Towards a Biobehavioral Understanding of Trait Externalization: Neural and Endocrine Responses during Acute Stress and Reactive Aggression within the Non-clinical Range

The externalizing spectrum is characterized by disinhibition, impulsivity, antisocial-aggressive behavior as well as substance (mis)use. Empirical work has shown that the externalizing spectrum is dimensionally distributed characteristic that can be found also in the non-pathological range of variation. Studies in forensic samples and mentally impaired children suggested that higher rates of externalization are linked to lower cortisol stress responses, to abnormalities in neural threat and reward responses as well as to deficits in the inhibitory control system. Furthermore, aggression is a main criterion when diagnosing externalizing disorders such as antisocial personality disorder (ASPD) and conduct disorder (CD). In aggression research, the Taylor Aggression Paradigm (TAP; Taylor, 1967) is widely used to measure reactive aggression in laboratory settings. While modified versions (mTAPs) with various stimulus characteristics (shocks, noise, pressure, heat) have already been established, a modified version with monetary stimuli has only been introduced very recently. Coming back to the externalizing spectrum, mechanisms within the non-clinical range remain still unclear, in particular with respect to stress responses and reactive aggression. The major aims of this thesis were to investigate whether interindividual differences in non-clinical externalizing behavior was associated with aberration in neural, emotional, and psychoendocrine stress responses. Differences in the extent of externalizing behavior might predict reactive aggression and differential neual activation patterns during a beforehand validated monetary variant of the mTAP. For the validation of a monetary variant of the mTAP (study 1), 209 young healthy participants (104 men, 105 women) completed a mock Competitive Reaction Time Task (CRTT), so called mTAP, with a fictional opponent with preprogrammed 40 win and 60 lose trials. In lose trials, participants were provoked by subtracting a low (0 – 20 euro cents), medium (30 – 60 cents) or high (70 – 90 cents) amount of money from their fictitious account. To check for sequence effects, provocation stimuli were either presented randomly or in a fixed sequence (experimental conditions). In contrast to a random sequence, the fixed sequence was generated by repeating trials from the same provocation category in series of three. Study 2 was a functional magnetic resonance imaging study (fMRI). Sixty-one healthy participants (31 men, 30 women) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization), as assessed by the subscales disinhibition and meanness of the Triarchic Psychopathy Measure (TriPM), were exposed to ScanSTRESS, a standardized psychosocial stress paradigm for the scanner environment. In study 3, participants performed the beforehand validated monetary modified Taylor Aggression Paradigm (study 1) in the scanner environment. During experiment 2 and 3, cortisol and testosterone samples were collected repeatedly and neural correlates were assessed by the blood-oxygen-level-dependent (BOLD) response. The present findings provide new evidence supporting the view that the monetary mTAP is able to induce and capture reactive aggression in the laboratory. Additionally, no advantage of a fixed sequence was found, as the level of reactive aggression in a given trial appeared to be mainly predicted by the preceding provocation trial. In the high and low externalization group, ScanSTRESS (study 2) induced a significant rise in cortisol levels with the high externalization group showing significantly lower cortisol stress responses than the low externalization group. Post-hoc analysis revealed that this effect was mainly observed in men. Individual increases in cortisol predicted neural response differences between externalization groups, indicating more activation in the dorsal striatum in low externalizing participants. In contrast to the lower cortisol stress responses, this effect was primarily driven by women. In study 3, high externalization predicted reduced anterior cingulate cortex (ACC) activation under high provocation during the monetary mTAP. However, high externalizing participants did not behave more aggressively than the low externalization group. Follow-up analyses revealed that aggression levels and salivary testosterone correlated positively in women and negatively in men. At the neural level, aggression-related activity in the supplementary motor cortex (SMA) was associated with gender-specific testosterone levels. In conclusion, individuals from the general population with high-level externalization show reduced cortisol stress responses and aberrations in fronto-striatal functioning (ACC, dorsal striatum), thus confirming earlier findings in clinical samples. However, the observed physiological changes did not lead to higher behavioral aggression levels. Provocation during monetary mTAP elicits testosterone-related aggression rather in women than in men. Moreover, SMA seems to play a relevant role in the neural network mediating this gender-specific testosterone-aggression relationship. Thus, the results support the view that the association between aggression and testosterone depends strongly on moderating factors (e.g., contextual, personal and biological influences)

Associations between cortisol stress responses and limbic volume and thickness in young adults: an exploratory study

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age, and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e., volume and thickness) were investigated in 66 healthy and young (18-33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our pre-liminary findings suggest that not only situation- and contextdependent reactions of the limbic system (i.e., blood oxygenation level dependent reactions) are related to acute (sex-specific) cortisol stress responses, but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic

Sexual motivation is reflected by stimulus-dependent motor cortex excitability

Sexual behavior involves motivational processes. Findings from both animal models and neuroimaging in humans suggest that the recruitment of neural motor networks is an integral part of the sexual response. However, no study so far has directly linked sexual motivation to physiologically measurable changes in cerebral motor systems in humans. Using transcranial magnetic stimulation in hetero- and homosexual men, we here show that sexual motivation modulates cortical excitability. More specifically, our results demonstrate that visual sexual stimuli corresponding with one's sexual orientation, compared with non-corresponding visual sexual stimuli, increase the excitability of the motor cortex. The reflection of sexual motivation in motor cortex excitability provides evidence for motor preparation processes in sexual behavior in humans. Moreover, such interrelationship links theoretical models and previous neuroimaging findings of sexual behavio

Associations between cortisol stress responses and limbic volume and thickness in young adults: An exploratory study

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e. volume and thickness) were investigated in 66 healthy and young (18–33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our preliminary findings suggest that not only situation- and context-dependent reactions of the limbic system (i.e. blood oxygenation level-dependent reactions) are related to acute (sex-specific) cortisol stress responses but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic

Dissociation of behavioral and neural responses to provocation during reactive aggression in healthy adults with high versus low externalization

The externalizing spectrum describes a range of heterogeneous personality traits and behavioral patterns, primarily characterized by antisocial behavior, disinhibition, and substance (mis)use. In psychopathology, abnormalities in neural threat, reward responses and the impulse-control system may be responsible for these externalizing symptoms. Within the non-clinical range, mechanisms remain still unclear. In this fMRI-study, 61 healthy participants (31 men) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure (TriPM) performed a monetary modified Taylor-Aggression-Paradigm (mTAP). This paradigm consisted of a mock competitive-reaction-time-task played against a fictional opponent with preprogrammed win- and lose-trials. In lose-trials, participants were provoked by subtraction of an amount of money between 0 and 90 cents. As a manipulation check, provocation induced a significant rise in behavioral aggression levels linked with an increased activation in the anterior cingulate cortex (ACC). High externalization predicted reduced ACC responses to provocation. However, high externalizing participants did not behave more aggressively than the low externalization group. Additionally, the high externalizing group showed a significantly lower positive affect while no group differences emerged for negative affect. In conclusion, high externalization in the non-clinical range was related to neural alterations in regions involved in affective decision-making as well as to changes in affect but did not lead to higher behavioral aggression levels in response to the mTAP. This is in line with previous findings suggesting that aberrations at multiple levels are essential for developing externalizing disorders

Sex-Specific Interaction Between Cortisol and Striato-Limbic Responses to Psychosocial Stress

Although women and men differ in psychological and endocrine stress responses as well as prevalence rates of stress-related disorders, knowledge on sex differences regarding stress regulation in the brain is scarce.Therefore, we performed an in-depth analysis of data from 67 healthy participants (31 women, taking oral contraceptives), who were exposed to the ScanSTRESS paradigm in an fMRI study. Changes in cortisol, affect, heart rate, and neural activation in response to psychosocial stress were examined in women and men as well as potential sex-specific interactions between stress response domains.Stress exposure led to significant cortisol increases with men exhibiting higher levels than women. Dependent on sex, cortisol elevations were differently associated with stress-related responses in striato-limbic structures: Higher increases were associated with activations in men but with deactivations in women. Regarding affect or heart rate responses, no sex differences emerged.Although women and men differ in their overall stress reactivity, our findings do not support the idea of distinct neural networks as base of this difference. Instead, we found differential stress reactions for women and men in identical structures. We propose considering quantitative predictors like sex-specific cortisol increases when exploring neural response differences of women and men

Neural responses to acute stress predict chronic stress perception in daily life over 13 months

The importance of amygdala, hippocampus, and medial prefrontal cortex (mPFC) for the integration of neural, endocrine, and affective stress processing was shown in healthy participants and patients with stress-related disorders. The present manuscript which reports on one study-arm of the LawSTRESS project, aimed at investigating the predictive value of acute stress responses in these regions for biopsychological consequences of chronic stress in daily life. The LawSTRESS project examined law students either in preparation for their first state examination (stress group [SG]) or in the mid-phase of their study program (control group [CG]) over 13 months. Ambulatory assessments comprising perceived stress measurements and the cortisol awakening response (CAR) were administered on six sampling points (t1 = − 1 year, t2 = − 3 months, t3 = − 1 week, t4 = exam, t5 =  + 1 week, t6 =  + 1 month). In a subsample of 124 participants (SG: 61; CG: 63), ScanSTRESS was applied at baseline. In the SG but not in the CG, amygdala, hippocampus, and (post-hoc analyzed) right mPFC activation changes during ScanSTRESS were significantly associated with the trajectory of perceived stress but not with the CAR. Consistent with our finding in the total LawSTRESS sample, a significant increase in perceived stress and a blunted CAR over time could be detected in the SG only. Our findings suggest that more pronounced activation decreases of amygdala, hippocampus, and mPFC in response to acute psychosocial stress at baseline were related to a more pronounced increase of stress in daily life over the following year

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC

Association between circadian physical activity patterns and mortality in the UK Biobank

Abstract Background The benefit of physical activity (PA) for increasing longevity is well-established, however, the impact of diurnal timing of PA on mortality remains poorly understood. We aimed to derive circadian PA patterns and investigate their associations with all-cause mortality. Methods We used 24 h PA time series from 96,351 UK Biobank participants aged between 42 and 79 years at accelerometry in 2013–2015. Functional principal component analysis (fPCA) was applied to obtain circadian PA patterns. Using multivariable Cox proportional hazard models, we related the loading scores of these fPCs to estimate risk of mortality. Results During 6.9 years of follow-up, 2,850 deaths occurred. Four distinct fPCs accounted for 96% of the variation of the accelerometry data. Using a loading score of zero (i.e., average overall PA during the day) as the reference, a fPC1 score of + 2 (high overall PA) was inversely associated with mortality (Hazard ratio, HR = 0.91; 95% CI: 0.84–0.99), whereas a score of -2 (low overall PA) was associated with higher mortality (1.69; 95% CI: 1.57–1.81; p for non-linearity < 0.001). Significant inverse linear associations with mortality were observed for engaging in midday PA instead of early and late PA (fPC3) (HR for a 1-unit increase 0.88; 95% CI: 0.83–0.93). In contrast, midday and nocturnal PA instead of early and evening PA (fPC4) were positively associated with mortality (HR for a 1-unit increase 1.16; 95% CI: 1.08–1.25). Conclusion Our results suggest that it is less important during which daytime hours one is active but rather, to engage in some level of elevated PA for longevity