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1.  Allopregnanolone Levels are Reduced in Temporal Cortex in Patients with Alzheimer’s Disease Compared to Cognitively Intact Control Subjects 
Biochimica et biophysica acta  2010;1801(8):951-959.
Background
The neurosteroid allopregnanolone has pronounced neuroprotective actions, increases myelination, and enhances neurogenesis. Evidence suggests that allopregnanolone dysregulation may play a role in the pathophysiology of Alzheimer’s disease (AD) and other neurodegenerative disorders. Our prior data demonstrate that allopregnanolone is reduced in prefrontal cortex in male patients with AD compared to male cognitively intact control subjects, and inversely correlated with neuropathological disease stage (Braak and Braak). We therefore determined if allopregnanolone levels are also reduced in AD patients compared to control subjects in temporal cortex, utilizing a larger set of samples from both male and female patients. In addition, we investigated if neurosteroids are altered in subjects who are APOE4 allele carriers.
Methods
Allopregnanolone, dehydroepiandrosterone (DHEA), and pregnenolone levels were determined in temporal cortex postmortem samples by gas chromatography/mass spectrometry, preceded by high performance liquid chromatography (40 subjects with AD/41 cognitively intact control subjects).
Results
Allopregnanolone levels are reduced in temporal cortex in patients with AD (median 2.68 ng/g, n= 40) compared to control subjects (median 5.64 ng/g, n=41), Mann-Whitney p=0.0002, and inversely correlated with Braak and Braak neuropathological disease stage (Spearman r= −0.38, p=0.0004). DHEA and pregnenolone are increased in patients with AD compared to control subjects. Patients carrying an APOE4 allele demonstrate reduced allopregnanolone levels in temporal cortex (Mann-Whitney p=0.04).
Conclusions
Neurosteroids are altered in temporal cortex in patients with AD and related to neuropathological disease stage. The APOE4 allele is associated with reduced allopregnanolone levels. Neurosteroids may be relevant to the neurobiology and therapeutics of AD.
doi:10.1016/j.bbalip.2010.05.006
PMCID: PMC2907131  PMID: 20488256
2.  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
3.  GABAergic neuroactive steroids: a new frontier in bipolar disorders? 
Neurosteroids are synthesized in the brain and modulate brain excitability. There is increasing evidence of their sedative, anesthetic and antiseizure properties, as well as their influence on mood. Currently neurosteroids are classified as pregnane neurosteroids (allopregnanolone and allotetrahydrodeoxycorticosterone), androstane neurosteroids (androstanediol and etiocholanone) or sulfated neurosteroids (pregnenolone sulfate and dehydroepiandrosterone sulfate). Both preclinical and clinical findings indicate that progesterone derivative neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone play a role in mood disorders. Clozapine and olanzapine, which were shown to be effective in stabilizing bipolar disorder, elevate pregnenolone levels in rat hippocampus, cerebral cortex, and serum. In lithium-treated mice, the blood levels of allopregnanolone and pregnenolone were elevated compared to control levels. Women diagnosed with bipolar disorder typically show symptomatic exacerbation in relation to the menstrual cycle, and show vulnerability to the onset or recurrence of mood disorders immediately after giving birth, when the levels of neurosteroid derivatives of progesterone drop. Whereas in women who had recovered from bipolar disorder, the plasma concentration of allopregnanolone was elevated compared to either healthy controls or women with major depressive disorder during the premenstrual period. During depressive episodes, blood level of allopregnanolone is low. Treatment with fluoxetine tends to stabilize the levels of neurosteroids in depression. These findings converge to suggest that these steroids have significant mood-stabilizing effect. This hypothesis is consistent with the observation that a number of anticonvulsants are effective therapies for bipolar disorder, a finding also consistent with the antiseizure properties of neurosteroids. Further exploration of action of neuroactive steroids is likely to open new frontiers in the investigation of the etiology and treatment of mood disorders, particularly bipolar disorders.
doi:10.1186/1744-9081-8-61
PMCID: PMC3573983  PMID: 23253178
4.  A retrospective cohort study of U.S. service members returning from Afghanistan and Iraq: is physical health worsening over time? 
BMC Public Health  2012;12:1124.
Background
High rates of mental health disorders have been reported in veterans returning from deployment to Afghanistan (Operation Enduring Freedom: OEF) and Iraq (Operation Iraqi Freedom: OIF); however, less is known about physical health functioning and its temporal course post-deployment. Therefore, our goal is to study physical health functioning in OEF/OIF veterans after deployment.
Methods
We analyzed self-reported physical health functioning as physical component summary (PCS) scores on the Veterans version of the Short Form 36 health survey in 679 OEF/OIF veterans clinically evaluated at a post-deployment health clinic. Veterans were stratified into four groups based on time post-deployment: (1Yr) 0 – 365 days; (2Yr) 366 – 730 days; (3Yr) 731 – 1095 days; and (4Yr+) > 1095 days. To assess the possibility that our effect was specific to a treatment-seeking sample, we also analyzed PCS scores from a separate military community sample of 768 OEF/OIF veterans evaluated pre-deployment and up to one-year post-deployment.
Results
In veterans evaluated at our clinic, we observed significantly lower PCS scores as time post-deployment increased (p = 0.018) after adjusting for probable post-traumatic stress disorder (PTSD). We similarly observed in our community sample that PCS scores were lower both immediately after and one year after return from deployment (p < 0.001) relative to pre-deployment PCS. Further, PCS scores obtained 1-year post-deployment were significantly lower than scores obtained immediately post-deployment (p = 0.02).
Conclusion
In our clinical sample, the longer the duration between return from deployment and their visit to our clinic, the worse the Veteran’s physical health even after adjusting for PTSD. Additionally, a decline is also present in a military community sample of OEF/OIF veterans. These data suggest that, as time since deployment length increases, physical health may deteriorate for some veterans.
doi:10.1186/1471-2458-12-1124
PMCID: PMC3543837  PMID: 23272950
Veterans; Military personnel; Veterans health; Quality of life; Operation enduring freedom; Operation iraqi freedom; Health surveys
5.  The association of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) with anxiety sensitivity and electronic diary negative affect among smokers with and without posttraumatic stress disorder 
Posttraumatic stress disorder (PTSD) is associated with increased smoking initiation, maintenance and relapse. Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are neurosteroids that have been associated with mood measures as well as smoking status, and nicotine is associated with increased DHEA and DHEAS levels. Given the difficulties with mood experienced by smokers with PTSD, the purpose of the current study was to evaluate the association between negative affect and anxiety sensitivity with DHEA and DHEAS levels. Ninety-six smokers with and without PTSD provided blood samples for neurosteroid analyses, and completed self-report measures of anxiety sensitivity and electronic diary ratings of negative affect. As expected, PTSD smokers reported higher levels of anxiety sensitivity (F[1,94]=20.67, partial η2= 0.18, p<.0001) and negative affect (F[1,91]=7.98, partial η2= .08, p=.006). After accounting for age and gender, DHEAS was significantly inversely associated with both anxiety sensitivity (F[3,92]=6.97, partial η2= 0.07, p=.01) and negative affect (F[3,87]=10.52, partial η2= 0.11, p=.002) across groups. Effect sizes indicated that these effects are moderate to high. No significant interactions of diagnosis and DHEA(S) levels with mood measures were detected. Given that nicotine is known to elevate DHEA(S) levels, these results suggest that DHEAS may serve as a biomarker of the association between mood and nicotine among smokers. Implications for the results include 1) the use of DHEAS measurement across time and across quit attempts; and 2) the potential for careful use of DHEA supplementation to facilitate abstinence during smoking cessation.
doi:10.1097/JCP.0b013e3182968962
PMCID: PMC3896952  PMID: 23771199
6.  Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia 
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n = 9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change = 10.38) compared with patients receiving placebo (mean change = 2.33), p = 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs = 0.81, p = 0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs = 0.74, p = 0.046). In addition, baseline pregnenolone (rs = −0.76, p = 0.037), pregnenolone sulfate (rs = − 0.83, p = 0.015), and allopregnanolone levels (rs = −0.83, p = 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs = 0.74, p <0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
doi:10.1038/npp.2009.26
PMCID: PMC3427920  PMID: 19339966
schizophrenia; negative symptoms; cognitive symptoms; neurosteroid; pregnenolone; allopregnanolone
7.  Pain in veterans of the Gulf War of 1991: a systematic review 
Background
Veterans of the Persian Gulf War of 1991 have reported a range of adverse health symptoms. This systematic review aims to identify all studies that have compared the prevalence of symptoms of pain in veterans of the Gulf War to that in a non-Gulf military comparison group, and to determine whether Gulf War veterans are at increased risk of reporting pain.
Methods
Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they reported the prevalence of any symptom or condition that included the word "pain" in Gulf War veterans and in a comparison group of non-Gulf veterans. 2401 abstracts were independently reviewed by two authors.
Results
Twenty studies fulfilled the inclusion criteria. Five main sites of pain were identified (muscle, joint, chest/heart, back and abdominal pain) and separate meta-analyses were performed to summarise the results related to each site. A greater proportion of Gulf veterans reported symptoms at each site of pain when compared to a non-Gulf military group. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain than a comparison group (OR 3.23; 95%CI 2.31–4.51). Statistical heterogeneity between study estimates was significant, probably due to variation in measured periods of prevalence and symptom measurement methods.
Conclusion
A higher proportion of veterans of the Persian Gulf War of 1991 reported symptoms of pain than military comparison groups. This is consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, post traumatic stress disorder) in these veterans compared with non-Gulf military groups. However, the primary studies were heterogeneous and varied greatly in quality.
doi:10.1186/1471-2474-7-74
PMCID: PMC1592094  PMID: 16987407
8.  Patterns and Correlates of Prescription Opioid Use in OEF/OIF Veterans with Chronic Non-Cancer Pain 
Pain medicine (Malden, Mass.)  2011;12(10):1502-1509.
Objectives
Little is known about the treatment Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans receive for chronic non-cancer pain (CNCP). We sought to describe the prevalence of prescription opioid use, types and doses of opioids received, and identify correlates of receiving prescription opioids for CNCP among OEF/OIF veterans.
Design
Retrospective review of VA administrative data.
Setting
Ambulatory clinics within a VA regional healthcare network.
Patients
OEF/OIF veterans who had at least 3 elevated pain screening scores within a 12-month period in 2008. Within this group, those prescribed opioids (n=485) over the next 12 months were compared to those not prescribed opioids (n=277). In addition, patients receiving opioids short term (<90 days, n=284) were compared to patients receiving them long-term (≥90 consecutive days, n=201).
Results
Of 762 OEF/OIF veterans with CNCP, 64% were prescribed at least one opioid medication over the 12 months following their index dates. Of those prescribed an opioid, 59% were prescribed opioids short-term and 41% were prescribed opioids long-term. The average morphine-equivalent opioid dose for short-term users was 23.7 mg (SD=20.5) compared with 40.8 mg (SD=36.1) for long-term users (p<0.001). Fifty-one percent of long-term opioid users were prescribed short-acting opioids only and one-third were also prescribed sedative-hypnotics. In adjusted analyses, diagnoses of low back pain, migraine headache, post-traumatic stress disorder, and nicotine use disorder were associated with an increased likelihood of receiving an opioid prescription.
Conclusion
Prescription opioid use is common among OEF/OIF veterans with CNCP and is associated with several pain diagnoses and medical conditions.
doi:10.1111/j.1526-4637.2011.01226.x
PMCID: PMC3724513  PMID: 21899715
Chronic pain; Opioids; Veteran; Pain/drug therapy
9.  A case–control study examining whether neurological deficits and PTSD in combat veterans are related to episodes of mild TBI 
BMJ Open  2012;2(2):e000312.
Background
Mild traumatic brain injury (mTBI) is a common injury among military personnel serving in Iraq or Afghanistan. The impact of repeated episodes of combat mTBI is unknown.
Objective
To evaluate relationships among mTBI, post-traumatic stress disorder (PTSD) and neurological deficits (NDs) in US veterans who served in Iraq or Afghanistan.
Methods
This was a case–control study. From 2091 veterans screened for traumatic brain injury, the authors studied 126 who sustained mTBI with one or more episodes of loss of consciousness (LOC) in combat. Comparison groups: 21 combat veterans who had definite or possible episodes of mTBI without LOC and 21 veterans who sustained mTBI with LOC as civilians.
Results
Among combat veterans with mTBI, 52% had NDs, 66% had PTSD and 50% had PTSD and an ND. Impaired olfaction was the most common ND, found in 65 veterans. The prevalence of an ND or PTSD correlated with the number of mTBI exposures with LOC. The prevalence of an ND or PTSD was >90% for more than five episodes of LOC. Severity of PTSD and impairment of olfaction increased with number of LOC episodes. The prevalence of an ND for the 34 combat veterans with one episode of LOC (4/34=11.8%) was similar to that of the 21 veterans of similar age and educational background who sustained civilian mTBI with one episode of LOC (2/21=9.5%, p-NS).
Conclusions
Impaired olfaction was the most frequently recognised ND. Repeated episodes of combat mTBI were associated with increased likelihood of PTSD and an ND. Combat setting may not increase the likelihood of an ND. Two possible connections between mTBI and PTSD are (1) that circumstances leading to combat mTBI likely involve severe psychological trauma and (2) that altered cerebral functioning following mTBI may increase the likelihood that a traumatic event results in PTSD.
Article summary
Article focus
Case–control study of mTBI associated with LOC among US veterans who were deployed to Iraq or Afghanistan during Operations Iraqi Freedom and Enduring Freedom.
Three study groups: (1) 126 veterans who had mTBI with LOC, (2) 21 OIF/OEF veterans who did not suffer mTBI with LOC and (3) 21 veterans who sustained mTBI with LOC in a civilian setting.
Evaluated NDs including a quantitative test of olfaction, PTSD with severity assessed using the PCL-M instrument and a cognitive function using the Montreal Cognitive Assessment Test.
Key messages
Olfaction was a sensitive test for neurological injury associated with mTBI with LOC.
More episodes of mTBI with LOC were associated with higher prevalence rates of NDs or of PTSD.
The severity of PTSD and extent of olfactory impairment increased with the number of episodes of LOC; cognitive function performance was inversely related to the number of episodes of LOC.
Strengths and limitations of this study
Case–control study of US combat veterans with mTBI who were assessed for NDs, PTSD and cognitive function.
Subjects and comparison groups had detailed assessments for NDs, and combat veterans were also assessed for PTSD.
The findings should be relevant to other groups of military personnel with combat mTBI.
The neurological examination was not blinded.
The selection of veterans in this study may be biased because veterans who do not have health issues may not seek care from the Department of Veterans Affairs.
The comparison groups were small.
The findings in veterans with mTBI with LOC may not apply to people with mTBI without LOC.
doi:10.1136/bmjopen-2011-000312
PMCID: PMC3312078  PMID: 22431700
10.  Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone 
A growing number of studies indicate that 3-alpha reduced neurosteroids are remarkable analgesics in various pain states. This is the case for allopregnanolone (AP), one of the most potent endogenous positive allosteric modulators of GABAA receptor function. From the pioneering work of Hans Selye, who described the sedative properties of steroids, synthetic compounds resembling the progesterone metabolite AP have been developed. If some of them have been used as anesthetics, it seems difficult to propose them as a therapeutic option for pain since they display several adverse side effects such as sedation, amnesia and functional tolerance. An alternative strategy, chosen by few laboratories around the world, is aimed at stimulating the local production of 3-alpha reduced neurosteroids in order to limit these well-known side effects. This pharmacological approach has the advantage of targeting specific structures, fully equipped with the necessary biosynthetic enzymatic machinery, where neurosteroids already act as endogenous pain modulators. The various pharmacological trials which attempted to treat pain symptoms by stimulating the production of 3-alpha reduced neurosteroids are reviewed here, as well as novel neurotransmitter systems possibly regulating their endogenous production.
doi:10.3389/fncel.2014.00174
PMCID: PMC4060572  PMID: 24987335
allodynia; hyperalgesia; nociception; pain; neurosteroids; etifoxine
11.  Neurosteroids in the context of stress: Implications for depressive disorders 
Pharmacology & therapeutics  2007;116(1):125-139.
Animal models indicate that the neuroactive steroids 3α,5α-THP (allopregnanolone) and 3α,5α-THDOC (allotetrahydroDOC) are stress responsive, serving as homeostatic mechanisms in restoring normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following stress. While neurosteroid increases to stress are adaptive in the short term, animal models of chronic stress and depression find lower brain and plasma neurosteroid concentrations and alterations in neurosteroid responses to acute stressors. It has been suggested that disruption in this homeostatic mechanism may play a pathogenic role in some psychiatric disorders related to stress. In humans, neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Women with the depressive disorder, premenstrual dysphoric disorder (PMDD), have greater daily stress and a greater rate of traumatic stress. While results on baseline concentrations of neuroactive steroids in PMDD are mixed, PMDD women have diminished functional sensitivity of GABAA receptors and our laboratory has found blunted allopregnanolone responses to mental stress relative to non-PMDD controls. Similarly, euthymic women with histories of clinical depression, which may represent a large proportion of PMDD women, show more severe dysphoric mood symptoms and blunted allopregnanolone responses to stress versus never-depressed women. It is suggested that failure to mount an appropriate allopregnanolone response to stress may reflect the price of repeated biological adaptations to the increased life stress that is well documented in depressive disorders and altered allopregnanolone stress responsivity may also contribute to the dysregulation seen in HPA axis function in depression.
doi:10.1016/j.pharmthera.2007.05.006
PMCID: PMC2650267  PMID: 17597217
Neurosteroids; Allopregnanolone; Stress; Premenstrual dysphoric disorder; Depressive disorders
12.  Pregnenolone and ganaxolone reduce operant ethanol self-administration in alcohol-preferring P rats 
Background
Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxalone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking – the alcohol preferring (P) rats.
Methods
P rats were trained to self-administer ethanol (15% v/v) vs. water on a concurrent schedule of reinforcement, and the effects of ganaxolone (0 – 30 mg/kg, SC) and pregnenolone (0 – 75 mg/kg, IP) were evaluated on the maintenance of ethanol self-administration. After completion of self-administration testing, doses of the neuroactive steroids that altered ethanol self-administration were assessed on spontaneous locomotor activity. Finally, the effect of pregnenolone administration on cerebral cortical levels of the GABAergic neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone, 3α,5α-THP) was determined in both ethanol experienced and inexperienced P rats since pregnenolone is a precursor of these steroids.
Results
Ganaxolone produced a dose-dependent biphasic effect on ethanol reinforcement, as the lowest dose (1 mg/kg) increased and the highest dose (30 mg/kg) decreased ethanol-reinforced responding. However, the highest ganaxolone dose also produced a nonspecific reduction in locomotor activity. Pregnenolone treatment significantly reduced ethanol self-administration (50 and 75 mg/kg), without altering locomotor activity. Pregnenolone (50 mg/kg) produced a significant increase in cerebral cortical allopregnanolone levels. This increase was observed in the self-administration trained animals, but not in ethanol naïve P rats.
Conclusions
These results indicate that pregnenolone dose-dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol.
doi:10.1111/j.1530-0277.2010.01300.x
PMCID: PMC2988984  PMID: 20946297
ethanol self-administration; GABA; neuroactive steroids; ganaxolone; pregnenolone
13.  Health Risk Behaviors of Afghanistan and Iraq War Veterans Attending College 
Purpose
The population military veterans attending college is rapidly growing as veterans return from Operations Enduring Freedom and Iraqi Freedom (OEF/OIF). We sought to describe patterns of student veterans’ health-related behaviors and how they might differ from their non-veteran peers.
Design
We analyzed data from the 2008 Boynton College Student Health Survey (CSHS).
Setting
CSHS participants completed an anonymous online survey.
Subjects
The CSHS sampled students (n=8,651) attending public, private, two-, and four-year postsecondary educational institutions in Minnesota.
Measures
The CSHS included items on substance use (including alcohol and tobacco), safety, nutrition, and physical activity.
Analysis
We described demographics of OEF/OIF veteran, non-OEF/OIF veteran, and non-veteran students and used poisson regression to compute adjusted relative risks (ARR) with 95% confidence intervals to characterize associations between veteran status and health behaviors.
Results
After controlling for demographics, veteran students reported more safety-, tobacco-, and alcohol-related risk behaviors compared to non-veteran students. For instance, compared to the non-veteran reference group, the ARR for past year smokeless tobacco use and physical fighting among for OEF/OIF veterans was 1.76 [CI: 1.31–2.35] and 1.48 [CI: 1.22–1.79] respectively. Veteran and non-veteran students display similar weight-related behaviors, though OEF/OIF veteran students were more likely to engage in strengthening exercises.
Conclusions
There are specific health risk behaviors which are particularly relevant for veterans attending postsecondary institutions. As veterans enroll in postsecondary education there is a unique window of opportunity for health promotion in this population.
doi:10.4278/ajhp.090826-QUAN-278
PMCID: PMC3579508  PMID: 22040391
Veterans; Young Adult; Tobacco; Substance Abuse; Obesity; Safety
14.  Gender Differences in Rates of Depression, PTSD, Pain, Obesity, and Military Sexual Trauma Among Connecticut War Veterans of Iraq and Afghanistan 
Journal of Women's Health  2010;19(2):267-271.
Abstract
Purpose
The current wars in Iraq and Afghanistan have led to an increasing number of female veterans seeking medical and mental healthcare in the Department of Veterans Affairs (VA) healthcare system. To better understand gender differences in healthcare needs among recently returned veterans, we examined the prevalence of positive screenings for depression, posttraumatic stress disorder (PTSD), military sexual trauma (MST), obesity, and chronic pain among female and male veterans of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) receiving care at the VA Connecticut Healthcare System.
Methods
We performed a retrospective, cross-sectional data analysis of OEF/OIF veterans at VA Connecticut who received services in either Primary Care or the Women's Health Clinic between 2001 and 2006.
Results
In this study, 1129 electronic medical records (1032 men, 197 women) were examined. Female veterans were more likely to screen positive for MST (14% vs. 1%, p < 0.001) and depression (48% vs. 39%, p = 0.01) and less likely to screen positive for PTSD (21% vs. 33%, p = 0.002). There was no significant gender difference in clinically significant pain scores. Men were more likely than women to have body mass index (BMI) >30 kg/m2 (21% vs. 13%, p = 0.008).
Conclusions
These results suggest that important gender differences exist in the prevalence of positive screenings for MST, depression, obesity, and PTSD. As the VA continues to review and improve its services for women veterans, clinicians, researchers, and senior leaders should consider innovative ways to ensure that female veterans receive the health services they need within the VA system.
doi:10.1089/jwh.2008.1262
PMCID: PMC3052274  PMID: 20109115
15.  Psychiatric Diagnoses and Neurobehavioral Symptom Severity Among OEF/OIF VA Patients with Deployment-Related Traumatic Brain Injury: A Gender Comparison 
Background
Traumatic brain injury (TBI) has substantial negative implications for the post-deployment adjustment of Veterans who served in Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF); however, most research on Veterans has focused on males. This study investigated gender differences in psychiatric diagnoses and neurobehavioral symptom severity among OEF/OIF Veterans with deployment-related TBI.
Methods
This population-based study examined psychiatric diagnoses and self-reported neurobehavioral symptom severity from administrative records for 12,605 United States OEF/OIF Veterans evaluated as having deployment-related TBI. Men (n = 11,951) and women (n = 654) who were evaluated to have deployment-related TBI during a standardized comprehensive TBI evaluation in Department of Veterans Affairs (VA) facilities were compared on the presence of psychiatric diagnoses and severity of neurobehavioral symptoms.
Findings
Posttraumatic stress disorder (PTSD) was the most common psychiatric condition for both genders, although women were less likely than men to have a PTSD diagnosis. In contrast, relative to men, women were 2 times more likely to have a depression diagnosis, 1.3 times more likely to have a non-PTSD anxiety disorder, and 1.5 times more likely to have PTSD with comorbid depression. Multivariate analyses indicated that blast exposure during deployment may account for some of these differences. Additionally, women reported significantly more severe symptoms across a range of neurobehavioral domains.
Conclusions
Although PTSD was the most common condition for both men and women, it is also critical for providers to identify and treat other conditions, especially depression and neurobehavioral symptoms, among women Veterans with deployment-related TBI.
doi:10.1016/j.whi.2011.04.019
PMCID: PMC3132395  PMID: 21724143
traumatic brain injury; Veterans; women; gender; psychiatric conditions; neurobehavioral symptoms; post-deployment adjustment
16.  The Boston Assessment of Traumatic Brain Injury–Lifetime (BAT-L) Semistructured Interview: Evidence of Research Utility and Validity 
Objective
Report the prevalence of lifetime and military-related traumatic brain injuries (TBIs) in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans and validate the Boston Assessment of TBI–Lifetime (BAT-L).
Setting
The BAT-L is the first validated, postcombat, semistructured clinical interview to characterize head injuries and diagnose TBIs throughout the life span.
Participants
Community-dwelling convenience sample of 131 OEF/OIF veterans.
Design
TBI criteria (alteration of mental status, posttraumatic amnesia, and loss of consciousness) were evaluated for all possible TBIs, including a novel evaluation of blast exposure.
Main Measures
BAT-L, Ohio State University TBI Identification Method (OSU-TBI-ID).
Results
About 67% of veterans incurred a TBI in their lifetime. Almost 35% of veterans experienced at least 1 military-related TBI; all were mild in severity, 40% of them were due to blast, 50% were due to some other (ie, blunt) mechanism, and 10% were due to both types of injuries. Predeployment TBIs were frequent (45% of veterans). There was strong correspondence between the BAT-L and the OSU-TBI-ID (Cohen κ = 0.89; Kendall τ-b 0.95). Interrater reliability of the BAT-L was strong (κs >0.80).
Conclusions
The BAT-L is a valid instrument with which to assess TBI across a service member’s lifetime and captures the varied and complex nature of brain injuries across OEF/OIF veterans’ life span.
doi:10.1097/HTR.0b013e3182865859
PMCID: PMC3997066  PMID: 23535389
assessment; blast; OEF/OIF; traumatic brain injury (TBI); veterans
17.  Web-Based Intervention for Returning Veterans with Symptoms of Posttraumatic Stress Disorder and Risky Alcohol Use 
A substantial number of military personnel who have served in Iraq (Operation Iraqi Freedom; OIF) and Afghanistan (Operating Enduring Freedom; OEF) develop symptoms of posttraumatic stress disorder (PTSD) in response to their military experiences and many of these same individuals will drink in a risky or problematic manner following deployment. If left untreated, PTSD symptoms and alcohol problems can become chronic and have a significant, negative impact on the lives of veterans, their families and communities. Further, OIF and OEF service members are often reluctant to seek treatment for mental health symptoms or alcohol problems secondary to stigma. In order to reach this population it is essential that new strategies and venues for delivering evidence-based care are explored. Web-based interventions are uniquely suited to this cohort of veterans in that they have the potential to reach a significant number of veterans who commonly use the Web and who might not otherwise receive care. This article will review the prevalence of PTSD and alcohol problems among OIF and OEF veterans, common barriers they experience with accessing care in traditional mental health settings, and what is known about the effectiveness of Web-based approaches for PTSD and alcohol problems. It also describes the components of a new Web-based intervention, developed by the authors, that uses motivational enhancement and cognitive-behavioral strategies to intervene with returning veterans who report PTSD symptoms and problem drinking. Recommendations for future directions in working with returning veterans with PTSD and alcohol problems will be offered.
doi:10.1007/s10879-011-9173-5
PMCID: PMC4219624  PMID: 25378713
Veterans; PTSD; Alcohol; Web intervention
18.  Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer’s Disease Diagnosis 
Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.
doi:10.3389/fendo.2011.00069
PMCID: PMC3356139  PMID: 22654823
Alzheimer’s disease; dehydroepiandrosterone; diagnostic tool; neurosteroids
19.  Pregnancy and Mental Health Among Women Veterans Returning from Iraq and Afghanistan 
Journal of Women's Health  2010;19(12):2159-2166.
Abstract
Background
Veterans of Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) may experience significant stress during military service that can have lingering effects. Little is known about mental health problems or treatment among pregnant OEF/OIF women veterans. The aim of this study was to determine the prevalence of mental health problems among veterans who received pregnancy-related care in the Veterans Health Administration (VHA) system.
Methods
Data from the Defense Manpower Data Center (DMDC) deployment roster of military discharges from October 1, 2001, through April 30, 2008, were used to assemble an administrative cohort of female OEF/OIF veterans enrolled in care at the VHA (n = 43,078). Pregnancy and mental health conditions were quantified according to ICD-9-CM codes and specifications. Mental healthcare use and prenatal care were assessed by analyzing VHA stop codes.
Results
During the study period, 2966 (7%) women received at least one episode of pregnancy-related care, and 32% of veterans with a pregnancy and 21% without a pregnancy received one or more mental health diagnoses (p < 0.0001). Veterans with a pregnancy were twice as likely to have a diagnosis of depression, anxiety, posttraumatic stress disorder (PTSD), bipolar disorder, or schizophrenia as those without a pregnancy.
Conclusions
Women OEF/OIF veterans commonly experience mental health problems after military service. The burden of mental health conditions is higher among women with an identified instance of pregnancy than among those without. Because women do not receive pregnancy care at the VHA, however, little is known about ongoing concomitant prenatal and mental healthcare or about pregnancy outcomes among these women veterans.
doi:10.1089/jwh.2009.1892
PMCID: PMC3052271  PMID: 21039234
20.  Reduced Amygdala Volume Is Associated with Deficits in Inhibitory Control: A Voxel- and Surface-Based Morphometric Analysis of Comorbid PTSD/Mild TBI 
BioMed Research International  2014;2014:691505.
A significant portion of previously deployed combat Veterans from Operation Enduring Freedom and Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) are affected by comorbid posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Despite this fact, neuroimaging studies investigating the neural correlates of cognitive dysfunction within this population are almost nonexistent, with the exception of research examining the neural correlates of diagnostic PTSD or TBI. The current study used both voxel-based and surface-based morphometry to determine whether comorbid PTSD/mTBI is characterized by altered brain structure in the same regions as observed in singular diagnostic PTSD or TBI. Furthermore, we assessed whether alterations in brain structures in these regions were associated with behavioral measures related to inhibitory control, as assessed by the Go/No-go task, self-reports of impulsivity, and/or PTSD or mTBI symptoms. Results indicate volumetric reductions in the bilateral anterior amygdala in our comorbid PTSD/mTBI sample as compared to a control sample of OEF/OIF Veterans with no history of mTBI and/or PTSD. Moreover, increased volume reduction in the amygdala predicted poorer inhibitory control as measured by performance on the Go/No-go task, increased self-reported impulsivity, and greater symptoms associated with PTSD. These findings suggest that alterations in brain anatomy in OEF/OIF/OND Veterans with comorbid PTSD/mTBI are associated with both cognitive deficits and trauma symptoms related to PTSD.
doi:10.1155/2014/691505
PMCID: PMC3958771  PMID: 24724093
21.  Neurosteroids Reduce Social Isolation-Induced Behavioral Deficits: A Proposed Link with Neurosteroid-Mediated Upregulation of BDNF Expression 
The pharmacological action of selective serotonin reuptake inhibitor antidepressants may include a normalization of the decreased brain levels of the brain-derived neurotrophic factor (BDNF) and of neurosteroids such as the progesterone metabolite allopregnanolone, which are decreased in patients with depression and posttraumatic stress disorders (PTSD). The allopregnanolone and BDNF level decrease in PTSD and depressed patients is associated with behavioral symptom severity. Antidepressant treatment upregulates both allopregnanolone levels and the expression of BDNF in a manner that significantly correlates with improved symptomatology, which suggests that neurosteroid biosynthesis and BDNF expression may be interrelated. Preclinical studies using the socially isolated mouse as an animal model of behavioral deficits, which resemble some of the symptoms observed in PTSD patients, have shown that fluoxetine and derivatives improve anxiety-like behavior, fear responses and aggressive behavior by elevating the corticolimbic levels of allopregnanolone and BDNF mRNA expression. These actions appeared to be independent and more selective than the action of these drugs on serotonin reuptake inhibition. Hence, this review addresses the hypothesis that in PTSD or depressed patients, brain allopregnanolone levels, and BDNF expression upregulation may be mechanisms at least partially involved in the beneficial actions of antidepressants or other selective brain steroidogenic stimulant molecules.
doi:10.3389/fendo.2011.00073
PMCID: PMC3355888  PMID: 22649384
allopregnanolone; 5α-reductase type I; selective brain steroidogenic stimulants; GABAA receptors; BDNF; anxiety; aggressive behavior; PTSD
22.  Neurosteroids: Endogenous Role in the Human Brian and Therapeutic Potentials 
Progress in brain research  2010;186:113-137.
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone, and androstane neurosteroids, such as androstanediol and etiocholanone. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids increases both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-Areceptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
doi:10.1016/B978-0-444-53630-3.00008-7
PMCID: PMC3139029  PMID: 21094889
Allopregnanolone; androstanediol; deoxycorticosterone; epilepsy; ganaxolone; GABA-A receptor; sex differences; neurosteroid; progesterone; seizure susceptibility; testosterone
23.  Development of Temporomandibular Disorders is associated with greater bodily pain experience 
The Clinical journal of pain  2010;26(2):116-120.
Objectives
The aim of this study is to examine the difference in the report of bodily pain experienced by subjects who develop temporomandibular disorders (TMD) and by those who do not develop TMD over a 3 year observation period.
Methods
This is a 3 year prospective study of 266 females aged 18–34 years initially free of TMD pain. All subjects completed the Symptom Report Questionnaire (SRQ) at baseline and yearly intervals, and at the time they developed TMD (if applicable). The SRQ is a self-report instrument evaluating the extent and location of pain experienced in the prior 6 months. Statistical analysis was carried out using repeated measures ANOVA.
Results
Over the 3 year period, 16 subjects developed TMD based on the Research Diagnostic Criteria for TMD. Subjects who developed TMD reported more headaches (P=0.0089), muscle soreness or pain (P=0.005), joint soreness or pain (P=0.0012), back pain (P=0.0001), chest pain (P=0.0004), abdominal pain (P=0.0021), and menstrual pain (P=0.0036) than subjects who did not develop TMD at both the baseline and final visits. Subjects who developed TMD also reported significantly more headache (P=0.0006), muscle soreness or pain (P=0.0059), and other pains (P=0.0188) when they were diagnosed with TMD compared to the baseline visit.
Discussion
The development of TMD was accompanied by increases in headaches, muscle soreness or pain, and other pains that were not observed in the subjects who did not develop TMD. Subjects who developed TMD also report higher experience of joint, back, chest and menstrual pain at baseline.
doi:10.1097/AJP.0b013e3181c507ef
PMCID: PMC2811336  PMID: 20090437
widespread pain; temporomandibular disorders
24.  In a mouse model relevant for PTSD, selective brain steroidogenic stimulants (SBSSs) improve behavioral deficits by normalizing allopregnanolone biosynthesis 
Behavioural pharmacology  2010;21(5-6):438-450.
The pathophysiological role of the neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) in neuropsychiatric disorders has been highlighted in several recent investigations. For instance, allopregnanolone levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants, including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms.
PTSD-like behavioral dysfunctions, including heightened aggression, exaggerated fear, and anxiety-like behavior associated with a decrease in corticolimbic allopregnanolone content are modeled in mice by protracted social isolation stress. Allopregnanolone is not only synthesized by principal glutamatergic and GABAergic neurons but also locally, potently, positively, and allosterically modulates GABA action at post- and extra-synaptic GABAA receptors. Hence, this paper will review preclinical studies which show that in socially-isolated mice, rather than SSRI mechanisms, allopregnanolone biosynthesis in glutamatergic corticolimbic neurons offers a non-traditional target for fluoxetine to decrease signs of aggression, normalize fear responses, and decrease anxiety-like behavior. At low SSRI-inactive doses, fluoxetine and related congeners potently increase allopregnanolone levels by acting as potent selective brain steroidogenic stimulants (SBSSs), thereby facilitating GABAA receptor neurotransmission and improving behavioral dysfunctions.
Although the precise molecular mechanisms that underlie the action of these drugs are not fully understood, findings from socially-isolated mice may ultimately generate insights into novel drug targets for the treatment of psychiatric disorders, such as anxiety and panic disorders, depression, and PTSD.
doi:10.1097/FBP.0b013e32833d8ba0
PMCID: PMC2942072  PMID: 20716970
Allopregnanolone; 5α-reductase type I; selective brain steroidogenic stimulants (SBSSs); aggressive behavior; GABAA receptors; social isolation; anxiety; PTSD; mouse
25.  Endogenous and synthetic neurosteroids in treatment of Niemann Pick Type C Disease 
Brain research reviews  2007;57(2):410-420.
The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABAA receptors may play a role. We treated NP-C mice with a synthetic GABAA neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABAA receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.
doi:10.1016/j.brainresrev.2007.05.012
PMCID: PMC2323675  PMID: 17629950
allopregnanolone; Niemann Pick Type C; GABAA receptor; pregnane-X-receptor

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