0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder FREE

Lisa M. Shin, PhD; Natasha B. Lasko, PhD; Michael L. Macklin, BA; Rachel D. Karpf, BA; Mohammed R. Milad, PhD; Scott P. Orr, PhD; Jared M. Goetz, BA; Alan J. Fischman, MD, PhD; Scott L. Rauch, MD; Roger K. Pitman, MD
[+] Author Affiliations

Author Affiliations: Department of Psychology, Tufts University, Medford, Massachusetts (Dr Shin); Departments of Psychiatry (Drs Shin, Lasko, Milad, Orr, Rauch, and Pitman; Ms Karpf; and Mr Goetz) and Radiology (Dr Fischman), Massachusetts General Hospital and Harvard Medical School, Boston; Veterans Affairs Research Service, Manchester, New Hampshire (Drs Lasko and Orr and Mr Macklin); and Department of Psychiatry, McLean Hospital, Belmont, Massachusetts, and Harvard Medical School, Boston (Dr Rauch).


Arch Gen Psychiatry. 2009;66(10):1099-1107. doi:10.1001/archgenpsychiatry.2009.138.
Text Size: A A A
Published online

Context  Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala, and hippocampus in individuals with posttraumatic stress disorder (PTSD).

Objective  To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors.

Design  Cross-sectional design including identical twins discordant for trauma exposure.

Setting  Academic medical center.

Participants  Combat-exposed veterans with PTSD (n = 14) and their identical co-twins not exposed to combat (n = 14) as well as combat-exposed veterans without PTSD (n = 19) and their identical co-twins not exposed to combat (n = 19).

Main Outcome Measures  We used positron emission tomography and fluorodeoxyglucose 18 to examine resting regional cerebral metabolic rate for glucose (rCMRglu).

Results  Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) compared with veterans without PTSD and their co-twins. Resting rCMRglu in the dACC/MCC in unexposed co-twins was positively correlated with combat exposure severity, PTSD symptom severity, and alcohol use in their exposed twins.

Conclusions  Enhanced resting metabolic activity in the dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.

Figures in this Article

Neuroimaging studies of posttraumatic stress disorder (PTSD) have reported functional abnormalities in several brain regions, including the anterior cingulate cortex (ACC), amygdala, and hippocampus. The ACC is a medial prefrontal structure composed of several functional subdivisions.1,2 In healthy individuals, rostral regions of the ACC (rACC) are activated during emotional states and tasks that involve interference from emotional stimuli.38 In contrast, dorsal regions of the ACC (dACC) have traditionally been thought to be involved in multiple cognitive processes like performance monitoring, response selection, error detection, and decision making,5,6,9,10 though a role for the dACC in fear learning has recently been reported.11 In PTSD, the rACC is hyporesponsive to trauma-related and other emotionally negative stimuli1223 and is hypoactive at rest.24 In addition, rACC activation appears to be inversely related to PTSD symptom severity.19,21,25 In contrast, the dACC appears to be hyperresponsive during fear conditioning, interference, and auditory oddball tasks in PTSD.23,2628

The amygdala is a medial temporal lobe structure that is involved in the detection of potential threat or biologically relevant predictive ambiguity in the environment.2931 In PTSD, the amygdala appears to be hyperresponsive during exposure to both trauma-related stimuli3238 and emotional stimuli unrelated to trauma,19,21,23,39 during the performance of neutral tasks,24,27 and even while at rest.40 Amygdala activation has been shown to be positively correlated with PTSD symptom severity36,37,39,41 and self-reported anxiety.34

The hippocampus is involved in explicit memory processes as well as memory for fear extinction and context in pavlovian fear conditioning.4245 Diminished hippocampal activation in PTSD has been observed during symptomatic states,12,13 administration of the α2-antagonist yohimbine,46 and memory tasks that involve words, passages, or spatial locations.4750

Most functional neuroimaging studies of PTSD have involved the examination of brain activation during symptom provocation or cognitive tasks. Fewer studies have examined resting brain activity in PTSD,24,40,46,5153 and their findings have been inconsistent. Nearly all previous resting-state studies have measured regional cerebral blood flow using single-photon emission computed tomography or positron emission tomography (PET). Only 2 previous PET studies have examined regional cerebral metabolic rate for glucose (rCMRglu) at rest in PTSD. One such study reported diminished rCMRglu in the temporal cortex in PTSD.46 The other study found diminished rCMRglu in cingulate gyri, hippocampus, and insula among other regions and increased rCMRglu in the cerebellum and fusiform, temporal, and occipital cortices.53

The origin of functional neuroimaging abnormalities in PTSD is largely unknown. It is tempting to conclude that because PTSD is defined as a result of a traumatic life event, all abnormalities associated with it are also caused by that event. However, PTSD is moderately heritable.5456 We studied identical twins who are discordant for combat exposure to determine whether resting rCMRglu abnormalities found in PTSD represent acquired signs of the disorder or familial risk factors for developing it upon trauma exposure. Vietnam combat veterans with and without PTSD as well as their combat-unexposed identical co-twins (without PTSD) were studied. We reasoned that resting rCMRglu abnormalities found in the combat veterans with PTSD but not in their identical co-twins would reflect acquired characteristics of PTSD, whereas resting rCMRglu abnormalities present in both the combat veterans with PTSD and their co-twins would represent familial risk factors. Based on the studies reviewed above, we hypothesized that combat veterans with PTSD would show lower rCMRglu in the rACC and hippocampus and higher rCMRglu in the dACC and amygdala compared with veterans without PTSD. However, given the dearth of informative research, we had no hypotheses regarding whether any rCMRglu abnormalities found to be associated with PTSD would represent acquired signs or risk factors. We chose to use PET over single-photon emission computed tomography owing to its superior spatial resolution. Measures of rCMRglu are closely coupled to neuronal function.57

PARTICIPANTS

Participants were drawn from a pool of identical twins who had participated in a previous study of physiological responses to loud tones. A description of the recruitment strategy and characteristics of the participant population has been reported elsewhere.58 Thirty-three pairs of male monozygotic twins participated (66 participants in total). Each exposed (Ex) twin had served in the Vietnam combat theater, whereas his unexposed (Ux) co-twin had not. Of the exposed twins, 14 developed current combat-related PTSD (P+) and 19 never did (P−), as determined by the Clinician-Administered PTSD Scale59 using criteria from the DSM-IV.60 Thus, the participants were divided into 4 different groups: (1) ExP+, combat-exposed veterans with current, combat-related PTSD (n = 14); (2) UxP+, their co-twins who were not exposed to combat and did not have PTSD (n = 14); (3) ExP−, combat-exposed veterans who never had combat-related PTSD (n = 19); and (4) UxP−, their co-twins who were not exposed to combat and did not have PTSD (n = 19). The study was approved by the institutional review board at Partners Healthcare System, Boston, Massachusetts. Written informed consent was obtained from each participant after a full explanation of the procedures.

DEMOGRAPHICS AND PSYCHOMETRICS

Fifty-six participants were right-handed, and 3 (1 ExP+ and 2 ExP−) were left-handed. (Handedness information was missing for 1 ExP+, 2 ExP−, 2 UxP+, and 2 UxP−.) None of the participants reported a history of major head injury involving loss of consciousness for more than 10 minutes, tumor, epilepsy, cerebrovascular accident, or other neurological disorders.

According to the Structured Clinical Interview for DSM-IV,61 participants in the ExP+ group met criteria for the following current comorbid diagnoses: major depression (n = 4), dysthymia (n = 2), panic disorder (n = 1), social phobia (n = 3), specific phobia (n = 1), generalized anxiety disorder (n = 1), eating disorder (n = 1), alcohol dependence (n = 1), and substance use disorder (n = 2). Participants in the other groups met criteria for the following current diagnoses: major depression (1 UxP+), dysthymia (1 ExP− and 2 UxP−), social phobia (1 UxP+), specific phobia (1 UxP+ and 1 ExP−), eating disorder (1 ExP−), and alcohol dependence (1 UxP+ and 2 UxP−).

Thirteen participants (5 ExP+, 3 UxP+, 2 ExP−, and 3 UxP−) were taking antidepressants at the time of study. Two (1 ExP+ and 1 UxP+) were taking benzodiazepines. These medications were included among the potentially confounding medications or drugs that were excluded in the subanalysis reported below. Potentially confounding drugs or medications were antihistamines, sympathomimetics, sympatholytics, parasympathomimetics, parasympatholytics, skeletal muscle relaxants, hypotensive agents, vasodilating agents, pressor agents, β-blockers, antiarrhythmics, calcium channel blockers, narcotics, anticonvulsants, antidepressants, neuroleptics, benzodiazepines, other psychotherapeutic agents, cerebral stimulants, sedatives, and hypnotics.

Participants completed the Beck Depression Inventory,62 the Michigan Alcohol Screening Test (MAST),63 the Childhood Trauma Questionnaire,64 the Positive and Negative Affect Schedule,65 and a measure of the severity of combat exposure.66 The latter scale, which has good reliability and validity, assesses the extent to which the veteran had experienced a variety of different situations in combat, including being wounded, ambushed, or captured (Table 1).66

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Combat-Exposed Vietnam Veterans With and Without PTSD and Their Unexposed, Identical Co-twins
FLUORODEOXYGLUCOSE F18–PET PROCEDURES

The PET equipment and procedures have been described previously.67 Participants were instructed to fast for at least 6 hours prior to PET scanning. Blood glucose levels were checked immediately before intravenous administration of fluorodeoxyglucose F18 (FDG) (approximately 185 MBq, 5 mCi). Then each participant was instructed to sit quietly with his eyes closed in a dedicated waiting room for a 40-minute uptake period. The participant was then escorted to an adjacent room that housed the HR+ PET scanner (CTI/Siemens Medical Solutions, Iselin, New Jersey), which had an in-plane and axial resolution of 4.5 mm full-width at half-maximum intensity, 63 contiguous slices with 2.5-mm separation, and a sensitivity of 200 000 cps/μCi/mL (2-dimensional) and 900 000 cps/μCi/mL (3-dimensional). After entering the scanner, each participant's head was fitted with an inflatable cushion to minimize movement and aligned in the scanner relative to the canthomeatal line.

MAGNETIC RESONANCE IMAGING PROCEDURES

Structural magnetic resonance imaging (MRI) scans were obtained from a Symphony/Sonata 1.5-T whole-body high-speed imaging device equipped for echo-planar imaging (Siemens Medical Systems) with a 3-axis gradient head coil. Head movement was restricted using expandable foam cushions. After an automated scout image was acquired and shimming procedures were performed to optimize field homogeneity, high-resolution structural MRI images (3-dimensional magnetization-prepared rapid gradient-echo; repetition time/echo time/flip angle = 2.73 seconds/3.31 milliseconds/7°) with a 1.33-mm slice thickness were collected. Functional MRIs were subsequently collected for separate studies, the results of which are to be reported elsewhere. The PET scans preceded MRI scans by 1 day.

STATISTICAL ANALYSIS

Two types of analyses were used: those conducted on (1) whole-brain voxelwise FDG-PET data and (2) FDG-PET data extracted from functional regions of interest (ROIs). These 2 different types of data required somewhat different but parallel 2-factor analytic strategies. Conceptually speaking, in both types of analyses we treated exposed vs unexposed co-twins as a repeated measure (ie, exposure). The twin pairs in which the combat-exposed twin had PTSD were treated as a separate group from the twin pairs in which the exposed twin never had PTSD. We reasoned that a significant difference between these 2 groups (ie, main effect of PTSD diagnosis) would be consistent with a familial risk factor (as long as there was also no interaction between PTSD diagnosis and exposure); in this case, the combat-exposed twins with PTSD (ExP+) would have the same functional abnormality as their unexposed co-twins without PTSD (UxP+). (Follow-up analyses were conducted to confirm differences between the ExP+ and ExP− subgroups, and between the UxP+ and UxP− subgroups.) A significant PTSD diagnosis by exposure interaction (reflecting an abnormality in the exposed twins with PTSD only) would indicate an acquired sign of PTSD. Lastly, a difference between all combat-exposed twins compared with all twins not exposed to combat (ie, a main effect of exposure) in the absence of an interaction would suggest that a functional abnormality is associated with exposure to combat and not PTSD per se.

Voxelwise Analysis

The whole-brain voxelwise analyses were conducted using the SPM2 software package (Wellcome Department of Cognitive Neurology, London, England). Within SPM2, each participant's PET image was coregistered to his high-resolution structural MRI. The resulting images were spatially normalized in a standard stereotactic space (Montreal Neurological Institute) and then smoothed (6 mm full-width at half-maximum). At each voxel, the rCMRglu data were normalized by the global mean and fit to a linear statistical model by the method of least squares. Hypotheses were tested as contrasts in which linear compounds of the model parameters were evaluated using t statistics, which were then transformed to z scores.

We used an approach that consisted of 2 hierarchical levels of analysis, in which the second level's random-effects analysis absorbed the random effects from the first level. For the purpose of examining the main effect of PTSD diagnosis, for each pair, the rCMRglu values of the exposed and unexposed participants were averaged (first level), and then the pairs with and without PTSD were contrasted (second level). For the purpose of examining the PTSD diagnosis × exposure interaction, for each pair, the rCMRglu values of the exposed and unexposed participants were subtracted one from the other (first level), and then the pairs with and without PTSD were contrasted (second level). For the purpose of examining the main effect of combat exposure, the rCMRglu values of the exposed and unexposed subjects were contrasted (first level only).

The statistical parametric maps resulting from the above voxelwise analyses were inspected for the main effect of PTSD diagnosis, main effect of exposure, and the PTSD diagnosis × exposure interaction in our a priori structures of interest (dACC, rACC, amygdala, and hippocampus). The amygdala and hippocampus were defined by their anatomical boundaries. The superior and lateral boundaries of the ACC were also defined anatomically. The dACC was defined as the portion of the anterior cingulate gyrus superior to the corpus callosum, between y = 0 and y = 30 mm.68 The rACC was defined as the portion of the anterior cingulate gyrus that is anterior to the genu of the corpus callosum and where y > 30 mm. (Most, though not all, previous findings of diminished function in ACC in PTSD have occurred at y > 30 mm.) Given our strong hypotheses, we applied a significance threshold of uncorrected, 2-tailed P < .001 (z score >3.29) to rCMRglu differences found in these structures. (Because the procedure of correcting P values based on region size is biased toward finding significance in small structures, we chose to use the above stated constant significance threshold.) To regions about which we had no a priori prediction, we applied a more conservative constant significance threshold of uncorrected, 2-tailed P < .00001 (z score >4.42).

ROI Analysis

We extracted rCMRglu data from clusters surrounding significant voxels identified in the SPM analyses. We then analyzed these clusters for the main effect of PTSD diagnosis, main effect of exposure, and their interaction using a mixed model that treated combat exposure as a within-pairs repeated measure, diagnosis as a between-pairs measure, and twin pairs as a random effect,69 including the covariates described in the “Results” section. Additional correlational analyses were performed on the ROI data, as shown below.

VOXELWISE ANALYSIS

No voxels met significance thresholds for a main effect of exposure or a PTSD diagnosis × exposure interaction. However, there were significant main effects of PTSD diagnosis in the dACC, midcingulate cortex, and left inferior parietal cortex (Table 2). In each case, combat-exposed veterans with PTSD and their unexposed co-twins (combined) exhibited greater rCMRglu than combat-exposed veterans without PTSD and their unexposed co-twins (combined). With one exception, these results remained significant when we temporarily removed from the voxelwise analyses data from (1) participants with current mood disorders or substance use disorders (all z scores >3.80), (2) participants taking potentially confounding medications (as defined above) (all z scores >3.77), or (3) participants who were left-handed or with missing handedness information (all z scores >4.41). The exception was that the z score of the left inferior parietal finding dropped below threshold after these participant exclusions; for this reason, we did not consider this brain region further. No voxels exhibited significantly lower rCMRglu in the PTSD twin pairs (ie, ExP+ and UxP+ groups) relative to the non-PTSD twin pairs (ie, ExP− and UxP− groups). Comparisons between subgroups (ExP+ vs ExP− and UxP+ vs UxP−) are presented in Table 2 and are consistent with the main effect of PTSD diagnosis.

ROI ANALYSIS
Dorsal Anterior Cingulate Cortex/Midcingulate Cortex

Inspection of the statistical parametric maps revealed that the most significant voxels in the dACC and midcingulate cortex (MCC) were part of a common cluster (k = 109 voxels), henceforth referred to as the dACC/MCC ROI (Figure 1). Individual subjects' values from this ROI were extracted and plotted by pairs in Figure 2. The within-pair correlation across PTSD and non-PTSD groups was r = 0.73, P < .001, indicating a high degree of familiality of the measure (non-PTSD subjects alone, r = 0.71, P < .001; PTSD subjects alone, r = 0.41, P = .07; these correlations were not significantly different from each other, P = .25).

Place holder to copy figure label and caption
Figure 1.

Main effect of posttraumatic stress disorder (PTSD) diagnosis on regional cerebral metabolic rate for glucose (rCMRglu). A, Resting rCMRglu in the dorsal anterior cingulate cortex/midcingulate cortex (arrow) that is greater in combat-exposed twins with PTSD and their unexposed identical co-twins compared with combat-exposed twins without PTSD and their identical co-twins. Fluorodeoxyglucose F18 data are superimposed on a standard SPM2 T1 template and displayed according to neurological convention. B, The accompanying bar graph presents group rCMRglu means. Error bars represent standard error of the mean.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Correlation of regional cerebral metabolic rate for glucose (rCMRglu) between co-twins. Individual subjects' rCMRglu values from the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) cluster plotted by pairs.

Graphic Jump Location

For the dACC/MCC rCMRglu ROI, the PTSD main effect yielded F1,31.2 = 18.0, P <.001. The following covariates were screened as potential confounders of this result by examining their association with the dependent measure using a screening threshold of P < .2: weeks born premature, birth weight, age, total score on the Childhood Trauma Questionnaire, education, Beck Depression Inventory score, MAST score, Positive and Negative Affect Schedule scores, and severity of combat exposure (in the exposed twin). Only combat severity met this threshold. Adjusted for combat severity, the PTSD main effect yielded F1,30.4 = 7.8, P = .009. Parallel analyses in combat-exposed participants alone indicated that only birth weight and combat severity were potential confounders. Unadjusted, the PTSD main effect yielded F1,31 = 11.5, P = .002 (adjusted for birth weight, F1,27 = 9.2, P = .005; adjusted for combat severity, F1,30 = 5.0, P = .03). Parallel analyses in participants not exposed to combat alone indicated that only MAST score and combat severity were potential confounders. Unadjusted, the PTSD main effect yielded F1,31 = 28.2, P < .001 (adjusted for MAST score, F1,27 = 28.2, P < .001; adjusted for combat severity, F1,30 = 10.1, P = .004).

Correlational Analysis With Clinical Variables

Significant correlations between dACC/MCC rCMRglu in the unexposed co-twins and other variables of interest included their own MAST scores (r = 0.53, P = .003), their exposed twins' MAST scores (r = 0.38, P = .04), their exposed twins' combat severity scale scores (r = 0.49, P = .004), and their exposed twins' lifetime Clinician-Administered PTSD Scale scores (r = 0.64, P < .001) (Figure 3). The last of these correlations adjusted for exposed twins' MAST and combat severity scores, which yielded partial r = 0.53, P = .003.

Place holder to copy figure label and caption
Figure 3.

Regional cerebral metabolic rates for glucose (rCMRglu) correlations with clinical variables. The scatterplots show the 0-order correlations between rCMRglu values extracted from the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) in co-twins not exposed to combat and their Michigan Alcoholism Screening Test (MAST) scores (A), their combat-exposed twins’ MAST scores (B), their exposed twins' combat severity scores (C), and their exposed twins' lifetime Clinician-Administered PTSD Scale (CAPS) scores (D).

Graphic Jump Location

The results presented herein showed greater resting rCMRglu, indicative of greater resting metabolic activity, in the dACC/MCC of combat-exposed veterans with PTSD and their identical, combat-unexposed co-twins compared with the combat-exposed veterans without PTSD and their co-twins. This finding remained significant after adjusting for potentially confounding factors. The finding of dACC/MCC hypermetabolism in combat veterans with PTSD is consistent with previous findings of increased activation in these structures in singletons with PTSD23,2628 and further suggests that this functional abnormality may be a risk factor rather than an acquired characteristic of PTSD. The current finding appears to be inconsistent with that of a previous FDG-PET study53 that reported rCMRglu decreases in the anterior cingulate in PTSD; however, because coordinates were not reported in that study, it is unclear whether those decreases occurred in rostral or dorsal portions of the anterior cingulate. One other previous FDG-PET study46 reported no rCMRglu difference in the cingulate between 10 Vietnam combat veterans with PTSD and 10 healthy participants unexposed to trauma. However, unlike the current study, the previous one used a structural ROI approach, which involved extracting FDG-PET data from manually traced brain structures. The cingulate region in that study did not appear to distinguish between its different subdivisions (ie, anterior vs posterior, dACC vs rACC). Extracting and analyzing FDG-PET data from the entire cingulate gyrus could easily obscure possible group differences in specific subregions of the cingulate, such as the dACC.

We did not find evidence of resting rCMRglu main effects or interactions in the rACC, amygdala, or hippocampus. Most of the previous findings of abnormal function in these regions have occurred in neuroimaging studies that used emotional or cognitive tasks; perhaps abnormalities in these brain structures are more likely to be manifest when participants are engaged in such tasks. Furthermore, amygdala responses are known to habituate7072 for seconds to minutes, even in PTSD.19,37 It is possible that such habituation occurred during the 40-minute FDG uptake period, thus obscuring any possible group differences that may have existed early in that period. Two previous resting FDG-PET studies46,53 reported no group differences between PTSD and comparison groups with regard to rCMRglu in the amygdala, though one of those studies reported diminished rCMRglu in the hippocampus.53 The fact that some of our a priori brain ROIs did not show abnormal glucose metabolic rates in PTSD at rest does not preclude their involvement in the pathophysiology of the disorder. In future research, we plan to use cognitive and emotional tasks during functional MRI to further probe these structures using the present twin design.

The dACC (also referred to as the dorsal anterior midcingulate cortex2,73) appears to be involved in many cognitive processes, such as conflict monitoring, response selection, and error detection.5,10 However, it also appears to be involved in aversive conditioning,11,74 the anticipation and perception of pain,75,76 and task/stimulus-related heart rate responses.77 In rhesus monkeys, increased dACC metabolism is positively correlated with increased freezing behavior in response to a human intruder.78 In humans, dACC activation is positively correlated with neuroticism and interoceptive accuracy79 and emotional awareness.80 Increased rCMRglu in the dACC has been reported recently in individuals with the short (s/s) allele of the serotonin transporter gene,81 the frequency of which has been found to be increased in PTSD.82,83

The MAST and the measure of combat severity were originally included in the design for use as covariates to control for potentially confounding variables. Additionally, we found that hypermetabolism in the dACC/MCC in the co-twins unexposed to combat positively and significantly correlated with their own and their exposed twins' alcoholism histories as well as their exposed twins' combat exposure severity and PTSD severity. Though not predicted, these results are of substantial interest in view of a study of 4072 male-male twin pairs, both of whom were in military service during the Vietnam War, which found that the same additive genetic influences that affect the level of combat exposure also influence the level of alcohol use and the level of avoidance/arousal and reexperiencing PTSD symptoms.84 The authors concluded that the genetic influences that lead to exposure to combat also lead to increased alcohol use and PTSD symptoms and further that some genetically transmitted personal characteristics, possibly including impulsivity and sensation seeking, influence the veteran's probability of being exposed to a high level of combat, PTSD symptoms, and alcohol use. The results of the present study suggest that resting dACC/MCC hypermetabolism may be an endophenotypic manifestation of these genetic influences and personality characteristics. Confidence in this conclusion, however, is limited by the lack of relevant personality measures in this twin sample as well as the dearth of prior studies regarding the relationship between dACC/MCC glucose metabolism, alcoholism, and personality characteristics such as impulsivity. However, one functional MRI study reported exaggerated dACC/MCC activation in individuals recovering from alcoholism in response to alcohol-related vs neutral pictures.85 Another functional MRI study that used a perceptual face-processing task found that activation of the dACC was positively correlated with impulsivity.86

If replicated in further twin or prospective singleton studies, the current findings could have specific theoretical implications. The finding of hypermetabolism in the dACC of individuals with PTSD is consistent with conditioning and extinction neurocircuitry models of PTSD87 that implicate the dACC in fear learning.11 More generally, the identification of regional brain metabolic activity as a familial risk factor challenges the notion that the traumatic event is the sole etiologic factor in the development of PTSD88 and is broadly consistent with many previous findings that suggest that certain psychological and biological factors appear to increase risk for PTSD following exposure to trauma.89 For example, smaller hippocampal volumes,90 diminished neurocognitive function,91,92 and increased neurological soft signs93 have been shown to be familial risk factors for the development of PTSD after psychological trauma. In contrast, diminished gray matter density in the rACC appears to be an acquired sign of PTSD.94

In summary, we found hypermetabolism in the dACC/MCC in individuals with PTSD and in their identical co-twins who were not exposed to combat and did not have PTSD. Enhanced resting metabolic activity in the dACC/MCC therefore appears to represent a familial risk factor for the development of PTSD after exposure to psychological trauma. The current study is limited by the presence of disorders other than PTSD, medication use in some participants, and missing handedness data in 7 of 66 participants; however, the finding of hypermetabolism in the dACC/MCC in the P+ pairs remained even when the above participants' data were temporarily excluded from the analyses. It is important to note that, in the absence of dizygotic twin participants, the current twin design cannot distinguish between genetic and environmental contributions to familial risk. Future research examining the relationship between dACC hypermetabolism and specific genotypes should help to address this issue. Future longitudinal studies will be needed to confirm that dACC hypermetabolism increases the risk of PTSD after trauma exposure. Finally, despite the fact that PTSD and non-PTSD pairs differed significantly on rCMRglu values in the dACC/MCC, there was both variability within groups and overlap between groups. Although this pattern of findings is typical in functional neuroimaging studies of psychiatric patient groups, it limits the ability to use rCMRglu in the dACC/MCC as a sole predictor of vulnerability to PTSD following psychological trauma. In future studies, factoring in other measures (such as genotypes) may increase separation between groups and the predictive power of the rCMRglu measure.

Correspondence: Lisa M. Shin, PhD, Department of Psychology, Tufts University, 490 Boston Ave, Medford, MA 02155 (lisa.shin@tufts.edu).

Submitted for Publication: August 13, 2008; final revision received January 17, 2009; accepted February 27, 2009.

Author Contributions: Drs Pitman and Shin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding/Support: This work was supported by grant R01MH54636 from the US Public Health Service (Dr Pitman). The US Department of Veterans Affairs provided financial support for the development and maintenance of the Vietnam Era Twin Registry. Through their support of the Vietnam Era Twin Registry, numerous other US organizations also provided invaluable assistance, including the Department of Defense; National Personnel Records Center, National Archives and Records Administration; Internal Revenue Service; National Institutes of Health; National Opinion Research Center; National Research Council, National Academy of Sciences; and Institute for Survey Research, Temple University.

Financial Disclosures: Although the authors do not anticipate any direct conflict, they report that Dr Rauch has the following financial disclosures: he has received funded research through Massachusetts General Hospital for brain-stimulation therapy from Medtronics Inc, through Massachusetts General Hospital for vagus nerve stimulation from Cyberonics; and through Massachusetts General Hospital for anxiolytic action from Cephalon. He also received honoraria from Novartis for consultation on emerging treatments; Neurogen for his participation as a consultant on emerging trends in anxiety associated with insomnia; Sepracor for his consultation on fear/conditioning/extinction; Primedia for his participation in developing a continuing education activity; and Medtronics Inc for his attendance of their advisory board meeting on the anatomy and neuroscience of anxiety and depression. Dr Rauch is a trustee at McLean Hospital and also serves on the board at the Massachusetts Society for Medical Research as well as on the National Foundation of Mental Health Board.

Previous Presentations: The data described herein were presented at the annual meeting of the Society of Biological Psychiatry, May 1, 2008, Washington, DC; and at the annual meeting of the American College of Neuropsychopharmacology, December 9, 2008, Scottsdale, Arizona.

Additional Contributions: The authors gratefully acknowledge the continued cooperation and participation of the members of the Vietnam Era Twin Registry and of the other participants, without whose contribution this research would not have been possible. Mary Foley and Lawrence White provided technical assistance.

Vogt  BAFinch  DMOlson  CR Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cereb Cortex 1992;2 (6) 435- 443
PubMed
Vogt  BABerger  GRDerbyshire  SW Structural and functional dichotomy of human midcingulate cortex. Eur J Neurosci 2003;18 (11) 3134- 3144
PubMed Link to Article
Bishop  SDuncan  JBrett  MLawrence  AD Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat Neurosci 2004;7 (2) 184- 188
PubMed Link to Article
Bush  GWhalen  PJRosen  BRJenike  MA McInerney  SCRauch  SL The counting Stroop: an interference task specialized for functional neuroimaging–validation study with functional MRI. Hum Brain Mapp 1998;6 (4) 270- 282
PubMed Link to Article
Bush  GLuu  PPosner  MI Cognitive and emotional influence in anterior cingulate cortex. Trends Cogn Sci 2000;4 (6) 215- 222
PubMed Link to Article
Mohanty  AEngels  ASHerrington  JDHeller  WHo  MHBanich  MTWebb  AGWarren  SLMiller  GA Differential engagement of anterior cingulate cortex subdivisions for cognitive and emotional function. Psychophysiology 2007;44 (3) 343- 351
PubMed Link to Article
Phan  KLWager  TTaylor  SFLiberzon  I Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16 (2) 331- 348
PubMed Link to Article
Whalen  PJBush  G McNally  RJWilhelm  S McInerney  SCJenike  MARauch  SL The emotional counting Stroop paradigm: a functional magnetic resonance imaging probe of the anterior cingulate affective division. Biol Psychiatry 1998;44 (12) 1219- 1228
PubMed Link to Article
Botvinick  MM Conflict monitoring and decision making: reconciling two perspectives on anterior cingulate function. Cogn Affect Behav Neurosci 2007;7 (4) 356- 366
PubMed Link to Article
Carter  CSBotvinick  MMCohen  JD The contribution of the anterior cingulate cortex to executive processes in cognition. Rev Neurosci 1999;10 (1) 49- 57
PubMed Link to Article
Milad  MRQuirk  GJPitman  RKOrr  SPFischl  BRauch  SL A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry 2007;62 (10) 1191- 1194
PubMed Link to Article
Bremner  JDNarayan  MStaib  LHSouthwick  SM McGlashan  TCharney  DS Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 1999;156 (11) 1787- 1795
PubMed
Shin  LM McNally  RJKosslyn  SMThompson  WLRauch  SLAlpert  NMMetzger  LJLasko  NBOrr  SPPitman  RK Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatry 1999;156 (4) 575- 584
PubMed
Lanius  RAWilliamson  PCDensmore  MBoksman  KGupta  MANeufeld  RWGati  JSMenon  RS Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatry 2001;158 (11) 1920- 1922
PubMed Link to Article
Lindauer  RJBooij  JHabraken  JBUylings  HBOlff  MCarlier  IVden Heeten  GJvan Eck-Smit  BLGersons  BP Cerebral blood flow changes during script-driven imagery in police officers with posttraumatic stress disorder. Biol Psychiatry 2004;56 (11) 853- 861
PubMed Link to Article
Yang  PWu  MTHsu  CCKer  JH Evidence of early neurobiological alternations in adolescents with posttraumatic stress disorder: a functional MRI study. Neurosci Lett 2004;370 (1) 13- 18
PubMed Link to Article
Britton  JCPhan  KLTaylor  SFFig  LMLiberzon  I Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry 2005;57 (8) 832- 840
PubMed Link to Article
Hou  CLiu  JWang  KLi  LLiang  MHe  ZLiu  YZhang  YLi  WJiang  T Brain responses to symptom provocation and trauma-related short-term memory recall in coal mining accident survivors with acute severe PTSD. Brain Res 2007;1144165- 174
PubMed Link to Article
Shin  LMWright  CICannistraro  PAWedig  MM McMullin  KMartis  BMacklin  MLLasko  NBCavanagh  SRKrangel  TSOrr  SPPitman  RKWhalen  PJRauch  SL A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 2005;62 (3) 273- 281
PubMed Link to Article
Phan  KLBritton  JCTaylor  SFFig  LMLiberzon  I Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. Arch Gen Psychiatry 2006;63 (2) 184- 192
PubMed Link to Article
Williams  LMKemp  AHFelmingham  KBarton  MOlivieri  GPeduto  AGordon  EBryant  RA Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage 2006;29 (2) 347- 357
PubMed Link to Article
Kim  MJChey  JChung  ABae  SKhang  HHam  BYoon  SJJeong  DULyoo  IK Diminished rostral anterior cingulate activity in response to threat-related events in posttraumatic stress disorder. J Psychiatr Res 2008;42 (4) 268- 277
PubMed Link to Article
Bremner  JDVermetten  ESchmahl  CVaccarino  VVythilingam  MAfzal  NGrillon  CCharney  DS Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol Med 2005;35 (6) 791- 806
PubMed Link to Article
Semple  WEGoyer  PF McCormick  RDonovan  BMuzic  RF  JrRugle  L McCutcheon  KLewis  CLiebling  DKowaliw  SVapenik  KSemple  MAFlener  CRSchulz  SC Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals. Psychiatry 2000;63 (1) 65- 74
PubMed
Hopper  JWFrewen  PAvan der Kolk  BALanius  RA Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery. J Trauma Stress 2007;20 (5) 713- 725
PubMed Link to Article
Shin  LMWhalen  PJPitman  RKBush  GMacklin  MLLasko  NBOrr  SP McInerney  SCRauch  SL An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol Psychiatry 2001;50 (12) 932- 942
PubMed Link to Article
Bryant  RAFelmingham  KLKemp  AHBarton  MPeduto  ASRennie  CGordon  EWilliams  LM Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol Psychiatry 2005;58 (2) 111- 118
PubMed Link to Article
Shin  LMBush  GWhalen  PJHandwerger  KCannistraro  PAWright  CIMartis  BMacklin  MLLasko  NBOrr  SPPitman  RKRauch  SL Dorsal anterior cingulate function in posttraumatic stress disorder. J Trauma Stress 2007;20 (5) 701- 712
PubMed Link to Article
Davis  MWhalen  PJ The amygdala: vigilance and emotion. Mol Psychiatry 2001;6 (1) 13- 34
PubMed Link to Article
LeDoux  JE Emotion circuits in the brain. Annu Rev Neurosci 2000;23155- 184
PubMed Link to Article
Whalen  PJ Fear, vigilance, and ambiguity: initial neuroimaging studies of the human amygdala. Curr Dir Psychol Sci 1998;7 (6) 177- 188
Link to Article
Shin  LMKosslyn  SM McNally  RJAlpert  NMThompson  WLRauch  SLMacklin  MLPitman  RK Visual imagery and perception in posttraumatic stress disorder: a positron emission tomographic investigation. Arch Gen Psychiatry 1997;54 (3) 233- 241
PubMed Link to Article
Liberzon  ITaylor  SFAmdur  RJung  TDChamberlain  KRMinoshima  SKoeppe  RAFig  LM Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 1999;45 (7) 817- 826
PubMed Link to Article
Pissiota  AFrans  OFernandez  Mvon Knorring  LFischer  HFredrikson  M Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci 2002;252 (2) 68- 75
PubMed Link to Article
Hendler  TRotshtein  PYeshurun  YWeizmann  TKahn  IBen-Bashat  DMalach  RBleich  A Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage 2003;19 (3) 587- 600
PubMed Link to Article
Shin  LMOrr  SPCarson  MARauch  SLMacklin  MLLasko  NBPeters  PMMetzger  LJDougherty  DDCannistraro  PAAlpert  NMFischman  AJPitman  RK Regional cerebral blood flow in amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry 2004;61 (2) 168- 176
PubMed Link to Article
Protopopescu  XPan  HTuescher  OCloitre  MGoldstein  MEngelien  WEpstein  JYang  YGorman  JLedoux  JSilbersweig  DStern  E Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 2005;57 (5) 464- 473
PubMed Link to Article
Vermetten  ESchmahl  CSouthwick  SMBremner  JD Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress disorder. Psychopharmacol Bull 2007;40 (1) 8- 30
PubMed
Rauch  SLWhalen  PJShin  LM McInerney  SCMacklin  MLLasko  NBOrr  SPPitman  RK Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000;47 (9) 769- 776
PubMed Link to Article
Chung  YAKim  SHChung  SKChae  JHYang  DWSohn  HSJeong  J Alterations in cerebral perfusion in posttraumatic stress disorder patients without re-exposure to accident-related stimuli. Clin Neurophysiol 2006;117 (3) 637- 642
PubMed Link to Article
Armony  JLCorbo  VClement  MHBrunet  A Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am J Psychiatry 2005;162 (10) 1961- 1963
PubMed Link to Article
Eichenbaum  H A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 2000;1 (1) 41- 50
PubMed Link to Article
Schacter  DL The cognitive neuroscience of memory: perspectives from neuroimaging research. Philos Trans R Soc Lond B Biol Sci 1997;352 (1362) 1689- 1695
PubMed Link to Article
Milad  MRWright  CIOrr  SPPitman  RKQuirk  GJRauch  SL Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007;62 (5) 446- 454
PubMed Link to Article
Maren  SHolt  W The hippocampus and contextual memory retrieval in Pavlovian conditioning. Behav Brain Res 2000;110 (1-2) 97- 108
PubMed Link to Article
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 1997;54 (3) 246- 254
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SM McGlashan  TStaib  LHSoufer  RCharney  DS Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 2003;53 (10) 879- 889
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SM McGlashan  TNazeer  AKhan  SVaccarino  LVSoufer  RGarg  PKNg  CKStaib  LHDuncan  JSCharney  DS MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry 2003;160 (5) 924- 932
PubMed Link to Article
Shin  LMShin  PSHeckers  SKrangel  TSMacklin  MLOrr  SPLasko  NBSegal  EMakris  NRichert  KLevering  JSchacter  DLAlpert  NMFischman  AJPitman  RKRauch  SL Hippocampal function in posttraumatic stress disorder. Hippocampus 2004;14 (3) 292- 300
PubMed Link to Article
Astur  RSSt Germain  SATolin  DFord  JRussell  DStevens  M Hippocampus function predicts severity of post-traumatic stress disorder. Cyberpsychol Behav 2006;9 (2) 234- 240
PubMed Link to Article
Sachinvala  NKling  ASuffin  SLake  RCohen  M Increased regional cerebral perfusion by 99mTc hexamethyl propylene amine oxime single photon emission computed tomography in post-traumatic stress disorder. Mil Med 2000;165 (6) 473- 479
PubMed
Bonne  OGilboa  ALouzoun  YBrandes  DYona  ILester  HBarkai  GFreedman  NChisin  RShalev  AY Resting regional cerebral perfusion in recent posttraumatic stress disorder. Biol Psychiatry 2003;54 (10) 1077- 1086
PubMed Link to Article
Molina  MEIsoardi  RPrado  MNBentolila  S Basal cerebral glucose distribution in long-term post-traumatic stress disorder. World J Biol Psychiatry September2007;1- 9
PubMed
Stein  MBJang  KLTaylor  SVernon  PALivesley  WJ Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002;159 (10) 1675- 1681
PubMed Link to Article
True  WRRice  JEisen  SAHeath  ACGoldberg  JLyons  MJNowak  J A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 1993;50 (4) 257- 264
PubMed Link to Article
Nugent  NRAmstadter  ABKoenen  KC Genetics of post-traumatic stress disorder: informing clinical conceptualizations and promoting future research. Am J Med Genet C Semin Med Genet 2008;148C (2) 127- 132
PubMed Link to Article
Sokoloff  L Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 1977;29 (1) 13- 26
PubMed Link to Article
Orr  SPMetzger  LJLasko  NBMacklin  MLHu  FBShalev  AYPitman  RKHarvard/Veterans Affairs Post-traumatic Stress Disorder Twin Study Investigators, Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch Gen Psychiatry 2003;60 (3) 283- 288
PubMed Link to Article
Weathers  FWKeane  TMDavidson  JR Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety 2001;13 (3) 132- 156
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed.text revision Washington, DC American Psychiatric Association2000;
First  MSpitzer  RGibbon  MWilliams  J Structured Clinical Interview for DSM-IV.  New York, NY New York State Psychiatric Institute, Biometrics Research Department1995;
Beck  ATSteer  RA Manual for the revised Beck Depression Inventory.  San Antonio, TX The Psychological Corporation1987;
Selzer  ML The Michigan alcoholism screening test: the quest for a new diagnostic instrument. Am J Psychiatry 1971;127 (12) 1653- 1658
PubMed
Bernstein  DPFink  LHandelsman  LFoote  JLovejoy  MWenzel  KSapareto  ERuggiero  J Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 1994;151 (8) 1132- 1136
PubMed
Watson  DClark  LATellegen  A Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54 (6) 1063- 1070
PubMed Link to Article
Janes  GRGoldberg  JEisen  SATrue  WR Reliability and validity of a combat exposure index for Vietnam era veterans. J Clin Psychol 1991;47 (1) 80- 86
PubMed Link to Article
Deckersbach  TMiller  KKKlibanski  AFischman  ADougherty  DDBlais  MAHerzog  DBRauch  SL Regional cerebral brain metabolism correlates of neuroticism and extraversion. Depress Anxiety 2006;23 (3) 133- 138
PubMed Link to Article
Bush  GVogt  BAHolmes  JDale  AMGreve  DJenike  MARosen  BR Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc Natl Acad Sci U S A 2002;99 (1) 523- 528
PubMed Link to Article
Littlell  RCMilliken  GAStroup  WWWolfinger  RD SAS System for Mixed Models.  Cary, NC SAS Institute1996;
Breiter  HCEtcoff  NLWhalen  PJKennedy  WARauch  SLBuckner  RLStrauss  MMHyman  SERosen  BR Response and habituation of the human amygdala during visual processing of facial expression. Neuron 1996;17 (5) 875- 887
PubMed Link to Article
Fischer  HWright  CIWhalen  PJ McInerney  SCShin  LMRauch  SL Brain habituation during repeated exposure to fearful and neutral faces: a functional MRI study. Brain Res Bull 2003;59 (5) 387- 392
PubMed Link to Article
Wright  CIFischer  HWhalen  PJ McInerney  SCShin  LMRauch  SL Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli. Neuroreport 2001;12 (2) 379- 383
PubMed Link to Article
Bush  G Spencer  TJHolmes  JShin  LMValera  EMSeidman  LJMakris  NSurman  CAleardi  MMick  EBiederman  J Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry 2008;65 (1) 102- 114
PubMed Link to Article
Büchel  CMorris  JDolan  RJFriston  KJ Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20 (5) 947- 957
PubMed Link to Article
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage 1999;9 (6, pt 1) 563- 571
PubMed Link to Article
Derbyshire  SW Exploring the pain “neuromatrix.” Curr Rev Pain 2000;4 (6) 467- 477
PubMed Link to Article
Critchley  HDMathias  CJJosephs  OO'Doherty  JZanini  SDewar  BKCipolotti  LShallice  TDolan  RJ Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 2003;126 (pt 10) 2139- 2152
PubMed Link to Article
Kalin  NHShelton  SEFox  ASOakes  TRDavidson  RJ Brain regions associated with the expression and contextual regulation of anxiety in primates. Biol Psychiatry 2005;58 (10) 796- 804
PubMed Link to Article
Eisenberger  NILieberman  MDSatpute  AB Personality from a controlled processing perspective: an fMRI study of neuroticism, extraversion, and self-consciousness. Cogn Affect Behav Neurosci 2005;5 (2) 169- 181
PubMed Link to Article
McRae  KReiman  EMFort  CLChen  KLane  RD Association between trait emotional awareness and dorsal anterior cingulate activity during emotion is arousal-dependent. Neuroimage 2008;41 (2) 648- 655
PubMed Link to Article
Graff-Guerrero  ADe la Fuente-Sandoval  CCamarena  BGomez-Martin  DApiquian  RFresan  AAguilar  AMendez-Nunez  JCEscalona-Huerta  CDrucker-Colin  RNicolini  H Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. Neuroimage 2005;25 (4) 1197- 1204
PubMed Link to Article
Lee  HJLee  MSKang  RHKim  HKim  SDKee  BSKim  YHKim  YKKim  JBYeon  BKOh  KSOh  BHYoon  JSLee  CJung  HYChee  ISPaik  IH Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety 2005;21 (3) 135- 139
PubMed Link to Article
Serretti  ACalati  RMandelli  LDe Ronchi  D Serotonin transporter gene variants and behavior: a comprehensive review. Curr Drug Targets 2006;7 (12) 1659- 1669
PubMed Link to Article
McLeod  DSKoenen  KCMeyer  JMLyons  MJEisen  STrue  WGoldberg  J Genetic and environmental influences on the relationship among combat exposure, posttraumatic stress disorder symptoms, and alcohol use. J Trauma Stress 2001;14 (2) 259- 275
PubMed Link to Article
Heinz  AWrase  JKahnt  TBeck  ABromand  ZGrusser  SMKienast  TSmolka  MNFlor  HMann  K Brain activation elicited by affectively positive stimuli is associated with a lower risk of relapse in detoxified alcoholic subjects. Alcohol Clin Exp Res 2007;31 (7) 1138- 1147
PubMed Link to Article
Brown  SMManuck  SBFlory  JDHariri  AR Neural basis of individual differences in impulsivity: contributions of corticolimbic circuits for behavioral arousal and control. Emotion 2006;6 (2) 239- 245
PubMed Link to Article
Rauch  SLShin  LMPhelps  EA Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research–past, present, and future. Biol Psychiatry 2006;60 (4) 376- 382
PubMed Link to Article
Yehuda  R McFarlane  AC Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. Am J Psychiatry 1995;152 (12) 1705- 1713
PubMed
Yehuda  RLeDoux  J Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 2007;56 (1) 19- 32
PubMed Link to Article
Gilbertson  MWShenton  MECiszewski  AKasai  KLasko  NBOrr  SPPitman  RK Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002;5 (11) 1242- 1247
PubMed Link to Article
Gilbertson  MWPaulus  LAWilliston  SKGurvits  TVLasko  NBPitman  RKOrr  SP Neurocognitive function in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder. J Abnorm Psychol 2006;115 (3) 484- 495
PubMed Link to Article
Gilbertson  MWWilliston  SKPaulus  LALasko  NBGurvits  TVShenton  MEPitman  RKOrr  SP Configural cue performance in identical twins discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal function. Biol Psychiatry 2007;62 (5) 513- 520
PubMed Link to Article
Gurvits  TVMetzger  LJLasko  NBCannistraro  PATarhan  ASGilbertson  MWOrr  SPCharbonneau  AMWedig  MMPitman  RK Subtle neurologic compromise as a vulnerability factor for combat-related posttraumatic stress disorder: results of a twin study. Arch Gen Psychiatry 2006;63 (5) 571- 576
PubMed Link to Article
Kasai  KYamasue  HGilbertson  MWShenton  MERauch  SLPitman  RK Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry 2008;63 (6) 550- 556
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Main effect of posttraumatic stress disorder (PTSD) diagnosis on regional cerebral metabolic rate for glucose (rCMRglu). A, Resting rCMRglu in the dorsal anterior cingulate cortex/midcingulate cortex (arrow) that is greater in combat-exposed twins with PTSD and their unexposed identical co-twins compared with combat-exposed twins without PTSD and their identical co-twins. Fluorodeoxyglucose F18 data are superimposed on a standard SPM2 T1 template and displayed according to neurological convention. B, The accompanying bar graph presents group rCMRglu means. Error bars represent standard error of the mean.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Correlation of regional cerebral metabolic rate for glucose (rCMRglu) between co-twins. Individual subjects' rCMRglu values from the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) cluster plotted by pairs.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Regional cerebral metabolic rates for glucose (rCMRglu) correlations with clinical variables. The scatterplots show the 0-order correlations between rCMRglu values extracted from the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) in co-twins not exposed to combat and their Michigan Alcoholism Screening Test (MAST) scores (A), their combat-exposed twins’ MAST scores (B), their exposed twins' combat severity scores (C), and their exposed twins' lifetime Clinician-Administered PTSD Scale (CAPS) scores (D).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic and Clinical Characteristics of Combat-Exposed Vietnam Veterans With and Without PTSD and Their Unexposed, Identical Co-twins

References

Vogt  BAFinch  DMOlson  CR Functional heterogeneity in cingulate cortex: the anterior executive and posterior evaluative regions. Cereb Cortex 1992;2 (6) 435- 443
PubMed
Vogt  BABerger  GRDerbyshire  SW Structural and functional dichotomy of human midcingulate cortex. Eur J Neurosci 2003;18 (11) 3134- 3144
PubMed Link to Article
Bishop  SDuncan  JBrett  MLawrence  AD Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli. Nat Neurosci 2004;7 (2) 184- 188
PubMed Link to Article
Bush  GWhalen  PJRosen  BRJenike  MA McInerney  SCRauch  SL The counting Stroop: an interference task specialized for functional neuroimaging–validation study with functional MRI. Hum Brain Mapp 1998;6 (4) 270- 282
PubMed Link to Article
Bush  GLuu  PPosner  MI Cognitive and emotional influence in anterior cingulate cortex. Trends Cogn Sci 2000;4 (6) 215- 222
PubMed Link to Article
Mohanty  AEngels  ASHerrington  JDHeller  WHo  MHBanich  MTWebb  AGWarren  SLMiller  GA Differential engagement of anterior cingulate cortex subdivisions for cognitive and emotional function. Psychophysiology 2007;44 (3) 343- 351
PubMed Link to Article
Phan  KLWager  TTaylor  SFLiberzon  I Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16 (2) 331- 348
PubMed Link to Article
Whalen  PJBush  G McNally  RJWilhelm  S McInerney  SCJenike  MARauch  SL The emotional counting Stroop paradigm: a functional magnetic resonance imaging probe of the anterior cingulate affective division. Biol Psychiatry 1998;44 (12) 1219- 1228
PubMed Link to Article
Botvinick  MM Conflict monitoring and decision making: reconciling two perspectives on anterior cingulate function. Cogn Affect Behav Neurosci 2007;7 (4) 356- 366
PubMed Link to Article
Carter  CSBotvinick  MMCohen  JD The contribution of the anterior cingulate cortex to executive processes in cognition. Rev Neurosci 1999;10 (1) 49- 57
PubMed Link to Article
Milad  MRQuirk  GJPitman  RKOrr  SPFischl  BRauch  SL A role for the human dorsal anterior cingulate cortex in fear expression. Biol Psychiatry 2007;62 (10) 1191- 1194
PubMed Link to Article
Bremner  JDNarayan  MStaib  LHSouthwick  SM McGlashan  TCharney  DS Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 1999;156 (11) 1787- 1795
PubMed
Shin  LM McNally  RJKosslyn  SMThompson  WLRauch  SLAlpert  NMMetzger  LJLasko  NBOrr  SPPitman  RK Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am J Psychiatry 1999;156 (4) 575- 584
PubMed
Lanius  RAWilliamson  PCDensmore  MBoksman  KGupta  MANeufeld  RWGati  JSMenon  RS Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatry 2001;158 (11) 1920- 1922
PubMed Link to Article
Lindauer  RJBooij  JHabraken  JBUylings  HBOlff  MCarlier  IVden Heeten  GJvan Eck-Smit  BLGersons  BP Cerebral blood flow changes during script-driven imagery in police officers with posttraumatic stress disorder. Biol Psychiatry 2004;56 (11) 853- 861
PubMed Link to Article
Yang  PWu  MTHsu  CCKer  JH Evidence of early neurobiological alternations in adolescents with posttraumatic stress disorder: a functional MRI study. Neurosci Lett 2004;370 (1) 13- 18
PubMed Link to Article
Britton  JCPhan  KLTaylor  SFFig  LMLiberzon  I Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatry 2005;57 (8) 832- 840
PubMed Link to Article
Hou  CLiu  JWang  KLi  LLiang  MHe  ZLiu  YZhang  YLi  WJiang  T Brain responses to symptom provocation and trauma-related short-term memory recall in coal mining accident survivors with acute severe PTSD. Brain Res 2007;1144165- 174
PubMed Link to Article
Shin  LMWright  CICannistraro  PAWedig  MM McMullin  KMartis  BMacklin  MLLasko  NBCavanagh  SRKrangel  TSOrr  SPPitman  RKWhalen  PJRauch  SL A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch Gen Psychiatry 2005;62 (3) 273- 281
PubMed Link to Article
Phan  KLBritton  JCTaylor  SFFig  LMLiberzon  I Corticolimbic blood flow during nontraumatic emotional processing in posttraumatic stress disorder. Arch Gen Psychiatry 2006;63 (2) 184- 192
PubMed Link to Article
Williams  LMKemp  AHFelmingham  KBarton  MOlivieri  GPeduto  AGordon  EBryant  RA Trauma modulates amygdala and medial prefrontal responses to consciously attended fear. Neuroimage 2006;29 (2) 347- 357
PubMed Link to Article
Kim  MJChey  JChung  ABae  SKhang  HHam  BYoon  SJJeong  DULyoo  IK Diminished rostral anterior cingulate activity in response to threat-related events in posttraumatic stress disorder. J Psychiatr Res 2008;42 (4) 268- 277
PubMed Link to Article
Bremner  JDVermetten  ESchmahl  CVaccarino  VVythilingam  MAfzal  NGrillon  CCharney  DS Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol Med 2005;35 (6) 791- 806
PubMed Link to Article
Semple  WEGoyer  PF McCormick  RDonovan  BMuzic  RF  JrRugle  L McCutcheon  KLewis  CLiebling  DKowaliw  SVapenik  KSemple  MAFlener  CRSchulz  SC Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals. Psychiatry 2000;63 (1) 65- 74
PubMed
Hopper  JWFrewen  PAvan der Kolk  BALanius  RA Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery. J Trauma Stress 2007;20 (5) 713- 725
PubMed Link to Article
Shin  LMWhalen  PJPitman  RKBush  GMacklin  MLLasko  NBOrr  SP McInerney  SCRauch  SL An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol Psychiatry 2001;50 (12) 932- 942
PubMed Link to Article
Bryant  RAFelmingham  KLKemp  AHBarton  MPeduto  ASRennie  CGordon  EWilliams  LM Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol Psychiatry 2005;58 (2) 111- 118
PubMed Link to Article
Shin  LMBush  GWhalen  PJHandwerger  KCannistraro  PAWright  CIMartis  BMacklin  MLLasko  NBOrr  SPPitman  RKRauch  SL Dorsal anterior cingulate function in posttraumatic stress disorder. J Trauma Stress 2007;20 (5) 701- 712
PubMed Link to Article
Davis  MWhalen  PJ The amygdala: vigilance and emotion. Mol Psychiatry 2001;6 (1) 13- 34
PubMed Link to Article
LeDoux  JE Emotion circuits in the brain. Annu Rev Neurosci 2000;23155- 184
PubMed Link to Article
Whalen  PJ Fear, vigilance, and ambiguity: initial neuroimaging studies of the human amygdala. Curr Dir Psychol Sci 1998;7 (6) 177- 188
Link to Article
Shin  LMKosslyn  SM McNally  RJAlpert  NMThompson  WLRauch  SLMacklin  MLPitman  RK Visual imagery and perception in posttraumatic stress disorder: a positron emission tomographic investigation. Arch Gen Psychiatry 1997;54 (3) 233- 241
PubMed Link to Article
Liberzon  ITaylor  SFAmdur  RJung  TDChamberlain  KRMinoshima  SKoeppe  RAFig  LM Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 1999;45 (7) 817- 826
PubMed Link to Article
Pissiota  AFrans  OFernandez  Mvon Knorring  LFischer  HFredrikson  M Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study. Eur Arch Psychiatry Clin Neurosci 2002;252 (2) 68- 75
PubMed Link to Article
Hendler  TRotshtein  PYeshurun  YWeizmann  TKahn  IBen-Bashat  DMalach  RBleich  A Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage 2003;19 (3) 587- 600
PubMed Link to Article
Shin  LMOrr  SPCarson  MARauch  SLMacklin  MLLasko  NBPeters  PMMetzger  LJDougherty  DDCannistraro  PAAlpert  NMFischman  AJPitman  RK Regional cerebral blood flow in amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry 2004;61 (2) 168- 176
PubMed Link to Article
Protopopescu  XPan  HTuescher  OCloitre  MGoldstein  MEngelien  WEpstein  JYang  YGorman  JLedoux  JSilbersweig  DStern  E Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biol Psychiatry 2005;57 (5) 464- 473
PubMed Link to Article
Vermetten  ESchmahl  CSouthwick  SMBremner  JD Positron tomographic emission study of olfactory induced emotional recall in veterans with and without combat-related posttraumatic stress disorder. Psychopharmacol Bull 2007;40 (1) 8- 30
PubMed
Rauch  SLWhalen  PJShin  LM McInerney  SCMacklin  MLLasko  NBOrr  SPPitman  RK Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol Psychiatry 2000;47 (9) 769- 776
PubMed Link to Article
Chung  YAKim  SHChung  SKChae  JHYang  DWSohn  HSJeong  J Alterations in cerebral perfusion in posttraumatic stress disorder patients without re-exposure to accident-related stimuli. Clin Neurophysiol 2006;117 (3) 637- 642
PubMed Link to Article
Armony  JLCorbo  VClement  MHBrunet  A Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am J Psychiatry 2005;162 (10) 1961- 1963
PubMed Link to Article
Eichenbaum  H A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 2000;1 (1) 41- 50
PubMed Link to Article
Schacter  DL The cognitive neuroscience of memory: perspectives from neuroimaging research. Philos Trans R Soc Lond B Biol Sci 1997;352 (1362) 1689- 1695
PubMed Link to Article
Milad  MRWright  CIOrr  SPPitman  RKQuirk  GJRauch  SL Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007;62 (5) 446- 454
PubMed Link to Article
Maren  SHolt  W The hippocampus and contextual memory retrieval in Pavlovian conditioning. Behav Brain Res 2000;110 (1-2) 97- 108
PubMed Link to Article
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 1997;54 (3) 246- 254
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SM McGlashan  TStaib  LHSoufer  RCharney  DS Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 2003;53 (10) 879- 889
PubMed Link to Article
Bremner  JDVythilingam  MVermetten  ESouthwick  SM McGlashan  TNazeer  AKhan  SVaccarino  LVSoufer  RGarg  PKNg  CKStaib  LHDuncan  JSCharney  DS MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am J Psychiatry 2003;160 (5) 924- 932
PubMed Link to Article
Shin  LMShin  PSHeckers  SKrangel  TSMacklin  MLOrr  SPLasko  NBSegal  EMakris  NRichert  KLevering  JSchacter  DLAlpert  NMFischman  AJPitman  RKRauch  SL Hippocampal function in posttraumatic stress disorder. Hippocampus 2004;14 (3) 292- 300
PubMed Link to Article
Astur  RSSt Germain  SATolin  DFord  JRussell  DStevens  M Hippocampus function predicts severity of post-traumatic stress disorder. Cyberpsychol Behav 2006;9 (2) 234- 240
PubMed Link to Article
Sachinvala  NKling  ASuffin  SLake  RCohen  M Increased regional cerebral perfusion by 99mTc hexamethyl propylene amine oxime single photon emission computed tomography in post-traumatic stress disorder. Mil Med 2000;165 (6) 473- 479
PubMed
Bonne  OGilboa  ALouzoun  YBrandes  DYona  ILester  HBarkai  GFreedman  NChisin  RShalev  AY Resting regional cerebral perfusion in recent posttraumatic stress disorder. Biol Psychiatry 2003;54 (10) 1077- 1086
PubMed Link to Article
Molina  MEIsoardi  RPrado  MNBentolila  S Basal cerebral glucose distribution in long-term post-traumatic stress disorder. World J Biol Psychiatry September2007;1- 9
PubMed
Stein  MBJang  KLTaylor  SVernon  PALivesley  WJ Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002;159 (10) 1675- 1681
PubMed Link to Article
True  WRRice  JEisen  SAHeath  ACGoldberg  JLyons  MJNowak  J A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 1993;50 (4) 257- 264
PubMed Link to Article
Nugent  NRAmstadter  ABKoenen  KC Genetics of post-traumatic stress disorder: informing clinical conceptualizations and promoting future research. Am J Med Genet C Semin Med Genet 2008;148C (2) 127- 132
PubMed Link to Article
Sokoloff  L Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 1977;29 (1) 13- 26
PubMed Link to Article
Orr  SPMetzger  LJLasko  NBMacklin  MLHu  FBShalev  AYPitman  RKHarvard/Veterans Affairs Post-traumatic Stress Disorder Twin Study Investigators, Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch Gen Psychiatry 2003;60 (3) 283- 288
PubMed Link to Article
Weathers  FWKeane  TMDavidson  JR Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety 2001;13 (3) 132- 156
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 4th ed.text revision Washington, DC American Psychiatric Association2000;
First  MSpitzer  RGibbon  MWilliams  J Structured Clinical Interview for DSM-IV.  New York, NY New York State Psychiatric Institute, Biometrics Research Department1995;
Beck  ATSteer  RA Manual for the revised Beck Depression Inventory.  San Antonio, TX The Psychological Corporation1987;
Selzer  ML The Michigan alcoholism screening test: the quest for a new diagnostic instrument. Am J Psychiatry 1971;127 (12) 1653- 1658
PubMed
Bernstein  DPFink  LHandelsman  LFoote  JLovejoy  MWenzel  KSapareto  ERuggiero  J Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 1994;151 (8) 1132- 1136
PubMed
Watson  DClark  LATellegen  A Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54 (6) 1063- 1070
PubMed Link to Article
Janes  GRGoldberg  JEisen  SATrue  WR Reliability and validity of a combat exposure index for Vietnam era veterans. J Clin Psychol 1991;47 (1) 80- 86
PubMed Link to Article
Deckersbach  TMiller  KKKlibanski  AFischman  ADougherty  DDBlais  MAHerzog  DBRauch  SL Regional cerebral brain metabolism correlates of neuroticism and extraversion. Depress Anxiety 2006;23 (3) 133- 138
PubMed Link to Article
Bush  GVogt  BAHolmes  JDale  AMGreve  DJenike  MARosen  BR Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc Natl Acad Sci U S A 2002;99 (1) 523- 528
PubMed Link to Article
Littlell  RCMilliken  GAStroup  WWWolfinger  RD SAS System for Mixed Models.  Cary, NC SAS Institute1996;
Breiter  HCEtcoff  NLWhalen  PJKennedy  WARauch  SLBuckner  RLStrauss  MMHyman  SERosen  BR Response and habituation of the human amygdala during visual processing of facial expression. Neuron 1996;17 (5) 875- 887
PubMed Link to Article
Fischer  HWright  CIWhalen  PJ McInerney  SCShin  LMRauch  SL Brain habituation during repeated exposure to fearful and neutral faces: a functional MRI study. Brain Res Bull 2003;59 (5) 387- 392
PubMed Link to Article
Wright  CIFischer  HWhalen  PJ McInerney  SCShin  LMRauch  SL Differential prefrontal cortex and amygdala habituation to repeatedly presented emotional stimuli. Neuroreport 2001;12 (2) 379- 383
PubMed Link to Article
Bush  G Spencer  TJHolmes  JShin  LMValera  EMSeidman  LJMakris  NSurman  CAleardi  MMick  EBiederman  J Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task. Arch Gen Psychiatry 2008;65 (1) 102- 114
PubMed Link to Article
Büchel  CMorris  JDolan  RJFriston  KJ Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20 (5) 947- 957
PubMed Link to Article
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage 1999;9 (6, pt 1) 563- 571
PubMed Link to Article
Derbyshire  SW Exploring the pain “neuromatrix.” Curr Rev Pain 2000;4 (6) 467- 477
PubMed Link to Article
Critchley  HDMathias  CJJosephs  OO'Doherty  JZanini  SDewar  BKCipolotti  LShallice  TDolan  RJ Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 2003;126 (pt 10) 2139- 2152
PubMed Link to Article
Kalin  NHShelton  SEFox  ASOakes  TRDavidson  RJ Brain regions associated with the expression and contextual regulation of anxiety in primates. Biol Psychiatry 2005;58 (10) 796- 804
PubMed Link to Article
Eisenberger  NILieberman  MDSatpute  AB Personality from a controlled processing perspective: an fMRI study of neuroticism, extraversion, and self-consciousness. Cogn Affect Behav Neurosci 2005;5 (2) 169- 181
PubMed Link to Article
McRae  KReiman  EMFort  CLChen  KLane  RD Association between trait emotional awareness and dorsal anterior cingulate activity during emotion is arousal-dependent. Neuroimage 2008;41 (2) 648- 655
PubMed Link to Article
Graff-Guerrero  ADe la Fuente-Sandoval  CCamarena  BGomez-Martin  DApiquian  RFresan  AAguilar  AMendez-Nunez  JCEscalona-Huerta  CDrucker-Colin  RNicolini  H Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism. Neuroimage 2005;25 (4) 1197- 1204
PubMed Link to Article
Lee  HJLee  MSKang  RHKim  HKim  SDKee  BSKim  YHKim  YKKim  JBYeon  BKOh  KSOh  BHYoon  JSLee  CJung  HYChee  ISPaik  IH Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety 2005;21 (3) 135- 139
PubMed Link to Article
Serretti  ACalati  RMandelli  LDe Ronchi  D Serotonin transporter gene variants and behavior: a comprehensive review. Curr Drug Targets 2006;7 (12) 1659- 1669
PubMed Link to Article
McLeod  DSKoenen  KCMeyer  JMLyons  MJEisen  STrue  WGoldberg  J Genetic and environmental influences on the relationship among combat exposure, posttraumatic stress disorder symptoms, and alcohol use. J Trauma Stress 2001;14 (2) 259- 275
PubMed Link to Article
Heinz  AWrase  JKahnt  TBeck  ABromand  ZGrusser  SMKienast  TSmolka  MNFlor  HMann  K Brain activation elicited by affectively positive stimuli is associated with a lower risk of relapse in detoxified alcoholic subjects. Alcohol Clin Exp Res 2007;31 (7) 1138- 1147
PubMed Link to Article
Brown  SMManuck  SBFlory  JDHariri  AR Neural basis of individual differences in impulsivity: contributions of corticolimbic circuits for behavioral arousal and control. Emotion 2006;6 (2) 239- 245
PubMed Link to Article
Rauch  SLShin  LMPhelps  EA Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research–past, present, and future. Biol Psychiatry 2006;60 (4) 376- 382
PubMed Link to Article
Yehuda  R McFarlane  AC Conflict between current knowledge about posttraumatic stress disorder and its original conceptual basis. Am J Psychiatry 1995;152 (12) 1705- 1713
PubMed
Yehuda  RLeDoux  J Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 2007;56 (1) 19- 32
PubMed Link to Article
Gilbertson  MWShenton  MECiszewski  AKasai  KLasko  NBOrr  SPPitman  RK Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002;5 (11) 1242- 1247
PubMed Link to Article
Gilbertson  MWPaulus  LAWilliston  SKGurvits  TVLasko  NBPitman  RKOrr  SP Neurocognitive function in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder. J Abnorm Psychol 2006;115 (3) 484- 495
PubMed Link to Article
Gilbertson  MWWilliston  SKPaulus  LALasko  NBGurvits  TVShenton  MEPitman  RKOrr  SP Configural cue performance in identical twins discordant for posttraumatic stress disorder: theoretical implications for the role of hippocampal function. Biol Psychiatry 2007;62 (5) 513- 520
PubMed Link to Article
Gurvits  TVMetzger  LJLasko  NBCannistraro  PATarhan  ASGilbertson  MWOrr  SPCharbonneau  AMWedig  MMPitman  RK Subtle neurologic compromise as a vulnerability factor for combat-related posttraumatic stress disorder: results of a twin study. Arch Gen Psychiatry 2006;63 (5) 571- 576
PubMed Link to Article
Kasai  KYamasue  HGilbertson  MWShenton  MERauch  SLPitman  RK Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry 2008;63 (6) 550- 556
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 37

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
JAMAevidence.com

Care at the Close of Life EDUCATION GUIDES
Adolescent Grief


Posttraumatic stress disorder (PTSD)