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1.  FUNCTIONAL NEUROIMAGING STUDIES IN POSTTRAUMATIC STRESS DISORDER: REVIEW OF CURRENT METHODS AND FINDINGS 
Depression and anxiety  2007;24(3):202-218.
Posttraumatic stress disorder (PTSD) is an anxiety disorder associated with changes in neural circuitry involving frontal and limbic systems. Altered metabolism in these brain structures after a traumatic event is correlated to PTSD. Developments in the field of neuroimaging have allowed researchers to look at the structural and functional properties of the brain in PTSD. Despite the relative novelty of functional imaging and its application to the field of PTSD, numerous publications have brought to light several of the circuits implied in this disorder. This article summarizes the findings with regard to PTSD in the functional imaging techniques of single-photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). Furthermore, we discuss strengths and weaknesses of the various techniques and studies. Finally, we explore the future potential of functional neuroimaging studies in PTSD.
doi:10.1002/da.20208
PMCID: PMC3233765  PMID: 16960853
PTSD; PET; fMRI; imaging; hippocampus; amygdala; SPECT; prefrontal cortex
2.  Prevalence of PTSD in Survivors of Stroke and Transient Ischemic Attack: A Meta-Analytic Review 
PLoS ONE  2013;8(6):e66435.
Background and Purpose
Posttraumatic stress disorder (PTSD) is common in survivors of acute life-threatening illness, but little is known about the burden of PTSD in survivors of stroke and transient ischemic attack (TIA). This study estimated the prevalence of stroke or TIA-induced posttraumatic stress disorder (PTSD) using systematic review and meta-analysis.
Methods
Potentially relevant peer-reviewed journal articles were identified by searching the Ovid MEDLINE, PsycINFO, PILOTS Database, The Cochrane Library and Scopus from inception to January 2013; all searches were conducted on January 31, 2013. Observational cohort studies that assessed PTSD with specific reference to a stroke or TIA that occurred at least 1 month prior to the PTSD assessment were included. PTSD rates and characteristics of the study and sample were abstracted from all included studies. The coding of all articles included demographics, sample size, study country, and method and timing of PTSD assessment.
Results
Nine studies (N = 1,138) met our inclusion criteria. PTSD rates varied significantly across studies by timing of PTSD assessment (i.e., within 1 year of stroke/TIA versus greater than 1 year post-stroke/TIA; 55% of heterogeneity explained; Q1 = 10.30; P = .001). Using a random effects model, the estimated rate of PTSD following stroke or TIA was 23% (95% CI, 16%–33%) within 1 year of the stroke or TIA and 11% (95% CI, 8%–14%) after 1 year.
Conclusions
Although PTSD is commonly thought to be triggered by external events such as combat or sexual assault, these results suggest that 1 in 4 stroke or TIA survivors develop significant PTSD symptoms due to the stroke or TIA. Screening for PTSD in a large population-based prospective cohort study with cardiovascular outcome assessments is needed to yield definitive prevalence, and determine whether stroke or TIA-induced PTSD is a risk factor for subsequent cardiovascular events or mortality.
doi:10.1371/journal.pone.0066435
PMCID: PMC3686746  PMID: 23840467
3.  Does neuroimaging research examining the pathophysiology of posttraumatic stress disorder require medication-free patients? 
Background
In an attempt to avoid unknown influence, most neuroimaging studies examining the pathophysiology of posttraumatic stress disorder (PTSD) exclude patients taking medications. Here we review the empirical evidence for relevant medications having a confounding effect on task performance or cerebral blood flow (CBF) in this population. The evidence for potentially confounding effects of psychotherapy in PTSD are also discussed.
Methods
The literature that we reviewed was obtained through a PubMed search from 1980 to 2009 using the search terms posttraumatic stress disorder, PTSD, psychotropic medications, neuroimaging, functional magnetic resonance imaging, positron emission tomography, cerebral blood flow, CBF, serotonin-specific reuptake blocker, benzodiazepine, ketamine, methamphetamine, lamotrigine and atypical antipsychotic agents.
Results
The empirical evidence for relevant medications having a confounding effect on task performance or CBF in relevant areas remains sparse for most psychotropic medications among patients with PTSD. However, considerable evidence is accumulating for 2 of the most commonly prescribed medication classes (serotonin-specific reuptake inhibitors and benzodiazepines) in healthy controls. Compelling data for the potentially confounding effects on brain areas relevant to PTSD for psychotherapeutic interventions are also accumulating.
Conclusion
Neuroimaging studies examining the pathophysiology of PTSD should ideally recruit both medicated (assuming that the medication treatment has not resulted in the remission of symptoms) and unmedicated participants, to allow the findings to be generalized with greater confidence to the entire population of patients with PTSD. More research is needed into the independent effects of medications on task performance and CBF in regions of interest in PTSD. Neuro-imaging studies should also take into account whether patients are currently engaged in psychotherapeutic treatment.
doi:10.1503/jpn.090047
PMCID: PMC2834789  PMID: 20184804
4.  The neural networks of inhibitory control in posttraumatic stress disorder 
Objective
Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD.
Methods
Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17).
Results
Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions.
Conclusion
The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.
PMCID: PMC2527717  PMID: 18787658
inhibition; stress disorders, posttraumatic; motor activity; neurophysiology
5.  Functional Neuroimaging of Anxiety: A Meta-Analysis of Emotional Processing in PTSD, Social Anxiety Disorder, and Specific Phobia 
The American Journal of Psychiatry  2007;164(10):1476-1488.
Objective
The study of human anxiety disorders has benefited greatly from functional neuroimaging approaches. Individual studies, however, vary greatly in their findings. The authors searched for common and disorder-specific functional neurobiological deficits in several anxiety disorders. The authors also compared these deficits to the neural systems engaged during anticipatory anxiety in healthy subjects.
Method
Functional magnetic resonance imaging and positron emission tomography studies of posttraumatic stress disorder (PTSD), social anxiety disorder, specific phobia, and fear conditioning in healthy individuals were compared by quantitative meta-analysis. Included studies compared negative emotional processing to baseline, neutral, or positive emotion conditions.
Results
Patients with any of the three disorders consistently showed greater activity than matched comparison subjects in the amygdala and insula, structures linked to negative emotional responses. A similar pattern was observed during fear conditioning in healthy subjects. Hyperactivation in the amygdala and insula were, of interest, more frequently observed in social anxiety disorder and specific phobia than in PTSD. By contrast, only patients with PTSD showed hypoactivation in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex—structures linked to the experience and regulation of emotion.
Conclusions
This meta-analysis allowed us to synthesize often disparate findings from individual studies and thereby provide neuroimaging evidence for common brain mechanisms in anxiety disorders and normal fear. Effects unique to PTSD furthermore suggested a mechanism for the emotional dysregulation symptoms in PTSD that extend beyond an exaggerated fear response. Therefore, these findings help refine our understanding of anxiety disorders and their interrelationships.
doi:10.1176/appi.ajp.2007.07030504
PMCID: PMC3318959  PMID: 17898336
6.  Neural Correlates of Exposure to Traumatic Pictures and Sound in Vietnam Combat Veterans with and without Posttraumatic Stress Disorder: A Positron Emission Tomography Study 
Biological psychiatry  1999;45(7):806-816.
Background
Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD.
Methods
Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD.
Results
Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas.
Conclusions
The findings suggest that functional alterations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.
PMCID: PMC3233761  PMID: 10202567
Positron emission tomography; memory; postttraumatic stress disorder; frontal cortex; cingulate; function
7.  Conditional Risk for PTSD among Latinos: A Systematic Review of Racial/Ethnic Differences and Sociocultural Explanations 
Clinical psychology review  2012;33(1):107-119.
Conditional risk for Posttraumatic Stress Disorder (PTSD)—defined as prevalence, onset, persistence, or severity of PTSD after traumatic exposure—appears to be higher among Latinos relative to non-Latinos after accounting for sociodemographic factors. This systematic review focuses on differences in conditional risk for PTSD between Latinos and non-Latinos (White, Black, or combined) and across Latino subgroups in studies that adjust for trauma exposure. We discuss methodological characteristics of existing articles and sociocultural explanatory factors. Electronic bibliographic searches were conducted for English-language articles published in peer-reviewed journals between 1991 and 2012. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Twenty-eight articles met inclusion criteria. Consistent support was found for elevated rates of PTSD onset and PTSD severity among Latinos relative to non-Latino Whites. The evidence on racial/ethnic differences in conditional risk for PTSD prevalence and PTSD persistence is mixed. Twenty-four articles evaluated sociocultural explanations, with the strongest support found for racial/ethnic variation in peritraumatic responses and structure of PTSD. There were also consistent main effects for social disadvantage in studies that simultaneously adjusted for effects of race/ethnicity. Future research should use theoretically-driven models to formally test for interactions between sociocultural factors, race/ethnicity, and PTSD probability.
doi:10.1016/j.cpr.2012.10.005
PMCID: PMC3535473  PMID: 23159328
PTSD; Hispanics; immigrants; mental health; psychosocial risk factors; trauma
8.  Neural processing of traumatic events in subjects suffering PTSD - a case study of two surgical patients with severe accident trauma 
Neuroimaging research on the neurobiology of chronic PTSD (posttraumatic stress disorder) has revealed structural and functional alterations primarily affecting areas of the medial temporal lobe (hippocampus, amygdala, and parahippocampal gyrus) and the frontal cortex known to be associated with the disorder. Using functional magnetic resonance imaging (fMRI), the present study studied the functional neuroanatomy of traumatic and non-traumatic emotional memory in two surgical patients who had sustained severe accident trauma. While patient 1 had developed acute PTSD following the traumatic event, patient 2 (control) did not. When confronted with traumatic (relative to negatively valenced non-traumatic) memory, the PTSD patient exhibited evidence for increased neural activity in the right and the left superior temporal lobe, the amygdala, the left angular gyrus, and the medial frontal gyrus, while the non-PTSD patient exposed to identical conditions showed increased activations in frontal and parietal regions. Both patients exhibited identical activation patterns when recalling non-traumatic memories relative to neutral memories. It is concluded that the pronounced activation patterns in the PTSD patient may be considered specific for acute PTSD, involved with the emotional arousal and the vivid visual recollections typical for the acute phase of the disorder.
PMCID: PMC2736480  PMID: 19742050
9.  Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder 
Background
Converging neuroimaging research suggests altered emotion neurocircuitry in individuals with posttraumatic stress disorder (PTSD). Emotion activation studies in these individuals have shown hyperactivation in emotion-related regions, including the amygdala and insula, and hypoactivation in emotion-regulation regions, including the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). However, few studies have examined patterns of connectivity at rest in individuals with PTSD, a potentially powerful method for illuminating brain network structure.
Methods
Using the amygdala as a seed region, we measured resting-state brain connectivity using 3 T functional magnetic resonance imaging in returning male veterans with PTSD and combat controls without PTSD.
Results
Fifteen veterans with PTSD and 14 combat controls enrolled in our study. Compared with controls, veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC.
Limitations
Only male veterans with combat exposure were tested, thus our findings cannot be generalized to women or to individuals with non–combat related PTSD.
Conclusion
These results demonstrate that studies of functional connectivity during resting state can discern aberrant patterns of coupling within emotion circuits and suggest a possible brain basis for emotion-processing and emotion-regulation deficits in individuals with PTSD.
doi:10.1503/jpn.110069
PMCID: PMC3380095  PMID: 22313617
10.  In Search of the Trauma Memory: A Meta-Analysis of Functional Neuroimaging Studies of Symptom Provocation in Posttraumatic Stress Disorder (PTSD) 
PLoS ONE  2013;8(3):e58150.
Notwithstanding some discrepancy between results from neuroimaging studies of symptom provocation in posttraumatic stress disorder (PTSD), there is broad agreement as to the neural circuit underlying this disorder. It is thought to be characterized by an exaggerated amygdalar and decreased medial prefrontal activation to which the elevated anxiety state and concomitant inadequate emotional regulation are attributed. However, the proposed circuit falls short of accounting for the main symptom, unique among anxiety disorders to PTSD, namely, reexperiencing the precipitating event in the form of recurrent, distressing images and recollections. Owing to the technical demands, neuroimaging studies are usually carried out with small sample sizes. A meta-analysis of their findings is more likely to cast light on the involved cortical areas. Coordinate-based meta-analyses employing ES-SDM (Effect Size Signed Differential Mapping) were carried out on 19 studies with 274 PTSD patients. Thirteen of the studies included 145 trauma-exposed control participants. Comparisons between reactions to trauma-related stimuli and a control condition and group comparison of reactions to the trauma-related stimuli were submitted to meta-analysis. Compared to controls and the neutral condition, PTSD patients showed significant activation of the mid-line retrosplenial cortex and precuneus in response to trauma-related stimuli. These midline areas have been implicated in self-referential processing and salient autobiographical memory. PTSD patients also evidenced hyperactivation of the pregenual/anterior cingulate gyrus and bilateral amygdala to trauma-relevant, compared to neutral, stimuli. Patients showed significantly less activation than controls in sensory association areas such as the bilateral temporal gyri and extrastriate area which may indicate that the patients’ attention was diverted from the presented stimuli by being focused on the elicited trauma memory. Being involved in associative learning and priming, the retrosplenial cortex may have an important function in relation to trauma memory, in particular, the intrusive reexperiencing of the traumatic event.
doi:10.1371/journal.pone.0058150
PMCID: PMC3607590  PMID: 23536785
11.  Alterations in the neural circuitry for emotion and attention associated with posttraumatic stress symptomatology 
Psychiatry research  2009;172(1):7-15.
Information processing models of posttraumatic stress disorder (PTSD) suggest that PTSD is characterized by preferential allocation of attentional resources to potentially threatening stimuli. However, few studies have examined the neural pattern underlying attention and emotion in association with PTSD symptomatology. In the present study, combat veterans with PTSD symptomatology engaged in an emotional oddball task while undergoing functional magnetic resonance imaging (fMRI). Veterans were classified into a high or low symptomatology group based on their scores on the Davidson Trauma Scale (DTS). Participants discriminated infrequent target stimuli (circles) from frequent standards (squares) while emotional and neutral distractors were presented infrequently and irregularly. Results revealed that participants with greater PTSD symptomatology showed enhanced neural activity in ventral-limbic and dorsal regions for emotional stimuli and attenuated activity in dorsolateral prefrontal and parietal regions for attention targets. In the anterior cingulate gyrus, participants with fewer PTSD symptoms showed equivalent responses to attentional and emotional stimuli while the high symptom group showed greater activation for negative emotional stimuli. Taken together, the results suggest that hyperresponsive ventral-limbic activity coupled with altered dorsal-attention and anterior cingulate function may be a neural marker of attention bias in PTSD.
doi:10.1016/j.pscychresns.2008.05.005
PMCID: PMC2692949  PMID: 19237269
PTSD; fMRI; information processing; attentional bias; trauma; oddball task
12.  Association of Posttraumatic Stress Disorder With Reduced In Vivo Norepinephrine Availability in the Locus Coeruleus 
JAMA psychiatry  2013;70(11):1199-1205.
IMPORTANCE
Animal data suggest that chronic stress is associated with a reduction in norepinephrine transporter (NET) availability in the locus coeruleus. However, it is unclear whether such models are relevant to posttraumatic stress disorder (PTSD), which has been linked to noradrenergic dysfunction in humans.
OBJECTIVES
To use positron emission tomography and the radioligand [11C]methylreboxetine to examine in vivo NET availability in the locus coeruleus in the following 3 groups of individuals: healthy adults (HC group), adults exposed to trauma who did not develop PTSD (TC group), and adults exposed to trauma who developed PTSD (PTSD group) and to evaluate the relationship between NET availability in the locus coeruleus and a contemporary phenotypic model of PTSD symptoms.
DESIGN, SETTING, AND PARTICIPANTS
Cross-sectional positron emission tomography study under resting conditions at academic and Veterans Affairs medical centers among 56 individuals in the following 3 study groups: HC (n = 18), TC (n = 16), and PTSD (n = 22).
MAIN OUTCOMES AND MEASURES
The [11C]methylreboxetine-binding potential of NET availability in the locus coeruleus and the severity of PTSD symptoms assessed using the Clinician-Administered PTSD Scale.
RESULTS
The PTSD group had significantly lower NET availability than the HC group (41% lower, Cohen d = 1.07). NET availability did not differ significantly between the TC and HC groups (31% difference, Cohen d = 0.79) or between the TC and PTSD groups (15% difference, Cohen d = 0.28). In the PTSD group, NET availability in the locus coeruleus was independently positively associated with the severity of anxious arousal (ie, hypervigilance) symptoms (r = 0.52) but not with any of the other PTSD symptom clusters.
CONCLUSIONS AND RELEVANCE
These results suggest that PTSD is associated with significantly reduced NET availability in the locus coeruleus and that greater NET availability in this brain region is associated with increased severity of anxious arousal symptoms in individuals with PTSD.
doi:10.1001/jamapsychiatry.2013.399
PMCID: PMC4026855  PMID: 24048210
13.  Reduced Amygdala Serotonin Transporter Binding in Posttraumatic Stress Disorder 
Biological psychiatry  2011;70(11):1033-1038.
Background
The amygdala is a key site where alterations in the regulation of the serotonin transporter (5-HTT) may alter stress response. Deficient 5-HTT function and abnormal amygdala activity have been hypothesized to contribute to the pathophysiology of posttraumatic stress disorder (PTSD), but no study has evaluated the 5-HTT in humans with PTSD. Based upon translational models, we hypothesized that patients diagnosed with PTSD would exhibit reduced amygdala 5-HTT expression as measured with positron emission tomography (PET) and the recently developed 5-HTT-selective radiotracer [11C]AFM.
Methods
Fifteen participants with PTSD and 15 healthy control (HC) subjects without trauma history underwent a resting-state PET scan.
Results
[11C]AFM binding potential (BPND) within the combined bilateral amygdala ROI was significantly reduced in the PTSD group compared to the HC group (p=0.027; 16.3% reduction), which was largely driven by the between-group difference in the left amygdala (p=0.008; 20.5% reduction). Further, amygdala [11C]AFM BPND was inversely correlated with both HAM-A scores (r=−0.55, p=0.035) and MARDS scores (r=−0.56, p=0.029).
Conclusions
Our findings of abnormally reduced amygdala 5-HTT binding in PTSD and its association with higher anxiety and depression symptoms in PTSD patients support a translational neurobiological model of PTSD directly implicating dysregulated 5-HTT signaling within neural systems underlying threat detection and fear learning.
doi:10.1016/j.biopsych.2011.07.003
PMCID: PMC3207037  PMID: 21855859
14.  Reduced Neural Activation During an Inhibition Task is Associated with Impaired Fear Inhibition in a Traumatized Civilian Sample 
Introduction
Impaired inhibition of fear in the presence of safety cues and a deficiency in the extinction of fear cues are increasingly thought to be important biological markers of Posttraumatic Stress Disorder (PTSD). Other studies have suggested that there may be altered neural activation during behavioral inhibition tasks in subjects with PTSD. The current study aimed to see whether neural activation during inhibition was reduced in a highly traumatized civilian population, and whether atypical activation was associated with impaired fear inhibition.
Methods
The participants were 41 traumatized women (20 PTSD+, 21 PTSD−) recruited from Grady Memorial Hospital in Atlanta, GA. We used a Go/NoGo procedure with functional magnetic resonance imaging (fMRI) in a high-resolution 3T scanner. Participants were instructed to press a button whenever an “X” or “O” appeared on the screen, but not if a red square appeared behind the letter. Participants were assessed for trauma history and PTSD diagnosis, and completed a fear-potentiated startle and extinction paradigm.
Results
We found stronger activation in the ventromedial prefrontal cortex (vmPFC) in traumatized subjects without PTSD compared to those with PTSD in the NoGo greater than Go contrast condition. Activation in the vmPFC was negatively correlated with fear-potentiated startle responses during safety signal learning (p=.02) and fear extinction (p=.0002).
Conclusions
These results contribute to understanding of how the neural circuitry involved in inhibitory processes may be deficient in PTSD. Furthermore, the same circuits involved in behavioral inhibition appear to be involved in fear inhibition processes during differential fear conditioning and extinction.
doi:10.1016/j.cortex.2012.08.011
PMCID: PMC3540153  PMID: 23020899
15.  PTSD and Gene Variants: New Pathways and New Thinking 
Neuropharmacology  2011;62(2):628-637.
Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.
doi:10.1016/j.neuropharm.2011.02.013
PMCID: PMC3136568  PMID: 21356219
16.  Neural Correlates of Attention Bias to Threat in Post-traumatic Stress Disorder 
Biological psychology  2012;90(2):134-142.
Attentional biases have been proposed to contribute to symptom maintenance in Posttraumatic Stress Disorder (PTSD), although the neural correlates of these processes have not been well defined; this was the goal of the present study. We administered an attention bias task, the dot probe, to a sample of 37 (19 control, 18 PTSD+) traumatized African-American adults during fMRI. Compared to controls, PTSD+ participants demonstrated increased activation in the dorsolateral prefrontal cortex (dlPFC) in response to threat cue trials. In addition, attentional avoidance of threat corresponded with increased ventrolateral prefrontal cortex (vlPFC) and dorsal anterior cingulate cortex (dACC) activation in the PTSD group, a pattern that was not observed in controls. These data provide evidence to suggest that relative increases in dlPFC, dACC and vlPFC activation represent neural markers of attentional bias for threat in individuals with PTSD, reflecting selective disruptions in attentional control and emotion processing networks in this disorder.
doi:10.1016/j.biopsycho.2012.03.001
PMCID: PMC3340884  PMID: 22414937
Attention bias; PTSD; Threat; fMRI; Prefrontal cortex; Neuroimaging; Posttraumatic Stress Disorder; Anterior cingulate cortex; Dorsolateral prefrontal cortex; Cognition
17.  Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder 
Archives of general psychiatry  2009;66(10):1099-1107.
Context
Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala and hippocampus in 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, combat-unexposed co-twins (n=14), as well as combat-exposed veterans without PTSD (n=19) and their identical, combat-unexposed co-twins (n=19).
Main Outcome Measures
We used positron emission tomography and [18F]-fluorodeoxyglucose to examine resting regional cerebral metabolic rates for glucose (rCMRglu).
Results
Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in dorsal anterior cingulate/mid cingulate cortex (dACC/MCC) compared to non-PTSD veterans and their co-twins. Resting rCMRglu in dACC/MCC in the combat-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 dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.
doi:10.1001/archgenpsychiatry.2009.138
PMCID: PMC3752096  PMID: 19805700
stress disorders; post-traumatic; twins; monozygotic; positron-emission tomography; fluorodexoyglucose F18; metabolism; cingulate gyrus
18.  Working memory processing of traumatic material in women with posttraumatic stress disorder 
Background
Posttraumatic stress disorder (PTSD) is associated with medial frontal and amygdala functional alterations during the processing of traumatic material and frontoparietal dysfunctions during working memory tasks. This functional magnetic resonance imaging (fMRI) study investigated the effects of trauma-related words processing on working memory in patients with PTSD.
Methods
We obtained fMRI scans during a 3-back task and an identity task on both neutral and trauma-related words in women with PTSD who had been sexually abused and in healthy, nonexposed pair-matched controls.
Results
Seventeen women with PTSD and 17 controls participated in the study. We found no behavioural working memory deficit for the PTSD group. In both tasks, deactivation of posterior parietal midline regions was more pronounced in patients than controls. Additionally, patients with PTSD recruited the left dorsolateral frontal sites to a greater extent during the processing of trauma-related material than neutral material.
Limitations
This study included only women and did not include a trauma-exposed non-PTSD control group; the results may, therefore, have been influenced by sex or by effects specific to trauma exposure.
Conclusion
Our results broadly confirm frontal and parietal functional variations in women with PTSD and suggest a compensatory nature of these variations with regard to the retreival of traumatic memories and global attentional deficits, respectively, during cognitively challenging tasks.
doi:10.1503/jpn.100167
PMCID: PMC3297067  PMID: 21971161
19.  Posttraumatic Stress Disorder Prevalence and Risk of Recurrence in Acute Coronary Syndrome Patients: A Meta-analytic Review 
PLoS ONE  2012;7(6):e38915.
Background
Acute coronary syndromes (ACS; myocardial infarction or unstable angina) can induce posttraumatic stress disorder (PTSD), and ACS-induced PTSD may increase patients’ risk for subsequent cardiac events and mortality. Objective: To determine the prevalence of PTSD induced by ACS and to quantify the association between ACS-induced PTSD and adverse clinical outcomes using systematic review and meta-analysis. Data Sources: Articles were identified by searching Ovid MEDLINE, PsycINFO, and Scopus, and through manual search of reference lists.
Methodology/Principal Findings
Observational cohort studies that assessed PTSD with specific reference to an ACS event at least 1 month prior. We extracted estimates of the prevalence of ACS-induced PTSD and associations with clinical outcomes, as well as study characteristics. We identified 56 potentially relevant articles, 24 of which met our criteria (N = 2383). Meta-analysis yielded an aggregated prevalence estimate of 12% (95% confidence interval [CI], 9%–16%) for clinically significant symptoms of ACS-induced PTSD in a random effects model. Individual study prevalence estimates varied widely (0%–32%), with significant heterogeneity in estimates explained by the use of a screening instrument (prevalence estimate was 16% [95% CI, 13%–20%] in 16 studies) vs a clinical diagnostic interview (prevalence estimate was 4% [95% CI, 3%–5%] in 8 studies). The aggregated point estimate for the magnitude of the relationship between ACS-induced PTSD and clinical outcomes (ie, mortality and/or ACS recurrence) across the 3 studies that met our criteria (N = 609) suggested a doubling of risk (risk ratio, 2.00; 95% CI, 1.69–2.37) in ACS patients with clinically significant PTSD symptoms relative to patients without PTSD symptoms.
Conclusions/Significance
This meta-analysis suggests that clinically significant PTSD symptoms induced by ACS are moderately prevalent and are associated with increased risk for recurrent cardiac events and mortality. Further tests of the association of ACS-induced PTSD and clinical outcomes are needed.
doi:10.1371/journal.pone.0038915
PMCID: PMC3380054  PMID: 22745687
20.  Effects of trauma-related cues on pain processing in posttraumatic stress disorder: an fMRI investigation 
Background
Imaging studies of pain processing in primary psychiatric disorders are just emerging. This study explored the neural correlates of stress-induced analgesia in individuals with posttraumatic stress disorder (PTSD). It combined functional magnetic resonance imaging (fMRI) and the traumatic script-driven imagery symptom provocation paradigm to examine the effects of trauma-related cues on pain perception in individuals with PTSD.
Methods
The study included 17 patients with PTSD and 26 healthy, trauma-exposed controls. Participants received warm (nonpainful) or hot (painful) thermal stimuli after listening to a neutral or a traumatic script while they were undergoing an fMRI scan at a 4.0 T field strength.
Results
Between-group analyses revealed that after exposure to the traumatic scripts, the blood oxygen level–dependent (BOLD) signal during pain perception was greater in the PTSD group than the control group in the head of the caudate. In the PTSD group, strong positive correlations resulted between BOLD signal and symptom severity in a number of brain regions previously implicated in stress-induced analgesia, such as the thalamus and the head of the caudate nucleus. Trait dissociation as measured by the Dissociative Experiences Scale correlated negatively with the right amygdala and the left putamen.
Limitations
This study included heterogeneous traumatic experiences, a different proportion of military trauma in the PTSD versus the control group and medicated patients with PTSD.
Conclusion
These data indicate that in patients with PTSD trauma recall will lead in a state-dependent manner to greater activation in brain regions implicated in stress-induced analgesia. Correlational analyses lend support to cortical hyperinhibition of the amygdala as a function of dissociation.
doi:10.1503/jpn.080188
PMCID: PMC3004970  PMID: 20964954
21.  Fear Conditioning, Synaptic Plasticity, and the Amygdala: Implications for Posttraumatic Stress Disorder 
Trends in Neurosciences  2011;35(1):24-35.
Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after a traumatic experience such as domestic violence, natural disasters or combat-related trauma. The cost of such disorders on society and the individual can be tremendous. In this article we will review how the neural circuitry implicated in PTSD in humans is related to the neural circuitry of fear. We then discuss how fear conditioning is a suitable model for studying the molecular mechanisms of the fear components which underlie PTSD, and the biology of fear conditioning with a particular focus on the brain derived neurotropic factor (BDNF)-TrkB, GABAergic and glutamatergic ligand-receptor systems. We then summarize how such approaches may help to inform our understanding of PTSD and other stress-related disorders and provide insight to new pharmacological avenues of treatment of PTSD.
doi:10.1016/j.tins.2011.06.007
PMCID: PMC3206195  PMID: 21798604
PTSD; BDNF; TrkB; Fear Conditioning; Extinction; Amygdala; Hippocampus; Prefrontal Cortex; Learning and Memory; Synaptic Plasticity
22.  Volumetric Structural Magnetic Resonance Imaging Findings in Pediatric Posttraumatic Stress Disorder and Obsessive Compulsive Disorder: A Systematic Review 
Objectives: Structural magnetic resonance imaging (sMRI) studies of anxiety disorders in children and adolescents are limited. Posttraumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD) have been best studied in this regard. We systematically reviewed structural neuroimaging findings in pediatric PTSD and OCD. Methods: The literature was reviewed for all sMRI studies examining volumetric parameters using PubMed, ScienceDirect, and PsychInfo databases, with no limit on the time frame of publication. Nine studies in pediatric PTSD and six in OCD were suitable for inclusion. Results: Volumetric findings were inconsistent in both disorders. In PTSD, findings suggest increased as well as decreased volumes of the prefrontal cortex (PFC) and corpus callosum; whilst in OCD studies indicate volumetric increase of the putamen, with inconsistent findings for the anterior cingulate cortex (ACC) and frontal regions. Conclusions: Methodological differences may account for some of this inconsistency and additional volume-based studies in pediatric anxiety disorders using more uniform approaches are needed.
doi:10.3389/fpsyg.2012.00568
PMCID: PMC3530132  PMID: 23272001
sMRI; pediatric; anxiety; voxel-based morphometry
23.  Insular cortex involvement in declarative memory deficits in patients with post-traumatic stress disorder 
BMC Psychiatry  2009;9:39.
Background
Neuroimaging studies have proved that hippocampus relate to the deficient of memory in patients with post-traumatic stress disorder (PTSD). Many studies in healthy subjects also shown that insular cortex (IC) be involved in the declarative memory. This study was designed to investigate whether insular cortex is involved in declarative memory deficits in patients with PTSD.
Methods
Twelve subjects with PTSD and 12 subjects without PTSD victims underwent functional magnetic resonance imaging and magnetic resonance imaging. All subjects performed encoding and retrieval memory tasks during the fMRI session. Voxel-based morphometry method was used to analyze gray-matter volume, and the Statistical Parametric Mapping (SPM2) was used to analyze activated brain areas when performing tasks.
Results
Grey matter volume was significantly reduced bilaterally in the insular cortex of PTSD subjects than non-PTSD. PTSD group also had lower level of activation in insular cortex when performing word encoding and retrieval tasks than non-PTSD group.
Conclusion
The study provides evidence on structural and function abnormalities of the insular cortex in patients with PTSD. Reduced grey-matter volume in insular cortex may be associated with declarative memory deficits in patients with PTSD.
doi:10.1186/1471-244X-9-39
PMCID: PMC2704184  PMID: 19538748
24.  Actigraphy in Post Traumatic Stress Disorder  
Patients with posttraumatic stress disorder (PTSD) frequently complain of sleep disturbances such as insomnia and nightmares. Evaluation of sleep disturbances is often difficult due to the subjective nature of the complaints. Polysomnography (PSG) and other sleep studies are generally not indicated in the evaluation of insomnia or nightmares associated with PTSD. Actigraphy, (electronic activity monitoring) has been used in research to evaluate sleep disturbances in patients with PTSD. We reviewed the literature on the use of actigraphy in evaluation of sleep problems in patients with PTSD.
Methods: A literature search for articles on the topic was conducted on PubMed using the search algorithm (actigraphy[Title/Abstract] OR actigraphic[Title/Abstract]) AND PTSD[Title/Abstract]. Out of 11 search results, 9 studies in which application of actigraphy had relevance to the primary objective and outcome in PTSD patients with sleep problems were selected for review. We also handpicked one additional article from personal communication with our colleagues who have done some of these studies.
Conclusion: Actigraphy has been used to evaluate circadian rhythm sleep disorders. Use of actigraphy in psychiatry clinics is uncommon. There is no data to support that there are specific actigraphic sleep related findings in PTSD patients. However, it can be a useful tool to complement the use of sleep diaries when assessing sleep and wake patterns in patients with PTSD.
PMCID: PMC3999025  PMID: 24772158
Actigraphy; PTSD; Sleep; Insomnia; Review Article
25.  HIGHER IN VIVO SEROTONIN-1A BINDING IN POSTTRAUMATIC STRESS DISORDER: A PET STUDY WITH [11C]WAY-100635 
Depression and anxiety  2013;30(3):10.1002/da.22019.
Background
Brain serotonin-1A receptors (5-HT1A) are implicated in anxiety. We compared regional brain 5-HT1A binding in medication-free participants with posttraumatic stress disorder (PTSD) and healthy volunteers using fully quantitative positron emission tomography (PET) methods.
Methods
Twenty patients with DSM-IV PTSD (13 with comorbid major depressive disorder, [MDD]) and 49 healthy volunteers underwent PET imaging with 5-HT1A antagonist radioligand [C-11]WAY100635. Arterial blood sampling provided a metabolite-corrected input function and the concentration of free ligand in plasma (fP) for estimation of regional binding potential, BPF ( = Bavailable /KD). Linear mixed modeling compared BPF between groups across regions of interest (ROIs).
Results
The PTSD group had higher 5-HT1A BPF across brain ROIs (P = .0006). Post hoc comparisons showed higher 5-HT1A BPF in PTSD in all cortical ROIs (26–33%), amygdala (34%), and brainstem raphe nuclei (43%), but not hippocampus. The subgroup of seven PTSD patients without comorbid MDD had higher 5-HT1A BPF compared with healthy volunteers (P = .03).
Conclusions
This is the first report of higher brainstem and forebrain 5-HT1A binding in vivo in PTSD. The finding is independent of MDD. PTSD and MDD have in common an upregulation of 5-HT1A binding including midbrain autoreceptors that would favor less firing and serotonin release. This abnormality may represent a common biomarker of these stress-associated brain disorders.
doi:10.1002/da.22019
PMCID: PMC3785097  PMID: 23408467
posttraumatic stress disorder (PTSD); serotonin-1A (5-HT1A); positron emission tomography; WAY100635; major depressive disorder

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