Should we keep some distance from distancing? Regulatory and post-regulatory effects of emotion downregulation.

Emotion regulation is an indispensable part of mental health and adaptive behavior. Research into emotion regulation processes has largely focused on the concurrent effects of volitional emotion regulation. However, there is scarce evidence considering post-regulatory effects with regard to neural mechanisms and emotional experiences. Therefore, we compared concurrent effects of cognitive emotion regulation with effects at different (immediate, short- and long-term) time intervals. In an fMRI study with N = 46 (N = 30 at re-exposure) young healthy adults, we compared neuronal responses to negative and neutral pictures while participants had to distance themselves from or to actively permit emotions in response to these pictures. We investigated the temporal dynamics of activation changes related to regulation in cognitive control brain networks as well as in the amygdala during stimulation (concurrent effects, timepoint 1) and post-stimulation (immediate, timepoint 2), as well as during re-exposure with the same pictures after short (10 minutes, timepoint 3) and long (1 week, timepoint 4) time intervals. At timepoint 1, negative pictures (versus neutral pictures) elicited a strong response in regions of affective processing, including the amygdala. Distancing (as compared to permit) led to a decrease of this response, and to an increase of activation in the right middle frontal and inferior parietal cortex. We observed an interaction effect of time (stimulation vs. post-stimulation) and regulation (distance vs. permit), indicating a partial reversal of regulation effects during the post-stimulation phase (timepoint 2). Similarly, after 10 minutes (timepoint 3) and after 1 week (timepoint 4), activation in the amygdala was higher during pictures that participants were previously instructed to distance from as compared to permit. These results show that the temporal dynamics are highly variable both within experimental trials and across brain regions. This can even take the form of paradoxical aftereffects at immediate and persistent effects at prolonged time scales.

Rhythm and blues: Influence of CLOCK T3111C on peripheral electrophysiological indicators of negative affective processing.

Dysfunction in the circadian system has been linked to emotion regulation and mood disorders with genetic variation in clock genes as likely contributors. Here, we focused on endophenotypes of affective processing and investigated in two independent samples of healthy individuals (n1=99, n2=108) whether genotypes of a functional single nucleotide polymorphism (SNP) in the gene encoding CLOCK (CLOCK T3111C, rs1801260) differed in physiological responses to emotional stimuli. Both samples underwent an emotional startle paradigm with startle responses being measured via EMG. In the second sample, skin conductance responses as well as corrugator and zygomaticus activity were also assessed. In both samples, CLOCK T3111C was associated with overall startle responses to loud noise bursts with T/T homozygotes showing consistently more marked responses. However, in the all-female second sample, the effects of CLOCK on skin conductance responses to the same loud noise bursts depended on hormone status: similar to the startle results, in free-cycling women T/T homozygotes showed more pronounced skin conductance response (SCR) compared to C allele carriers. The opposite was true for women using combined oral contraceptives (COC). A further CLOCK × hormone status interaction effect was found for corrugator activity. In free-cycling women, T/T homozygotes presented with less corrugator activity to affective pictures compared to C allele carriers, while the opposite pattern emerged for COC users. The findings emphasize the potential role of CLOCK for affect and mood.

Impact of FAAH genetic variation on fronto-amygdala function during emotional processing.

Recent translational studies identified a common endocannabinoid polymorphism, FAAH C385A, in the gene for the fatty acid amide hydrolase (FAAH). This polymorphism alters endocannabinoid anandamide levels, which are known to be involved in the fronto-amygdala circuitry implicated in mood regulation and anxiety-like behaviors. While it has been shown that the variant that selectively enhances fronto-amygdala connectivity at rest is associated with decreased anxiety-like behaviors, no study so far has investigated whether this finding of FAAH-related differential plasticity extends to task-related differential functional expression and regulation during negative emotional processing. Using an imaging genetics approach, this study aimed to replicate and extend prior findings by examining functional activity and task-related connectivity in fronto-amygdala regions during emotion reactivity and emotional down-regulation of negative affect. Therefore, 48 healthy young adults underwent a functional MRI resting state measurement, completed an emotion regulation paradigm and provided self-reports on anxiety and use of emotion regulation strategies. In line with previous studies, preliminary evidence suggests that A-allele carriers demonstrate stronger fronto-amygdala connectivity during rest. In addition, exploratory whole-brain analyses indicate differential functional activity of A-allele carriers during emotion reactivity and emotion regulation. There were no associations with anxiety-related self-reports and use of emotional regulation strategies. Further research using larger samples and polygenic approaches is indicated to clarify the precise role and its underlying mechanisms in emotion processing.

Cognitive emotion regulation and personality: an analysis of individual differences in the neural and behavioral correlates of successful reappraisal.

A common and mostly effective emotion regulation strategy is reappraisal. During reappraisal, activity in cognitive control brain regions increases and activity in brain regions associated with emotion responding (e.g., the amygdala) diminishes. Immediately after reappraisal, it has been observed that activity in the amygdala increases again, which might reflect a paradoxical aftereffect. While there is extensive empirical evidence for these neural correlates of emotion regulation, only few studies targeted the association with individual differences in personality traits. The aim of this study is to investigate these associations more thoroughly. Seventy-six healthy participants completed measures of broad personality traits (Big Five, Positive and Negative Affect) as well as of more narrow traits (habitual use of emotion regulation) and performed an experimental fMRI reappraisal task. Participants were instructed to either permit their emotions or to detach themselves from the presented negative and neutral pictures. After each picture, a relaxation period was included. Reappraisal success was determined by arousal ratings and activity in the amygdala. During reappraisal, we found activation in the prefrontal cortex and deactivation in the left amygdala. During the relaxation period, an immediate aftereffect was found in occipital regions and marginally in the amygdala. Neither personality traits nor habitual use of emotion regulation predicted reappraisal success or the magnitude of the aftereffect. We replicated typical activation and deactivation patterns during intentional emotion regulation and partially replicated the immediate aftereffect in the amygdala. However, there was no association between personality traits and emotion regulation success.

Winter is coming: Seasonality and the acoustic startle reflex.

Circannual rhythms and seasonality have long been in the interest of research. In humans, seasonal changes in mood have been extensively investigated since a substantial part of the population experiences worsening of mood during winter. Questions remain regarding accompanying physiological phenomena. We report seasonal effects on the acoustic startle response in a cross-sectional (n=124) and a longitudinal sample (n=23). Startle magnitudes were larger in winter (sample 1: p=0.026; sample 2: p=0.010) compared to summer months. Although the findings need to be replicated they may have implications regarding the timing of startle experiments.

BDNF val(66)met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children.

Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val(66)met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val(66)met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1=117, N2=104, N3=116) as well as a children sample (N4=123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p=0.039) and children (p=0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p=0.004; N2: p=0.045; N3: n.s., N4: p=0.043) pointing to differential effects of BDNF val(66)met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors.

Reduced default mode network suppression during a working memory task in remitted major depression.

Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent-onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment.

The impact of sex and menstrual cycle on the acoustic startle response.

Sex differences in fear and anxiety have been widely reported although results are not entirely consistent depending on measures used. Also, a possible influence of the menstrual cycle is often not taken into account, and effect sizes are not always discussed. In a sample of healthy young adults (n=111 women without hormonal contraceptives and n=107 men) the acoustic startle response (ASR) and emotional ASR modulation were analysed. We found no significant effect of sex on ASR (p=.269) but a significant effect of menstrual cycle (p=.027, η(2)=0.105). Compared to men, women showed increased ASR during the late luteal phase probably reflecting elevated negative emotionality, and during ovulation which, however, might be due to increased auditory sensitivity and changes in general CNS arousal. Neither sex nor menstrual cycle affected startle modulation. Thus, at least in young adults, menstrual cycle but not sex per se appears to contribute significantly to ASR variance.

Additive gene-environment effects on hippocampal structure in healthy humans.

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

Instructions matter: a comparison of baseline conditions for cognitive emotion regulation paradigms.

The choice of a meaningful baseline condition is a crucial issue for each experimental design. In the case of cognitive emotion regulation, it is common to either let participants passively view emotional stimuli without any further specific instructions or to instruct them to actively attend to and permit any arising emotions, and to contrast one of these baseline conditions with a regulation condition. While the "view" strategy can be assumed to allow for a more spontaneous emotional response, the "permit" strategy may result in a more pronounced affective and cognitive response. As these conceptual differences may be associated with differences both in subjective emotional experience and neural activation, we compared these two common control conditions within a single functional magnetic resonance imaging (fMRI) experiment, during which participants were instructed to either passively view a set of unpleasant and neutral pictures or to actively permit any emotions arising in response to the unpleasant pictures. Trial-by-trial ratings confirmed that participants perceived the unpleasant pictures as more arousing than the neutral pictures, but also indicated higher subjective arousal during the "permit negative" as compared to the "view negative" and "view neutral" conditions. While both the "permit negative" and "view negative" conditions led to increased activation of the bilateral amygdala when contrasted with the passive viewing of neutral pictures, activation in the left amygdala was increased in response to the "permit" instruction as compared to the "view" instruction for unpleasant pictures. The increase in amygdala activation in both the "permit" and "view" conditions renders both strategies as suitable baseline conditions for studies of cognitive emotion regulation. Conceptual and activation differences, however, indicate that these two variants are not exchangeable and should be chosen depending on the experimental context.

Comparison of cerebral blood flow acquired by simultaneous [15O]water positron emission tomography and arterial spin labeling magnetic resonance imaging.

Until recently, no direct comparison between [(15)O]water positron emission tomography (PET) and arterial spin labeling (ASL) for measuring cerebral blood flow (CBF) was possible. With the introduction of integrated, hybrid magnetic resonance (MR)-PET scanners, such a comparison becomes feasible. This study presents results of CBF measurements recorded simultaneously with [(15)O]water and ASL. A 3T MR-BrainPET scanner was used for the simultaneous acquisition of pseudo-continuous ASL (pCASL) magnetic resonance imaging (MRI) and [(15)O]water PET. Quantitative CBF values were compared in 10 young healthy male volunteers at baseline conditions. A statistically significant (P<0.05) correlation was observed between the two modalities; the whole-brain CBF values determined with PET and pCASL were 43.3±6.1 mL and 51.9±7.1 mL per 100 g per minute, respectively. The gray/white matter (GM/WM) ratio of CBF was 3.0 for PET and 3.4 for pCASL. A paired t-test revealed differences in regional CBF between ASL and PET with higher ASL-CBF than PET-CBF values in cortical areas. Using an integrated, hybrid MR-PET a direct simultaneous comparison between ASL and [(15)O]water PET became possible for the first time so that temporal, physiologic, and functional variations were avoided. Regional and individual differences were found despite the overall similarity between ASL and PET, requiring further detailed investigations.

Platelet serotonin transporter function predicts default-mode network activity.

BACKGROUND: The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. METHODS: A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. RESULTS: The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. CONCLUSION: This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

Children under stress - COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm.

Dopamine and norepinephrine are key regulators of cognitive and affective processes. The enzyme catechol-O-methyltransferase (COMT) catabolizes catecholamines and the COMT Val158Met polymorphism has been linked to several neuropsychiatric variables. Additionally, stressful life events (SLEs) contribute substantially to affective processes. We used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the effects of COMT and SLEs on the cortisol response in 119 healthy children (8-12 yr). Saliva cortisol was measured during and after the Trier Social Stress Test for Children. SLEs were assessed with a standardized interview with one of the children's parents. Linear regression analysis revealed a significant effect for COMT, with Met allele carriers showing a higher cortisol response (ß=0.300, p=0.001). In turn, more SLEs lead to a less pronounced cortisol increase (ß=-0.192, p=0.029) probably indicating increased resilience. Our results further underscore the essential and differential role of genetic variation and environmental factors on stress responsivity.

Genetic contributions to acute autonomic stress responsiveness in children.

Identification of genetic factors that influence stress reactivity is important in order to link environmental demands, particularly adversity to disease outcome. There is ample literature on genetic contribution to the endocrine stress response, while evidence for genetic contribution to individual differences in autonomic nervous system function is sparse and produced conflicting results. Here, we investigated the influence of two polymorphisms in the Catechol-o-methyltransferase (COMT) and serotonin transporter (5-HTT; SCL6A4) gene. We examined the autonomic stress response to the Trier Social Stress Test for Children in 115 children. Salivary α-amylase (sAA) was obtained prior to the stressor and repeatedly during recovery as a marker of autonomic reactivity. Furthermore, heart rate (HR) and heart rate variability (HRV) were monitored continuously. We found differences in ANS stress response associated with each polymorphism (all p<.05). Children with the L variant of 5-HTTLPR showed a higher increase and sharper recovery of sAA in response to stress than those with S variants. For HR, we found differences associated with COMT, i.e. children carrying at least one met allele showed lower mean HR increase and slower HR recovery in response to the stressor compared to those with two val alleles (p<.001) as well as a significant decrease in heart rate variability (p<.05). Our findings indicate that these two polymorphisms do indeed influence the ANS response to stress. This study provides further evidence for the crucial role of genetic factors in the modulation of differences in the acute stress response during childhood.

Predicting cortisol stress responses in older individuals: influence of serotonin receptor 1A gene (HTR1A) and stressful life events.

Considerable variability in the activity of the hypothalamus-pituitary-adrenal (HPA) axis in response to stress has been found in quantitative genetic studies investigating healthy individuals suggesting that at least part of this variance is due to genetic factors. Since the HPA axis is regulated by a neuronal network including amygdala, hippocampus, prefrontal cortex as well as brainstem circuits, the investigation of candidate genes that impact neurotransmitter systems related to these brain regions might further elucidate the genetic underpinnings of the stress response. However, aside from genetic risk factors, past stressful life events might also result in long-term adjustments of HPA axis reactivity. Here, we investigated the effects of the -1019 G/C polymorphism in the HTR1A gene encoding the serotonin (5-HT) receptor 1A (5-HT(1A)) and stressful life events experienced during childhood and adolescence on changes in cortisol levels in response to the Trier Social Stress Test (TSST) in a sample of healthy older adults (N=97). Regression analyses revealed a significant effect of HTR1A genotype with the G allele being associated with a less pronounced stress response. In addition, an inverse relationship between past stressful life events and cortisol release but no gene × environment interaction was detected. The results further underscore the crucial role of functional serotonergic genetic variation as well as stressful events during critical stages of development on the acute stress response later in life.

Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response.

There has been significant controversy whether stressful life events (SLEs) experienced over the lifespan may elevate the risk of depression in individuals who are homozygous for the short (S) allele of the repeat length polymorphism (5-HTTLPR) in the regulatory region of the serotonin transporter gene (SLC6A4), compared with individuals homozygous for the long (L) allele. On the basis of the hypothesis that age may be a critical variable, by which such a gene-by-environment interaction may be present in younger adults, but not in older adults and in children, aim of this study was to investigate the role of 5-HTTLPR and SLEs on the endocrine stress response in multiple age cohorts. A total of 115 children (8-12 years), 106 younger adults (18-31 years), and 99 older adults (54-68 years) were subjected to the Trier Social Stress Test (TSST) and structured interviews on SLEs. The TSST induced significant endocrine stress responses in all groups. There was a main effect of genotype in younger and older adults with individuals homozygous for the more active L allele showing a significantly larger cortisol response to the TSST than individuals carrying at least one of the low-expressing S alleles. As predicted, there was a significant interaction of 5-HTTLPR genotype and SLEs, but this interaction was only significant in younger adults and only when the measured SLEs had occurred during the first 5 years of life, suggesting that both age and the specific type of SLE has a role in whether a significant gene-environment interaction is observed.

Variation in genes involved in dopamine clearance influence the startle response in older adults.

The dopamine transporter (DAT) and the enzyme catechol-O-methyltransferase (COMT) both terminate synaptic dopamine action. Here, we investigated the influence of two polymorphisms in the respective genes: DAT1 (SLC6A3) VNTR and COMT val(158)met (rs4680). Startle magnitudes to intense noise bursts as measured with the eye blink response were recorded during the presentation of pictures of three valence conditions (unpleasant, pleasant and neutral) and during baseline without additional pictorial stimulation in a sample of healthy older adults (N = 94). There was a significant Bonferroni corrected main effect of COMT genotype on the overall startle responses, with met/met homozygotes showing the highest and participants with the val/val genotype showing the lowest startle response, while participants with the val/met genotype displayed intermediate reactions. There was also a DAT1 VNTR main effect, which, after Bonferroni correction, still showed a tendency toward significance with carriers of at least one 9-repeat (R) allele showing smaller overall startle responses compared to 10R/10R homozygotes. Thus, older adult carriers of COMT variants, which result in lower enzyme activity and therefore probably enhanced dopamine signaling, showed stronger startle activity. Although the functional significance of DAT1 VNTR is less defined, our results point to a potential influence of SLC6A3 on startle magnitude.

Temporo-spatial dynamics of event-related EEG beta activity during the initial contingent negative variation.

In the electroencephalogram (EEG), early anticipatory processes are accompanied by a slow negative potential, the initial contingent negative variation (iCNV), occurring between 500 and 1500 ms after cue onset over prefrontal cortical regions in tasks with cue-target intervals of about 3 s or longer. However, the temporal sequence of the distributed cortical activity contributing to iCNV generation remains unclear. During iCNV generation, selectively enhanced low-beta activity has been reported. Here we studied the temporal order of activation foci in cortical regions assumed to underlie iCNV generation using source reconstruction of low-beta (13-18 Hz) activity. During the iCNV, elicited by a cued simple reaction-time task, low-beta power peaked first (750 ms after cue onset) in anterior frontal and limbic regions and last (140 ms later) in posterior areas. This activity occurred 3300 ms before target onset and provides evidence for the temporally ordered involvement of both cognitive-control and motor-preparation processes already at early stages during the preparation for speeded action.

Influence of functional tryptophan hydroxylase 2 gene variation and sex on the startle response in children, young adults, and older adults.

Serotonin, a key regulator of emotional behavior, is synthesized by tryptophan hydroxylase (TPH). Allelic variation of TPH2 gene expression influences serotonin synthesis in the brain and therefore may modulate emotional processing. Here, we investigated the influence of the -703 G/T polymorphism in the regulatory promoter region of the TPH2 gene on the startle response in three different age samples: children (N=110), young adults (N=209), and older adults (N=95). Startle magnitudes to intense noise bursts were recorded during baseline and while participants viewed unpleasant, pleasant or neutral pictures. There was a significant TPH2xsex interaction effect in young adults with male T allele carriers showing stronger overall startle responses compared to male G/G homozygotes while in young women this effect appeared to be reversed. The difference between TPH2 genotype groups also reached significance in the female subsample when including menstrual cycle phase. In contrast, there was no effect of TPH2 or a TPH2xsex interaction effect in children or in older adults.

Same or different? Clarifying the relationship of need for cognition to personality and intelligence.

Need for cognition (NFC) refers to an individual's tendency to engage in and enjoy effortful cognitive processing. So far, little attention has been paid to a systematic evaluation of the distinctiveness of NFC from traits with similar conceptualization and from intelligence. The present research contributes to filling this gap by examining the relation of NFC to well-established personality concepts (Study 1) and to a comprehensive measure of intelligence in a sample with broad educational backgrounds (Study 2). We observed NFC to be positively correlated with openness, emotional stability, and traits indicating goal orientation. Using confirmatory factor analysis and event-related potentials, incremental validity of NFC and openness to ideas was demonstrated, showing that NFC is more predictive of drive-related and goal-oriented behavior and attentional resource allocation. Regarding intelligence, NFC was more associated with fluid than with crystallized aspects of intelligence. Altogether, the results provide strong support for the conceptual autonomy of NFC.