Matthew F. Muldoon

Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene

BACKGROUND Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. METHODS Locally recruited men and women (n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). RESULTS Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. CONCLUSIONS Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

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.

A PROSPECTIVE EVALUATION OF THE DIRECTIONALITY OF THE DEPRESSION-INFLAMMATION RELATIONSHIP

Cross-sectional studies have found that individuals with depressive disorders or symptoms have elevated levels of inflammatory markers predictive of coronary artery disease, including interleukin-6 (IL-6) and C-reactive protein (CRP). Due to the paucity of prospective studies, however, the directionality of the depression-inflammation relationship is unclear. We evaluated the longitudinal associations between depressive symptoms and both IL-6 and CRP among 263 healthy, older men and women enrolled in the Pittsburgh Healthy Heart Project, a 6-year prospective cohort study. During the baseline and follow-up visits, participants completed the Beck Depression Inventory-II (BDI-II) to assess depressive symptoms and underwent blood draws to quantify serum IL-6 and CRP. Path analyses revealed that baseline BDI-II (beta=0.18, p=0.01, DeltaR(2)=0.02) was a predictor of 6-year change in IL-6, even after adjustment for demographic, biomedical, and behavioral factors as well as other negative emotions. Of all the factors examined, only body-mass index was a stronger predictor of IL-6 change than depressive symptoms. In contrast to these results, baseline IL-6 did not predict 6-year change in BDI-II. Evidence of a weak bidirectional relationship between BDI-II and CRP was also observed; however, neither of these longitudinal associations was significant. The present findings indicate that depressive symptoms may precede and augment some inflammatory processes relevant to coronary artery disease among healthy, older adults. Therefore, our results imply that depression may lead to inflammation and that inflammation may be one of the mechanisms through which depression contributes to cardiovascular risk.

Individual Differences in Cellular Immune Response to Stress

Correlational studies suggest that psychological stress suppresses cellular immune function in some, but not all, individuals. Here, effects of acute mental stress on lymphocyte subpopulations and T-lymphocyte mitogenesis were examined experimentally in healthy young adults. CD8 (T-suppressor/cytotoxic) lymphocytes increased in number and T-cell response to stimulation by phytohemagglutinin was attenuated following exposure to a 20-min laboratory stressor, but only in persons who also showed heightened catecholamine and cardiovascular reactions to stress. Hence, individuals differ substantially in their immunologic responsivity to behavioral stimuli, and such differences parallel (and may be predicted by) interindividual variability in stress-induced sympathetic nervous system activation.

Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.

&NA; Epidemiologic studies link plasma cholesterol reduction to increased mortality rates as a result of suicide, violence, and accidents. Deficient central serotonergic activity is similarly associated with violence and suicidal behavior. We investigated the relationship among dietary and plasma cholesterol, social behavior, and the serotonin system as a possible explanation for these findings. Juvenile cynomolgus monkeys (eight female and nine male) were fed a diet high in fat and either high or low in cholesterol. We then evaluated their behavior over an 8‐month period. Plasma lipids and cerebrospinal fluid metabolites of serotonin, norepinephrine, and dopamine were assessed on two occasions, at 4 and 5.5 months after the initiation of behavioral observations. Animals that consumed a low‐cholesterol diet were more aggressive, less affiliative, and had lower cerebrospinal fluid concentrations of 5‐hydroxyindoleacetic acid than did their high‐cholesterol counterparts (p < .05 for each). The association among dietary cholesterol, serotonergic activity, and social behavior was consistent with data from other species and experiments and suggested that dietary lipids can influence brain neurochemistry and behavior; this phenomenon could be relevant to our understanding of the increase in suicide and violence‐related death observed in cholesterol‐lowering trials.

Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials

Abstract Objective: To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). Design: Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. Studies reviewed: 19 out of 21 eligible trials that had data available on non-illness mortality. Interventions reviewed: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years Main outcome measure: Deaths from suicides, accidents, and violence in treatment groups compared with control groups. Results: Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). Conclusion: Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.

Cardiovascular reactivity and the course of immune response to an acute psychological stressor

&NA; This study evaluated the temporal nature of cellular immune responses, as well as the effects of cardiovascular reactivity on immune responses after exposure to an acute psychological stressor. Lymphocyte subsets and lymphocyte proliferative response to phytohemagglutinin were assessed at baseline and at 5 and 21 minutes after stressor onset in the experimental group and at the same time points in a nonstressor control group. By 5 minutes after stressor onset, the number of CD8 suppressor/cytotoxic T and CD16/56 natural killer cells increased and proliferative response to phytohemagglutinin decreased. These changes were maintained at 21 minutes. Those subjects showing the greatest cardiovascular reactivity had the largest immune alterations. These data did not indicate that gender significantly moderated immune responses. Results are consistent with the hypothesis that sympathetic activation mediates stressor‐induced quantitative alterations of peripheral blood lymphocyte subpopulations and nonspecific mitogen stimulated proliferation.

Neuroticism is not associated with the serotonin transporter (5-HTTLPR) polymorphism

A deletion/insertion polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) was reported to be associated with dimensional measures of neuroticism,1 although subsequent replication attempts have failed.2–5 These replication attempts, however, have been dissimilar to the initial study in sample size, distribution of allelic frequency and/or assessment of neuroticism. The current study was conducted in a further attempt to replicate the initial finding using: (a) a sample that was more comparable to each of the individual samples in the initial report; and (b) identical psychometric methodology to assess neuroticism. Two hundred and twenty-five Caucasian adults were genotyped for the 5-HTTLPR polymorphism and completed the NEO Personality Inventory.6 Results did not replicate the association between the 5-HTTLPR polymorphism and neuroticism; individuals with the short form of this variant did not report higher NEO Neuroticism. Indeed, men with the short form reported lower Anxiety, a finding that is directionally opposite to the initial results. These findings, combined with other failures to replicate, indicate that the reproducibility of the association between the 5-HTTLPR polymorphism and neuroticism must be regarded as questionable. The contradictory findings suggest the need for a replication attempt in a large, normative sample that is stratified by ethnicity and sex.

Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults

BACKGROUND In animals, dendritic arborization and levels of brain derived neurotrophic factor are positively associated with intake of the omega-3 fatty acids. Here, we test whether omega-3 fatty acid intake in humans varies with individual differences in gray matter volume, an in vivo, systems-level index of neuronal integrity. METHODS Fifty-five healthy adults completed two 24h dietary recall interviews. Intake of long-chain omega-3 fatty acids was categorized by tertiles. Regional gray matter volumes in a putative emotional brain circuitry comprised of the anterior cingulate cortex (ACC), amygdala and hippocampus were calculated using optimized voxel-based morphometry on high-resolution structural magnetic resonance images. RESULTS Region of interest analyses revealed positive associations between reported dietary omega-3 intake and gray matter volume in the subgenual ACC, the right hippocampus and the right amygdala, adjusted for total gray matter volume of brain. Unconstrained whole-brain analyses confirmed that higher intake of omega-3 fatty acids was selectively associated with increased greater gray matter volume in these and not other regions. CONCLUSIONS Higher reported consumption of the long-chain omega-3 fatty acids is associated with greater gray matter volume in nodes of a corticolimbic circuitry supporting emotional arousal and regulation. Such associations may mediate previously observed effects of omega-3 fatty acids on memory, mood and affect regulation.

Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers

Objective: Recent evidence suggests that higher peripheral levels of interleukin 6 (IL-6) are associated with poorer cognitive function and predict future cognitive decline among the elderly. The current investigation extends the study of relationships between plasma IL-6 and cognitive performance to healthy middle-aged adults and to an examination of more specific cognitive domains. Methods: Five hundred relatively healthy community volunteers aged 30 to 54 had blood drawn for the determination of plasma IL-6 levels and completed a battery of neuropsychological tests evaluating memory and executive function. Results: After controlling for age, gender, race, and education, hierarchical regression analyses revealed an inverse relationship between circulating levels of IL-6 and performance on clusters of tests assessing auditory recognition memory, attention/working memory, and executive function. In contrast, there was no association between IL-6 and performance on tests of general memory. Secondary analyses demonstrated that relationships between IL-6 and auditory recognition and working memory and executive function were independent of a number of health factors, including body mass index, smoking, and hypertension. Conclusions: These findings contribute to a growing body of evidence linking chronic inflammation to poorer cognitive functioning and extend these findings to a midlife community sample, raising the possibility that IL-6 may represent a biomarker for risk of future cognitive decline. IL = interleukin; CNS = central nervous system; BMI = body mass index; WMS = Wechsler Memory Scale; BP = blood pressure.