James D. Bremner

Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)

A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala. Chronic stress also affects the hippocampus, a brain area involved in declarative memories, suggesting that hippocampal dysfunction may partly account for the deficits in declarative memory in PTSD-patients. Deficits in the medial prefrontal cortex, a structure that normally inhibits the amygdala, may further enhance the effects of the amygdala, thereby increasing the frequency and intensity of the traumatic memories. Thus, by way of its influence on these brain structures, exposure to severe stress may simultaneously result in strong emotional reactions and in difficulties to recall the emotional event. This model is also relevant for understanding the distinction between declarative and non-declarative memory-functions in processing trauma-related information in PTSD. Implications of our model are reviewed.

Global DNA methylation is associated with insulin resistance: a monozygotic twin study.

Insulin resistance (IR), the hallmark of type 2 diabetes, may be under epigenetic control. This study examines the association between global DNA methylation and IR using 84 monozygotic twin pairs. IR was estimated using homeostasis model assessment (HOMA). Global DNA methylation of Alu repeats in peripheral blood leukocytes was quantified by bisulfite pyrosequencing. The association between global DNA methylation and IR was examined using generalized estimating equation (GEE) and within–twin pair analyses, adjusting for potential confounders. Results show that methylation levels at all four CpG sites were individually associated with IR by GEE (all false discovery rate–adjusted P values ≤0.026). A 10% increase in mean Alu methylation was associated with an increase of 4.55 units (95% CI 2.38–6.73) in HOMA. Intrapair difference in IR was significantly associated with intrapair difference in global methylation level. A 10% increase in the difference in mean Alu methylation was associated with an increase of 4.54 units (0.34–8.71; P = 0.036) in the difference in HOMA. Confirmation of the results by intrapair analyses suggests that genetic factors do not confound the association between global DNA methylation and IR. Exclusion of twins taking diabetes medication (n = 17) did not change our results.

Association between promoter methylation of serotonin transporter gene and depressive symptoms: a monozygotic twin study.

Objective Epigenetic mechanisms have been implicated in the pathogenesis of psychiatric disorders. The serotonin transporter gene (SLC6A4) is a key candidate gene for depression. We examined the association between SLC6A4 promoter methylation variation and depressive symptoms using 84 monozygotic twin pairs. Methods DNA methylation level in the SLC6A4 promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The number of current depressive symptoms was assessed using the Beck Depressive Inventory II (BDI-II). The association between methylation variation and depressive symptoms was examined using matched twin-pair analyses, adjusting for body mass index, smoking, physical activity, and alcohol consumption. Multiple testing was controlled by adjusted false discovery rate (q value). Results Intrapair difference in DNA methylation variation at 10 of the 20 studied CpG sites is significantly correlated with intrapair difference in BDI scores. Linear regression using intrapair differences demonstrates that intrapair difference in BDI score was significantly associated with intrapair differences in DNA methylation variation after adjusting for potential confounders and correction for multiple testing. On average, a 10% increase in the difference in mean DNA methylation level was associated with 4.4 increase in the difference in BDI score (95% confidence interval = 0.9–7.9, p = .01). Conclusions This study provides evidence that variation in methylation level within the promoter region of the serotonin transporter gene is associated with variation in depressive symptoms in a large sample of monozygotic twin pairs. This relationship is not confounded by genetic and shared environment. The 5-HTTLPR genotype also does not modulate this association.

Sex differences in mental stress-induced myocardial ischemia in young survivors of an acute myocardial infarction.

Objectives 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 in men. Methods We studied 98 post-MI patients (49 women and 49 men) aged 38 to 60 years. Women and men were matched for age, MI type, and months since MI. Patients underwent technetium-99m 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. Results Women 50 years or younger, but not older women, showed a more adverse psychosocial profile than did age-matched men but did not differ for conventional risk factors and tended to have less angiographic coronary artery disease. Compared with age-matched men, women 50 years or younger exhibited a higher SDS with mental stress (3.1 versus 1.5, p = .029) and had twice the rate of MSIMI (SDS ≥3; 52% versus 25%), whereas ischemia with physical stress did not differ (36% versus 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 life-style factors, coronary artery disease severity, and depression. Conclusions MSIMI post-MI is more common in women 50 years or younger compared with age-matched men. These sex differences are not observed in post-MI patients who are older than 50 years.

Is heart rate variability related to memory performance in middle-aged men?

Objective: 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. Methods: We performed power spectral analysis on 24-hour ambulatory ECGs in 416 middle-aged male twins from the Vietnam Era Twin Registry. Memory and learning were measured by verbal and visual Selective Reminding Tests (SRTs). Mixed-effect regression models were used to calculate associations between and within twin pairs, while adjusting for covariates. Results: The mean age (standard deviation) 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 HRV and verbal total recall SRT, such that each logarithm of increase in very low frequency was associated with an increased verbal SRT score of 4.85 points (p =.002). The association persisted despite the 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 posttraumatic 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. Conclusions: 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 c decline.ECG = electrocardiogram; HRV = heart rate variability; SD = standard deviation; SRT = selective reminding test

Compartmental Modeling of 11C-HOMADAM Binding to the Serotonin Transporter in the Healthy Human Brain

The novel PET radioligand 11C-N,N-dimethyl-2-(2′-amino-4′-hydroxymethylphenylthio)benzylamine (11C-HOMADAM) binds with high affinity and selectively to the serotonin transporter (SERT). The purpose of this study was to develop a reliable kinetic model to describe the uptake of 11C-HOMADAM in the healthy human brain. Methods: Eight volunteers participated in the study; 5 of them were fitted with arterial catheters for blood sampling and all were scanned on a high-resolution research tomograph after the injection of 11C-HOMADAM. Regional distribution volumes and binding potentials were calculated with 2- and 4-parameter arterial-input compartment models, a 3-parameter reference tissue compartment model, and the Logan graphic approach. Results: The 2-parameter arterial-input compartment model was statistically superior to the 4-parameter model and described all brain regions. Calculated binding potentials agreed well between the arterial-input model and the reference tissue model when the cerebellum was used as the reference tissue. The Logan graphic approach was not able to estimate the higher concentration of SERT in the dorsal raphe than in the midbrain. Conclusion: 11C-HOMADAM is a highly promising radioligand with high ratios of specific binding to nonspecific binding in known SERT-rich structures, such as the raphe nuclei. The 3-parameter reference tissue model approach permits a simplified quantitatively accurate method for estimating SERT binding potentials.

Comorbid Posttraumatic Stress Disorder and Opiate Addiction: A Literature Review

Treatment of comorbid posttraumatic stress disorder (PTSD) and opioid dependence has been a challenge for many clinicians. There are limited evidence-based guidelines for treatment of this comorbidity. Symptoms of PTSD and opiate dependence may converge, and it is sometimes difficult to differentiate between both conditions. For example, opioid withdrawal symptoms may mimic the hypervigilance and exacerbated startle response of patients with PTSD. A common neurobiologic circuit is suggested for the pathophysiologic mechanism of this comorbidity. There is evidence that opioid substitution therapy may improve treatment outcomes for opioid addiction in patients with comorbid PTSD and opioid dependence. Evidence-based psychotherapeutic intervention is recommended for this population to improve the psychological outcome as well. Combining opioid substitution therapy with evidence-based cognitive behavioral therapy designed for individuals with comorbid PTSD and substance abuse (e.g., Seeking Safety) may improve treatment outcomes in this population. More research is needed to understand the underlying mechanisms for this comorbidity and to improve treatment response.

Pleiotropy of C-reactive protein gene polymorphisms with C-reactive protein levels and heart rate variability in healthy male twins.

Reduced heart rate variability (HRV) and increased C-reactive protein (CRP) levels are both predictors of coronary artery disease and correlate with each other. We examined whether these 2 phenotypes share a common genetic substrate and investigated the relations of the CRP gene polymorphisms with both CRP levels and HRV indexes. We examined 236 male twins free of symptomatic coronary artery disease, with a mean age +/- SD of 54 +/- 2.9 years. The plasma CRP levels were measured and the frequency domain measures of HRV were assessed using a 24-hour electrocardiographic recording, including ultra-low-, very-low-, low-, and high-frequency power. Three single-nucleotide polymorphisms in the CRP gene were genotyped. Generalized estimating equations were used to examine the association between CRP and HRV, as well as the genotype-phenotype association. Bivariate structural equation modeling was performed to estimate the genetic and environmental correlations between CRP and HRV and the explanatory effect of CRP gene polymorphisms on the CRP-HRV association. Both CRP (h(2) = 0.76) and HRV indexes (h(2) = 0.56 to 0.64) showed high heritability. Greater CRP levels were significantly associated with lower HRV. A robust genetic correlation was found between CRP and ultra-low-frequency power (r(G) = -0.3, p = 0.001). One CRP single nucleotide polymorphism (rs1205) was significantly associated with both CRP (p = 0.003) and ultra-low-frequency power (p = 0.005) and explained 11% of the genetic covariance between them. In conclusion, reduced HRV correlates significantly with increased CRP plasma levels and this correlation is due, in large part, to common genetic influences. A polymorphism in the CRP gene contributes to both CRP levels and HRV.

Monoamine oxidase A genotype, childhood trauma, and subclinical atherosclerosis: a twin study.

Objective A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated in neuropsychiatric disorders and also moderates the association between early-life stress and mental disorders, which often co-occur with cardiovascular disease. No study has examined the relationship between MAOA genotype, childhood trauma, and subclinical atherosclerosis. The objective of this investigation was to examine whether childhood trauma moderates the association between MAOA genotype and subclinical atherosclerosis. Methods A sample including 289 middle-aged male twin pairs was studied. Subclinical atherosclerosis was assessed by brachial flow-mediated dilation (FMD) using ultrasound. Childhood trauma, before age 18 years, was measured with the Early Trauma Inventory and included physical, emotional, and sexual abuse as well as general trauma. Generalized estimating equation models were used to test the main and interactive effects of the MAOA genotype and each domain of childhood trauma on FMD, adjusting for known risk factors. Results General trauma was the most prevalent childhood trauma (28.4%), followed by physical abuse (25.0%), emotional abuse (19.4%), and sexual abuse (11.6%). MAOA genotype was not associated with any domain of childhood trauma. There was no significant evidence for a main effect for the MAOA genotype (&bgr; = .02, p = .82) or childhood trauma (.005 < &bgr; < .10, p > .54) FMD. However, a significant interaction was observed between MAOA genotype and physical (&bgr;interaction = .37, p = .026) or emotional abuse (&bgr;interaction = .43, p = .025) on subclinical atherosclerosis. Conclusions Childhood trauma modulates the impact of MAOA variant on subclinical atherosclerosis, independent of traditional cardiovascular risk factors.

A Pilot Study of the Effects of Mindfulness-Based Stress Reduction on Post-traumatic Stress Disorder Symptoms and Brain Response to Traumatic Reminders of Combat in Operation Enduring Freedom/Operation Iraqi Freedom Combat Veterans with Post-traumatic Stress Disorder

Objective Brain imaging studies in patients with post-traumatic stress disorder (PTSD) have implicated a circuitry of brain regions including the medial prefrontal cortex, amygdala, hippocampus, parietal cortex, and insula. Pharmacological treatment studies have shown a reversal of medial prefrontal deficits in response to traumatic reminders. Mindfulness-based stress reduction (MBSR) is a promising non-pharmacologic approach to the treatment of anxiety and pain disorders. The purpose of this study was to assess the effects of MBSR on PTSD symptoms and brain response to traumatic reminders measured with positron-emission tomography (PET) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) combat veterans with PTSD. We hypothesized that MBSR would show increased prefrontal response to stress and improved PTSD symptoms in veterans with PTSD. Method Twenty-six OEF/OIF combat veterans with PTSD who had recently returned from a combat zone were block randomized to receive eight sessions of MBSR or present-centered group therapy (PCGT). PTSD patients underwent assessment of PTSD symptoms with the Clinician-Administered PTSD Scale (CAPS), mindfulness with the Five Factor Mindfulness Questionnaire (FFMQ) and brain imaging using PET in conjunction with exposure to neutral and Iraq combat-related slides and sound before and after treatment. Nine patients in the MBSR group and 8 in the PCGT group completed all study procedures. Results Post-traumatic stress disorder patients treated with MBSR (but not PCGT) had an improvement in PTSD symptoms measured with the CAPS that persisted for 6 months after treatment. MBSR also resulted in an increase in mindfulness measured with the FFMQ. MBSR-treated patients had increased anterior cingulate and inferior parietal lobule and decreased insula and precuneus function in response to traumatic reminders compared to the PCGT group. Conclusion This study shows that MBSR is a safe and effective treatment for PTSD. Furthermore, MBSR treatment is associated with changes in brain regions that have been implicated in PTSD and are involved in extinction of fear responses to traumatic memories as well as regulation of the stress response.