Daphne Everaerd

Normal sexual dimorphism in the human basal ganglia.

Male and female brains differ in both structure and function. Investigating this sexual dimorphism in healthy subjects is an important first step to ultimately gain insight into sex‐specific differences in behavior and risk for neuropsychiatric disorders. The basal ganglia are among the main regions containing sex steroid receptors in the brain and play a central role in cognitive (dys)functioning. However, little is known about sexual dimorphism of different basal ganglia nuclei. The aim of the present study was to investigate sex‐specific differences in basal ganglia morphology using MRI. We applied automatic volumetry on anatomical MRI data of two large cohorts of healthy young adults (n = 463 and n = 541) and assessed the volume of four major nuclei of the basal ganglia: caudate nucleus, globus pallidus, nucleus accumbens, and putamen, while controlling for total gray matter volume, total white matter volume, and age of the participant. No significant sex differences were found for caudate nucleus and nucleus accumbens, but males showed significantly larger volumes for globus pallidus and putamen, as confirmed in both cohorts. These results show that sexual dimorphism is neither a general effect in the basal ganglia nor confined to just one specific nucleus, and will aid the interpretation of differences in basal ganglia (dys)function between males and females. Hum Brain Mapp, 2011.

Sex Modulates the Interactive Effect of the Serotonin Transporter Gene Polymorphism and Childhood Adversity on Hippocampal Volume

The common genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been related to depressive symptoms, in particular after stressful life events. Although it has been investigated in the past, results suggesting that the 5-HTTLPR genotype also affects hippocampal volume are often inconsistent and it remains unclear to what extent reduced hippocampal volume is influenced by the effect of stressful life events and 5-HTTLPR genotype. Moreover, sex, which is known to affect the prevalence of depression substantially, has not been taken into account when trying to disentangle the interactive effect of common genetic variation and environmental stressors on the hippocampus. We investigated this potentially relevant three-way interaction using an automatic magnetic resonance imaging (MRI)-based segmentation of the hippocampus in 357 healthy individuals. We determined the 5-HTTLPR genotype as a biallelic locus and childhood adversity (CA) using a standard questionnaire. An interaction for hippocampal volume was found between the factors sex, genotype, and severe CA (p=0.010) as well as an interaction between genotype and severe CA (p=0.007) in men only. Post hoc tests revealed that only male S’-allele carriers with severe CA had smaller hippocampi (p=0.002). Interestingly, there was no main effect of genotype in men, while female S’-allele carriers had smaller hippocampi than L’L’ carriers (p=0.023). Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S’-allele is associated with hippocampal volume independent of CA in women, men only have smaller hippocampi if they carry the risk allele and experienced severe CA.

Association between neuroticism and amygdala responsivity emerges under stressful conditions

Increased amygdala reactivity in response to salient stimuli is seen in patients with affective disorders, in healthy subjects at risk for these disorders, and in stressed individuals, making it a prime target for mechanistic studies into the pathophysiology of affective disorders. However, whereas individual differences in neuroticism are thought to modulate the effect of stress on mental health, the mechanistic link between stress, neuroticism and amygdala responsivity is unknown. Thus, we studied the relationship between experimentally induced stress, individual differences in neuroticism, and amygdala responsivity. To this end, fearful and happy faces were presented to a large cohort of young, healthy males (n=120) in two separate functional MRI sessions (stress versus control) in a randomized, controlled cross-over design. We revealed that amygdala reactivity was modulated by an interaction between the factors of stress, neuroticism, and the emotional valence of the facial stimuli. Follow-up analysis showed that neuroticism selectively enhanced amygdala responses to fearful faces in the stress condition. Thus, we show that stress unmasks an association between neuroticism and amygdala responsivity to potentially threatening stimuli. This effect constitutes a possible mechanistic link within the complex pathophysiology of affective disorders, and our novel approach appears suitable for further studies targeting the underlying mechanisms.

Dynamic shifts in large-scale brain network balance as a function of arousal

The ability to temporarily prioritize rapid and vigilant reactions over slower higher-order cognitive functions is essential for adaptive responding to threat. This reprioritization is believed to reflect shifts in resource allocation between large-scale brain networks that support these cognitive functions, including the salience and executive control networks. However, how changes in communication within and between such networks dynamically unfold as a function of threat-related arousal remains unknown. To address this issue, we collected functional MRI data and continuously assessed the heart rate from 120 healthy human adults as they viewed emotionally arousing and ecologically valid cinematographic material. We then developed an analysis method that tracks dynamic changes in large-scale network cohesion by quantifying the level of within-network and between-network interaction. We found a monotonically increasing relationship between heart rate, a physiological index of arousal, and within-network cohesion in the salience network, indicating that coordination of activity within the salience network dynamically tracks arousal. Strikingly, salience–executive control between-network cohesion peaked at moderate arousal. These findings indicate that at moderate arousal, which has been associated with optimal noradrenergic signaling, the salience network is optimally able to engage the executive control network to coordinate cognitive activity, but is unable to do so at tonically elevated noradrenergic levels associated with acute stress. Our findings extend neurophysiological models of the effects of stress-related neuromodulatory signaling at the cellular level to large-scale neural systems, and thereby explain shifts in cognitive functioning during acute stress, which may play an important role in the development and maintenance of stress-related mental disorders. SIGNIFICANCE STATEMENT How does brain functioning change in arousing or stressful situations? Extant literature suggests that through global projections, arousal-related neuromodulatory changes can rapidly alter coordination of neural activity across brain-wide neural systems or large-scale networks. Since it is unknown how such processes unfold, we developed a method to dynamically track levels of within-network and between-network interaction. We applied this technique to human neuroimaging data acquired while participants watched realistic and emotionally arousing cinematographic material. Results demonstrate that cohesion within the salience network monotonically increases with arousal, while cohesion of this network with the executive control network peaks at moderate arousal. Our findings explain how cognitive performance shifts as a function of arousal, and provide new insights into vulnerability for stress-related psychopathology.

Interindividual differences in stress sensitivity: basal and stress-induced cortisol levels differentially predict neural vigilance processing under stress

Stress exposure is known to precipitate psychological disorders. However, large differences exist in how individuals respond to stressful situations. A major marker for stress sensitivity is hypothalamus-pituitary-adrenal (HPA)-axis function. Here, we studied how interindividual variance in both basal cortisol levels and stress-induced cortisol responses predicts differences in neural vigilance processing during stress exposure. Implementing a randomized, counterbalanced, crossover design, 120 healthy male participants were exposed to a stress-induction and control procedure, followed by an emotional perception task (viewing fearful and happy faces) during fMRI scanning. Stress sensitivity was assessed using physiological (salivary cortisol levels) and psychological measures (trait questionnaires). High stress-induced cortisol responses were associated with increased stress sensitivity as assessed by psychological questionnaires, a stronger stress-induced increase in medial temporal activity and greater differential amygdala responses to fearful as opposed to happy faces under control conditions. In contrast, high basal cortisol levels were related to relative stress resilience as reflected by higher extraversion scores, a lower stress-induced increase in amygdala activity and enhanced differential processing of fearful compared with happy faces under stress. These findings seem to reflect a critical role for HPA-axis signaling in stress coping; higher basal levels indicate stress resilience, whereas higher cortisol responsivity to stress might facilitate recovery in those individuals prone to react sensitively to stress.

Childhood abuse and deprivation are associated with distinct sex-dependent differences in brain morphology

Childhood adversity (CA) has been associated with long-term structural brain alterations and an increased risk for psychiatric disorders. Evidence is emerging that subtypes of CA, varying in the dimensions of threat and deprivation, lead to distinct neural and behavioral outcomes. However, these specific associations have yet to be established without potential confounders such as psychopathology. Moreover, differences in neural development and psychopathology necessitate the exploration of sexual dimorphism. Young healthy adult subjects were selected based on history of CA from a large database to assess gray matter (GM) differences associated with specific subtypes of adversity. We compared voxel-based morphometry data of subjects reporting specific childhood exposure to abuse (n=127) or deprivation (n=126) and a similar sized group of controls (n=129) without reported CA. Subjects were matched on age, gender, and educational level. Differences between CA subtypes were found in the fusiform gyrus and middle occipital gyrus, where subjects with a history of deprivation showed reduced GM compared with subjects with a history of abuse. An interaction between sex and CA subtype was found. Women showed less GM in the visual posterior precuneal region after both subtypes of CA than controls. Men had less GM in the postcentral gyrus after childhood deprivation compared with abuse. Our results suggest that even in a healthy population, CA subtypes are related to specific alterations in brain structure, which are modulated by sex. These findings may help understand neurodevelopmental consequences related to CA.

Acute stress enhances emotional face processing in the aging brain

BACKGROUND Healthy aging has been associated with stable emotional well-being and attenuated brain responses to negative stimuli. At the same time, depressive symptoms are common in older adults. The neural mechanisms behind this paradox remain to be clarified. We hypothesized that acute stress could alter emotion processing in healthy aging brain and constitute a pathway to vulnerability. METHODS Using a randomized, controlled crossover design, we explored the influence of acute stress on brain responses to happy and fearful facial expressions in 25 older adults (60-75 years of age) and 25 young (18-30 years of age) control subjects. Groups were matched on trait anxiety and education. Subjects underwent two separate functional magnetic resonance imaging sessions involving acute stress or a control procedure. RESULTS Affective and physiological responses to the stressor were similar between the two age groups. On a whole-brain level, we revealed a significant age by stress interaction in the fusiform gyrus, indicating a selective enhancement of neural activity with stress in elderly subjects only. When specifically aiming analysis at the amygdala, we found the same stress-related increase in activity in elderly subjects only. Modulation of amygdala reactivity due to stress correlated with trait conscientiousness in elderly subjects exclusively. CONCLUSIONS Compared with younger adults, healthy older adults showed increased responsivity of brain regions involved in face and emotion processing while stressed. These findings suggest that increased reactivity of this neural circuitry after acute stress may constitute one mechanism by which emotional well-being during healthy aging could rapidly change into heightened vulnerability for affective disorders.

Author's response to commentary 'Depressive symptomatology should be systematically controlled for in neuroticism research'

In the commentary by Bianchi and Laurent (2015), the authors suggest that depressive symptoms should be controlled for when examining the neurobiology associated with trait neuroticism. We fully agree that the relation between neuroticism and symptoms of stress-related psychiatric disorders, such as major depressive disorder and anxiety disorders, should not be overlooked when studying its neural correlates. However, instead of treating this relation as a potential confound, we consider it to be of particular importance to include depressive symptoms when studying the influence of acute psychological stress on neural mechanisms related to trait neuroticism. Regardless of this principal disagreement, we also confirmed empirically that depression scores did not affect our voxel-wise results. In sum, our results were not confounded by depression scores and more importantly, our study question and design do not warrant including depression scores in our analysis.

Sekseverschillen in het effect op hippocampusvolume van de interactie tussen het serotoninetransportergenpolymorfisme en stressvolle gebeurtenissen in de kindertijd

Depressie is een zeer invaliderende, veel voorkomende aandoening met bovendien een hoog recidiverisico. Onderzoeken naar depressie richten zich steeds meer op de etiologie van depressie. Een belangrijke tak van onderzoek focust daarbij op veel voorkomende genetische variaties die geassocieerd zijn met depressie of met depressieve symptomen bij gezonde volwassenen. Caspi (Caspi et al., 2003) toonde reeds in 2003 aan dat dragers van het korte (S) allel van het serotoninetransportergenpolymorfisme (5-HTTLPR) meer depressieve symptomen rapporteerden na het doormaken van stressvolle gebeurtenissen. Sindsdien hebben veel onderzoekers geprobeerd deze resultaten te repliceren. Aanvankelijk konden twee meta-analyses dit effect niet repliceren (Munafò, Durrant, Lewis & Flint, 2009; Risch et al., 2009). Een recentere en grotere meta-analyse waarbij meer onderzoeken konden worden geïncludeerd, bevestigde echter wel de relatie tussen 5-HTTLPR, stress en depressie (Karg, Burmeister, Shedden & Sen, 2011). Deze onderzoekers vonden met name een erg sterk verband tussen stress in de vorm van mishandeling in de kindertijd bij dragers van het S-allel en depressieve symptomatologie.AbstractBackground:The common genetic variation of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been related to depressive symptoms, in particular after stressful life events. Although it has been investigated in the past, results suggesting that the 5-HTTLPR genotype also affects hippocampal volume are often inconsistent. It remains unclear to what extent reduced hippocampal volume is influenced by the effect of stressful life events and 5-HTTLPR genotype. Moreover, sex, which is known to affect the prevalence of depression substantially, has not been taken into account when trying to disentangle the interactive effect of common genetic variation and environmental stressors on the hippocampus.Methods:We investigated this potentially relevant three-way interaction using an automatic magnetic resonance imaging (MRI) based segmentation of the hippocampus in 357 healthy individuals. We determined the 5-HTTLPR genotype as a biallelic locus and childhood adversity (CA) using a standard questionnaire.Results:An interaction for hippocampal volume was found between the factors sex, genotype, and severe CA (p = 0.010) as well as an interaction between genotype and severe CA (p = 0.007) in men only. Post hoc tests revealed that only male S-allele carriers with severe CA had smaller hippocampi (p = 0.002). Interestingly, there was no main effect of genotype in men, while female S-allele carriers had smaller hippocampi than L/L carriers (p = 0.023).Conclusions:Our results indicate that sex modulates the interactive effect of the 5-HTTLPR genotype and CA on hippocampal volume. While the S-allele is associated with hippocampal volume independent of CA in women, men only have smaller hippocampi if they carry the risk allele and experienced severe CA.