohol dependence 18.8% (n�3) 50.0% (n�8) �2�3.46, df�1, p�0.06Past drug dependence 12.5% (n�2) 31.3% (n�5) �2�1.65, df�1, p�0.20CAPS total PTSD symptoms 2.3 (3.7) 47.1 (25.4) t��7.00, df�30, p�0.0005

Brain VolumesWhole brain volume in mm3 1,280,943 (109,450) 1,255,965 (89,031) t�0.71, df�30, p�0.48Left hippocampal volume in mm3 3,747 (696) 3,997 (373) t��1.27, df�30, p�0.22Right hippocampal volume in mm3 4,067 (576) 4,121 (447) t��0.30, df�30, p�0.77Dorsal amygdala volume in mm3 1,637 (338) 1,699 (242) t��0.60, df�30, p�0.55Ventral amygdala volume in mm3 1,800 (382) 1,903 (223) t��0.93, df�30, p�0.36

CAPS�Clinician Administered PTSD Scale

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alcohol abuse and dependence ranged from 2.5 to 43years, with a mean abstinence period of 19.9 years anda median of 19.5 years.

Hippocampus rGMR for Placebo and in Response toHCORTMean rGMR are presented in Figure 1, Panel A. On theplacebo day, there was a main effect of Group on hip-pocampal rGMR (F�4.31, df�1, 28, p�0.047) reflectinglower rGMR in the PTSD� (0.827�0.012) than thePTSD� (0.863�0.012) group. A significant group �hemisphere interaction (F�4.87, df�1, 28, p�0.036) re-flected that the group difference was only significant inthe right (F�7.45, df�1, 28, p�0.011; PTSD�:0.822�0.013, PTSD�: 0.875�0.013) but not the left(F�1.12, df�1, 28, p�0.298; PTSD�: 0.832�0.012,PTSD�: 0.852�0.012) hemisphere. The data are ex-pressed in terms of laterality (left minus right rGMR) inFigure 1, Panel B. Here the mean values demonstratethat in the PTSD� group, rGMR was higher in the leftthan the right hippocampus; in the PTSD� grouprGMR was higher in the right than the left hippocam-pus. However, significant hemispheric differences inrGMR were present in the PTSD� group (t��2.09,df�15, p�0.054) but not the PTSD� group (t�0.24,,df�15, p�0.81), as assessed by paired sample t tests.

When the analysis was repeated adding drug as amain effect, there was a significant drug � group inter-

action (F�4.63, df�1, 28, p�0.04) and a drug � group� hemisphere interaction (F�4.23, df�1, 28, p�0.049).This reflects that there was a significant drug by hemi-sphere interaction in the PTSD� group (F�5.40, df�1,14, p�0.04) but not in the PTSD� group (F�2.08, df�1,14, p�0.17), controlling for age. Figure 1, Panel A dem-onstrates that the effect of HCORT was to increaserGMR in the PTSD� group but decrease rGMR in thePTSD� group. The effect in the PTSD� group wasgreater in the right hemisphere. This had the result ofeliminating group differences in laterality (Figure 1,Panel B).

Ventral and Dorsal Amygdala rGMR at Placebo and inResponse to HCORT

Ventral Amygdala In the absence of an overall maineffect of group (F�0.75, df�1, 29, p�0.39), there was asignificant group � hemisphere interaction (F�4.94,df�1, 29, p�0.034) in rGMR of the ventral amygdala inthe placebo condition, as shown in Figure 2, Panel A,resulting in significant group differences in laterality(Panel B). Post-hoc testing confirmed that, as with thehippocampus, trend-level higher rGMR in the rightthan left hemisphere (t��2.10, df�15, p�0.053) wasonly present in the PTSD� group, whereas no signifi-cant hemispheric differences in rGMR were observed inthe PTSD� group (t�0.87, df�15, p�0.40).

FIGURE 1. Relative Glucose Metabolic Rate (rGMR) Following Placebo and Hydrocortisone (HCORT) Administration in theHippocampus in Veterans With and Without PTSD

A: Data represents the adjusted mean rGMR values (corrected for age) in each hemisphere after placebo and HCORT administration. ThePTSD� group (n�16) is represented by filled circles, and the PTSD� group (n�16) is represented by open circles. The mean�SE values arerepresented by SE bars.

B: Data from Panel A are redrawn from the perspective of laterality, as defined by left rGMR minus right rGMR, the placebo and HCORTdays. The zero line represents no left versus right differences. Negative numbers reflect greater rGMR on the right and positive numbersreflect greater rGMR on the left.



Here too, the effect of HCORT was to reduce thediscrepancy between groups in rGMR observed on theplacebo day, and to eliminate group differences in lat-erality, as suggested by a significant drug � group �hemisphere interaction (F�4.23, df�1, 29, p�0.049).Figure 2, Panel A, demonstrates that rGMR increased inboth groups in both hemispheres in response toHCORT, but post hoc testing demonstrated that theincrease was significant only in the left hemisphere inthe PTSD� group (t��2.49, df�15, p�0.025), but notin the right hemisphere (t��0.61, df�15, p�0.550); forthe PTSD� groups, the increases were not significant ineither hemisphere (left: t��0.15, df�15, p�0.880; right:t�1.09, df�15, p�0.292). As a result, laterality scoresfollowing HCORT no longer differed in the two groups(Figure 2, Panel B).

Dorsal Amygdala There were no significant main ef-fects or interaction of group and hemisphere in theplacebo condition or following treatment with HCORT.The data are graphed in Figure 2 to demonstrate thatwhile significant effects were not observed, the patternsin the dorsal amygdala were similar to those in theventral amygdala

ACC in Response to Placebo and HCORTThe analyses of the ACC were conducted in a similarmanner but included an additional main effect of mat-

ter (which was highly significant (F�43.73, df�1, 29,p�0.0005), reflecting greater activity in the gray thanwhite matter, and did not differ by group (F�2.15,df�1, 29, p�0.15). A main effect of Brodmann’s areawas also included so that subdivisions of the ACCbased on the three Brodmann’s area from which it wascomprised could be more closely examined. No maineffect of Brodmann’s area or group � Brodmann’s areaeffects were noted.

The only significant effect of HCORT was a drug �

group � matter interaction (F�8.48, df�1, 29, p�0.007).This interaction reflected that the effects of HCORTwere in different directions in the two groups in thegray matter (Figure 3, Panel A), but post hoc testing didnot confirm significance within group effects.

Figure 3, Panel B demonstrates that when the mag-nitude of change (rGMR HCORT�rGMR placebo) wasexamined in all four regions (hippocampus, ventralamygdala, dorsal amygdala, ACC) in a three-wayMANCOVA, there was a group � region interaction(F�4.08, df�1, 28, p�0.053). The regions of the limbicsystem showed quite different patterns of response toHCORT, with PTSD� subjects showing increases inboth the hippocampus and ventral amygdala, but de-creases in the ACC. In contrast PTSD� subjects showeddecreases in the hippocampus, increases in the ACC,and little change in the amygdala.

FIGURE 2. Relative Glucose Metabolic Rate (rGMR) Following Placebo and Hydrocortisone (HCORT) Administration in the Ventraland Dorsal Amygdala in Veterans With and Without PTSD

Panel A Panel B

rGM

R

rGM

R (le

ft-rig

ht)

Right

–0.08

0.880.870.860.850.840.830.820.810.80

0.02

0.01

0.00

–0.02

–0.04

–0.06

0.04PTSD+

PTSD–

0.780.79

Placebo HCORTLeft

Placebo HCORT Placebo HCORTLeft

Placebo HCORTRight

Ventral Dorsal

Placebo HCORT Placebo HCORT

Ventral Dorsal

A: Data represents the adjusted mean rGMR values (corrected for age) in each hemisphere after placebo and HCORT administration. ThePTSD� group (n�16) is represented by filled circles, and the PTSD� group (n�16) is represented by open circles. The mean�SE values arerepresented by SE bars.

B: Data from Panel A are redrawn from the perspective of laterality, as defined by left rGMR minus right rGMR, the placebo and HCORTdays. The zero line represents no left versus right differences. Negative numbers reflect greater rGMR on the right and positive numbersreflect greater rGMR on the left.

YEHUDA et al.


Correlations Between the Amygdala and ACCOn the placebo day a significant inverse relationshipbetween the total amygdala and ACC rGMR was foundin the PTSD� group (r��0.55, df�14, p�0.028) (Figure4, Panel A), reflecting strong negative relationshipswith the dorsal (r��0.56, df�14, p�0.025) and the ven-tral (r��0.42, df�14, p�0.10) regions (not graphedseparately). A similar association between the amyg-dala and ACC was not present in the PTSD� group(r�0.28, df�14, p�0.29), and tended toward the oppo-site direction [though it was not significantly differentfrom the PTSD- group using Fisher’s Z (z��0.84,df�14, p�0.40)]. Following HCORT, the two groupsshowed similar (though nonsignificant) correlations[PTSD� group (r��0.15, df�14, p�0.58), PTSD�group (r��0.19, df�14, p�0.49)], (Figure 4, Panel B).

Correlations Between Memory and rGMR Changes inResponse to HCORTGiven our previous finding of a significant improve-ment in working memory in PTSD� following HCORTcompared to performance on the placebo day, com-pared to effects in the PTSD� group (which were com-parable on both days),9 we examined the relationshipbetween change in memory performance and rGMRand change in rGMR and laterality in each region ofinterest. The only significant correlation (r��0.53,df�30, p�0.002) was between change in working mem-ory and change in laterality of the dorsal amygdala

(Figure 5). This remained significant after adjusting thesignificance level by the Bonferroni inequality for mul-tiple correlations, and was further enhanced by a partialcorrelation procedure controlling for age, group, andthe other seven changes in rGMR and laterality(r��0.64, df�21, p�0.001).

DISCUSSION

The results demonstrate regional differences in re-sponse to HCORT. The PTSD� group showed a de-crease in activity in the ACC with HCORT while thePTSD� group showed an increase, which reflects dif-ferences in central glucocorticoid responsiveness. Theeffect of HCORT was more prominent in the gray thanwhite matter, consistent with a greater concentration ofglucocorticoid responsiveness in gray than white mat-ter in the human prefrontal cortex.53 However, the pat-tern of decreased rGMR following HCORT was notrecapitulated in the hippocampus and amygdala. Com-pared to the PTSD� group, the PTSD� group re-sponded to HCORT by increasing metabolism in theright hippocampus and the right ventral amygdala.The effect of HCORT administration in the PTSD�group is consistent with findings in similarly agedhealthy adults who also showed decreased hippocam-pal metabolism without effect in the prefrontal cortexfollowing injection of an even larger dose of HCORT.39

FIGURE 3. Relative Glucose Metabolic Rate (rGMR) Following Placebo and Hydrocortisone (HCORT) Administration in the ACC inVeterans With and Without PTSD

Placebo HCORT

rGM

R

1.08

0

1.07

1.06

1.05

1.04

1.03

PTSD+

PTSD–

rGM

R (H

CORT

-Pla

cebo

)

Hippocampus Ventral amygdala

Dorsal amygdala

ACC

PTSD+

PTSD–

0.02

–0.04

0.01

0.0

–0.01

–0.02

–0.03

0.03

A: In the ACC, there was a drug � group � matter interaction showing that the effect of HCORT was confined to the gray matter, shownin Panel A. In the PTSD� group rGMR decreased from 1.059�0.012 to 1.038�0.014, while the PTSD� group increased from 1.041�0.12 to1.051�0.014.

B: Panel B shows the delta rGMR (HCORT – placebo) for hippocampus, amygdala, and gray matter of the anterior cingulate gyrus. Thedrug effect was most pronounced in the ACC (F�4.076, df�1, 28, p�0.053).



The negligible response to HCORT in the ACC in thePTSD� group is compatible with the demonstration ofa relatively modest effect on rGMR in the ACC in com-bat comparison subjects following exposure to an olfac-tory stimulus designed to trigger traumatic memorycompared to a neutral olfactory condition.25 Yet, in thePTSD� group, this exposure resulted in increasedrGMR in the ACC compared to the neutral condition.Some recent studies have demonstrated increased ac-tivity in the medial prefrontal cortex/ACC in PTSD inresponse to a script-driven provocation paradigm,26

and following nonconscious processing of fear.27 How-ever, the majority of reports demonstrate decreased ac-tivity in response to provocation,20–23,28 leading to thehypothesis that the medial prefrontal cortex is hypore-sponsive in PTSD. Similarly, many studies in PTSDreport increased brain activity in the amygdala in re-sponse to provocation,13,22–23,25 as observed in the ven-tral amygdala in the current study in response toHCORT. Together, the findings of decreased activity inthe medial prefrontal cortex/ACC and increased activ-ity in the amygdala during various conditions in PTSDlead to the hypothesis that disruptions in the normalneurocircuitry of these regions manifest as a failed con-tainment of amygdala activity by the medial prefrontalcortex/ACC.39

In the present study, stronger effects were detected inthe ACC than hippocampus or amygdala, possibly at-tributed to a greater concentration of glucocorticoid re-sponsiveness in the prefrontal cortex.54 Interestingly,

regardless of the extent or direction of group differ-ences in rGMR on the placebo day, the effect ofHCORT, in all cases, was to reduce the differences ob-served on the placebo day. In the hippocampus andamygdala, this was manifest by decreasing group dif-ferences in hemispheric laterality, whereas in the ACCthis was demonstrated by a reduction in rGMR in thePTSD� group.

The current findings showing hemispheric differ-ences may reflect the fact that the right hemisphereoperates with a greater range of activity—thus, the ad-dition of HCORT would be greater due to increasedvariation. However, differences in hemispheric lateral-ity may underlie differences observed regarding rightand left hemispheric differences in provocation-relatedactivation patterns, in association with ACC activity, inthe previously published literature. To date, almost ev-ery study examining the hippocampus, amygdala, orACC has found effects to be restricted to one hemi-sphere, or directionally different in the two hemi-spheres.17,19,21,22 That there is an association betweenbrain laterality and PTSD risk has recently been con-firmed in a large epidemiologic study demonstratingmixed lateral preferences for handedness was associ-ated with PTSD.55 Differences in handedness do notexplain the current findings because only one subject inthe sample was left handed. However, the original hy-pothesis regarding brain laterality emphasized thatthose with a reduced cerebral lateralization may be lessable to detect and/or engage in corrective cognitive

FIGURE 4. Relationship Between the Amygdala and the ACC in Response to Placebo and Hydrocortisone (HCORT) in Veterans Withand Without PTSD

Arm

ygda

la r

GM

R

ACC rGMR

4.0

3.8

3.6

3.4

3.2

3.0

2.84.03.83.63.43.2 4.2

Arm

ygda

la r

GM

R

ACC rGMR

4.0

3.8

3.6

3.4

3.2

3.0

2.83.24.4 4.03.83.63.43.2 4.2 4.4

Baseline HCORT

PTSD+

PTSD–

PTSD+

PTSD–

In both Panel A and B the PTSD� group (n�16) is represented by filled circles, and the comparison group (n�16) by open circles. ForPanel A the solid line shows the trend line for the PTSD� group, r�0.277, and the dotted line shows the trend line for the comparisongroup, r��0.547. For Panel B, the solid line shows the trend line for the PTSD� group, r��0.187, and the dotted line shows the trend linefor the comparison group, r��0.149 (both ns)

YEHUDA et al.


processing of threatening stimuli.56 In the currentstudy, there was less laterality in hippocampal andamygdala rGMR in PTSD on the placebo day, andHCORT reduced these group differences by increasinglateralization in the PTSD� group and decreasing it inthe PTSD� group. Resting data with 18FDG-PET canassess trait-like laterality differences present without aspecific psychological stimulus. Blood-oxygen-level-de-pendent (BOLD) activation studies are only able to in-terpret laterality (or hemispheric) differences in connec-tivity between PTSD and comparison groups inresponse to stimulation. Yet, numerous such observa-tions have been made, supporting the importance oflaterality differences in brain function in PTSD.

Interestingly, the only region to demonstrate an acti-vation-related association with improvement in work-ing memory was the dorsal amygdala. Though groupdifferences for this region did not approach statisticalsignificance, the correlation between brain activity inthis region and memory performance is compatiblewith results of animal studies demonstrating that glu-cocorticoid induced effects on memory are enabled bynoradrenergic activation of the basolateral amygdala.57

The findings add to the literature not only in theirdemonstration of group differences in the effects ofHCORT, but also in their description of group differ-ences in rGMR under resting conditions without phar-

macological challenge. The differences on the placeboday, in particular, provide a context for interpretingdata in response to provocation. Previously reportedgroup differences in the direction of amygdala and/orACC activity in response to provocation may be mis-leading without consideration of baseline activation.Had our study simply examined metabolic effects ofHCORT administration on PTSD� compared toPTSD� we would have likely concluded that effectswere minimal, if not absent.

The negative correlation between ACC and amygdalametabolism observed on the placebo day in the PTSD�

group implies that this neural circuit may regulateamygdala activity even under ambient conditions.58–60

In the present study, this relationship was absent, andeven in the opposite direction (although nonsignifi-cant), in subjects with PTSD. Furthermore, in PTSD therGMR in the ACC under placebo conditions was in-creased relative to comparison subjects. It is difficult tointerpret the effect of this activity on the amygdala sinceright and left hemispheres showed different responsesin PTSD. In that the PTSD� group on the placebo dayshowed greater activity of the amygdala in the left, butlower activity in the right compared to the PTSD�

group, the placebo ACC/amygdala relationship can ei-ther be interpreted as inverse or positive depending onthe hemisphere. In response to a single dose of HCORT,the associations between ACC and amygdala metabo-lism were no longer discrepant between the PTSD�

and PTSD� groups, nor were differences in these asso-ciations present in the two hemispheres. It is particu-larly noteworthy that the effect of HCORT resulted insimilar associations between amygdala and ACC activ-ity in both groups on the active treatment day since theeffect of HCORT in PTSD� subjects was to restore anormal inverse association, while PTSD� subjects ex-perienced a disruption of this normal neural network. Alimitation of the study is that without a healthy com-parison group not exposed to combat it is unclearwhether the PTSD� group also represents a group withaltered glucocorticoid function. Additionally, as weonly studied male veterans, these results may not begeneralizable.

Regarding possible treatment implications, the bene-ficial effects of glucocorticoids have been investigatedand continue to be of interest, particularly in PTSDprophylaxis.3,61 The current observations are consistentwith the beneficial effects noted on memory observed in

FIGURE 5. Relationship Between the Change, From Placebo toHCORT Day, in Letter Number Sequencing Scoresand Change in Laterality in the Dorsal Amygdala

Change in Laterality (Left-Right) in the Dorsal Amygdala (HCORT-Placebo)

–0.2 –0.20.10.0–0.1 0.3

Chan

ge in

Let

ter

Num

ber

Sequ

enci

ng (H

CORT

-Pla

cebo

)

–4

43210

–1–2–3

5PTSD+

PTSD–

The PTSD� group (n�16) is represented by filled circles, and thecomparison group (n�16) by open circles. The solid line shows thetrend line for the relationship between the change in letter numbersequencing scores from placebo to HCORT days and the change inthe laterality (left-right) in the dorsal amygdala, r��0.527.



this older cohort. However, in a younger cohortHCORT resulted in impairment of working memory,8

consistent with a larger literature in healthy sub-jects.62–63 Regionally specific differential responses toglucocorticoids have been noted according to age,64–69

and their relevance should be fully explored since itmay be that therapeutic approaches that are optimal atsome phases of illness are contraindicated in othersbased on age, chronicity, or other factors contributing todynamic changes in pathophysiology and brain func-tion. Little is known about the efficacy of standard treat-ments of PTSD in the elderly. However the currentdiscrepancies between aging PTSD and normal agingprofiles suggests that we cannot extrapolate on the basis

of the literature on normal aging to what might be trueas persons with PTSD advance in age.

This work was supported by a VA Merit Review Grant(RY) and, in part by a grant (5 M01 RR00071) for theMount Sinai General Clinical Research Center from the Na-tional Institute of Health. The authors wish to thank KarinaStavitsky for expert and professional coordination of thisresearch project, Dr. Linda Bierer for database construction,Yuliya Torosjan for scanner operation, Dr. King-Wai Chu forprogram development and support, and Drs. Lisa Tischlerand Alicia Hirsch for conducting diagnostic evaluations. Dr.Yehuda had full access to all of the data in the study and takesresponsibility for the integrity of the data and the accuracy ofthe data analysis.

References

1. Yehuda R: Advances in understanding neuroendocrine alter-ations in PTSD and their therapeutic implications. Ann N YAcad Sci 2006; 1071:137–166

2. Aerni A, Traber R, Hock C, et al: Low-dose cortisol for symp-toms of posttraumatic stress disorder. Am J Psychiatry 2004;161:1488–1490

3. Schelling G, Kilger E, Roozendaal B, et al: Stress doses ofhydrocortisone, traumatic memories, and symptoms of post-traumatic stress disorder in patients after cardiac surgery: arandomized study. Biol Psychiatry 2004; 55:627–633

4. Schelling G, Roozendaal B, de Quervain DJ: Can posttrau-matic stress disorder be prevented with glucocorticoids? AnnN Y Acad Sci 2004; 1032:158–166

5. Sher L, Oquendo MA, Li S, et al: Higher cerebrospinal fluidhomovanillic acid levels in depressed patients with comorbidposttraumatic stress disorder. Eur Neuropsychopharmacol2005; 15:203–209

6. Geracioti TD Jr, Baker DG, Ekhator NN, et al: CSF norepi-nephrine concentrations in posttraumatic stress disorder.Am J Psychiatry 2001; 158:1227–1230

7. Baker DG, West SA, Nicholson WE, et al: Serial CSF cortico-tropin-releasing hormone levels and adrenocortical activity incombat veterans with posttraumatic stress disorder. Am J Psy-chiatry 1999; 156:585–588

8. Grossman R, Yehuda R, Golier J, et al: Cognitive effects ofintravenous hydrocortisone in subjects with PTSD andhealthy control subjects. Ann N Y Acad Sci 2006; 1071:410–421

9. Yehuda R, Harvey PD, Buchsbaum M, et al: Enhanced effectsof cortisol administration on episodic and working memory inaging veterans with PTSD. Neuropsychopharmacology 2007;32:2581–2591

10. Perlman WR, Webster MJ, Herman MM, et al: Age-relateddifferences in glucocorticoid receptor mRNA levels in the hu-man brain. Neurobiol Aging 2007; 28:447–458

11. Bizon JL, Helm KA, Han JS, et al: Hypothalamic-pituitary-adrenal axis function and corticosterone receptor expressionin behaviourally characterized young and aged long-evansrats. Eur J Neurosci 2001; 14:1739–1751

12. Yau JL, Olsson T, Morris RG, et al: Glucocorticoids, hippocam-

pal corticosteroid receptor gene expression and antidepres-sant treatment: relationship with spatial learning in youngand aged rats. Neuroscience 1995; 66:571–581

13. Shin LM, Rauch SL, Pitman RK: Amygdala, medial prefrontalcortex, and hippocampal function in PTSD. Ann N Y Acad Sci2006; 1071:67–79

14. Liberzon I, Britton JC, Phan KL: Neural correlates of traumaticrecall in posttraumatic stress disorder. Stress 2003; 6:151–156

15. Rauch SL, Shin LM, Phelps EA: Neurocircuitry models ofposttraumatic stress disorder and extinction: human neuroim-aging research–past, present, and future. Biol Psychiatry 2006;60:376–382

16. Lanius RA, Bluhm R, Lanius U, et al: A review of neuroim-aging studies in PTSD: heterogeneity of response to symptomprovocation. J Psychiatr Res 2006; 40:709–729

17. McEwen BS: Glucocorticoids, depression, and mood disor-ders: structural remodeling in the brain. Metabolism 2005;54:20–23

18. Kim JJ, Haller J: Glucocorticoid hyper- and hypofunction:stress effects on cognition and aggression. Ann N Y Acad Sci2007; 1113:291–303

19. Roozendaal B, McReynolds JR, McGaugh JL: The basolateralamygdala interacts with the medial prefrontal cortex in regu-lating glucocorticoid effects on working memory impairment.J Neurosci 2004; 24:1385–1392

20. Shin LM, Orr SP, Carson MA, et al: Regional cerebral bloodflow in the amygdala and medial prefrontal cortex duringtraumatic imagery in male and female Vietnam veterans withPTSD. Arch Gen Psychiatry 2004; 61:168–176

21. Shin LM, Wright CI, Cannistraro PA, et al: A functional mag-netic resonance imaging study of amygdala and medial pre-frontal cortex responses to overtly presented fearful faces inposttraumatic stress disorder. Arch Gen Psychiatry 2005; 62:273–281

22. Williams LM, Kemp AH, Felmingham K, et al: Trauma mod-ulates amygdala and medial prefrontal responses to con-sciously attended fear. Neuroimage 2006; 29:347–357

23. Bremner JD, Vermetten E, Schmahl C, et al: Positron emissiontomographic imaging of neural correlates of a fear acquisition

YEHUDA et al.


and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol Med2005; 35:791–806

24. Phan KL, Britton JC, Taylor SF, et al: Corticolimbic blood flowduring nontraumatic emotional processing in posttraumaticstress disorder. Arch Gen Psychiatry 2006; 63:184–192

25. Vermetten E, Schmahl C, Southwick SM, et al: Positron tomo-graphic emission study of olfactory induced emotional recallin veterans with and without combat-related posttraumaticstress disorder. Psychopharmacol Bull 2007; 40:8–30

26. Lanius RA, Williamson PC, Boksman K, et al: Brain activationduring script-driven imagery induced dissociative responsesin PTSD: a functional magnetic resonance imaging investiga-tion. Biol Psychiatry 2002; 52:305–311

27. Bryant RA, Kemp AH, Felmingham KL, et al: Enhancedamygdala and medial prefrontal activation during noncon-scious processing of fear in posttraumatic stress disorder: anfMRI study. Hum Brain Mapp 2008; 29:517–523

28. Britton JC, Phan KL, Taylor SF, et al: Corticolimbic blood flowin posttraumatic stress disorder during script-driven imagery.Biol Psychiatry 2005; 57:832–840

29. Gilboa A, Shalev AY, Laor L, et al: Functional connectivity ofthe prefrontal cortex and the amygdala in posttraumatic stressdisorder. Biol Psychiatry 2004; 55:263–272

30. Kim H, Somerville LH, Johnstone T, et al: Inverse amygdalaand medial prefrontal cortex responses to surprised faces.Neuroreport 2003; 14:2317–2322

31. Nomura M, Ohira H, Haneda K, et al: Functional associationof the amygdala and ventral prefrontal cortex during cogni-tive evaluation of facial expressions primed by masked angryfaces: an event-related fMRI study. Neuroimage 2004; 21:352–363

32. Smith AP, Stephan KE, Rugg MD, et al: Task and contentmodulate amygdala-hippocampal connectivity in emotionalretrieval. Neuron 2006; 49:631–638

33. Taylor SF, Liberzon I, Fig LM, et al: The effect of emotionalcontent on visual recognition memory: a PET activation study.Neuroimage 1998; 8:188–197

34. Whalen PJ, Shin LM, McInerney SC, et al: A functional MRIstudy of human amygdala responses to facial expressions offear versus anger. Emotion 2001; 1:70–83

35. Urry HL, van Reekum CM, Johnstone T, et al: Amygdala andventromedial prefrontal cortex are inversely coupled duringregulation of negative affect and predict the diurnal pattern ofcortisol secretion among older adults. J Neurosci 2006; 26:4415–4425

36. Bremner JD, Vythilingam M, Vermetten E, et al: Neural cor-relates of declarative memory for emotionally valenced wordsin women with posttraumatic stress disorder related to earlychildhood sexual abuse. Biol Psychiatry 2003; 53:879–889

37. Lanius RA, Frewen PA, Girotti M, et al: Neural correlates oftrauma script-imagery in posttraumatic stress disorder withand without comorbid major depression: a functional MRIinvestigation. Psychiatry Res 2007; 155:45–56

38. Yehuda R, Yang RK, Buchsbaum MS, et al: Alterations incortisol negative feedback inhibition as examined using theACTH response to cortisol administration in PTSD. Psycho-neuroendocrinology 2006; 31:447–451

39. de Leon MJ, McRae T, Rusinek H, et al: Cortisol reduceshippocampal glucose metabolism in normal elderly, but not in

Alzheimer’s disease. J Clin Endocrinol Metab 1997; 82:3251–3259

40. Golier JA, Harvey PD, Legge J, et al: Memory performance inolder trauma survivors: implications for the longitudinalcourse of PTSD. Ann NY Acad Sci 2006; 1071:54–66

41. Gazdzinski S, Durazzo TC, Meyerhoff DJ: Temporal dynamicsand determinants of whole brain tissue volume changes dur-ing recovery from alcohol dependence. Drug Alcohol Depend2005; 78:263–273

42. Pfefferbaum A, Sullivan EV, Mathalon DH, et al: Longitudinalchanges in magnetic resonance imaging brain volumes in ab-stinent and relapsed alcoholics. Alcohol Clin Exp Res 1995;19:1177–1191

43. Spitzer RL, Williams JBW, Gibbon M: Structured Clinical In-terview for DSM-IV (SCID). New York, New York State Psy-chiatric Institute, Biomedical Research, 1995

44. Blake DD, Weathers FW, Nagy LM, et al: The development ofa clinician-administered PTSD scale. J Trauma Stress 1995;8:75–90

45. Hazlett EA, Buchsbaum MS, Mohs RC, et al: Age-related shiftin brain region activity during successful memory perfor-mance. Neurobiol Aging 1998; 19:437–445

46. Jenkinson M, Smith S: A global optimisation method for ro-bust affine registration of brain images. Med Image Anal 2001;5:143–156

47. Yehuda R, Golier JA, Tischler L, et al: Hippocampal volume inaging combat veterans with and without post-traumatic stressdisorder: relation to risk and resilience factors. J Psychiatr Res2007; 41:435–445

48. Haznedar MM, Buchsbaum MS, Wei TC, et al: Limbic cir-cuitry in patients with autism spectrum disorders studiedwith positron emission tomography and magnetic resonanceimaging. Am J Psychiatry 2000; 57:1994–2001

49. Perry RH: Personal communication, 199350. Buchsbaum MS, Nenadic I, Hazlett EA, et al: Differential met-

abolic rates in prefrontal and temporal brodmann areas inschizophrenia and schizotypal personality disorder. Schizo-phr Res 2002; 54:141–150

51. Stein DJ, Buchsbaum MS, Hof PR, et al: Greater metabolic ratedecreases in hippocampal formation and proisocortex than inneocortex in Alzheimer’s disease. Neuropsychobiology 1998;37:10–19

52. Mitelman SA, Buchsbaum MS, Brickman AM, et al: Corticalintercorrelations of frontal area volumes in schizophrenia.Neuroimage 2005; 27:753–770

53. Sanchez MM, Young LJ, Plotsky PM, et al: Distribution ofcorticosteroid receptors in the rhesus brain: relative absence ofglucocorticoid receptors in the hippocampal formation. J Neu-rosci 2000; 20:4657–4668

54. Boscarino JA, Hoffman SN: Consistent association betweenmixed lateral preference and PTSD: confirmation among anational study of 2490 US army Vietnam veterans. PsychosomMed 2007; 69:365–369

55. Chemtob CM, Wang Y, Dugan KL, et al: Mixed lateral pref-erence and peritraumatic reactions to the World Trade Centerattacks. J Nerv Ment Dis 2006; 194:874–876

56. Roozendaal B, Hahn EL, Nathan SV, et al: Glucocorticoideffects on memory retrieval require concurrent noradrenergicactivity in the hippocampus and basolateral amygdala. J Neu-rosci 2004; 24:8161–8169



57. Das P, Kemp AH, Liddell BJ, et al: Pathways for fear percep-tion: modulation of amygdala activity by thalamo-cortical sys-tems. Neuroimage 2005; 26:141–148

58. Likhtik E, Pelletier JG, Paz R, et al: Prefrontal control of theamygdala. J Neurosci 2005; 25:7429–7437

59. Schelling G, Roozendaal B, Krauseneck T, et al: Efficacy ofhydrocortisone in preventing posttraumatic stress disorderfollowing critical illness and major surgery. Ann N Y Acad Sci2006; 1071:46–53

60. New AS, Hazlett EA, Buchsbaum MS, et al: Amygdala-pre-frontal disconnection in borderline personality disorder. Neu-ropsychopharm 2007; 32:1629–1640

61. Lupien SJ, Wilkinson CW, Briere S, et al: The modulatory effectsof corticosteroids on cognition: studies in young human popu-lations. Psychoneuroendocrinology 2002; 27:401–416

62. Newcomer JW, Selke G, Melson AK, et al: Decreased memoryperformance in healthy humans induced by stress-level corti-sol treatment. Arch Gen Psychiatry 1999; 56:527–533

63. Miller DB, O’Callaghan JP: Aging, stress and the hippocam-pus. Ageing Res Rev 2005; 4:123–140

64. De Leon MJ, George AE, Golomb J, et al: Frequency of hip-pocampal formation atrophy in normal aging and Alzheimer’sdisease. Neurobiol Aging 1997; 18:1–11

65. de Kloet ER: Corticosteroids, stress, and aging. Ann N Y AcadSci 1992; 663:357–371

66. Sapolsky RM: Glucocorticoids, stress, and their adverse neu-rological effects: relevance to aging. Exp Gerontol 1999; 34:721–732

67. Heffelfinger AK, Newcomer JW: Glucocorticoid effects onmemory function over the human life span. Dev Psychopathol2001; 13:491–513

68. Lupien SJ, Wilkinson CW, Briere S, et al: Acute modulation ofaged human memory by pharmacological manipulation ofglucocorticoids. J Clin Endocrinol Metab 2002; 87:3798–3807

69. Murphy EK, Spencer RL, Sipe KJ, et al: Decrements in nuclearglucocorticoid receptor (GR) protein levels and DNA bindingin aged rat hippocampus. Endocrinology 2002; 143:1362–1370

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