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1.  Neural circuits in anxiety and stress disorders: a focused review 
Anxiety and stress disorders are among the most prevalent neuropsychiatric disorders. In recent years, multiple studies have examined brain regions and networks involved in anxiety symptomatology in an effort to better understand the mechanisms involved and to develop more effective treatments. However, much remains unknown regarding the specific abnormalities and interactions between networks of regions underlying anxiety disorder presentations. We examined recent neuroimaging literature that aims to identify neural mechanisms underlying anxiety, searching for patterns of neural dysfunction that might be specific to different anxiety disorder categories. Across different anxiety and stress disorders, patterns of hyperactivation in emotion-generating regions and hypoactivation in prefrontal/regulatory regions are common in the literature. Interestingly, evidence of differential patterns is also emerging, such that within a spectrum of disorders ranging from more fear-based to more anxiety-based, greater involvement of emotion-generating regions is reported in panic disorder and specific phobia, and greater involvement of prefrontal regions is reported in generalized anxiety disorder and posttraumatic stress disorder. We summarize the pertinent literature and suggest areas for continued investigation.
doi:10.2147/TCRM.S48528
PMCID: PMC4315464
fear; anxiety; neuroimaging
2.  Incidence and Predictors of Acute Psychological Distress and Dissociation after Motor Vehicle Collision: a Cross-Sectional Study 
Objective
The authors examined the incidence and predictors of peritraumatic distress and dissociation after one of the most common forms of civilian trauma exposure: motor vehicle collision (MVC).
Methods
In this study, patients presenting to the emergency department after MVC who were without serious injury and discharged to home after evaluation (n = 935) completed an emergency department interview evaluating sociodemographic, collision-related, and psychological characteristics.
Results
The incidence and predictors of distress (Peritraumatic Distress Inventory score ≥ 23) and dissociation (Michigan Critical Events Perception Scale score >3) were assessed. Distress was present in 355 of 935 patients (38%) and dissociation was present in 260 of 942 patients (28%). These outcomes showed only moderate correlation (r = 0.45), and had both shared and distinct predictors. Female gender, anxiety symptoms prior to MVC, and vehicle damage severity predicted both distress and dissociation. Higher socioeconomic status (higher education, higher income, full time employment) had a protective effect against distress but not dissociative symptoms. Better physical health and worse overall mental health were associated with increased risk of dissociation, but not distress. Distress but not dissociation was associated with lower patient confidence in recovery and a longer expected duration of recovery.
Conclusion
There are unique predictors of peritraumatic distress and dissociation. Further work is needed to better understand the neurobiology of peritraumatic distress and dissociation, and the influence of these peritraumatic outcomes on persistent psychological sequelae.
doi:10.1080/15299732.2014.908805
PMCID: PMC4182147  PMID: 24983475
Distress; Dissociation; Post-Traumatic Stress Disorder; Trauma; Motor Vehicle Collision
3.  Distributed effects of methylphenidate on the network structure of the resting brain: a connectomic pattern classification analysis 
NeuroImage  2013;81:213-221.
Methylphenidate is a psychostimulant medication that produces improvements in functions associated with multiple neurocognitive systems. To investigate the potentially distributed effects of methylphenidate on the brain’s intrinsic network architecture, we coupled resting state imaging with multivariate pattern classification. In a within-subject, double-blind, placebo-controlled, randomized, counterbalanced, cross-over design, 32 healthy human volunteers received either methylphenidate or placebo prior to two fMRI resting state scans separated by approximately one week. Resting state connectomes were generated by placing regions of interest at regular intervals throughout the brain, and these connectomes were submitted for support vector machine analysis. We found that methylphenidate produces a distributed, reliably detected, multivariate neural signature. Methylphenidate effects were evident across multiple resting state networks, especially visual, somatomotor, and default networks. Methylphenidate reduced coupling within visual and somatomotor networks. In addition, default network exhibited decoupling with several task positive networks, consistent with methylphenidate modulation of the competitive relationship between these networks. These results suggest that connectivity changes within and between large-scale networks is potentially involved in the mechanisms by which methylphenidate improves attention functioning.
doi:10.1016/j.neuroimage.2013.05.016
PMCID: PMC3729859  PMID: 23684862
methylphenidate; fMRI; resting state; multivariate pattern classification; connectome; intrinsic connectivity networks
4.  DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli 
Neuropsychopharmacology  2013;38(9):1798-1807.
Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been multiple reports of DHEA's antidepressant and anxiolytic effects, no research to date has examined the neural pathways involved. In particular, brain imaging has not been used to link neurosteroid effects to emotion neurocircuitry. To investigate the brain basis of DHEA's impact on emotion modulation, patients were administered 400 mg of DHEA (N=14) or placebo (N=15) and underwent 3T fMRI while performing the shifted-attention emotion appraisal task (SEAT), a test of emotional processing and regulation. Compared with placebo, DHEA reduced activity in the amygdala and hippocampus, enhanced connectivity between the amygdala and hippocampus, and enhanced activity in the rACC. These activation changes were associated with reduced negative affect. DHEA reduced memory accuracy for emotional stimuli, and also reduced activity in regions associated with conjunctive memory encoding. These results demonstrate that DHEA reduces activity in regions associated with generation of negative emotion and enhances activity in regions linked to regulatory processes. Considering that activity in these regions is altered in mood and anxiety disorders, our results provide initial neuroimaging evidence that DHEA may be useful as a pharmacological intervention for these conditions and invite further investigation into the brain basis of neurosteroid emotion regulatory effects.
doi:10.1038/npp.2013.79
PMCID: PMC3717538  PMID: 23552182
androsterone; dehydroepiandrosterone; emotion regulation; imaging; clinical or preclinical; learning & memory; mood/anxiety/stress disorders; neuroendocrinology; neurosteroid; dehydroepiandrosterone; neurosteroid; androsterone; fMRI; emotion regulation
5.  Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits 
Biological psychiatry  2013;73(11):1045-1053.
Background
The neurosteroid allopregnanolone is a potent allosteric modulator of the GABA(A) receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning. However, the neural mechanism whereby allopregnanolone improves mood and reduces anxiety is unknown. In particular, brain imaging has not been used to link neurosteroid effects to emotion regulation neurocircuitry.
Methods
To investigate the brain basis of allopregnanolone’s impact on emotion regulation, participants were administered 400mg of pregnenolone (N=16) or placebo (N=15) and underwent 3T fMRI while performing the Shifted-Attention Emotion Appraisal Task (SEAT), which probes emotional processing and regulation.
Results
Compared to placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions. During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.
Conclusions
These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacological intervention in the treatment of anxiety disorders, and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.
doi:10.1016/j.biopsych.2012.12.008
PMCID: PMC3648625  PMID: 23348009
Allopregnanolone; neuroactive steroid; fMRI; pharmaco-fMRI; emotion regulation; anxiety; pregnenolone
6.  Smoking is a predictor of depression onset among National Guard soldiers 
Psychiatry research  2013;206(0):321-323.
This paper aimed to investigate the relationship between smoking and depression in a sample of American soldiers. Persistent, active smoking is associated with increased risk of incident depression at follow up. History of smoking in the absence of current smoking at baseline was not associated with depression at follow-up.
doi:10.1016/j.psychres.2012.11.025
PMCID: PMC3701300  PMID: 23291043
smoking; depression; military
7.  Aberrant Reward Center Response to Partner Reputation During a Social Exchange Game in Generalized Social Phobia 
Depression and anxiety  2013;30(4):353-361.
Objective
Generalized social anxiety disorder (GSAD) is characterized by excessive fear of public scrutiny and reticence in social engagement. Previous studies have probed the neural basis of GSAD often using static, non-interactive stimuli (e.g., face photographs) and have identified dysfunction in fear circuitry. We sought to investigate brain-based dysfunction in GSAD during more real-world, dynamic social interactions, focusing on the role of reward-related regions that are implicated in social decision-making.
Methods
Thirty-six healthy individuals (HC) and 36 individuals with GSAD underwent fMRI scanning while participating in a behavioral economic game (‘Trust Game’) involving iterative exchanges with fictive partners who acquire differential reputations for reciprocity. We investigated brain responses to reciprocation of trust in one’s social partner, and how these brain responses are modulated by partner reputation for repayment.
Results
In both HC and GSAD, receipt of reciprocity robustly engaged ventral striatum, a region implicated in reward. In HC, striatal responses to reciprocity were specific to partners who have consistently returned the investment (‘cooperative partners’), and were absent for partners who lack a cooperative reputation. In GSAD, modulation of striatal responses by partner reputation was absent. Social anxiety severity predicted diminished responses to cooperative partners.
Conclusion
These results suggest abnormalities in GSAD in reward-related striatal mechanisms that may be important for the initiation, valuation, and maintenance of cooperative social relationships. Moreover, this study demonstrates that dynamic, interactive task paradigms derived from economics can help illuminate novel mechanisms of pathology in psychiatric illnesses in which social dysfunction is a cardinal feature.
doi:10.1002/da.22091
PMCID: PMC3987865  PMID: 23576237
8.  Exogenous Glucocorticoids Decrease Subgenual Cingulate Activity Evoked by Sadness 
Neuropsychopharmacology  2013;38(5):826-845.
The glucocorticoid hormone cortisol is known to have wide-ranging effects on a variety of physiological systems, including the morphology and physiology of the amygdala and hippocampus. Disruptions of cortisol regulation and signaling are also linked with psychiatric disorders involving emotional disturbances. Although there is much evidence to suggest a relationship between cortisol signaling and the brain physiology underlying emotion, few studies have attempted to test for direct effects of cortisol on the neurophysiology of emotion. We administered exogenous synthetic cortisol (hydrocortisone, HCT) using two different dosing regimens (25 mg/day over 4 days, 100 mg single dose), in a double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study. During fMRI scanning, healthy subjects viewed images designed to induce happy, sad, and neutral emotional states. Subjective emotional reactions were collected for each experimental stimulus after fMRI scanning. Mood ratings were also collected throughout the 4 days of the study. Both dose regimens of HCT resulted in decreased subgenual cingulate activation during sadness conditions. The 25 mg/day regimen also resulted in higher arousal ratings of sad stimuli. No effects of HCT were observed on any mood ratings. Few reliable effects of HCT were observed on brain activity patterns or subjective emotional responses to stimuli that were not sad. The inhibitory effects of cortisol on sadness-induced subgenual cingulate activity may have critical relevance to the pathophysiology of major depression, as both subgenual hyperactivity and decreased sensitivity to cortisol signaling have been documented in patients with depression.
doi:10.1038/npp.2012.249
PMCID: PMC3599059  PMID: 23303057
cortisol; emotion; fMRI; glucocorticoids; corticosteroids; subgenual; Imaging; Clinical or Preclinical; Neuroendocrinology; Psychopharmacology; Neurophysiology; Cortisol; Emotion; fMRI; Glucocorticoids; Corticosteroids
9.  Haplotype-based study of the association of alcohol and acetaldehyde-metabolising genes with alcohol dependence (with or without comorbid anxiety symptoms) in a Cape Mixed Ancestry population 
Metabolic Brain Disease  2014;29(2):333-340.
Alcohol dependence (AD) has a large heritable component. Genetic variation in genes involved in the absorption and elimination of ethanol have been associated with AD. However, some of these polymorphisms are not present in an African population. Previous studies have reported that a type of AD which is characterized by anxious behaviour may be a genetically specific subtype of AD. We investigated whether variation in genes encoding cytochrome P450 2E1 (CYP2E1) or acetaldehyde-metabolising enzymes (ALDH1A1, ALDH2) might alter the risk of AD, with and without symptoms of anxiety, in a Cape population with mixed ancestry. Eighty case control pairs (one with AD, one without AD) were recruited and individually matched for potential confounders. Genotype data were available for 29 single-nucleotide polymorphisms (SNPs) across the three genes. Linkage disequilibrium D′ values were evaluated for all pairwise comparisons. Allele and haplotype frequencies were compared between cases and controls using a χ2 test. The ACAG haplotype in block 4 of the ALDH1A1 gene provided evidence of an association with AD (p = 0.03) and weak evidence of an association with AD without symptoms of anxiety (p = 0.06). When a genetic score was constructed using SNPs showing nominal evidence of association with AD, every extra risk allele increased the odds of AD by 35 % (OR 1.35, 95%CI 1.08, 1.68, p = 0.008) and the odds of having AD with anxiety symptoms increased by 53 % (OR 1.53, 95%CI 1.14, 2.05, p = 0.004). Although our results are supported by previous studies in other populations, they must be interpreted with caution due to the small sample size and the potential influence of population stratification.
doi:10.1007/s11011-014-9503-x
PMCID: PMC4023075  PMID: 24567230
Alcohol dependence; Anxiety; Genetics
10.  Corticolimbic Brain Reactivity to Social Signals of Threat Before and After Sertraline Treatment in Generalized Social Phobia 
Biological psychiatry  2012;73(4):329-336.
Objective
Generalized social phobia (gSP), also known as generalized social anxiety disorder, is characterized by excessive fear of scrutiny by others and pervasive avoidance of social interactions. Pathophysiological models of gSP implicate exaggerated reactivity of the amygdala and insula in response to social evaluative threat, making them plausible targets for treatment. Although selective serotonin reuptake inhibitor (SSRI) treatment is known to be an effective treatment, little is known about the mechanism by which these agents exert their anxiolytic effects at a brain level in gSP.
Method
We acquired functional magnetic resonance imaging (fMRI) data of brain response to social signals of threat (fearful/angry faces) in twenty-one GSAD patients before and after they completed 12 weeks of open label treatment with the SSRI sertraline. For comparison, nineteen healthy control (HC) subjects also underwent two fMRI scans, 12 weeks apart.
Results
Whole-brain voxel-wise analysis of variance revealed significant Group×Time interactions in the amygdala and the ventral medial prefrontal cortex (vmPFC). Follow up analyses showed that treatment in gSP subjects: 1) reduced amygdala reactivity to fearful faces (which was exaggerated relative to HCs prior to treatment); and 2) enhanced vmPFC activation to angry faces (which was attenuated relative to HCs prior to treatment). However, these brain changes were not significantly related to social anxiety symptom improvement.
Conclusions
SSRI treatment response in gSP is associated with changes in a discrete limbic-paralimbic brain network, representing a neural mechanism by which SSRIs may exert their actions.
doi:10.1016/j.biopsych.2012.10.003
PMCID: PMC3557668  PMID: 23164370
treatment; fMRI; amygdala; ventromedial prefrontal cortex; SSRI; anxiety
11.  Cigarette smoking and subsequent risk of suicidal ideation among National Guard Soldiers 
Journal of affective disorders  2012;145(1):111-114.
BACKGROUND
Suicide rates are alarmingly high among military personnel, and particularly Army National Guard soldiers. Smoking is also disproportionately common in the military. In this study, we intend to investigate the relationship between cigarette smoking and suicidal ideation among a representative sample of national guard soldiers.
METHODS
A representative sample of Ohio Army National Guard soldiers were followed prospectively and information was gathered on smoking, suicidal ideation and depression at baseline and one year later.
RESULTS
Smoking at baseline was associated with significantly increased likelihood of suicidal ideation at follow-up (OR=2.0 (1.3, 3.2)). This association persisted after adjusting for demographics and history of depression at baseline, but was no longer statistically significant after adjusting for depression at follow-up.
LIMITATIONS
Measurement of smoking was somewhat limited.
CONCLUSIONS
Army National Guard soldiers who smoke have a greater risk of subsequent suicidal ideation. Depression concurrent with suicidal ideation appears to explain this relationship. If these results are replicated, screening of soldiers who smoke may be recommended as a proactive step towards mitigating the high risk of suicide in military personnel.
doi:10.1016/j.jad.2012.05.003
PMCID: PMC3701306  PMID: 23141668
military; smoking; suicide; epidemiology; depression
12.  Single prolonged stress enhances hippocampal glucocorticoid receptor and phosphorylated protein kinase B levels 
Neuroscience research  2012;75(2):130-137.
Animal models of posttraumatic stress disorder (PTSD) can explore neurobiological mechanisms by which trauma enhances fear and anxiety reactivity. Single prolonged stress (SPS) shows good validity in producing PTSD-like behavior. While SPS-induced behaviors have been linked to enhanced glucocorticoid receptor (GR) expression, the molecular ramifications of enhanced GR expression have yet to be identified. Phosphorylated protein kinase B (pAkt) is critical for stress-mediated enhancement in general anxiety and memory, and may be regulated by GRs. However, it is currently unknown if pAkt levels are modulated by SPS, as well as if the specificity of GR and pAkt related changes contribute to anxiety-like behavior after SPS. The current study set out to examine the effects of SPS on GR and pAkt protein levels in the amygdala and hippocampus and to examine the specificity of these changes to unconditioned anxiety-like behavior. Levels of GR and pAkt were increased in the hippocampus, but not amygdala. Furthermore, SPS had no effect on unconditioned anxiety-like behavior suggesting that generalized anxiety is not consistently observed following SPS. The results suggest that SPS-enhanced GR expression is associated with phosphorylation of Akt, and also suggest that these changes are not related to an anxiogenic phenotype.
doi:10.1016/j.neures.2012.11.001
PMCID: PMC3604057  PMID: 23201176
single prolonged stress; Akt; glucocorticoid receptor; hippocampus; posttraumatic stress disorder; anxiety
13.  Cannabinoid facilitation of fear extinction memory recall in humans 
Neuropharmacology  2012;64(1):396-402.
A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing.
doi:10.1016/j.neuropharm.2012.06.063
PMCID: PMC3445738  PMID: 22796109
14.  Exploring dissociation and oxytocin as pathways between trauma exposure and trauma-related hyperemesis gravidarum: a test-of-concept pilot 
Posttraumatic stress disorder (PTSD) is associated with gastrointestinal and genitourinary comorbidities. These map onto the somatization disorder symptoms in the Diagnostic and Statistical Manual of Mental Disorders (APA, 1994) and the dissociative [conversion] disorders symptoms in the International Classification of Diseases taxonomy (WHO, 2007). Hyperemesis gravidarum (HG) is one of these symptoms and a gastrointestinal comorbidity of PTSD occurring in pregnancy. It is an idiopathic condition defined as severe vomiting with dehydration, metabolic imbalance, wasting, and hospital care-seeking. HG is more severe than the normative phenomenon of nausea and vomiting of pregnancy (NV). This test-of-concept pilot (N=25) explored the hypothesis that there is a trauma-related subtype of HG characterized by (1) high levels of dissociative symptoms and (2) altered plasma concentrations of oxytocin. This hypothesis is informed by a theory of posttraumatic oxytocin dysregulation positing altered oxytocin function as a mechanism of gut smooth muscle peristalsis dysfunction. A four-group analysis compared controls with nausea and vomiting of pregnancy (NV only) and cases with HG only, NV and PTSD, or HG and PTSD. Oxytocin was correlated with nausea and vomiting symptom severity score (r = .464, p = .019) and with the dissociation symptom score (r = .570, p = .003). Women in the group with both PTSD and HG (the “trauma-related HG subtype”) had the highest levels of dissociation and the highest levels of oxytocin. A linear regression model indicated that the independent association of the trauma-related HG subtype with oxytocin level was mediated by high levels of dissociative symptoms.
doi:10.1080/15299732.2012.694594
PMCID: PMC3539231  PMID: 23282046
Oxytocin; Dissociative disorder; hyperemesis gravidarum; posttraumatic stress
15.  Childhood abuse history, posttraumatic stress disorder, postpartum mental health and bonding: A prospective cohort study 
Introduction
Research is needed that prospectively characterizes the intergenerational pattern of effects of childhood maltreatment and lifetime posttraumatic stress disorder (PTSD) on women’s mental health in pregnancy and on postpartum mental health and bonding outcomes. This prospective study included 566 nulliparous women in 3 cohorts: PTSD-positive, trauma-exposed resilient, and non-exposed to trauma.
Methods
Standardized telephone interviews with women who were less than 28 gestational weeks ascertained trauma history, PTSD diagnosis, and depression diagnosis. A six-week postpartum interview reassessed interim trauma, labor experience, PTSD, depression, and bonding outcomes.
Results
Regression modeling indicates posttraumatic stress in pregnancy, alone, or comorbid with depression, is associated with postpartum depression (R2=.204, P<.001). Postpartum depression alone, or comorbid with posttraumatic stress, was associated with impaired bonding (R2=.195, P<.001). In both models, higher quality of life ratings in pregnancy were associated with better outcomes, while reported dissociation in labor was a risk for worse outcomes. The effect of a history of childhood maltreatment on both postpartum mental health and bonding outcomes was mediated by pre-existing mental health status.
Discussion
Pregnancy represents an opportune time to interrupt the pattern of intergenerational transmission of abuse and psychiatric vulnerability. Further dyadic research is warranted beyond six weeks postpartum. Trauma-informed interventions for women who enter care with abuse-related PTSD or depression should be developed and tested.
doi:10.1111/j.1542-2011.2012.00237.x
PMCID: PMC3564506  PMID: 23374491
Pregnancy; childhood maltreatment; depression; posttraumatic stress; postpartum mental health; bonding
16.  Early handling attenuates enhancement of glucocorticoid receptors in the prefrontal cortex in an animal model of post-traumatic stress disorder 
Background
Changes in glucocorticoid receptors (GRs) have been implicated in the pathogenesis of stress related psychiatric disorders such as depression and post-traumatic stress disorder (PTSD). Abnormal adaptation of the stress-response system following traumatic stress can lead to an altered hypothalamic-pituitary-adrenal axis that may contribute to PTSD development. Indeed, elevated GR expression in the hippocampus and prefrontal cortex linked to PTSD-like characteristics have been reported in the validated animal model of PTSD, single-prolonged stress. These findings implicate increased levels of GRs in the development of post-traumatic psychopathology and suggest that exploration of GR-targeted interventions may have potential for PTSD prevention. Early handling during the neonatal phase alters GR expression and is proposed to confer resilience to stress. We therefore examined the effects of combined early handling and single prolonged stress treatments on GR expression.
Methods
Timed pregnant dams gave birth to pups that were subjected to early handling (n = 11) or control (n = 13) procedures during the neonatal phase. At postnatal day 45 animals underwent single prolonged stress or a control procedure. Rats were euthanized one day later and GR levels were assayed using western blot electrophoresis.
Results
Single prolonged stress exposure enhanced GR expression in the hippocampus and prefrontal cortex. Early handling treatment protected against single prolonged stress-induced enhancement of GR expression in the prefrontal cortex, but not in the hippocampus.
Conclusions
These data are a first step in highlighting the importance of targeting GR systems in prevention/resilience and may suggest that preventive strategies targeting GR upregulation might be particularly effective when prefrontal rather than hippocampal GRs are the target.
doi:10.1186/2045-5380-3-22
PMCID: PMC4175489  PMID: 24289278
Hippocampus; HPA axis; Maternal care; Single prolonged stress; Stress
17.  Neural Dysregulation in Posttraumatic Stress Disorder: Evidence for Disrupted Equilibrium between Salience and Default Mode Brain Networks 
Psychosomatic medicine  2012;74(9):904-911.
Objective
Convergent neuroimaging and neuropsychological research demonstrates disrupted attention and heightened threat sensitivity in PTSD. This might be linked to aberrations in large-scale networks subserving detection of salient stimuli, i.e. the salience network (SN), and stimulus-independent, internally-focused thought, i.e. the default mode network (DMN).
Methods
Resting state brain activity was measured in returning veterans who served in Iraq or Afghanistan with (n=15) and without PTSD (n=15) and in healthy community controls (n=15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions (posterior cingulate, ventromedial prefrontal cortex, and bilateral anterior insula) and all other voxels of the brain.
Results
Compared to control groups, PTSD participants showed reduced functional connectivity within DMN (between DMN seeds and other DMN regions), including rostral ACC/vmPFC (Z=3.31; p=.005, corrected) and hippocampus (Z=2.58; p=.005), and increased connectivity within SN (between insula seeds and other SN regions), including amygdala (Z=3.03; p=.01, corrected). PTSD participants also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions, including insula (Z=3.06; p=.03, corrected), putamen, and supplementary motor area (Z=4.14; Z=4.08; p<.001), and SN seeds exhibited elevated connectivity with DMN regions, including hippocampus (Z=3.10; p=.048, corrected).
Conclusions
During resting state scanning, PTSD participants showed reduced coupling within DMN, greater coupling within SN, and increased coupling between DMN and SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-free conditions. Disequilibrium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSD pathophysiology.
doi:10.1097/PSY.0b013e318273bf33
PMCID: PMC3498527  PMID: 23115342
PTSD; default mode network; salience network; functional connectivity; resting-state; fMRI
18.  Acute Severe Pain is a Common Consequence of Sexual Assault 
Sexual assault (SA) is common, but the epidemiology of acute pain after SA has not previously been reported. We evaluated the severity and distribution of pain symptoms in the early aftermath of SA among women receiving sexual assault nurse examiner (SANE) care, and the treatment of pain by SANE nurses. Severe pain (≥7 on a 0–10 numeric rating scale) was reported by 53/83 women sexual assault survivors (64% [95% CI, 53%–74%]) at the time of SANE evaluation and 43/83 women (52% [95% CI, 41%–63%]) one week later. Pain in four or more body regions was reported by 44/83 women (53% [95% CI, 42%–64%]) at the time of initial evaluation and 49/83 women (59% [95% CI, 48%–70%]) at one week follow-up. Among survivors with severe pain at the time of initial post-assault evaluation, only 7/53 (13% [95% CI, 6%–26%]) received any pain medication at the time of initial SANE treatment. These findings suggest that pain is common in SA survivors in the early post-assault period, but rarely treated.
Perspective
Acute pain is common after sexual assault. Practice guidelines for SANE nurses and others who provide care to sexual assault survivors in the early aftermath of assault should include specific recommendations for pain evaluation and treatment. Prospective longitudinal studies of pain outcomes among sexual assault survivors are needed.
doi:10.1016/j.jpain.2012.04.008
PMCID: PMC3437775  PMID: 22698980
Sexual assault; musculoskeletal pain; stress; pain; treatment
21.  Avoidant symptoms in PTSD predict fear circuit activation during multimodal fear extinction 
Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies.
doi:10.3389/fnhum.2013.00672
PMCID: PMC3797966  PMID: 24146643
fear conditioning; avoidance; posttraumatic stress disorder; fMRI; neuroimaging; amygdala; hippocampus
22.  Posttraumatic stress disorder, child abuse history, birth weight, and gestational age: A prospective cohort study 
Objective
To determine the extent to which prenatal posttraumatic stress disorder (PTSD) is associated with lower birth weight and shorter gestation, and to explore the effects of childhood maltreatment as the antecedent trauma exposure.
Design
Prospective three-cohort study
Setting
Ann Arbor and Detroit, Michigan, United States
Sample
839 diverse nulliparas in PTSD-positive (n=255), trauma-exposed, resilient (n=307), and non-exposed to trauma (n=277) cohorts
Methods
Standardised telephone interview prior to 28 weeks to ascertain trauma history, PTSD, depression, substance use, mental health treatment history, and sociodemographics, with chart abstraction to obtain chronic condition history, antepartum complications, and prenatal care data, as well as outcomes.
Main outcome measures
Infant birth weight and gestational age per delivery record.
Results
Women with PTSD during pregnancy had a mean birth weight 283 grams less than trauma-exposed, resilient women and 221 grams less than non-exposed women (F(3, 835) = 5.4, p = .001). PTSD was also associated with shorter gestation in multivariate models that took childhood abuse history into account. Stratified models indicated that PTSD subsequent to child abuse trauma exposure was most strongly associated with adverse outcomes. PTSD was a stronger predictor than African American race of shorter gestation and a nearly equal predictor of birth weight. Prenatal care was not associated with better outcomes among women abused in childhood.
Conclusions
Abuse-related PTSD may be an additional or alternative explanation for adverse perinatal outcomes associated with low socioeconomic status and African American race in the United States. Biological and interventions research is warranted along with replication studies in other nations.
doi:10.1111/j.1471-0528.2011.03071.x
PMCID: PMC3171570  PMID: 21790957
Stress disorder; posttraumatic; perinatal outcomes; birth weight; gestational age; health disparities; childhood maltreatment; abuse
23.  Stress modulation of cognitive and affective processes 
Stress (Amsterdam, Netherlands)  2011;14(5):503-519.
This review summarizes the major discussion points of a symposium on stress modulation of cognitive and affective processes, which was held during the 2010 workshop on the neurobiology of stress (Boulder, CO, USA). The four discussants addressed a number of specific cognitive and affective factors that are modulated by exposure to acute or repeated stress. Dr David Morilak discussed the effects of various repeated stress situations on cognitive flexibility, as assessed with a rodent model of attentional set-shifting task, and how performance on slightly different aspects of this test is modulated by different prefrontal regions through monoaminergic neurotransmission. Dr Serge Campeau summarized the findings of several studies exploring a number of factors and brain regions that regulate habituation of various autonomic and neuroendocrine responses to repeated audiogenic stress exposures. Dr Kerry Ressler discussed a body of work exploring the modulation and extinction of fear memories in rodents and humans, especially focusing on the role of key neurotransmitter systems including excitatory amino acids and brain-derived neurotrophic factor. Dr Israel Liberzon presented recent results on human decision-making processes in response to exogenous glucocorticoid hormone administration. Overall, these discussions are casting a wider framework on the cognitive/affective processes that are distinctly regulated by the experience of stress and some of the brain regions and neurotransmitter systems associated with these effects.
doi:10.3109/10253890.2011.596864
PMCID: PMC3313908  PMID: 21790481
Cognitive flexibility; prefrontal cortex; decision making; habituation; extinction; fear conditioning
24.  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
25.  Social appraisal in chronic psychosis: Role of medial frontal and occipital networks 
Journal of psychiatric research  2010;45(4):526-538.
Persons with schizophrenia often appraise other individuals as threatening or persecutory. To evaluate social appraisal in schizophrenia, we probed brain networks with a task in which subjects judged whether or not they liked face stimuli with emotional expressions. We predicted that appraising negative expressions would engage patients, more than controls, and negative faces would be related to higher levels of negative affect and produce increased activity in the medial frontal cortex, an area involved in social appraisal. Twenty-one stable outpatients with chronic non-affective psychosis (16 schizophrenic, 5 schizoaffective) and 21 healthy subjects underwent functional magnetic resonance imaging. Compared with the control subjects, patients were slower to respond, but particularly slow when they judged negatively-valenced faces, a slowness correlated with negative affect in the psychosis patients. Appraisal activated the medial prefrontal cortex (mPFC) across all face valences. For negative expressions, patients exhibited greater activation of the dorsal anterior cingulate cortex (dACC). A psychophysiological interaction analysis of the dACC revealed co-modulation of the mPFC in controls, significantly less in patients, and a trend for co-modulation of occipital cortex in the patients. Activity in occipital cortex correlated with poor social adjustment and impaired social cognition, and co-modulation of the occipital gyrus by the dACC was correlated with poorer social cognition. The findings link appraisal of negative affect with aberrant activation of the medial frontal cortex, while early sensory processing of this social cognitive task was linked with poor social function, reflecting either top down or bottom up influences.
doi:10.1016/j.jpsychires.2010.08.004
PMCID: PMC2994990  PMID: 20797730
schizophrenia; anterior cingulate cortex; faces; visual cortex; fMRI BOLD

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