Erno J. Hermans

Acute Psychological Stress Reduces Working Memory-Related Activity in the Dorsolateral Prefrontal Cortex

BACKGROUND Acute psychological stress impairs higher-order cognitive function such as working memory (WM). Similar impairments are seen in various psychiatric disorders that are associated with higher susceptibility to stress and with prefrontal cortical dysfunctions, suggesting that acute stress may play a potential role in such dysfunctions. However, it remains unknown whether acute stress has immediate effects on WM-related prefrontal activity. METHODS Using functional magnetic resonance imaging (fMRI), we investigated neural activity of 27 healthy female participants during a blocked WM task (numerical N-back) while moderate psychological stress was induced by viewing strongly aversive (vs. neutral) movie material together with a self-referencing instruction. To assess stress manipulation, autonomic and endocrine, as well as subjective, measurements were acquired throughout the experiment. RESULTS Successfully induced acute stress resulted in significantly reduced WM-related activity in the dorsolateral prefrontal cortex (DLPFC), and was accompanied by less deactivation in brain regions that are jointly referred to as the default mode network. CONCLUSIONS This study demonstrates that experimentally induced acute stress in healthy volunteers results in a reduction of WM-related DLPFC activity and reallocation of neural resources away from executive function networks. These effects may be explained by supraoptimal levels of catecholamines potentially in conjunction with elevated levels of cortisol. A similar mechanism involving acute stress as a mediating factor may play an important role in higher-order cognitive deficits and hypofrontality observed in various psychiatric disorders.

Exogenous testosterone enhances responsiveness to social threat in the neural circuitry of social aggression in humans

BACKGROUND In a range of species, the androgen steroid testosterone is known to potentiate neural circuits involved in intraspecific aggression. Disorders of impulsive aggression in humans have likewise been associated with high testosterone levels, but human evidence for the link between testosterone and aggression remains correlational and inconclusive. METHODS Twelve female participants underwent functional magnetic resonance imaging during three sessions while viewing stimuli differing in social threat value: angry and happy facial expressions. The first session served to establish associations between baseline hormone levels and neural activation. Participants were retested in a second and third session after placebo-controlled sublingual administration of .5 mg testosterone. RESULTS Findings demonstrate consistent activation to angry versus happy faces in areas known to be involved in vertebrate reactive aggression, such as the amygdala and hypothalamus. Suprathreshold clusters were also found in the orbitofrontal cortex (Brodmann area 47), a region implicated in impulse control in humans. Baseline endocrine profiles of high testosterone and low cortisol were associated with stronger activation in subcortical structures. Neural responses in most activated regions were more persistent after testosterone administration than after placebo. CONCLUSIONS These data demonstrate that testosterone enhances responsiveness in neural circuits of social aggression. Based on animal literature, it is argued that actions of testosterone on subcortical reactive aggression circuits give rise to this effect. Implications for our understanding of the pathophysiology of disorders of impulsive aggression are discussed.

Testosterone shifts the balance between sensitivity for punishment and reward in healthy young women

Animal research has demonstrated reductions in punishment sensitivity and enhanced reward dependency after testosterone administration. In humans, elevated levels of testosterone have been associated with violent and antisocial behavior. Interestingly, extreme forms of violent and antisocial behavior can be observed in the psychopath. Moreover, it has been argued that reduced punishment sensitivity and heightened reward dependency are crucially involved in the etiology and maintenance of psychopathy. A task that has been proven to be capable of simulating punishment-reward contingencies is the IOWA gambling task. Decisions to choose from decks of cards become motivated by punishment and reward schedules inherent in the task. Importantly, clinical and subclinical psychopaths demonstrate a risky, disadvantageous pattern of decision-making in the task, indicating motivational imbalance (insensitivity for punishment and enhanced reward dependency). Here, in a double-blind placebo-controlled crossover design (n = 12), whether a single administration of testosterone would shift the motivational balance between the sensitivity for punishment and reward towards this tendency to choose disadvantageously was investigated. As hypothesized, subjects showed a more disadvantageous pattern of decision-making after testosterone compared to placebo administration. These findings not only provide the first direct evidence for the effects of testosterone on punishment-reward contingencies in humans, but they also give further insights into the hypothetical link between testosterone and psychopathy.

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.

From Specificity to Sensitivity: How Acute Stress Affects Amygdala Processing of Biologically Salient Stimuli

BACKGROUND A vital component of an organisms response to acute stress is a surge in vigilance that serves to optimize the detection and assessment of threats to its homeostasis. The amygdala is thought to regulate this process, but in humans, acute stress and amygdala function have up to now only been studied in isolation. Hence, we developed an integrated design using functional magnetic resonance imaging to investigate the immediate effects of controlled stress induction on amygdala function. METHODS In 27 healthy female participants, we studied brain responses to emotional facial stimuli, embedded in an either acutely stressful or neutral context by means of adjoining movie clips. RESULTS A variety of physiological and psychological measures confirmed successful induction of moderate levels of acute stress. More importantly, this context manipulation shifted the amygdala toward higher sensitivity as well as lower specificity, that is, stress induction augmented amygdala responses to equally high levels for threat-related and positively valenced stimuli, thereby diminishing a threat-selective response pattern. Additionally, stress amplified sensory processing in early visual regions and the face responsive area of the fusiform gyrus but not in a frontal region involved in task execution. CONCLUSIONS A shift of amygdala function toward heightened sensitivity with lower levels of specificity suggests a state of indiscriminate hypervigilance under stress. Although this represents initial survival value in adverse situations where the risk for false negatives in the detection of potential threats should be minimized, it might similarly play a causative role in the sequelae of traumatic events.

Persistent schema-dependent hippocampal-neocortical connectivity during memory encoding and postencoding rest in humans

The hippocampus is thought to promote gradual incorporation of novel information into long-term memory by binding, reactivating, and strengthening distributed cortical-cortical connections. Recent studies implicate a key role in this process for hippocampally driven crosstalk with the (ventro)medial prefrontal cortex (vmPFC), which is proposed to become a central node in such representational networks over time. The existence of a relevant prior associative network, or schema, may moreover facilitate this process. Thus, hippocampal-vmPFC crosstalk may support integration of new memories, particularly in the absence of a relevant prior schema. To address this issue, we used functional magnetic resonance imaging (fMRI) and prior schema manipulation to track hippocampal-vmPFC connectivity during encoding and postencoding rest. We manipulated prior schema knowledge by exposing 30 participants to the first part of a movie that was temporally scrambled for 15 participants. The next day, participants underwent fMRI while encoding the movies final 15 min in original order and, subsequently, while resting. Schema knowledge and item recognition performance show that prior schema was successfully and selectively manipulated. Intersubject synchronization (ISS) and interregional partial correlation analyses furthermore show that stronger prior schema was associated with more vmPFC ISS and less hippocampal-vmPFC interregional connectivity during encoding. Notably, this connectivity pattern persisted during postencoding rest. These findings suggest that additional crosstalk between hippocampus and vmPFC is required to compensate for difficulty integrating novel information during encoding and provide tentative support for the notion that functionally relevant hippocampal-neocortical crosstalk persists during off-line periods after learning.

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.

A single administration of testosterone reduces fear-potentiated startle in humans

BACKGROUND Ample evidence from animal research indicates that the gonadal steroid hormone testosterone has fear-reducing properties. Human data on this topic, however, are scarce and far less unequivocal. The present study therefore aimed to scrutinize anxiolytic effects of a single dose of testosterone, using a direct physiological index of fear in humans. METHODS Twenty healthy female participants were tested in a double-blind, placebo-controlled crossover design involving sublingual administration of a single dose of testosterone. Four hours after intake, we assessed effects on baseline startle and fear-potentiated startle in a verbal threat-of-shock paradigm. RESULTS In accordance with predictions, testosterone administration resulted in reduced fear-potentiated startle, without affecting baseline startle. CONCLUSIONS This study provides direct evidence that a single dose of testosterone reduces fear in humans. The relationship of this effect to previous research on anxiolytic effects of benzodiazepines, as well as possible mechanisms of action, is discussed.

A single administration of testosterone induces cardiac accelerative responses to angry faces in healthy young women.

Recently, it was demonstrated how individuals with high levels of testosterone selectively attend toward angry faces. It was argued that this suggests that high levels of testosterone are associated with an aggressive, dominating personality style. In this study, the authors used a double-blind, placebo-controlled design to examine whether exogenous testosterone would induce cardiac acceleration in response to angry faces. Participants (healthy young women) were exposed to neutral, happy, or angry faces. Administration of a single dosage of testosterone (0.5 mg) induced an accelerative cardiac response to angry faces. It is argued that this effect is due to the encouragement of dominance behavior and the inclination toward aggression. Possible mechanisms behind testosterone-driven changes in behavior are discussed with relevance to steroid-responsive networks in the limbic system that drive and control motivational and physiological aspects of social behavior.