The interaction of child abuse and rs1360780 of the FKBP5 gene is associated with amygdala resting-state functional connectivity in young adults.

Extensive research has demonstrated that rs1360780, a common single nucleotide polymorphism within the FKBP5 gene, interacts with early-life stress in predicting psychopathology. Previous results suggest that carriers of the TT genotype of rs1360780 who were exposed to child abuse show differences in structure and functional activation of emotion-processing brain areas belonging to the salience network. Extending these findings on intermediate phenotypes of psychopathology, we examined if the interaction between rs1360780 and child abuse predicts resting-state functional connectivity (rsFC) between the amygdala and other areas of the salience network. We analyzed data of young European adults from the general population (N = 774; mean age = 18.76 years) who took part in the IMAGEN study. In the absence of main effects of genotype and abuse, a significant interaction effect was observed for rsFC between the right centromedial amygdala and right posterior insula (p < .025, FWE-corrected), which was driven by stronger rsFC in TT allele carriers with a history of abuse. Our results suggest that the TT genotype of rs1360780 may render individuals with a history of abuse more vulnerable to functional changes in communication between brain areas processing emotions and bodily sensations, which could underlie or increase the risk for psychopathology.

Natural sleep loss is associated with lower mPFC activity during negative distracter processing.

Previous research has demonstrated that loss of sleep has a negative impact on both emotional and cognitive functioning. We examined whether subjectively reported natural sleep loss is associated with the interplay between emotion and cognition, as was probed by brain activity in response to emotional distraction during a working memory task. Forty-six healthy male adults reported their typical weekly sleep pattern using the Munich Chronotype Questionnaire (MCTQ), while recent sleep loss was enquired using a sleep diary in the 7 days preceding scanning. Participants performed a delayed match-to-sample task with negative and neutral distracters during the delay period inside the MRI scanner. Activity differences between negative and neutral distracters were associated to both sleep loss measures across participants. The amount of typically encountered sleep loss indicated by the MCTQ, but not sleep diary, was negatively associated with activity in the rostral anterior cingulate cortex and dorsomedial prefrontal cortex during emotionally negative compared to neutral distraction (p < 0.025, whole brain corrected). Participants showed less distracter-related activity in the ACC and dorsomedial PFC with increasing sleep loss, which, in the long run, might contribute to less adaptive emotional processing, and therefore a greater vulnerability to develop affective disorders.

Physiological responding to stress in middle-aged males enriched for longevity: a social stress study.

Individuals enriched for familial longevity display a lower prevalence of age-related diseases, such as cardiovascular- and metabolic diseases. Since these diseases are associated with stress and increased cortisol levels, one of the underlying mechanisms that may contribute to healthy longevity might be a more adaptive response to stress. To investigate this, male middle-aged offspring from long-lived families (n = 31) and male non-offspring (with no familial history of longevity) (n = 26) were randomly allocated to the Trier Social Stress Test or a control condition in an experimental design. Physiological (cortisol, blood pressure, heart rate) and subjective responses were measured during the entire procedure. The results showed that Offspring had lower overall cortisol levels compared to Non-offspring regardless of condition, and lower absolute cortisol output (AUCg) during stress compared to Non-Offspring, while the increase (AUCi) did not differ between groups. In addition, systolic blood pressure in Offspring was lower compared to Non-offspring during the entire procedure. At baseline, Offspring had significantly lower systolic blood pressure and reported less subjective stress than Non-offspring and showed a trend towards lower heart rate. Offspring from long-lived families might thus be less stressed prior to potentially stressful events and consequently show overall lower levels in physiological responses. Although attenuated physiological responding cannot be ruled out, lower starting points and a lower peak level in physiological responding when confronted with an actual stressor, might already limit damage due to stress over a lifetime. Lower physiological responding may also contribute to the lower prevalence of cardiovascular diseases and other stress-related diseases in healthy longevity.

Dopamine-dependent architecture of cortico-subcortical network connectivity.

Maladaptive dopaminergic mediation of reward processing in humans is thought to underlie multiple neuropsychiatric disorders, including addiction, Parkinson's disease, and schizophrenia. Mechanisms responsible for the development of such disorders may depend on individual differences in neural signaling within large-scale cortico-subcortical circuitry. Using a combination of functional neuroimaging and pharmacological challenges in healthy volunteers, we identified opposing dopamine agonistic and antagonistic neuromodulatory effects on distributed functional interactions between specific subcortical regions and corresponding neocortical "resting-state" networks, known to be involved in distinct aspects of cognition and reward processing. We found that, relative to a placebo, levodopa and haloperidol challenges, respectively, increased or decreased the functional connectivity between (1) the midbrain and a "default mode" network, (2) the right caudate and a right-lateralized frontoparietal network, and (3) the ventral striatum and a fronto-insular network. Further, we found drug-specific associations between brain circuitry reactivity to dopamine modulation and individual differences in trait impulsivity, revealing dissociable drug-personality interaction effects across distinct dopamine-dependent cortico-subcortical networks. Our findings identify possible systems underlying pathogenesis and treatment efficacy in disorders of dopamine deficiency.

Susceptibility to distraction by social cues in borderline personality disorder.

BACKGROUND/AIMS: Individuals with borderline personality disorder (BPD) are highly sensitive to social rejection and show alterations in social perception. Increased susceptibility to social cues in patients with BPD might interfere with executive functions that play an important role in goal-directed behavior. The aim of this study was to investigate the influence of task-irrelevant (neutral vs. negatively arousing) social cues on working memory performance in BPD patients compared to healthy controls (HC). METHODS: 28 unmedicated female BPD patients and 28 female HC (matched for age and education) performed a Sternberg item recognition task, while being distracted by neutral versus negatively arousing pictures from the International Affective Picture System (interpersonal scenes) and the Karolinska Directed Emotional Faces Set (faces). Additionally, self-ratings of aversive inner tension were assessed and correlated with task performance. RESULTS: Compared to HC, BPD patients showed significantly impaired accuracy after distraction by negatively arousing stimuli (both scenes and faces) and neutral faces (but not neutral scenes). Significant negative correlations between overall accuracy and self-reported aversive inner tension were observed in BPD patients. CONCLUSIONS: Findings of the present study suggest increased susceptibility to distracting (negatively arousing) social cues in individuals with BPD, which might interfere with cognitive functioning.

Differential and distributed effects of dopamine neuromodulations on resting-state network connectivity.

Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear ('inverted U-shaped') effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans. We hypothesised that diverse effects of dopamine neuromodulation could be characterised using systems-level neuroimaging approaches. Using 'resting-state' functional magnetic resonance imaging (FMRI), combined with dopaminergic challenges, we examined the dopamine-dependent functional connectivity of brain 'resting-state networks' (RSNs). We compared RSN connectivity in 3 groups of healthy volunteers given dopamine antagonist (haloperidol; N=18) or agonistic (levodopa; N=16) drugs, or a placebo (N=15). As RSNs have been shown to be relevant for numerous psychological functions and dysfunctions, we investigated both linear and nonlinear effects on RSN connectivity of manipulating dopamine neurotransmission pharmacologically. A basal ganglia RSN displayed both linear and nonlinear effects of dopamine manipulation on functional connectivity, respectively, with lateral frontoparietal and medial frontal neocortical areas. Conversely, a cognitive 'default mode' network showed only linear dopaminergic effects on connectivity with lateral frontal and parietal cortices. Our findings highlight diverse functional effects of dopamine neuromodulations on systems-level neural interactions. The observation that dopamine modulates distinct large-scale network connectivity patterns differentially, in both linear and nonlinear fashions, provides support for the objective utility of RSN metrics in classifying the effects and efficacy of psychopharmacological medications.

Childhood adversity and vagal regulation: A systematic review and meta-analysis.

Childhood adversity (CA) is associated with increased risk for physical and mental health problems, with alterations in vagal regulation (an aspect of autonomic functioning indexed by vagally-mediated heart rate variability [vmHRV]) implicated as a mechanism. Three-level meta-analyses were conducted to synthesize research on the relationship between CA and 1) baseline vagal activity, and 2) vagal reactivity to challenges including stress tests, emotion-eliciting tasks and cognitive tasks. No significant overall association was found between CA and vagal activity (r = -.015; p = .11) or vagal reactivity (r = -.017; p = .13). However, analyses controlling for moderator interrelatedness revealed an association between CA and lower baseline vagal activity in samples including participants diagnosed with a psychiatric disorder, and for direct adversities such as maltreatment. For vagal reactivity, CA was associated with lower reactivity if the adversity was experienced less recently, and for studies operationalizing reactivity using task mean levels of vmHRV. These findings indicate that small alterations in vagal functioning occur for specific CA subtypes and subgroups of individuals.

Beyond acute social stress: increased functional connectivity between amygdala and cortical midline structures.

Whereas we know a fair amount on the role of the amygdala in the acute stress response, virtually nothing is known about its role during the recovery period after the stress has waned. Functional connectivity analysis of the amygdala during this period might be useful in revealing brain circuits promoting adaptive recovery from a stressful event, as well as consolidation of emotionally relevant information in preparing for future challenges. Healthy participants were randomly assigned to either a psychosocial stress task (n=18; stress group) or a comparable non-stressful control procedure (n=20; controls). To study the prolonged effects of stress on amygdala functional connectivity, resting-state fMRI scans were acquired an hour after the stress task. Amygdala functional connectivity with other brain regions was assessed using seed-based correlations. The stress group exhibited a strong physiological and behavioral reaction to psychosocial stress exposure. Compared with controls the stress group showed increased amygdala functional connectivity with three cortical midline structures: the posterior cingulate cortex and precuneus (p<.05, corrected), and the medial prefrontal cortex (p<.05, small volume corrected). An hour after psychosocial stress, changes in amygdala functional connectivity were detected with cortical midline structures involved in the processing and regulation of emotions, as well as autobiographical memory. It is hypothesized that these effects could relate to top-down control of the amygdala and consolidation of self-relevant information after a stressful event. These results on functional connectivity in the recovery phase after stress might provide an important new vantage point in studying both sensitivity and resilience to stress.

Non-parametric model selection for subject-specific topological organization of resting-state functional connectivity.

In recent years, graph theory has been successfully applied to study functional and anatomical connectivity networks in the human brain. Most of these networks have shown small-world topological characteristics: high efficiency in long distance communication between nodes, combined with highly interconnected local clusters of nodes. Moreover, functional studies performed at high resolutions have presented convincing evidence that resting-state functional connectivity networks exhibits (exponentially truncated) scale-free behavior. Such evidence, however, was mostly presented qualitatively, in terms of linear regressions of the degree distributions on log-log plots. Even when quantitative measures were given, these were usually limited to the r(2) correlation coefficient. However, the r(2) statistic is not an optimal estimator of explained variance, when dealing with (truncated) power-law models. Recent developments in statistics have introduced new non-parametric approaches, based on the Kolmogorov-Smirnov test, for the problem of model selection. In this work, we have built on this idea to statistically tackle the issue of model selection for the degree distribution of functional connectivity at rest. The analysis, performed at voxel level and in a subject-specific fashion, confirmed the superiority of a truncated power-law model, showing high consistency across subjects. Moreover, the most highly connected voxels were found to be consistently part of the default mode network. Our results provide statistically sound support to the evidence previously presented in literature for a truncated power-law model of resting-state functional connectivity.

Are psychotic-like experiences related to a discontinuation of cannabis consumption in young adults?

OBJECTIVE: To assess changes in cannabis use in young adults as a function of psychotic-like experiences. METHOD: Participants were initially recruited at age 14 in high schools for the longitudinal IMAGEN study. All measures presented here were assessed at follow-ups at age 19 and at age 22, respectively. Perceived stress was only assessed once at age 22. Ever users of cannabis (N = 552) gave qualitative and quantitative information on cannabis use and psychotic-like experiences using the Community Assessment of Psychic Experiences (CAPE). Of those, nearly all n = 549 reported to have experienced at least one psychotic experience of any form at age 19. RESULTS: Mean cannabis use increased from age 19 to 22 and age of first use of cannabis was positively associated with a change in cannabis use between the two time points. Change in cannabis use was not significantly associated with psychotic-like experiences at age 19 or 22. In exploratory analysis, we observed a positive association between perceived stress and the experience of psychotic experiences at age 22. CONCLUSION: Age of first use of cannabis influenced trajectories of young cannabis users with later onset leading to higher increase, whereas the frequency of psychotic-like experiences was not associated with a change in cannabis use. The observed association between perceived stress and psychotic-like experiences at age 22 emphasizes the importance of stress experiences in developing psychosis independent of cannabis use.

Propranolol reduces emotional distraction in working memory: a partial mediating role of propranolol-induced cortisol increases?

Noradrenalin modulates prefrontal function, such as working memory (WM), and is associated with enhanced distractibility, and enhanced memory for emotional events and stimuli. The beta-blocker propranolol has been shown to reduce memory for emotional stimuli. Herein we describe investigations aimed at assessing whether the administration of propranolol would reduce the interference by emotional distractions during WM performance. In a between-subjects design, 48 young, healthy men received 80 mg propranolol (n=25) or placebo (n=23), before performing an "emotional Sternberg task" with neutral and negatively arousing distracters. Compared to placebo, propranolol impaired WM at low load, however, it also reduced the interference by emotional distracters at high load. Furthermore, an explorative moderated-mediation analysis indicated that the observed propranolol effects on emotional distraction were partially mediated by cortisol. In future non-clinical and clinical memory studies using propranolol administration, cortisol elevations should be monitored to further investigate the potential mediating role of cortisol.

Association of naturally occurring sleep loss with reduced amygdala resting-state functional connectivity following psychosocial stress.

Enduring sleep loss is a risk factor for a variety of both somatic and mental health issues. When subjected to sleep loss, the brain becomes vulnerable to critical alterations in cognitive and emotional processing. In our study, we examined the effect of psychosocial stress on amygdala resting-state functional connectivity in participants with cumulative sleep loss calculated across the seven days preceding scanning. For this purpose, forty-five healthy male participants completed a one-week sleep diary and underwent resting-state scans before and after taking part in the ScanSTRESS paradigm, which allows social stress induction during functional magnetic resonance imaging. Sleep loss was negatively associated with seed-based functional connectivity of the left amygdala with the medial prefrontal cortex, dorsal anterior cingulate cortex, anterior insula, posterior cingulate cortex, and dorsolateral prefrontal cortex. That is, participants with higher amounts of sleep loss showed reduced left amygdala connectivity after social stress induction to cortical regions encompassing main nodes of the brain's default mode network and salience network. Our results shed more light on how brain functional connectivity may shape the brain's stress response in the context of naturally occurring sleep loss, revealing a potential neural mechanism for increased vulnerability to stress-related psychopathology.

Stress evokes stronger medial posterior cingulate deactivations during emotional distraction in slower paced aging.

INTRODUCTION: Middle-aged offspring from long-lived families are thought to have a slower pace of aging, possibly related to HPA-axis function. Here, we investigated the neural and behavioral effects of social stress in offspring compared to their regular aging partners on emotional distraction during working memory (WM). METHODS: 104 middle-aged participants (53 males) consisting of offspring and their partners underwent the Trier Social Stress Test or a control procedure. Hereafter, a WM task with emotional distracters was performed using fMRI. Saliva cortisol levels were obtained during the procedure. RESULTS: Partners had higher overall cortisol levels than offspring. In addition, partners had decreased deactivations compared to offspring in the medial posterior cingulate cortex (mPCC) during emotional distraction, which were significantly correlated with lower accuracy during emotional distraction. DISCUSSION: mPCC-deactivations are known to be modulated by chronological aging, with more deactivations in the young than in the old. Here we show the same pattern in familial longevity versus regular aging after mild stress, with more deactivations related to better accuracy during emotional distraction. Functional mPCC deactivations might thus be related to pace of aging, and can be revealed by inducing mild stress.

Recall bias in reporting medically unexplained symptoms comes from semantic memory.

OBJECTIVE: When people report somatic complaints retrospectively, they depend on their memory. Therefore, retrospective reports can be influenced by general beliefs on sickness and health from semantic memory. We hypothesized that individuals with medically unexplained symptoms (MUS) would have recall biases stronger than those of people without complaints when reporting symptoms retrospectively, and that this effect would be a function of time between symptom experience and report. METHODS: To compare two time frames, 37 participants who were high and low on MUS reported momentary symptoms combined by daily recall and weekly recall using an electronic diary. RESULTS: Both groups reported more symptoms when recalling the entire week than what could be expected from average momentary reports. However, participants high on MUS also reported more symptoms when recalling a week than when recalling a day. For this group, recall bias was not associated with peak heuristic or symptoms variability. CONCLUSION: Symptom reports in people high on MUS increases as time passes by, probably as a results of a shift in memory retrieval strategy from using episodic knowledge to using semantic beliefs.

Evidence for smaller right amygdala volumes in posttraumatic stress disorder following childhood trauma.

Hippocampus and amygdala volumes in posttraumatic stress disorder (PTSD) related to childhood trauma are relatively understudied, albeit the potential importance to the disorder. Whereas some studies reported smaller hippocampal volumes, little evidence was found for abnormal amygdala volumes. Here we investigated hippocampus and amygdala volumes and shapes in an adult sample of PTSD patients related to childhood trauma. T1-weighted MR images were acquired from 12 female PTSD patients with trauma related to physical, sexual, and/or emotional abuse before age 18, and from 12 matched controls. Hippocampus and amygdala were segmented, and volumes were calculated and corrected for the total intracranial volume. Additionally, a shape analysis was done on the surface of the structures to explore abnormalities in specific subnuclei. Smaller right amygdala volumes were found in PTSD patients as compared with the controls. This difference appeared to be located specifically in the basolateral and superficial nuclei groups. Severity of sexual abuse during childhood was negatively correlated with the size of the amygdala. No difference in hippocampal volumes was found. Although our results are not conclusive, traumatic events in childhood might impede normal development of the amygdala, which could render a person more vulnerable to develop PTSD later in life.

Acute stress-induced cortisol elevations mediate reward system activity during subconscious processing of sexual stimuli.

Stress is thought to alter motivational processes by increasing dopamine (DA) secretion in the brain's "reward system", and its key region, the nucleus accumbens (NAcc). However, stress studies using functional magnetic resonance imaging (fMRI), mainly found evidence for stress-induced decreases in NAcc responsiveness toward reward cues. Results from both animal and human PET studies indicate that the stress hormone cortisol may be crucial in the interaction between stress and dopaminergic actions. In the present study we therefore investigated whether cortisol mediated the effect of stress on DA-related responses to -subliminal-presentation of reward cues using the Trier Social Stress Test (TSST), which is known to reliably enhance cortisol levels. Young healthy males (n = 37) were randomly assigned to the TSST or control condition. After stress induction, brain activation was assessed using fMRI during a backward-masking paradigm in which potentially rewarding (sexual), emotionally negative and neutral stimuli were presented subliminally, masked by pictures of inanimate objects. A region of interest analysis showed that stress decreased activation in the NAcc in response to masked sexual cues (voxel-corrected, p<05). Furthermore, with mediation analysis it was found that high cortisol levels were related to stronger NAcc activation, showing that cortisol acted as a suppressor variable in the negative relation between stress and NAcc activation. The present findings indicate that cortisol is crucially involved in the relation between stress and the responsiveness of the reward system. Although generally stress decreases activation in the NAcc in response to rewarding stimuli, high stress-induced cortisol levels suppress this relation, and are associated with stronger NAcc activation. Individuals with a high cortisol response to stress might on one hand be protected against reductions in reward sensitivity, which has been linked to anhedonia and depression, but they may ultimately be more vulnerable to increased reward sensitivity, and addictions. Future studies investigating effects of stress on reward sensitivity should take into account the severity of the stressor and the individual cortisol response to stress.

Amygdala and Dorsal Anterior Cingulate Connectivity during an Emotional Working Memory Task in Borderline Personality Disorder Patients with Interpersonal Trauma History.

Working memory is critically involved in ignoring emotional distraction while maintaining goal-directed behavior. Antagonistic interactions between brain regions implicated in emotion processing, e.g., amygdala, and brain regions involved in cognitive control, e.g., dorsolateral and dorsomedial prefrontal cortex (dlPFC, dmPFC), may play an important role in coping with emotional distraction. We previously reported prolonged reaction times associated with amygdala hyperreactivity during emotional distraction in interpersonally traumatized borderline personality disorder (BPD) patients compared to healthy controls (HC): Participants performed a working memory task, while neutral versus negative distractors (interpersonal scenes from the International Affective Picture System) were presented. Here, we re-analyzed data from this study using psychophysiological interaction analysis. The bilateral amygdala and bilateral dorsal anterior cingulate cortex (dACC) were defined as seed regions of interest. Whole-brain regression analyses with reaction times and self-reported increase of dissociation were performed. During emotional distraction, reduced amygdala connectivity with clusters in the left dorsolateral and ventrolateral PFC was observed in the whole group. Compared to HC, BPD patients showed a stronger coupling of both seeds with a cluster in the right dmPFC and stronger positive amygdala connectivity with bilateral (para)hippocampus. Patients further demonstrated stronger positive dACC connectivity with left posterior cingulate, insula, and frontoparietal regions during emotional distraction. Reaction times positively predicted amygdala connectivity with right dmPFC and (para)hippocampus, while dissociation positively predicted amygdala connectivity with right ACC during emotional distraction in patients. Our findings suggest increased attention to task-irrelevant (emotional) social information during a working memory task in interpersonally traumatized patients with BPD.

Dopamine modulates reward system activity during subconscious processing of sexual stimuli.

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication.

Stress shifts brain activation towards ventral 'affective' areas during emotional distraction.

Acute stress has been shown to impair working memory (WM), and to decrease prefrontal activation during WM in healthy humans. Stress also enhances amygdala responses towards emotional stimuli. Stress might thus be specifically detrimental to WM when one is distracted by emotional stimuli. Usually, emotional stimuli presented as distracters in a WM task slow down performance, while evoking more activation in ventral 'affective' brain areas, and a relative deactivation in dorsal 'executive' areas. We hypothesized that after acute social stress, this reciprocal dorsal-ventral pattern would be shifted towards greater increase of ventral 'affective' activation during emotional distraction, while impairing WM performance. To investigate this, 34 healthy men, randomly assigned to a social stress or control condition, performed a Sternberg WM task with emotional and neutral distracters inside an MRI scanner. Results showed that WM performance after stress tended to be slower during emotional distraction. Brain activations during emotional distraction was enhanced in ventral affective areas, while dorsal executive areas tended to show less deactivation after stress. These results suggest that acute stress shifts priority towards processing of emotionally significant stimuli, at the cost of WM performance.

Endogenous cortisol is associated with functional connectivity between the amygdala and medial prefrontal cortex.

Whether glucocorticoids mediate medial prefrontal cortex (mPFC) regulation of the amygdala in humans remains unclear. In the current study we investigated whether cortisol levels under relatively stress-free circumstances are related to amygdala resting-state functional connectivity with the mPFC. Resting-state fMRI data were acquired from 20 healthy male participants. Salivary cortisol was sampled at multiple times throughout the experiment. The cortisol area under the curve increase (AUCi) was calculated as a measure of cortisol dynamics. Next, seed based correlations were employed on the resting-state fMRI data to reveal regions of amygdala functional connectivity related to variations in cortisol AUCi. The resulting statistical maps were corrected for multiple comparisons using cluster based thresholding (Z>2.3, p<.05). Two regions in the mPFC showed decreasing negative functional connectivity with the amygdala when a lesser decrease in cortisol AUCi was observed: the perigenual anterior cingulate cortex and medial frontal pole (BA10). Although we initially showed a relation with cortisol AUCi, it seemed that the baseline cortisol levels were actually driving this effect: higher baseline cortisol levels related to stronger negative functional connectivity with the mPFC. Endogenous cortisol levels may modulate amygdala functional connectivity with specific regions in the mPFC, even under relatively stress-free circumstances. Our results corroborate previous findings from both animal and human studies, suggesting cortisol-mediated regulation of the amygdala by the mPFC. We propose that through this feedback mechanism the stress response might be adjusted, pointing to the putative role of cortisol in modulating stress- and, more generally, emotional responses.