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author:("Flory, canine")
1.  COMT met Allele Differentially Predicts Risk versus Severity of Aberrant Eating in a Large Community Sample 
Psychiatry research  2014;220(0):513-518.
Prefrontal dopamine (DA) transmission participates in the reinforcement of reward-driven behaviors like eating. Because catechol-O-methyltransferase (COMT) degrades DA and is expressed in the prefrontal cortex, variation in the COMT gene may modulate eating behavior. Previous studies have shown that the met allele of the COMT val158met single nucleotide polymorphism (SNP) is associated with Bulimia Nervosa (BN). The specific aim of this study was to test whether the met allele increased risk for, and severity of, eating disorder symptomatology in community volunteers. Caucasian adults (N = 1,003; 51.2% female) from the University of Pittsburgh Adult Health and Behavior Project (AHAB) were genotyped and completed the Eating Disorders Inventory (EDI). Logistic and Poisson regression analyses assessed genotype-dependent presence and severity of eating disorder symptomatology. The met allele was significantly associated with the presence of symptoms on the Bulimia subscale and the severity of Body Dissatisfaction scores. All EDI subscales significantly predicted BMI. To our knowledge, these are the first data indicating that the COMT met allele increases risk for some symptoms of disordered eating, while increasing severity of others, in a community sample. These novel findings may have important implications for understanding the etiology of heterogeneous disordered eating phenotypes.
PMCID: PMC4252581  PMID: 25216558
Catechol-O-methyltransferase gene; prefrontal cortex; dopamine; aberrant eating; eating disorders; Bulimia
2.  Glucocorticoid-related predictors and correlates of post-traumatic stress disorder treatment response in combat veterans 
Interface Focus  2014;4(5):20140048.
The identification of biomarkers for post-traumatic stress disorder (PTSD) and resilience/recovery is critical for advancing knowledge about pathophysiology and treatment in trauma-exposed persons. This study examined a series of glucocorticoid-related biomarkers prior to and in response to psychotherapy. Fifty-two male and female veterans with PTSD were randomized 2 : 1 to receive either prolonged exposure (PE) therapy or a weekly minimal attention (MA) intervention for 12 consecutive weeks. Psychological and biological assessments were obtained prior to and following treatment and after a 12-week naturalistic follow-up. Response was defined dichotomously as no longer meeting criteria for PTSD at post-treatment based on the Clinician Administered PTSD Scale for DSM-IV (CAPS). Clinical improvement on the CAPS was apparent for both PE and MA, with no significant difference according to treatment condition. Biomarkers predictive of treatment gains included the BCLI polymorphism of the glucocorticoid receptor gene. Additional predictors of treatment response were higher bedtime salivary cortisol and 24 h urinary cortisol excretion. Pre-treatment plasma dehydroepiandrosterone/cortisol ratio and neuropetide Y (NPY) levels were predictors of reductions in PTSD symptoms, and, for NPY only, of other secondary outcomes as well, including anxiety and depression ratings. Glucocorticoid sensitivity changed in association with symptom change, reflecting clinical state. It is possible to distinguish prognostic and state biomarkers of PTSD using a longitudinal approach in the context of treatment. Identified markers may also be relevant to understanding mechanisms of action of symptom reduction.
PMCID: PMC4142020  PMID: 25285201
post-traumatic stress disorder; psychotherapy; glucocorticoid receptor; neuropetide Y; hypothalamic pituitary adrenal axis; biomarkers
3.  The BDNF Val66Met polymorphism does not moderate the effect of self-reported physical activity on depressive symptoms in midlife 
Psychiatry research  2014;218(0):93-97.
The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism may be associated with clinical and subsyndromal depression, but physical activity improves mood and increases BDNF expression.
To examine whether the BDNF polymorphism moderates an effect of physical activity on depressive symptoms.
BDNF genotype, physical activity measured by the Paffenbarger Questionnaire, and depressive symptoms using the Center for Epidemiology Depression Scale (CES-D) were collected on 1072 participants (Mean Age=44). Multiple linear regression was used to examine the association between BDNF genotype, physical activity, and depressive symptoms.
After adjusting for family income, age, and education, depressive symptoms were higher in Met carriers compared to Val homozygotes (p=0.03), but this was only significant in men. Physical activity was associated with fewer depressive symptoms, but only in women (p=0.01). BDNF genotype did not moderate the effect of physical activity on depressive symptoms (p= 0.94).
In midlife, the BDNF Val66Met polymorphism neither attenuates nor magnifies the effect of physical activity on depressive symptoms.
PMCID: PMC4059542  PMID: 24745471
Depression; Exercise; BDNF polymorphism
4.  Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring 
The American journal of psychiatry  2014;171(8):872-880.
Differential effects of maternal and paternal PTSD have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The current study examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor gene (NR3C1) in peripheral blood mononuclear cells (PBMCs), and its relationship to glucocorticoid receptor sensitivity, in Holocaust offspring.
Adult offspring with at least one Holocaust survivor parent (n=80), and demographically similar participants without parental Holocaust exposure or PTSD (n=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of glucocorticoid receptor gene exon 1F (GR-1F) promoter methylation and cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical-clustering analysis was used to permit visualization of maternal vs. paternal PTSD effects on clinical variables.
A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater post-dexamethasone cortisol suppression. The clustering analysis confirmed that maternal and paternal PTSD effects were differentially associated with clinical indicators.
This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.
PMCID: PMC4127390  PMID: 24832930
Holocaust; epigenetic; methylation; intergenerational; glucocorticoid receptor; NR3C1 gene; GR-1F promoter; PTSD; HPA axis; cortisol
5.  Omega-3 Fatty Acids Moderate Effects of Physical Activity on Cognitive Function 
Neuropsychologia  2014;59:103-111.
Greater amounts of physical activity (PA) and omega-3 fatty acids have both been independently associated with better cognitive performance. Because of the overlapping biological effects of omega-3 fatty acids and PA, fatty acid intake may modify the effects of PA on neurocognitive function. The present study tested this hypothesis by examining whether the ratio of serum omega-6 to omega-3 fatty acid levels would moderate the association between PA and executive and memory functions in 344 participants (Mean age = 44.42 years, SD = 6.72). The Paffenbarger Physical Activity Questionnaire (PPAQ), serum fatty acid levels, and performance on a standard neuropsychological battery were acquired on all subjects. A principal component analysis reduced the number of cognitive outcomes to three factors: n-back working memory, Trail Making test, and Logical Memory. We found a significant interaction between PA and the ratio of omega-6 to omega-3 fatty acid serum levels on Trail Making performance and n-back performance, such that higher amounts of omega-3 levels offset the deleterious effects of lower amounts of PA. These effects remained significant in a subsample (n=299) controlling for overall dietary fat consumption. There were no significant additive or multiplicative benefits of higher amounts of both omega-3 and PA on cognitive performance. Our results demonstrate that a diet high in omega-3 fatty acids might mitigate the effect of lower levels of PA on cognitive performance. This study illuminates the importance of understanding dietary and PA factors in tandem when exploring their effects on neurocognitive health.
PMCID: PMC4104997  PMID: 24813150
omega-3; physical activity; working memory; task-switching; logical memory; DHA
6.  Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations 
Approximately half of people with post-traumatic stress disorder (PTSD) also suffer from Major Depressive Disorder (MDD). The current paper examines evidence for two explanations of this comorbidity. First, that the comorbidity reflects overlapping symptoms in the two disorders. Second, that the co-occurrence of PTSD and MDD is not an artifact, but represents a trauma-related phenotype, possibly a subtype of PTSD. Support for the latter explanation is inferred from literature that examines risk and biological correlates of PTSD and MDD, including molecular processes. Treatment implications of the comorbidity are considered.
PMCID: PMC4518698  PMID: 26246789
PTSD; MOD; comorbidity; glucocorticoid receptor; FKBP5
7.  Context Processing in Schizotypal Personality Disorder: Evidence of Specificity of Impairment to the Schizophrenia Spectrum 
Journal of abnormal psychology  2008;117(2):342-354.
Working memory abnormalities, which are particularly pronounced on context processing tasks, appear relatively specific to schizophrenia spectrum illnesses compared with other psychotic disorders. However, the specificity of context processing deficits to schizotypal personality disorder (SPD), a prototype of schizophrenia, has not been studied. The authors administered 3 versions of the modified AX Continuous Performance Test and an N-back working memory test to 63 individuals with SPD and 25 with other personality disorders, as well as 42 healthy controls. For the AX Continuous Performance Test standard and degraded versions, there was a significant Trial Type × Delay × Group interaction, as SPDs made significantly more errors reflecting poor maintenance of context and fewer errors reflecting good maintenance of context. SPDs also demonstrated poor performance on the N-back, especially at the 2-back condition. Context processing errors and N-back accuracy scores were related to disorganization symptoms. These findings, which are quite similar to those previously reported in patients with schizophrenia, suggest that context processing deficits are specific to the schizophrenia spectrum and are not a reflection of overall psychopathology.
PMCID: PMC4176884  PMID: 18489210
schizotypal personality; context processing; cognition; schizophrenia spectrum; personality disorders
8.  Neural Correlates of Emotion Processing in Borderline Personality Disorder 
Psychiatry research  2009;172(3):192-199.
Emotional instability is a hallmark feature of borderline personality disorder (BPD), yet its biological underpinnings are poorly understood. We employed functional MRI to compare patterns of regional brain activation in BPD patients and healthy volunteers as they process positive and negative social emotional stimuli. fMRI images were acquired while 19 BPD patients and 17 healthy controls (HC) viewed emotion-inducing pictures from the IAPS set. Activation data were analyzed with SPM5 ANCOVA models to derive the effects of diagnosis and stimulus type. BPD patients demonstrated greater differences in activation than controls, when viewing negative pictures compared to rest, in the amygdala, fusiform gyrus, primary visual areas, superior temporal gyrus (STG), and premotor areas, while healthy controls showed greater differences than BPD’s in the insula, middle temporal gyrus and dorsolateral prefrontal cortex (BA46). When viewing positive pictures compared to rest, BPD patients showed greater differences in the STG, premotor cortex, and ventrolateral prefrontal cortex. These findings suggest that BPD patients show greater amygdala activity and heightened activity of visual processing regions than HC’s, when processing negative social emotional pictures compared to rest. They activate neural networks in emotion processing that are phylogenetically older and more reflexive than healthy controls.
PMCID: PMC4153735  PMID: 19394205
Affective Instability; Emotion; fMRI; Social-Emotional Cues; Borderline Personality Disorder
9.  Cigarette smoking and measures of impulsivity in a college sample 
An association between impulsivity and smoking has been consistently reported in the literature, but few studies have examined how distinct dimensions of impulsivity may relate differentially to smoking initiation versus persistent smoking. The aim of the current study was to examine the relationship between self-report and behavioral measures of impulsivity and smoking status in college students. Participants (n=243) completed a self-report history of tobacco use, two self-report measures of impulsivity (the Barratt Impulsiveness Scale and Zuckerman Sensation-Seeking Scale) and two behavioral measures (the Delay Discounting Task and Iowa Gambling Task). All participants were classified as never-smokers, triers, or smokers based on their smoking history, and between-group differences on the four measures were examined. On the self-report measures, all three groups differed on sensation seeking with the never-smokers reporting the lowest levels and the smokers reporting the highest. Furthermore, the smokers reported significantly higher disinhibitory impulsivity than the triers and never-smokers. The groups did not differ on the behavioral measures. Our results indicate that distinct dimensions of impulsivity characterize different smoking phenotypes. In particular, sensation seeking is associated with the initiation of smoking whereas disinhibitory impulsivity is associated with the transition to more persistent and regular use of cigarettes.
PMCID: PMC3711662  PMID: 23844956
delay discounting; disinhibition; impulsivity; reward seeking; tobacco use
10.  Polymorphic variation in the dopamine D4 receptor predicts delay discounting as a function of childhood socioeconomic status: evidence for differential susceptibility 
Inconsistent or null findings among studies associating behaviors on the externalizing spectrum—addictions, impulsivity, risk-taking, novelty-seeking traits—with presence of the 7-repeat allele of a common length polymorphism in the gene encoding the dopamine D4 receptor (DRD4) may stem from individuals’ variable exposures to prominent environmental moderators (gene × environment interaction). Here, we report that relative preference for immediate, smaller rewards over larger rewards delayed in time (delay discounting), a behavioral endophenotype of impulsive decision-making, varied by interaction of DRD4 genotype with childhood socioeconomic status (SES) among 546 mid-life community volunteers. Independent of age, sex, adulthood SES and IQ, participants who were both raised in families of distinctly low SES (low parental education and occupational grade) and carried the DRD4 7-repeat allele discounted future rewards more steeply than like-reared counterparts of alternate DRD4 genotype. In the absence of childhood socioeconomic disadvantage, however, participants carrying the 7-repeat allele discounted future rewards less steeply. This bidirectional association of DRD4 genotype with temporal discounting, conditioned by participants’ early life circumstances, accords with a recently proposed developmental model of gene × environment interaction (‘differential susceptibility’) that posits genetically modulated sensitivity to both adverse and salubrious environmental influences.
PMCID: PMC3682430  PMID: 22345368
gene–environment interaction; differential susceptibility; delay discounting; DRD4; childhood socioeconomic status; impulsivity
11.  The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance 
Psychological science  2013;24(9):1770-1779.
Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition.
PMCID: PMC3947596  PMID: 23907543
BDNF; physical activity; working memory; executive function; genetics; visual memory; episodic memory
12.  Hostile Mood and Social Strain during Daily Life: A Test of the Transactional Model 
Hostility is a multidimensional construct related to cardiovascular (CV) disease risk. Daily hostile mood and social interactions may precipitate stress-related CV responses in hostile individuals.
Determine whether trait cognitive hostility best predicts daily hostile mood and social interactions relative to other trait hostility factors and explore the temporal links between these daily measures.
171 participants completed assessments of 4 trait hostility scales. Participants completed an electronic diary across 3 days, assessing current hostile mood and social interaction quality.
Multiple regression analyses revealed both affective and cognitive hostility to be significant predictors of daily hostile mood, and cognitive hostility alone to predict daily social strain. Additional analyses revealed previous social strain to predict elevated subsequent hostile mood.
Episodes of social strain may give rise to elevated hostile mood. Trait cognitive hostility may be an important factor in predicting daily social strain.
PMCID: PMC3508292  PMID: 22899302
hostility; hostile mood; social strain; transactional model
13.  Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD 
Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.
PMCID: PMC3784793  PMID: 24098286
PTSD; veterans; epigenetics; methylation; promoter; glucocorticoid receptor; FK506 binding protein 5; psychotherapy
Preventive medicine  2012;54(0):229-233.
Background and Aims
Commuting by public transportation (PT) entails more physical activity and energy expenditure than by cars, but its biologic consequences are unknown.
In 2009-2010, we randomly sampled New York adults, usually commuting either by car (n=79) or PT (n=101). Measures comprised diet and physical activity questionnaires, weight and height, white blood cell (WBC) count, C reactive protein, (CRP) gene-specific methylation (IL-6), and global genomic DNA methylation (LINE-1 methylation).
Compared to the 101 PT commuters, the 79 car drivers were about 9 years older, 2 kg/m2 heavier, more often non-Hispanic whites, and ate more fruits and more meats. The 2005 guidelines for physical activity were met by more car drivers than PT users (78.5% vs. 65.0%). There were no differences in median levels of CRP (car vs. PT: 0.6 vs. 0.5 mg/dl), mean levels of WBC (car vs. PT: 6.7 vs. 6.5 cells/mm3), LINE-1 methylation (car vs. PT: 78.0% vs. 78.3%), and promoter methylation of IL-6 (car vs. PT: 56.1% vs. 58.0%).
PT users were younger and lighter than car drivers, but their commute mode did not translate into a lower inflammatory response or a higher DNA methylation, maybe because, overall, car drivers were more physically active.
PMCID: PMC3670595  PMID: 22313796
15.  Using Confirmatory Factor Analysis to Measure Contemporaneous Activation of Defined Neuronal Networks in Functional Magnetic Resonance Imaging 
Neuroimage  2012;60(4):1982-1991.
Functional neuroimaging often generates large amounts of data on regions of interest. Such data can be addressed effectively with a widely-used statistical technique based on measurement theory that has not yet been applied to neuroimaging. Confirmatory factor analysis is a convenient hypothesis-driven modeling environment that can be used to conduct formal statistical tests comparing alternative hypotheses regarding the elements of putative neuronal networks. In such models, measures of each activated region of interest are treated as indicators of an underlying latent construct that represents the contemporaneous activation of the elements in the network. As such, confirmatory factor analysis focuses analyses on the activation of hypothesized networks as a whole, improves statistical power by modeling measurement error, and provides a theory-based approach to data reduction with a robust statistical basis. This approach is illustrated using data on seven regions of interest in a hypothesized mesocorticostriatal reward system in a sample of 262 adult volunteers assessed during a card-guessing reward task. A latent construct reflecting contemporaneous activation of the reward system was found to be significantly associated with a latent construct measuring impulsivity, particularly in males.
PMCID: PMC3321108  PMID: 22348884
confirmatory factor analysis; functional neuroimaging; measurement theory; mesocorticostriatal reward system; impulsivity; sex differences
16.  Alcohol dependence, disinhibited behavior and variation in the prodynorphin gene 
Biological psychology  2011;88(1):51-56.
The results of the current analyses present preliminary evidence of an association between putatively functional variation in the prodynorphin (PDYN) gene and a dimensional measure of disinhibited behavior. A 68 bp sequence in the core promoter region of the PDYN gene was genotyped in a community sample of 1021 adults aged 30–54. Participants were interviewed for lifetime history of DSM-IV alcohol dependence and completed two self-report measures of sensation seeking and impulsiveness. Fifteen percent (n=151) of the sample met DSM-IV criteria for alcohol dependence and while results did not support an association between the PDYN polymorphism and the diagnosis of alcohol dependence, we did observe an association between the “low” expressing L allele of the PDYN gene and a preference for engaging in disinhibited behavior. Additionally, people who had both a history of alcohol dependence and higher scores on this Disinhibited Behavior scale were most likely to carry an L allele. These results indicate that variation in the PDYN gene is associated with a dimensional trait or intermediate phenotype that reflects a preference for heavy drinking and engaging in related risky behaviors (e.g., drug use, sexual activity).
PMCID: PMC3171516  PMID: 21736916
17.  Citalopram Improves Metabolic Risk Factors Among High Hostile Adults: Results of a Placebo-Controlled Intervention 
Psychoneuroendocrinology  2011;36(7):1070-1079.
Hostility is associated with a number of metabolic risk factors for cardiovascular disease, including waist-hip ratio, glucose, and triglycerides. Along with hostility, many of these measures have also been shown to be associated with reduced central serotonergic function. We have previously reported that a citalopram intervention was successful in reducing hostility by self-report assessment (Kamarck, et al., 2009). Here we examine the effects of this serotonergic intervention on metabolic risk factors in the same sample. 159 healthy adults with elevated hostility scores were randomized to citalopram or placebo for a 2-month period. Citalopram favorably changed metabolic risk factors, including waist circumference (p = .003), glucose (p=.02), HDL cholesterol (p= .04), triglycerides (p=.03), insulin sensitivity (p = .045) and diastolic blood pressure by automated assessment (p = .0021). All of these metabolic changes were significantly mediated by treatment-related changes in body mass index (in most cases, p < .01). In addition, the changes in blood glucose were significantly mediated by treatment-related changes in hostility (p < .05). Mechanisms accounting for these associations remain to be explored.
PMCID: PMC3118402  PMID: 21306829
hostility; citalopram; metabolic syndrome; randomized clinical trial; ssri; glucose
18.  Joint Effect of Childhood Abuse and Family History of Major Depressive Disorder on Rates of PTSD in People with Personality Disorders 
Objective. Childhood maltreatment and familial psychopathology both lead to an increased risk of the development of posttraumatic stress disorder (PTSD) in adulthood. While family history of psychopathology has traditionally been viewed as a proxy for genetic predisposition, such pathology can also contribute to a stress-laden environment for the child. Method. Analyses were conducted to evaluate the joint effect of childhood abuse and a family history of major depressive disorder (MDD) on diagnoses of PTSD and MDD in a sample of 225 adults with DSM-IV Axis II disorders. Results. Results showed that the rate of PTSD in the presence of both childhood abuse and MDD family history was almost six-fold (OR = 5.89, P = .001) higher relative to the absence of both factors. In contrast, the rate of MDD in the presence of both factors was associated with a nearly three-fold risk relative to the reference group (OR = 2.75, P = .01). Conclusions. The results from this observational study contribute to a growing understanding of predisposing factors for the development of PTSD and suggest that joint effects of family history of MDD and childhood abuse on PTSD are greater than either factor alone.
PMCID: PMC3335173  PMID: 22577531
19.  Reported Early Family Environment Covaries with Menarcheal Age as a Function of Polymorphic Variation in Estrogen Receptor-α (ESR1) 
Age at menarche, a sentinel index of pubertal maturation, was examined in relation to early family relationships (conflict, cohesion) and polymorphic variation in the gene encoding estrogen receptor-α (ESR1) in a midlife sample of 455 European American women. Consistent with prior literature, women who reported being raised in families characterized by close interpersonal relationships and little conflict tended to reach menarche at a later age than participants reared in families lacking cohesion and prone to discord. Moreover, this association was moderated by ESR1 variation, such that quality of the family environment covaried positively with menarcheal age among participants homozygous for minor alleles of the two ESR1 polymorphisms studied here (rs9304799, rs2234693), but not among women of other ESR1 genotypes. In addition, a) family relationship variables were unrelated to ESR1 variation, and b) genotype-dependent effects of childhood environment on age at menarche could not be accounted for by personality traits elsewhere shown to explain heritable variation in reported family conflict and cohesion. These findings are consistent with theories of differential susceptibility to environmental influence, as well as the more specific hypothesis (by Belsky) that girls differ genetically in their sensitivity to rearing effects on pubertal maturation.
PMCID: PMC3077552  PMID: 21262040
Pubertal Timing; Menarche; Family Environment; Estrogen Receptor-α; Gene-Environment Interaction; Differential Susceptibility
20.  Psychometric properties of a short form of the Affective Lability Scale (ALS-18) 
Psychometric properties of a short form of the Affective Lability Scale (ALS) that was developed in a nonclinical sample (i.e., undergraduate students) were examined in a sample of people diagnosed with Cluster B DSM-IV Axis II personality disorders (n=236), other personality disorders (n=180), and healthy comparison participants (n=164). The total score of the ALS-18 score correlated strongly with the original 54-item scale (r = .97) and aspects of convergent and discriminant validity of the ALS-18 subscales (Anxiety/Depression, Depression/Elation, and Anger) were evaluated using self-report measures of affective and psychosocial functioning in the domains of affect intensity, anxiety, anger, and minimization/denial. Clinical utility of the scale was also demonstrated; participants diagnosed with Cluster B personality disorders reported higher affective lability scores, and healthy control participants reported lower scores, relative to individuals with Cluster A or Cluster C personality disorders (p’s < .001). Confirmatory factor analyses were conducted and demonstrated reasonably good fit to the data but future research is needed to test the three factor substructure of the ALS-18 against alternative factor models in samples that include clinical and non-clinical participants.
PMCID: PMC2893358  PMID: 20606710
affective lability scale; affect dysregulation; cluster B personality
21.  Neural Correlates of Using Distancing to Regulate Emotional Responses to Social Situations 
Neuropsychologia  2010;48(6):1813-1822.
Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one’s self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.
PMCID: PMC2905649  PMID: 20226799
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
22.  Pergolide Treatment of Cognitive Deficits Associated with Schizotypal Personality Disorder: Continued Evidence of the Importance of the Dopamine System in the Schizophrenia Spectrum 
Neuropsychopharmacology  2010;35(6):1356-1362.
Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D1 and D2 receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
PMCID: PMC3055340  PMID: 20130535
schizotypal personality; schizotypy; schizophrenia spectrum; cognition; pergolide; dopamine; Schizophrenia/Antipsychotics; Dopamine; Cognition; Clinical Pharmacology/Trials; schizotypal personality; pergolide
23.  The Role of Genes in Defining a Molecular Biology of PTSD 
Disease markers  2011;30(2-3):67-76.
Because environmental exposure to trauma is the sine qua non for the development of Post Traumatic Stress Disorder (PTSD), the recent focus on genetic studies has been noteworthy. The main catalyst for such studies is the observation from epidemiological studies that not all trauma survivors develop this disorder. Furthermore, neuroendocrine findings suggest pre-existing hormonal alterations that confer risk for PTSD. This paper presents the rationale for examining genetic factors in PTSD and trauma exposure, but suggests that studies of genotype may only present a limited picture of the molecular biology of this disorder. We describe the type of information that can be obtained from candidate gene and genomic studies that incorporate environmental factors in the design (i.e., gene – environment interaction and gene-environment correlation studies) and studies that capitalize on the idea that environment modifies gene expression, via epigenetic or other molecular mechanisms. The examination of epigenetic mechanisms in tandem with gene expression will help refine models that explain how PTSD risk, pathophysiology, and recovery is mediated by the environment. Since inherited genetic variation may also influence the extent of epigenetic or gene expression changes resulting from the environment, such studies should optimally be followed up by studies of genotype.
PMCID: PMC3825239  PMID: 21508511
24.  Maternal Exposure to the Holocaust and Health Complaints in Offspring 
Disease markers  2011;30(2-3):133-139.
Although the link between chronic stress and the development of cardiovascular and metabolic diseases of adulthood has been known for some time, there is growing recognition that early environmental influences may result in developmental programming via epigenetic mechanisms, thereby affecting the developmental trajectory of disease progression. Previous studies support the idea that offspring of Holocaust survivors may have been subjected to early developmental programming. We evaluated the relationship between parental exposure to the Holocaust and self-reported health ratings and disorders made by their adult offspring (i.e., second generation Holocaust survivors). A total of 137 subjects were evaluated. Regression analyses demonstrated that maternal but not paternal exposure to the Holocaust was related to poorer subjective impressions of emotional and physical health. This relationship was diminished when the offspring’s own level of trait anxiety was considered. Offspring with maternal, but not paternal, Holocaust exposure also reported greater use of psychotropic and other medications, including medications for the treatment of hypertension and lipid disorders. The mechanism linking these health outcomes and maternal exposure deserves further investigation, including the possibility that fetal or early developmental programming is involved.
PMCID: PMC3825248  PMID: 21508517
25.  Subjective Socioeconomic Status and Presence of the Metabolic Syndrome in Midlife Community Volunteers 
Psychosomatic medicine  2009;72(1):35-45.
Objective indices of socioeconomic status (SES) predict diverse sources of morbidity and mortality, as well as numerous biological and behavioral risk factors for disease. Here we examine whether subjective SES may be similarly associated with measured risk factors, including the metabolic syndrome and its components of elevated blood pressure, high fasting glucose, dyslipidemia, and central adiposity.
Observations were based on a community sample of 981 adults (30–54 years of age; 52% female; 84% white, 16% African American). Subjective SES was measured using the nationally referenced (U.S.) MacArthur Scale of Subjective Social Status, and objective SES indexed by composite of years of education and family income.
Likelihood of meeting criteria for presence of the metabolic syndrome varied inversely with subjective SES (Odds Ratio [OR] =0.75; 95% CI: 0.64, 0.88, for a 1 SD increase in subjective SES, adjusted for age, sex, and race), and this association persisted on further adjustment for objective SES (OR = 0.82; 95% CI: 0.68, 0.99). Subjective SES was also associated inversely with blood pressure, waist circumference, and serum triglycerides, and positively with HDL cholesterol. Level of physical activity and smoking status were predicted by subjective SES as well, but adjusting for these health behaviors did not appreciably reduce associations of subjective SES with metabolic syndrome and syndrome components.
These findings support speculation that perceived social standing is associated with prominent cardiovascular risk factors and may prove a useful adjunct to conventional socioeconomic indicators in epidemiological research.
PMCID: PMC2807361  PMID: 19933505
socioeconomic status; subjective social status; metabolic syndrome; blood pressure; central adiposity; dyslipidemia

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