Jeanne M. McCaffery

Early Life Stress and Morphometry of the Adult Anterior Cingulate Cortex and Caudate Nuclei

BACKGROUND Early life stress (ELS) is linked to adult psychopathology and may contribute to long-term brain alterations, as suggested by studies of women who suffered childhood sexual abuse. We examine whether reported adverse ELS defined as stressful and/or traumatic adverse childhood events (ACEs) is associated with smaller limbic and basal ganglia volumes. METHOD 265 healthy Australian men and women without psychopathology or brain disorders were studied. ACEs were assessed by the ELSQ and current emotional state by the DASS. Anterior cingulate cortex (ACC), hippocampus, amygdala, and caudate nucleus volumes were measured from T1-weighted MRI. Analyses examined ROI volumetric associations with reported ACEs and DASS scores. RESULTS Participants with greater than two ACEs had smaller ACC and caudate nuclei than those without ACEs. A significant association between total ACEs and ROI volumes for these structures was observed. Regression analysis also revealed that ELS was more strongly associated than current emotional state (DASS) with these ROI volumes. CONCLUSIONS Reported ELS is associated with smaller ACC and caudate volumes, but not the hippocampal or amygdala volumes. The reasons for these brain effects are not entirely clear, but may reflect the influence of early stress and traumatic events on the developing brain.

Aggression, Impulsivity, and Central Nervous System Serotonergic Responsivity in a Nonpatient Sample

To test the hypothesis that traits of aggression and impulsivity correlate negatively with central serotonergic system function in a nonpatient population, a standard fenfluramine challenge (for assessment of serotonergic responsivity) and behavioral measurements germane to aggression/impulsivity were administered to a community-derived sample of 119 men and women. In men, peak prolactin responses to fenfluramine correlated significantly with an interview-assessed life history of aggression (r = −.40, p < .002), the Barratt Impulsiveness Scale (r = −.30, p < .03), and traits of Conscientiousness (r = +.30, p < .03), Neuroticism (r = −.31, p < .02) and Angry Hostility (r = −.35, p < .01) on the NEO-Personality Inventory. No significant relationships were observed across all women, although subanalyses restricted to postmenopausal subjects (in whom ovarian influences on prolactin secretion may be mitigated because of diminished estrogen) showed a pattern of behavioral associations somewhat similar to that seen in men. By extending documented relationships between an index of central serotonergic system function and traits of aggression and impulsivity to a more normative range of population variability than is represented in prior literature, this study supports speculation that these associations reflect a basic neurobehavioral dimension of individual differences.

Common genetic vulnerability to depressive symptoms and coronary artery disease: a review and development of candidate genes related to inflammation and serotonin.

Objective: Although it is well established that depressive symptoms are associated with recurrent cardiac events among cardiac patients and novel cardiac events among participants with no known coronary artery disease (CAD), the nature of this association remains unclear. In this regard, little attention has been paid to the possibility that common genetic vulnerability contributes to both depressive symptoms and CAD. In this paper, we review the existing evidence for common genetic contributions to depression and CAD, primarily using evidence from twin and family studies, followed by a review of two major pathophysiological mechanisms thought to underlie covariation between depressive symptoms and CAD: inflammation and serotonin. We conclude with an overview of select candidate genes within these pathways. Methods: Literature review. Results: In twin studies, both depression and CAD appear heritable. In the only twin study to consider depression and CAD jointly, the correlation across heritabilities was 0.42, suggesting that nearly 20% of variability in depressive symptoms and CAD was attributable to common genetic factors. In addition, although it is plausible that genetic variation related to inflammation and serotonin may be associated with both depression and CAD, genetic variation related to inflammation has been primary examined in relation to CAD, whereas genetic variation in the serotonin system has been primarily examined in relation to depression. Conclusions: It appears that the covariation of depressive symptoms and CAD may be attributable, in part, to a common genetic vulnerability. Although several pathways may be involved, genes within the inflammation and serotonin pathways may serve as good candidates for the first steps in identifying genetic variation important for depression, CAD or both. CAD = coronary artery disease; MI = myocardial infarction; MZ = monozygotic; DZ = dizygotic; CES-D = Centers for Epidemiological Studies–Depression Scale; BDI = Beck Depression Inventory; VET = Vietnam-Era Twin; LOD = log10 of odds ratio; CSF 5-HIAA = 5-hydroxyindoleatic acid in cerebrospinal fluid; CYP2A6 = cytochrome P450, subfamily IIA, polypeptide 6 gene; CHRB2 = beta2 nicotine receptor subunit gene; DRD4 = dopamine D4 receptor gene; AVP1B = arginine vasopressin receptor 1b gene; FACL4 = long-chain fatty acid-CoA ligase Type 4 gene; MEF2A = myocyte-enhancing factor 2A; IL-6 = interleukin 6; TNF-α = tumor necrosis factor-α; ICAM-1 = intercellular adhesion molecule-1; CRP = c-reactive protein; IL-1β = interleukin 1β; V-CAM-1 = vascular adhesion molecule 1; 5-HT = serotonin; TPH = tryptophan hydroxylase; 5-HTT = serotonin transporter; MPO = myeloperoxydase; A = adenine nucleic acid; C = cytosine nucleic acid; G = guanine nucleic acid; T = thymine nucleic acid; mRNA = messenger ribonucleic acid; IL-1B, TNFA, MPO, IL-6, ICAM-1, VCAM-1, 5-HTT, 5-HT2A, 5-HT2B, TPH1, TPH2 = genes coding for these proteins, respectively, s allele “short,” or deletion, allele at the common variation in 5-HTT, l allele “long,” or insertion, allele at the common variation in 5-HTT; SELE = E-selectin gene; SELP = P-selectin gene.

Differential functional magnetic resonance imaging response to food pictures in successful weight-loss maintainers relative to normal-weight and obese controls

BACKGROUND Prior research indicates that successful weight-loss maintainers (SWLs) work harder than people of normal weight to maintain their weight loss, including greater dietary restriction of fat and higher physical activity levels. However, little work to date has examined how SWLs differ biologically from normal-weight (NW) and obese controls. OBJECTIVE The objective was to compare the brain responses of SWLs to food pictures with those of NW and obese controls. DESIGN Blood oxygen level-dependent responses to high- and low-energy food pictures were measured in 18 NW controls, 16 obese controls, and 17 SWLs. RESULTS Group differences were identified in 4 regions, which indicated significant change in activation in response to the food pictures. SWLs showed greater activation in the left superior frontal region and right middle temporal region than did NW and obese controls-a pattern of results confirmed in exploratory voxel-wise analyses. Obese controls also showed greater activation in a bilateral precentral region. CONCLUSIONS These results suggest that SWLs show greater activation in frontal regions and primary and secondary visual cortices-a pattern consistent with greater inhibitory control in response to food cues and greater visual attention to the food cues. A greater engagement of inhibitory control regions in response to food cues as well as a greater monitoring of foods may promote control of food intake and successful weight-loss maintenance.

Gene-Environment Interaction

With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G×E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G×E interactions, review conceptual models meant to inform G×E interpretations from a psychological perspective, discuss points of common critique to which G×E research is vulnerable, and address the role of the environment in G×E interactions.

Maintaining large weight losses: the role of behavioral and psychological factors.

Few studies have examined predictors of weight regain after significant weight losses. This prospective study examined behavioral and psychological predictors of weight regain in 261 successful weight losers who completed an 18-month trial of weight regain prevention that compared a control condition with self-regulation interventions delivered face-to-face or via the Internet. Linear mixed effect models were used to examine behavioral and psychological predictors of weight regain, both as main effects and as interactions with treatment group. Decreases in physical activity were related to weight regain across all 3 groups, and increased frequency of self-weighing was equally protective in the 2 intervention groups but not in the control group. Increases in depressive symptoms, disinhibition, and hunger were also related to weight regain in all groups. Although the impact of changes in restraint was greatest in the Internet group and weakest in the face-to-face group, the latter was the only group with increases in restraint over time and consequent decreases in magnitude of weight regain. Future programs should focus on maintaining physical activity, dietary restraints, and frequent self-weighing and should include stronger components to modify psychological parameters.

Depressive symptoms and metabolic risk in adult male twins enrolled in the National Heart, Lung, and Blood Institute twin study.

Objective To determine the extent to which depressive symptoms are associated with metabolic risk factors and whether genetic or environmental factors account for this association. Method Twin structural equation modeling was employed to estimate genetic and environmental contributions to the covariation of depressive symptoms, as indexed by the Centers for Epidemiological Studies–Depression Scale, and common variance among blood pressure, body mass index, waist-to-hip ratio, and serum triglycerides and glucose among 87 monozygotic and 86 dizygotic male twin pairs who participated in the NHLBI twin study. Results Depressive symptoms were associated with individual components of the metabolic syndrome and common variance among the risk factors. Twin structural equation modeling indicated that the associations were attributable to environmental (nongenetic) factors. Conclusions These results support the hypothesis that depressive symptoms may increase risk for a pattern of physiological risk consistent with the metabolic syndrome.

Obesity susceptibility loci and dietary intake in the Look AHEAD Trial

BACKGROUND Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear. OBJECTIVE The objective was to determine the association between obesity susceptibility loci and dietary intake. DESIGN The association of GWAS-identified obesity risk alleles (FTO, MC4R, SH2B1, BDNF, INSIG2, TNNI3K, NISCH-STAB1, MTIF3, MAP2K5, QPCTL/GIPR, and PPARG) with dietary intake, measured through food-frequency questionnaires, was investigated in 2075 participants from the Look AHEAD (Action for Health in Diabetes) clinical trial. We adjusted for age, sex, population stratification, and study site. RESULTS Obesity risk alleles at FTO rs1421085 significantly predicted more eating episodes per day (P = 0.001)-an effect that persisted after adjustment for body weight (P = 0.004). Risk variants within BDNF were significantly associated with more servings from the dairy product and the meat, eggs, nuts, and beans food groups (P ≤ 0.004). The risk allele at SH2B1 rs4788099 was significantly associated with more servings of dairy products (P = 0.001), whereas the risk allele at TNNI3K rs1514176 was significantly associated with a lower percentage of energy from protein (P = 0.002). CONCLUSION These findings suggest that obesity risk loci may affect the pattern and content of food consumption among overweight or obese individuals with type 2 diabetes. The Look AHEAD Genetic Ancillary Study was registered at clinicaltrials.gov as NCT01270763 and the Look AHEAD study as NCT00017953.

Early Life Stress and Adult Emotional Experience: An International Perspective

Early life stress (ELS) has been linked to adult psychopathology, though few studies have examined the universality of specific adverse childhood events (ACEs) in healthy adults. We examined the co-occurrence of specific ACEs and their relationship to current emotional distress in an international sample of adults without psychopathology. Participants were 1659 men and women recruited for an international neurocognitive-neuroimaging database from sites in the United States, Australia, England, and the Netherlands. Participants had no current or prior diagnosis of major depression, anxiety, substance abuse, or neurological brain disorder. The occurrence and age on onset of 19 ACEs was assessed by a self-report questionnaire (ELSQ), and current symptoms of stress, depression, and anxiety by the Depression Anxiety Stress Scale (DASS). The relationship of specific ACEs to DASS symptoms was examined. Participants reported relatively high prevalence of ACEs. Only 27.6% of the sample reported no ACEs, while 39.5% reported one or two significant experiences and 32.9% reported more than two ACEs. Rates of most ACEs were quite similar across the three continents. Various ACEs were significantly associated with current DASS severity, particularly ACEs involving emotional abuse, neglect, and family conflict, violence, and breakup. Finding nearly one-third of the sample reported three or more ACEs suggest a high prevalence of ELS in otherwise healthy “normal” adults around the world. Associations between ELS and current emotional distress suggest that these events have functional relevance and deserve further investigation.

Systemic inflammation and the metabolic syndrome among middle-aged community volunteers.

The metabolic syndrome is conceptualized as a clustering of risk factors--including insulin resistance, dyslipidemia, central adiposity, and elevated blood pressure (BP)--that increase the risk for cardiovascular disease and type 2 diabetes mellitus. Recent evidence suggests that markers of systemic inflammation may be included in the definition of the syndrome and play some role in its pathogenesis. In this study, we use a statistical modeling technique, confirmatory factor analysis, to evaluate relationships of systemic inflammation, as measured by plasma concentrations of C-reactive protein and interleukin-6, with the component factors of the metabolic syndrome (insulin resistance, dyslipidemia, central adiposity, and elevated BP) and to examine whether inflammation is a potential common pathway linking established components to the full syndrome. Subjects were 645 community volunteers aged 30 to 54 years (48% male, 82% European American, 18% African American). Consistent with existing literature, structural equation modeling adjusting for age, sex, and race confirmed a higher-order common factor underlying the covariation of insulin resistance, dyslipidemia, adiposity, and BP. Inflammation was positively associated with this common factor, accounting for 54% of its variance and partially mediating statistical aggregation of the component factors comprising the metabolic syndrome. These results were particularly strong for adiposity, raising the possibility that inflammatory processes stimulated by intraabdominal adipose tissue contribute to the development of the metabolic syndrome. The inclusion of inflammatory markers in the clinical definition of metabolic syndrome seems warranted and may improve prognostic assessment of risk of type 2 diabetes mellitus and cardiovascular disease.