Marloes J. A. G. Henckens

Stress-related noradrenergic activity prompts large-scale neural network reconfiguration

Acute stress leads to reorganization of large-scale neural network connectivity in the brain that is driven by noradrenaline. Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

Dynamic adaptation of large-scale brain networks in response to acute stressors

Stress initiates an intricate response that affects diverse cognitive and affective domains, with the goal of improving survival chances in the light of changing environmental challenges. Here, we bridge animal data at cellular and systems levels with human work on brain-wide networks to propose a framework describing how stress-related neuromodulators trigger dynamic shifts in network balance, enabling an organism to comprehensively reallocate its neural resources according to cognitive demands. We argue that exposure to acute stress prompts a reallocation of resources to a salience network, promoting fear and vigilance, at the cost of an executive control network. After stress subsides, resource allocation to these two networks reverses, which normalizes emotional reactivity and enhances higher-order cognitive processes important for long-term survival.

Stressed Memories: How Acute Stress Affects Memory Formation in Humans

Stressful, aversive events are extremely well remembered. Such a declarative memory enhancement is evidently beneficial for survival, but the same mechanism may become maladaptive and culminate in mental diseases such as posttraumatic stress disorder (PTSD). Stress hormones are known to enhance postlearning consolidation of aversive memories but are also thought to have immediate effects on attentional, sensory, and mnemonic processes at memory formation. Despite their significance for our understanding of the etiology of stress-related mental disorders, effects of acute stress at memory formation, and their brain correlates at the system scale, remain elusive. Using an integrated experimental approach, we probed the neural correlates of memory formation while participants underwent a controlled stress induction procedure in a crossover design. Physiological (cortisol level, heart rate, and pupil dilation) and subjective measures confirmed acute stress. Remarkably, reduced hippocampal activation during encoding predicted stress-enhanced memory performance, both within and between participants. Stress, moreover, amplified early visual and inferior temporal responses, suggesting that hypervigilant processing goes along with enhanced inferior temporal information reduction to relay a higher proportion of task-relevant information to the hippocampus. Thus, acute stress affects neural correlates of memory formation in an unexpected manner, the understanding of which may elucidate mechanisms underlying psychological trauma etiology.

Time-Dependent Effects of Corticosteroids on Human Amygdala Processing

Acute stress is associated with a sensitized amygdala. Corticosteroids, released in response to stress, are suggested to restore homeostasis by normalizing/desensitizing brain processing in the aftermath of stress. Here, we investigated the effects of corticosteroids on amygdala processing using functional magnetic resonance imaging. Since corticosteroids exert rapid nongenomic and slow genomic effects, we administered hydrocortisone either 75 min (rapid effects) or 285 min (slow effects) before scanning in a randomized, double-blind, placebo-controlled design. Seventy-two healthy males were scanned while viewing faces morphing from a neutral facial expression into fearful or happy expressions. Imaging results revealed that hydrocortisone desensitizes amygdala responsivity rapidly, while it selectively normalizes responses to negative stimuli slowly. Psychophysiological interaction analyses suggested that this slow normalization is related to an altered coupling of the amygdala with the medial prefrontal cortex. These results reveal a temporarily fine-tuned mechanism that is critical for avoiding amygdala overshoot during stress and enabling adequate recovery thereafter.

Time-dependent corticosteroid modulation of prefrontal working memory processing

Corticosteroids are potent modulators of human higher cognitive function. They are released in response to stress, and are thought to be involved in the modulation of cognitive function by inducing distinct rapid nongenomic, and slow genomic changes, affecting neural plasticity throughout the brain. However, their exact effects on the neural correlates of higher-order cognitive function as performed by the prefrontal cortex at the human brain system level remain to be elucidated. Here, we targeted these time-dependent effects of corticosteroids on prefrontal cortex processing in humans using a working memory (WM) paradigm during functional MRI scanning. Implementing a randomized, double-blind, placebo-controlled design, 72 young, healthy men received 10 mg hydrocortisone either 30 min (rapid corticosteroid effects) or 240 min (slow corticosteroid effects), or placebo before a numerical n-back task with differential load (0- to 3-back). Corticosteroids’ slow effects appeared to improve working memory performance and increased neuronal activity during WM performance in the dorsolateral prefrontal cortex depending on WM load, whereas no effects of corticosteroids’ rapid actions were observed. Thereby, the slow actions of corticosteroids seem to facilitate adequate higher-order cognitive functioning, which may support recovery in the aftermath of stress exposure.

Fear bradycardia and activation of the human periaqueductal grey

Animal models of predator defense distinguish qualitatively different behavioral modes that are activated at increasing levels of predation threat. A defense mode observed at intermediate threat levels is freezing: a cessation of locomotion that is characterized by a parasympathetically dominated autonomic nervous system response that causes heart rate deceleration, or fear bradycardia. Studies in rodents have shown that freezing depends on amygdalar projections to the periaqueductal grey (PAG). In humans, freezing-like behaviors are implicated in development and maintenance of psychopathology, but neural mechanisms underlying freezing or its characteristic autonomic response profile have not been identified. Here, we combined event-related blood oxygenation level-dependent functional MRI (BOLD-fMRI) with autonomic response measures in a picture viewing paradigm to probe activity and interconnectivity within the amygdala-PAG pathway and test for an association with parasympathetic as opposed to sympathetic activation. In response to negatively arousing pictures, we observed parasympathetic (bradycardia) and sympathetic (pupil dilation) autonomic responses, BOLD responses in the amygdala and PAG, and effective connectivity between these regions. Critically, BOLD responses in the PAG to negative pictures correlated on a trial-by-trial basis with bradycardia but not pupil dilation. This correlation with bradycardia remained significant when partialling out pupil dilation. Additionally, activity in regions associated with motor planning and inhibition mirrored the PAG response. Thus, our findings implicate the human PAG in a parasympathetically dominated defense mode that subserves a state of attentive immobility. Mechanistic insight into this qualitatively distinct defense mode may importantly advance translational models of anxiety disorders.

Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain.

Corticotropin-releasing factor (CRF) acts through CRF 1 and CRF 2 receptors (CRF1, CRF2). To test the hypothesis that CRF controls the expression of these receptors in a brain site- and receptor-type specific manner, we studied CRF1 mRNA and CRF2 mRNA expressions in mice with central CRF over-expression (CRF-OE) and using in situ hybridization. CRF1 and CRF2 mRNAs appear to be differentially distributed across the brain. The brain structures expressing the receptors are the same in wild-type (WT) and in CRF-OE mice. We therefore conclude that chronically elevated CRF does not induce or inhibit expression of these receptors in structures that normally do not or do, respectively, show these receptors. However, from counting cell body profiles positive for CRF1 and CRF2 mRNAs, clear differences appear in receptor expression between CRF-OE and WT mice, in a brain-structure-specific fashion. Whereas some structures do not differ, CRF-OE mice exhibit remarkably lower numbers of CRF1 mRNA-positive profiles in the subthalamic nucleus (-38.6%), globus pallidus (-31.5%), dorsal part of the lateral septum (-23.5%), substantia nigra (-22,8%), primary somatosensory cortex (-18.9%) and principal sensory nucleus V (-18.4%). Furthermore, a higher number of CRF2 mRNA-positive profiles are observed in the dorsal raphe nucleus (+32.2%). These data strongly indicate that central CRF over-expression in the mouse brain is associated with down-regulation of CRF1 mRNA and up-regulation of CRF2 mRNA in a brain-structure-specific way. On the basis of these results and the fact that CRF-OE mice reveal a number of physiological and autonomic symptoms that may be related to chronic stress, we suggest that CRF1 in the basal nuclei may be involved in disturbed information processing and that CRF2 in the dorsal raphe nucleus may play a role in mediating stress-induced release of serotonin by CRF.

Time-dependent effects of cortisol on selective attention and emotional interference: a functional MRI study

Acute stress is known to induce a state of hypervigilance, allowing optimal detection of threats. Although one may benefit from sensitive sensory processing, it comes at the cost of unselective attention and increased distraction by irrelevant information. Corticosteroids, released in response to stress, have been shown to profoundly influence brain function in a time-dependent manner, causing rapid non-genomic and slow genomic effects. Here, we investigated how these time-dependent effects influence the neural mechanisms underlying selective attention and the inhibition of emotional distracters in humans. Implementing a randomized, double-blind, placebo-controlled design, 65 young healthy men received 10 mg hydrocortisone either 60 min (rapid effects) or 270 min (slow effects), or placebo prior to an emotional distraction task, consisting of color-naming of either neutral or aversive words. Overall, participants responded slower to aversive compared to neutral words, indicating emotional interference with selective attention. Importantly, the rapid effects of corticosteroids increased emotional interference, which was associated with reduced amygdala inhibition to aversive words. Moreover, they induced enhanced amygdala connectivity with frontoparietal brain regions, which may reflect increased influence of the amygdala on an executive network. The slow effects of corticosteroids acted on the neural correlates of sustained attention. They decreased overall activity in the cuneus, possibly indicating reduced bottom-up attentional processing, and disrupted amygdala connectivity to the insula, potentially reducing emotional interference. Altogether, these data suggest a time-specific corticosteroid modulation of attentive processing. Whereas high circulating corticosteroid levels acutely increase emotional interference, possibly facilitating the detection of threats, a history of elevation might promote sustained attention and thereby contribute to stress-recovery of cognitive function.

Stress-induced alterations in large-scale functional networks of the rodent brain

Stress-related psychopathology is associated with altered functioning of large-scale brain networks. Animal research into chronic stress, one of the most prominent environmental risk factors for development of psychopathology, has revealed molecular and cellular mechanisms potentially contributing to human mental disease. However, so far, these studies have not addressed the system-level changes in extended brain networks, thought to critically contribute to mental disorders. We here tested the effects of chronic stress exposure (10 days immobilization) on the structural integrity and functional connectivity patterns in the brain, using high-resolution structural MRI, diffusion kurtosis imaging, and resting-state functional MRI, while confirming the expected changes in neuronal dendritic morphology using Golgi-staining. Stress effectiveness was confirmed by a significantly lower body weight and increased adrenal weight. In line with previous research, stressed animals displayed neuronal dendritic hypertrophy in the amygdala and hypotrophy in the hippocampal and medial prefrontal cortex. Using independent component analysis of resting-state fMRI data, we identified ten functional connectivity networks in the rodent brain. Chronic stress appeared to increase connectivity within the somatosensory, visual, and default mode networks. Moreover, chronic stress exposure was associated with an increased volume and diffusivity of the lateral ventricles, whereas no other volumetric changes were observed. This study shows that chronic stress exposure in rodents induces alterations in functional network connectivity strength which partly resemble those observed in stress-related psychopathology. Moreover, these functional consequences of stress seem to be more prominent than the effects on gross volumetric change, indicating their significance for future research.

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.