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1.  Meta-Analysis of Mental Stress—Induced Myocardial Ischemia and Subsequent Cardiac Events in Patients With Coronary Artery Disease 
The American journal of cardiology  2014;114(2):187-192.
Mental stress—induced myocardial ischemia (MSIMI) has been associated with adverse prognosis in patients with coronary artery disease (CAD), but whether this is a uniform finding across different studies has not been described. We conducted a systematic review and meta-analysis of prospective studies examining the association between MSIMI and adverse outcome events in patients with stable CAD. We searched PubMed, EMBASE, Web of Science, and PsycINFO databases for English language prospective studies of patients with CAD who underwent standardized mental stress testing to determine presence of MSIMI and were followed up for subsequent cardiac events or total mortality. Our outcomes of interest were CAD recurrence, CAD mortality, or total mortality. A summary effect estimate was derived using a fixed-effects meta-analysis model. Only 5 studies, each with a sample size of <200 patients and fewer than 50 outcome events, met the inclusion criteria. The pooled samples comprised 555 patients with CAD (85% male) and 117 events with a range of follow-up from 35 days to 8.8 years. Pooled analysis showed that MSIMI was associated with a twofold increased risk of a combined end point of cardiac events or total mortality (relative risk 2.24, 95% confidence interval 1.59 to 3.15). No heterogeneity was detected among the studies (Q = 0.39, I2 = 0.0%, p = 0.98). In conclusion, although few selected studies have examined the association between MSIMI and adverse events in patients with CAD, all existing investigations point to approximately a doubling of risk. Whether this increased risk is generalizable to the CAD population at large and varies in patient subgroups warrant further investigation.
PMCID: PMC4126399  PMID: 24856319
2.  Sex Differences in Mental Stress-Induced Myocardial Ischemia in Young Survivors of an Acute Myocardial Infarction 
Psychosomatic medicine  2014;76(3):171-180.
Emotional stress may disproportionally affect young women with ischemic heart disease. We sought to examine whether mental stress-induced myocardial ischemia (MSIMI), but not exercise-induced ischemia, is more common in young women with previous myocardial infarction (MI) than men.
We studied 98 post-MI patients (49 women and 49 men) aged 38-60 years. Women and men were matched for age, MI type, and months since MI. Patients underwent [99mTc]sestamibi perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Perfusion defect scores were obtained with observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify ischemia under both stress conditions.
Women aged 50 or younger, but not older women, showed a more adverse psychosocial profile than age-matched men, but did not differ for conventional risk factors and tended to have less angiographic coronary artery disease (CAD). Compared with age-matched men, women aged 50 or younger exhibited a higher SDS with mental stress (3.1 vs. 1.5, p=0.029) and had twice the rate of MSIMI (SDS ≥3), 52% vs. 25%, while ischemia with physical stress did not differ (36% vs 25%). In older patients there were no sex differences in MSIMI. The higher prevalence of MSIMI in young women persisted when adjusting for sociodemographic and lifestyle factors, CAD severity and depression.
MSIMI post-MI is more common in women aged 50 or younger compared to age-matched men. These sex differences are not observed in post-MI patients who are older than 50 years.
PMCID: PMC4008686  PMID: 24608039
cardiovascular diseases; stress; ischemia; gender
3.  Measurement of heritability of myocardial blood flow by positron emission tomography: the Twins Heart Study 
Heart (British Cardiac Society)  2012;98(6):495-499.
To estimate the heritability of myocardial blood flow (MBF) and coronary flow reserve (CFR) measured with positron emission tomography (PET).
Cross-sectional twin study.
General clinical research centre of a university hospital at Atlanta, USA.
A sample of 180 middle-aged (mean±SD 55±2.9 years) male twins, including 107 monozygotic and 73 dizygotic twins.
Main outcome measures
All twins underwent imaging of MBF with PET 13NH3 at rest and after adenosine stress during a single imaging session. Structural equation modelling was used to estimate the heritability of MBF at rest and during adenosine stress, as well as of CFR.
The basal MBF (mean±SD) was 0.69±0.20 ml/min/g, and the MBF during adenosine stress was 1.70±0.49 ml/min/g; the CFR was 2.62±0.99. There was substantial heritability for MBF both at rest (0.48, 95% CI 0.29 to 0.64) and during adenosine stress (0.51, 95% CI 0.29 to 0.68), as well as CFR (0.48, 95% CI 0.26 to 0.65).
For the first time, a substantial genetic contribution to the interindividual variation in MBF and CFR measured with PET in middle-aged men has been demonstrated. The data suggest that a fruitful direction for future work would be the identification of genetic variants for early atherosclerotic stages assessed by PET imaging.
PMCID: PMC4380432  PMID: 22323242
4.  Retinoic Acid and Affective Disorders: The Evidence for an Association 
Isotretinoin (13-cis-retinoic acid, or 13-cis-RA) (Accutane), approved by the FDA for the treatment of acne, carries a black box warning related to the risk of depression, suicide, and psychosis. Retinoic acid (RA), the active form of vitamin A, regulates gene expression in the brain, and isotretinoin is its 13-cis isomer. Retinoids represent a group of compounds derived from vitamin A that perform a large variety of functions in many systems, in particular the CNS, and abnormal retinoid levels can have neurological effects. Although infrequent, proper recognition and treatment of psychiatric side effects in acne patients is critical given the risk of death and disability. This paper reviews the evidence for a relationship between isotretinoin, depression and suicidality.
Data Sources
Evidence examined includes: 1) case reports; 2) temporal association between onset of depression and exposure to the drug; 3) challenge-rechallenge cases; 4) class effect (other compounds in the same class, like vitamin A, having similar neuropsychiatric effects); 5) dose response; and 6) biologically plausible mechanisms.
Study Selection
All papers in the literature related to isotretinoin, depression and suicide were reviewed, as well as papers related to class effect, dose response, and biological plausibility.
Data Extraction
Information from individual articles in the literature was extracted.
Data Synthesis
The literature reviewed is consistent with an association between isotretinoin administration, depression and suicide in some individuals.
The relationship between isotretinoin and depression may have implications for a greater understanding of the neurobiology of affective disorders.
PMCID: PMC3276716  PMID: 21903028
5.  The Relationship Between Cognitive and Brain Changes in Posttraumatic Stress Disorder 
Preclinical studies show that stress is associated with changes in structure of the hippocampus, a brain area that plays a critical role in memory, inhibition of neurogenesis, and memory deficits. Studies in animals showed that both serotonin reuptake inhibitors (SSRIs) and the epilepsy medication phenytoin (dilantin) block the effects of stress on the hippocampus. Imaging studies in posttraumatic stress disorder (PTSD) have found smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI) in patients with PTSD related to both combat and childhood abuse. These patients were also found to have deficits in memory on neuropsychological testing. Functional imaging studies using positron emission tomography (PET) found decreased hippocampal activation with memory tasks. In an initial study, we found that a year of treatment with paroxetine led to a 5% increase in hippocampal volume and a 35% increase in memory function. A second study showed that phenytoin was efficacious for symptoms of PTSD and led to a significant 6% increase in both right hippocampal and right whole brain volume, with no significant change in memory. These studies suggest that medications may counteract the effects of stress on the brain in patients with PTSD.
PMCID: PMC3233753  PMID: 16891564
PTSD; hippocampus; pharmacotherapy; stress; neurogenesis; paroxetine; depression
6.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder 
Psychological medicine  2005;35(6):791-806.
In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).
Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.
Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
PMCID: PMC3233760  PMID: 15997600
7.  Neural Correlates of Exposure to Traumatic Pictures and Sound in Vietnam Combat Veterans with and without Posttraumatic Stress Disorder: A Positron Emission Tomography Study 
Biological psychiatry  1999;45(7):806-816.
Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD.
Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD.
Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas.
The findings suggest that functional alterations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.
PMCID: PMC3233761  PMID: 10202567
Positron emission tomography; memory; postttraumatic stress disorder; frontal cortex; cingulate; function
8.  Regional Brain Metabolic Correlates of α-Methylparatyrosine–Induced Depressive Symptoms 
We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion–induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using α-methylparatyrosine (AMPT).
To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.
Design, Setting, and Participants
Randomized, controlled, double-blind trial in which 18 patients recruited in 1997–2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.
After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.
Main Outcome Measures
Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.
AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P=.002) and dorsolateral prefrontal (P=.03) cortex and thalamus (P=.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.
Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.
PMCID: PMC3233764  PMID: 12813118
9.  Psychometric Properties of the Early Trauma Inventory–Self Report 
Childhood trauma is an important public health problem, but there are limitations in our ability to measure childhood abuse. The purpose of this study was to develop a self-report instrument for the assessment of childhood trauma that is valid but simple to administer. A total of 288 subjects with and without trauma and psychiatric disorders were assessed with the Early Trauma Inventory– Self Report (ETI-SR), an instrument for the assessment of physical, emotional, and sexual abuse, as well as general traumas, which measures frequency, onset, emotional impact, and other variables. Validity and consistency of the ETI-SR using different methods of scoring was assessed. The ETI-SR was found to have good validity and internal consistency. No method was found to be superior to the simple method of counting the number of items endorsed as having ever occurred in terms of validity. Some items were found to be redundant or not necessary for the accurate measurement of trauma severity within specific domains. Subsequent analyses with a shortened checklist of items showed acceptable validity and internal consistency. These findings suggest that the ETI-SR is a valid measure of early trauma, and suggest future directions for a shortened version of the ETI-SR that could be more easily incorporated into clinical research studies and practice settings.
PMCID: PMC3229091  PMID: 17468680
Depressive disorders; stress disorders; posttraumatic; psychometrics; measurement; abuse; trauma
10.  Magnetic Resonance Imaging-Based Measurement of Hippocampal Volume in Posttraumatic Stress Disorder Related to Childhood Physical and Sexual Abuse—A Preliminary Report 
Biological psychiatry  1997;41(1):23-32.
We have previously reported smaller hippocampal volume and deficits in short-term memory in patients with combat-related posttraumatic stress disorder (PTSD) relative to comparison subjects. The purpose of this study was to compare hippocampal volume in adult survivors of childhood abuse to matched controls. Magnetic resonance imaging was used to measure volume of the hippocampus in adult survivors of childhood abuse (n = 17) and healthy subjects (n = 17) matched on a case-by-case basis for age, sex, race, handedness, years of education, body size, and years of alcohol abuse. All patients met criteria for PTSD secondary to childhood abuse. PTSD patients had a 12% smaller left hippocampal volume relative to the matched controls (p < .05), without smaller volumes of comparison regions (amygdala, caudate, and temporal lobe). The findings were significant after controlling for alcohol, age, and education, with multiple linear regression. These findings suggest that a decrease in left hippocampal volume is associated with abuse-related PTSD.
PMCID: PMC3229101  PMID: 8988792
Hippocampus; stress; posttraumatic stress disorder; cortisol; childhood abuse
11.  Surfing the Net for medical information about psychological trauma: An empirical study of the quality and accuracy of trauma-related websites 
Psychological trauma is a major public-health problem, and trauma victims frequently turn to the Internet for medical information related to trauma. The Internet has many advantages for trauma victims, including low cost, privacy, use of access, and reduced direct social interactions. However, there are no regulations on what is posted on the Internet, or by whom, and little is known about the quality of information currently available related to the topic of psychological trauma. The purpose of this study was to evaluate the quality of Internet sites related to the topic of psychological trauma. The top 20 hits for searches on Google, AllTheWeb, and Yahoo were tabulated, using search words of ‘psychological trauma’, ‘stress’, ‘PTSD’, and ‘trauma’. From these searches, a list of 94 unique unsponsored hits that represented accessible websites was generated. Fourteen sites were unrelated or only peripherally related, and eight were related but were not comprehensively evaluated because they represented brochures, online book sales, etc. Seventy-two websites underwent evaluation of the content, design, disclosure, ease of use, and other factors based on published guidelines for medical information sites. Forty-two per cent of sites had inaccurate information, 82% did not provide a source of their information, and 41% did not use a mental-health professional in the development of the content. Ratings of content (e.g. accuracy, reliability, etc.) were 4 (2 SD) on a scale of 1 – 10, with 10 being the best. There were similar ratings for the other variables assessed. These findings suggest that although abundant, websites providing information about psychological trauma are often not useful, and can sometimes provide inaccurate and potentially harmful information to consumers of medical information.
PMCID: PMC3226702  PMID: 16954059
Informatics; PTSD; trauma; stress; anxiety; Internet
12.  Cognitive Processes in Dissociation: Comment on Giesbrecht et al. (2008) 
Psychological bulletin  2010;136(1):1-11.
In “Cognitive Processes in Dissociation: An Analysis of Core Theoretical Assumptions,” published in Psychological Bulletin, Giesbrecht, Lynn, Lilienfeld, and Merckelbach (2008) have challenged the widely accepted trauma theory of dissociation, which holds that dissociative symptoms are caused by traumatic stress. In doing so the authors outline a series of links between various constructs, such as fantasy proneness, cognitive failures, absorption, suggestibility, altered information-processing, dissociation, and amnesia, claiming that these linkages lead to the false conclusion that trauma causes dissociation. A review of the literature, however, shows that these are not necessarily related constructs. Careful examination of their arguments reveals no basis for the conclusion that there is no association between trauma and dissociation. The current comment offers a critical review and rebuttal of the argument of Giesbrecht et al. that there is no relationship between trauma and dissociation.
PMCID: PMC2835500  PMID: 20063920
trauma; PTSD; dissociative disorders; dissociation; memory; absorption
13.  Posttraumatic Stress Disorder and Incidence of Coronary Heart Disease: A Twin Study 
Journal of the American College of Cardiology  2013;62(11):10.1016/j.jacc.2013.04.085.
To determine whether posttraumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD.
It has long been hypothesized that PTSD increases the risk of CHD but empirical evidence using objective measures is limited.
We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [N13] positron emission tomography, including a stress total severity score (STSS) and coronary flow reserve (CFR).
A total of 562 twins (281 pairs) were included with mean age of 42.6 yrs at baseline. The incidence of CHD was more than double in twins with PTSD (22.6%) than those without PTSD (8.9%; p<0.001). The association remained robust after adjusting for lifestyle factors, other CHD risk factors and major depression (OR=2.2, 95% confidence interval, 1.2-4.1). STSS was significantly higher (+ 95%, p=0.001) and CFR lower (−0.21, p=0.02) in twins with PTSD than those without, denoting worse myocardial perfusion. Associations were only mildly attenuated within 117 twin pairs discordant for PTSD.
Among Vietnam era veterans, PTSD is a risk factor for CHD.
PMCID: PMC3823367  PMID: 23810885
cardiovascular diseases; risk factors; epidemiology; stress
14.  Depressive Symptoms Are Associated with Mental Stress-Induced Myocardial Ischemia after Acute Myocardial Infarction 
PLoS ONE  2014;9(7):e102986.
Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI.
We studied 98 patients (49 women and 49 men) age 38–60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores.
There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [β = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [β = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress.
Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress.
PMCID: PMC4111307  PMID: 25061993
15.  Neuroimaging in Posttraumatic Stress Disorder and Other Stress-related Disorders 
Traumatic stress has a broad range of effects on the brain. Brain areas implicated in the stress response include the amygdala, hippocampus, and prefrontal cortex. Studies in patients with posttraumatic stress disorder (PTSD) and other psychiatric disorders related to stress have replicated findings in animal studies by finding alterations in these brain areas. Brain regions implicated in PTSD also play an important role in memory function, highlighting the important interplay between memory and the traumatic stress response. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders.
PMCID: PMC2729089  PMID: 17983968
16.  The Neurobiology of Retinoic Acid in Affective Disorders 
Current models of affective disorders implicate alterations in norepinephrine, serotonin, dopamine, and CRF/cortisol; however treatments targeted at these neurotransmitters or hormones have led to imperfect resolution of symptoms, suggesting that the neurobiology of affective disorders is incompletely understood. Until now retinoids have not been considered as possible contributors to affective disorders. Retinoids represent a family of compounds derived from Vitamin A that perform a large number of functions, many via the vitamin A product, retinoic acid. This signaling molecule binds to specific retinoic acid receptors in the brain which, like the glucocorticoid and thyroid hormone receptors, are part of the nuclear receptor superfamily and regulate gene transcription. Research in the field of retinoic acid in the CNS has focused on the developing brain, in part stimulated by the observation that isotretinoin (13-cis retinoic acid), an isomer of retinoic acid used in the treatment of acne, is highly teratogenic for the CNS. More recent work has suggested that retinoic acid may influence the adult brain; animal studies indicated that the administration of isotretinoin is associated with alterations in behavior as well as inhibition of neurogenesis in the hippocampus. Clinical evidence for an association between retinoids and depression includes case reports in the literature, studies of health care databases, and other sources. A preliminary PET study in human subjects showed that isotretinoin was associated with a decrease in orbitofrontal metabolism. Several studies have shown that the molecular components required for retinoic acid signaling are expressed in the adult brain ; the overlap of brain areas implicated in retinoic acid function and stress and depression suggest that retinoids could play a role in affective disorders. This report reviews the evidence in this area and describes several systems that may be targets of retinoic acid and which contribute to the pathophysiology of depression.
PMCID: PMC2704911  PMID: 17707566
17.  Posttraumatic Stress Disorder and Impaired Autonomic Modulation in Male Twins 
Biological psychiatry  2013;73(11):1103-1110.
Posttraumatic stress disorder (PTSD) has been linked to increased morbidity. An inflexibility of the autonomic nervous system may be the underlying mechanism. We aimed to assess whether PTSD and combat trauma exposure are associated with lower heart rate variability (HRV), a measure of autonomic function and a predictor of death.
We measured HRV by power spectral analysis on 24-hour ambulatory ECG in 459 middle-aged veteran male twins. Combat trauma was assessed with the combat exposure scale, and current and remitted PTSD with the Structured Clinical Interview for Psychiatry Disorders. Mixed-effects regression models were used to test associations of PTSD and HRV between and within twin pairs.
Of all twins, 211 had combat exposure, 31 had current PTSD, and 43 had remitted PTSD. Current PTSD was inversely associated with very-low frequency (VLF) and low frequency (LF) HRV both in individual twins and within 20 pairs discordant for current PTSD. Twins with current PTSD had a 49% lower LF HRV than their brothers without PTSD (p<0.001). Remitted PTSD was not associated with HRV. Results were robust to adjustment for depression and other risk factors. Combat exposure was inversely associated with most HRV frequencies, but this association mostly diminished after adjustment for current PTSD.
In middle-aged veteran men, combat exposure and current PTSD are associated with measures of autonomic inflexibility previously shown to have prognostic significance. The negative health impact of combat exposure on autonomic function is mediated largely through PTSD and may reverse with remission of PTSD.
PMCID: PMC3648627  PMID: 23434412
Autonomic nervous system; heart rate variability; posttraumatic stress disorder; military combat trauma; mental stress; heart disease
18.  Association between Posttraumatic Stress Disorder and Inflammation: A Twin Study 
Brain, behavior, and immunity  2013;30:125-132.
The association of posttraumatic stress disorder (PTSD) with cardiovascular disease risk may be mediated by inflammation. Our objective was to examine the association between PTSD and measures of inflammation and to determine whether these associations are due to shared familial or genetic factors. We measured lifetime history of PTSD using the Structured Clinical Interview for DSM-IV in 238 male middle-aged military veteran twin pairs (476 individuals), selected from the Vietnam Era Twins Registry, who were free of cardiovascular disease at baseline. We assessed inflammation using levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), fibrinogen, white blood cells, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1). Geometric mean levels and percent differences by PTSD were obtained from mixed-model linear regression analyses with adjustment for potential confounders. Within-pair analysis was conducted to adjust for shared family environment and genetics (monozygotic pairs). Overall, 12.4% of participants had a lifetime history of PTSD. Adjusted mean levels of hsCRP and ICAM-1 were significantly higher among those with vs. without PTSD [hsCRP: 1.75 vs. 1.31 mg/l (33% difference); ICAM-1: 319 vs. 293 ng/ml (9% difference)]. Adjustment for depression rendered the association of PTSD with hsCRP non-statistically significant. For IL-6, no consistent association was seen. Within-pair analysis produced associations that were similar in direction for all three markers but lesser in magnitude for hsCRP and IL-6. There was no evidence of interaction by zygosity. Elevated hsCRP and ICAM-1 are associated with PTSD, and these associations may be confounded by shared non-genetic, antecedent familial and environmental factors.
PMCID: PMC3641167  PMID: 23379997
posttraumatic stress disorder; inflammation; cardiovascular disease; twins; Vietnam veterans
19.  Association Between Ideal Cardiovascular Health and Carotid Intima‐Media Thickness: A Twin Study 
The American Heart Association (AHA) recently developed the Cardiovascular Health Index (CVHI), a health metric consisting of 7 modifiable risk factors. The relationship of the CVHI with preclinical markers, such as carotid intima‐media thickness (CIMT) has not been assessed.
We examined 490 male monozygotic and dizygotic twins without overt cardiovascular disease. CIMT was measured using B‐mode ultrasonography. Each of the 7 CVHI components (blood pressure, fasting glucose, total cholesterol, body mass index, physical activity, healthy diet, and smoking) was given a point score of 0, 1, or 2 to represent poor, intermediate, or ideal health, respectively. A CVHI summation score was computed (range 0 to 14) and categorized as inadequate (0 to 4), average (5 to 9), or optimum (10 to 14) cardiovascular health. Mixed‐model regression was used to examine the association of the CVHI with CIMT.
The mean age of the twins was 55.4 years, and 61% were monozygotic. The mean CIMT was 0.75 (±0.11) mm and the mean CVHI score was 7.7 (±2.1). There was an inverse correlation between CVHI and CIMT (Spearman r=−0.22, P<0.01). For every 5‐unit increase in overall CVHI score (indicating better cardiovascular health category), CIMT decreased by 0.045 mm (P<0.001) after adjusting for demographic variables and other confounders. Within monozygotic twin pairs, a 5‐unit increment in CVHI score was associated with a 0.05 mm lower CIMT (P<0.001).
The CVHI is independently associated with CIMT and the association is not confounded by shared genetic and other familial factors.
PMCID: PMC3959690  PMID: 24385450
epidemiology; prevention; risk factors
20.  Early Trauma and Inflammation: Role of Familial Factors in a Study of Twins 
Psychosomatic Medicine  2012;74(2):146-152.
Although early trauma (trauma in childhood) has been linked to adult inflammation and adult disease of inflammatory origin, it remains unknown whether this relationship is due to long-term consequences of early life stress or other familial factors.
We examined 482 male middle aged twins (241 pairs) born between 1946 and 1956 from the Vietnam Era Twin Registry. Childhood traumatic experiences, before age 18, were measured retrospectively with the Early Trauma Inventory (ETI) and included physical, sexual, emotional abuse, and general trauma. Lifetime major depressive disorder and posttraumatic stress disorder were assessed with the Structured Clinical Interview for DSM IV. Traditional risk factors for cardiovascular disease were also assessed. Plasma C-reactive protein (CRP) and interleukin-6 (IL-6) were measured to determine levels of inflammation. Mixed-effect regression models with a random intercept for pair were used to separate between and within twin pair effects.
When twins were analyzed as individuals, increasing levels of early trauma were positively related to CRP (p=0.03) but not IL-6 (p=0.12). When estimating within and between pair effects, only the between pair association of early trauma with the inflammatory markers remained significant.
The link between early trauma and inflammation is largely explained by familial factors shared by the twins, because levels of inflammation were highest when both twins were exposed to trauma. Exposure to early trauma may be a marker for an unhealthy familial environment. Clarification of familial factors associated with early stress and adult inflammation will be important to uncover correlates of stress and disease.
PMCID: PMC3307790  PMID: 22286843
childhood maltreatment; Interleukin-6; C-reactive protein; stress; risk factor
21.  Is Heart Rate Variability Related To Memory Performance in Middle Aged Men? 
Psychosomatic Medicine  2011;73(6):475-482.
Heart rate variability (HRV), a measure of autonomic function, has been associated with cognitive function, but studies are conflicting. Previous studies have also not controlled for familial and genetic influences.
We performed power spectral analysis on 24-hour ambulatory ECG’s in 416 middle-aged male twins from the Vietnam Era Twin Registry. Memory and learning were measured by verbal and visual selective reminding tests (SRT). Mixed-effect regression models were used to calculate associations between and within twin pairs, while adjusting for covariates.
The mean age (SD) was 55 (2.9) years. A statistically significant positive association was found between measures of HRV and verbal, but not visual, SRT scores. The most statistically significant unadjusted association was found between very low frequency (VLF) HRV and verbal total recall SRT, such that each logarithm of increase in VLF was associated with an increased verbal SRT score of 4.85 points (p=0.002). The association persisted despite adjustment for demographic and cardiovascular risk factors, and after accounting for familial, and genetic factors by comparing twins within pairs. A significant interaction was found between post-traumatic stress disorder (PTSD) and HRV, such that total power and ultra low frequency were associated with SRT in twins (n=362) without PTSD, but not in those with PTSD.
In conclusion, lower frequency spectra of HRV are associated with verbal, but not visual, learning and memory, particularly in subjects without PTSD. This association may indicate that autonomic nervous system dysregulation plays a role in cognitive decline.
PMCID: PMC3307789  PMID: 21715297
memory; autonomic function; heart rate variability; cognitive function
22.  Effects of Smoking on Coronary Microcirculatory Function: A Twin Study 
Atherosclerosis  2011;215(2):500-506.
In asymptomatic smokers, coronary microcirculatory dysfunction, assessed by coronary flow reserve (CFR), is an early indicator of cardiovascular risk. Inflammation and oxidative stress may be the mechanisms through which smoking affects the microvasculature.
The purpose of this study was to determine the relationship between smoking and CFR, taking into account potential shared genetic effects.
We examined 360 male middle aged twins (288 non-smokers and 72 smokers), including 46 twin pairs discordant for current smoking. Coronary flow reserve (CFR) in response to adenosine was measured with positron emission tomography [N13] ammonia and quantitation of coronary blood flow at rest and after adenosine stress. Inflammation was assessed by measuring interleukin-6 and C-reactive protein, and oxidative stress was determined by measuring plasma hydroperoxides, glutathione (GSH), the oxidized form of GSH, GSSG, and the ratio of GSH to GSSG.
CFR was significantly lower in smokers compared to nonsmokers (2.25 vs. 2.75, p<0.01). This relationship persisted after accounting for known cardiovascular disease risk factors, and was marginally affected by adjusting for inflammatory and oxidative stress biomarkers. In addition, in smoking-discordant twin pairs, CFR in the smoking twin was significantly lower than in the non-smoking co-twin (2.25 vs. 2.67, p = 0.03) even after adjustment for cardiovascular risk factors.
Our results demonstrate the adverse effects of smoking in the early phases of cardiovascular disease. Mechanisms other than peripherally-measured inflammation and oxidative stress are involved.
PMCID: PMC3082474  PMID: 21315354
biomarkers; smoking; cardiovascular disease; oxidative stress; inflammation
24.  Inflammation is Related to Coronary Flow Reserve Detected by Positron Emission Tomography in Asymptomatic Male Twins 
To examine the relationship between inflammation and coronary microvascular function in asymptomatic individuals using positron emission tomography (PET) and assessment of coronary flow reserve (CFR).
Coronary microvascular dysfunction is an early precursor of coronary artery disease (CAD) thought to result from endothelial cell activation and inflammation, but data are limited.
We examined 268 asymptomatic male monozygotic and dizygotic twins. Plasma biomarkers of inflammation and endothelial cell activation included C-reactive protein (CRP), interleukin-6 (IL-6), white blood cell count (WBC), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Blood flow quantitation was obtained with [13N] ammonia PET at rest and after adenosine stress. CFR was measured as the ratio of maximum flow to baseline flow at rest; abnormal CFR was defined as a ratio <2.5. A summed stress score for visible perfusion defects was calculated.
In within-pair analyses, all biomarkers, except VCAM-1, were higher in twins with lower CFR than their brothers with higher CFR (p<0.05). This was observed in the entire sample, as well as within pairs discordant for a CFR of <2.5. Associations persisted after adjusting for summed stress score and CAD risk factors. In contrast no biomarker, except IL-6, was related to the summed stress score of visible defects.
Even in asymptomatic subjects, a decrease in coronary microvascular function is accompanied by a systemic inflammatory response, independent of CAD risk factors. Our results, using a controlled twin design, highlight the importance of coronary microvascular function in the early phases of CAD.
PMCID: PMC3073445  PMID: 21392641
circulation; imaging; inflammation; coronary disease; endothelium
25.  Stress and Brain Atrophy 
Studies in animals showed that stress is associated with changes in hippocampal function and structure, an effect mediated through decreased neurogenesis, increased glucocorticoids, and/or decreased brain derived neurotrophic factor. Antidepressants and some anticonvulsants block the effects of stress and/or promote neurogenesis in animal studies. Patients with posttraumatic stress disorder (PTSD) have been shown to have smaller hippocampal volume on magnetic resonance imaging and deficits in hippocampal-based memory. Symptom activation is associated with decreased anterior cingulate and medial prefrontal function, which is proposed as the neural correlate of a failure of extinction seen in these patients. Treatment with antidepressants and phenytoin reverse hippocampal volume reduction and memory deficits in PTSD patients, suggesting that these agents may promote neurogenesis in humans.
PMCID: PMC3269810  PMID: 17073653

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