Vanessa A. van Ast

Brain mediators of cardiovascular responses to social threat, Part II: Prefrontal-subcortical pathways and relationship with anxiety

Social evaluative threat (SET) is a potent stressor in humans that causes autonomic changes, endocrine responses, and multiple health problems. Neuroimaging has recently begun to elucidate the brain correlates of SET, but as yet little is known about the mediating cortical-brainstem pathways in humans. This paper replicates and extends findings in a companion paper (Wager et al., 2009) using an independent cohort of participants and different image acquisition parameters. Here, we focused specifically on relationships between the medial prefrontal cortex (MPFC), midbrain periaqueductal gray (PAG), and heart rate (HR). We applied multi-level path analysis to localize brain mediators of SET effects on HR and self-reported anxiety. HR responses were mediated by opposing signals in two distinct sub-regions of the MPFC-increases in rostral dorsal anterior cingulate cortex (rdACC) and de-activation in ventromedial prefrontal cortex (vmPFC). In addition, HR responses were mediated by PAG. Additional path analyses provided support for two cortical-subcortical pathways: one linking vmPFC, PAG, and HR, and another linking rdACC, thalamus, and HR. PAG responses were linked with HR changes both before and during SET, whereas cortical regions showed stronger connectivity with HR during threat. Self-reported anxiety showed a partially overlapping, but weaker, pattern of mediators, including the vmPFC, dorsomedial prefrontal cortex, and lateral frontal cortex, as well as substantial individual differences that were largely unexplained. Taken together, these data suggest pathways for the translation of social threats into both physiological and experiential responses, and provide targets for future research on the generation and regulation of emotion.

Time-dependent effects of cortisol on the contextualization of emotional memories

BACKGROUND The inability to store fearful memories into their original encoding context is considered to be an important vulnerability factor for the development of anxiety disorders like posttraumatic stress disorder. Altered memory contextualization most likely involves effects of the stress hormone cortisol, acting via receptors located in the memory neurocircuitry. Cortisol via these receptors induces rapid nongenomic effects followed by slower genomic effects, which are thought to modulate cognitive function in opposite, complementary ways. Here, we targeted these time-dependent effects of cortisol during memory encoding and tested subsequent contextualization of emotional and neutral memories. METHODS In a double-blind, placebo-controlled design, 64 men were randomly assigned to one of three groups: 1) received 10 mg hydrocortisone 30 minutes (rapid cortisol effects) before a memory encoding task; 2) received 10 mg hydrocortisone 210 minutes (slow cortisol) before a memory encoding task; or 3) received placebo at both times. During encoding, participants were presented with neutral and emotional words in unique background pictures. Approximately 24 hours later, context dependency of their memories was assessed. RESULTS Recognition data revealed that cortisols rapid effects impair emotional memory contextualization, while cortisols slow effects enhance it. Neutral memory contextualization remained unaltered by cortisol, irrespective of the timing of the drug. CONCLUSIONS This study shows distinct time-dependent effects of cortisol on the contextualization of specifically emotional memories. The results suggest that rapid effects of cortisol may lead to impaired emotional memory contextualization, while slow effects of cortisol may confer protection against emotional memory generalization.

Individual Differences in Heart Rate Variability Predict the Degree of Slowing during Response Inhibition and Initiation in the Presence of Emotional Stimuli.

Response inhibition is a hallmark of executive control and crucial to support flexible behavior in a constantly changing environment. Recently, it has been shown that response inhibition is influenced by the presentation of emotional stimuli (Verbruggen and De Houwer, 2007). Healthy individuals typically differ in the degree to which they are able to regulate their emotional state, but it remains unknown whether individual differences in emotion regulation (ER) may alter the interplay between emotion and response inhibition. Here we address this issue by testing healthy volunteers who were equally divided in groups with high and low heart rate variability (HRV) during rest, a physiological measure that serves as proxy of ER. Both groups performed an emotional stop-signal task, in which negative high arousing pictures served as negative emotional stimuli and neutral low arousing pictures served as neutral non-emotional stimuli. We found that individuals with high HRV activated and inhibited their responses faster compared to individuals with low HRV, but only in the presence of negative stimuli. No group differences emerged for the neutral stimuli. Thus, individuals with low HRV are more susceptible to the adverse effects of negative emotion on response initiation and inhibition. The present research corroborates the idea that the presentation of emotional stimuli may interfere with inhibition and it also adds to previous research by demonstrating that the aforementioned relationship varies for individuals differing in HRV. We suggest that focusing on individual differences in HRV and its associative ER may shed more light on the dynamic interplay between emotion and cognition.

Ready and waiting: Freezing as active action preparation under threat

Freezing is a defensive response characterized by rigidity and bradycardia, but it is unclear whether it is a passive versus active preparatory state. We developed a shooting task in which preparation and threat were manipulated independently: Participants were either helpless or able to respond to a possible upcoming attack, and attacks were either associated with an electric shock or not. Essentially, a purely anticipatory preparatory period was used during which no stimuli occurred. Freezing was assessed during this period. In addition to heart rate, body sway was measured, using a stabilometric force platform. The efficacy of the threat manipulation was confirmed via self-report. The ability to prepare led to decreases in heart rate and postural sway, while threat led to decreased heart rate. Further, exploratory analyses suggested that aggressive participants showed reduced initial freezing for threatening opponents, but increased postural freezing when armed. The results suggest that freezing may involve active preparation. Relations to results in passive viewing tasks are discussed.

Brain Mechanisms of Social Threat Effects on Working Memory

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level.

Modulatory mechanisms of cortisol effects on emotional learning and memory: Novel perspectives

It has long been known that cortisol affects learning and memory processes. Despite a wealth of research dedicated to cortisol effects on learning and memory, the strength or even directionality of the effects often vary. A number of the factors that alter cortisols effects on learning and memory are well-known. For instance, effects of cortisol can be modulated by emotional arousal and the memory phase under study. Despite great advances in understanding factors that explain variability in cortisols effects, additional modulators of cortisol effects on memory exist that are less widely acknowledged in current basic experimental research. The goal of the current review is to disseminate knowledge regarding less well-known modulators of cortisol effects on learning and memory. Since several models for the etiology of anxiety, such as post-traumatic stress disorder (PTSD), incorporate stress and the concomitant release of cortisol as important vulnerability factors, enhanced understanding of mechanisms by which cortisol exerts beneficial as opposed to detrimental effects on memory is very important. Further elucidation of the factors that modulate (or alter) cortisols effects on memory will allow reconciliation of seemingly inconsistent findings in the basic and clinical literatures. The present review is based on a symposium as part of the 42nd International Society of Psychoneuroendocrinology Conference, New York, USA, that highlighted some of those modulators and their underlying mechanisms.

Cortisol mediates the effects of stress on the contextual dependency of memories

Stress is known to exert considerable impact on learning and memory processes. Typically, human studies have investigated memory for single items (e.g., pictures, words), but it remains unresolved how exactly stress may alter the storage of memories into their original encoding context (i.e., memory contextualization). Since neurocircuitry underlying memory contextualization processes is sensitive to the well-known stress hormone cortisol, we here investigated whether cortisol mediates stress effects on memory contextualization. Forty healthy young men were randomly assigned to a psychosocial stress or control group. Ten minutes after stress manipulation offset, participants were instructed to learn and remember neutral and negative words, each of which was depicted against a unique background picture. Approximately 24h later, memory was tested by means of cued retrieval and recognition tasks. To assess memory contextualization half of the words were tested in intact item-contexts pairs, and half in rearranged item-context combinations. Recognition data showed that cortisol, but no other indices of stress such as heart rate or subjective stress, mediated the effects of stress on contextualization of neutral and negative memories. The mediation analysis further showed that stress resulted in increases in cortisol and that cortisol was positively related to memory contextualization, but unrelated to other measures of memory. Thus, there seems to be a specific role for cortisol in the integration of a central memory into its surrounding context.

Delayed effects of cortisol enhance fear memory of trace conditioning

Corticosteroids induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It is presently unknown how these time-dependent effects of cortisol affect fear memory of delay and trace conditioning. This distinction is of special interest because the neural substrates underlying these types of conditioning may be differently affected by time-dependent cortisol effects. Delay conditioning is predominantly amygdala-dependent, while trace conditioning additionally requires the hippocampus. Here, we manipulated the timing of cortisol action during acquisition of delay and trace fear conditioning, by randomly assigning 63 men to one of three possible groups: (1) receiving 10mg hydrocortisone 240 min (slow cort) or (2) 60 min (rapid cort) before delay and trace acquisition, or (3) placebo at both times, in a double-blind design. The next day, we tested memory for trace and delay conditioning. Fear potentiated startle responses, skin conductance responses and unconditioned stimulus expectancy scores were measured throughout the experiment. The fear potentiated startle data show that cortisol intake 240 min before actual fear acquisition (slow cort) uniquely strengthened subsequent trace conditioned memory. No effects of cortisol delivery 60 min prior to fear acquisition were found on any measure of fear memory. Our findings emphasize that slow, presumably genomic, but not more rapid effects of corticosteroids enhance hippocampal-dependent fear memories. On a broader level, our findings underline that basic experimental research and clinically relevant pharmacological treatments employing corticosteroids should acknowledge the timing of corticosteroid administration relative to the learning phase, or therapeutic intervention.

Time-Dependent Effect of Hydrocortisone Administration on Intertemporal Choice

Intertemporal choices, involving decisions which trade o ff outcomes at different points in time, are often made under stress. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the release of corticosteroids. Recent studies provide evidence that corticosteroids can induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It remains unknown, however, how corticosteroids affect intertemporal choice. To target time-dependent effects of cortisol on intertemporal choice, we randomly assigned healthy men to one of three possible groups: 1) receiving 10 mg hydrocortisone 195 minutes (slow cort) or 2) 15 minutes (rapid cort), or 3) placebo at both times, before measuring intertemporal choice by offering subjects decisions between small rewards available sooner vs. large rewards available later, in a double-blind design. We demonstrate a time-dependent effect of cortisol administration on intertemporal choice: when tested 15 minutes after hydrocortisone administration, subjects showed a strongly increased preference for the small, soon reward over the larger, delayed reward. In contrast, this effect was not found when testing occurred 195 minutes after hydrocortisone administration. Together, these results suggest that the physiological effects of acute, but not delayed, stress may increase temporal discounting.

Visuospatial context learning and configuration learning is associated with analogue traumatic intrusions

BACKGROUND AND OBJECTIVES Cognitive and information processing theories of Post-Traumatic Stress Disorder (PTSD) assert that trauma intrusions are characterized by poor contextual embedding of visuospatial memories. Therefore, efficient encoding of visuospatial contextual information might protect against intrusions. We tested this idea using indices of visuospatial memory embedding along with the trauma film paradigm. METHODS Individual differences in spatial configuration learning, as well as the degree to which visual recognition memory depends on its visual encoding context (i.e., memory contextualization), were assessed in 81 healthy participants. Next, participants viewed a distressing film. Intrusions and other PTSD analogue symptoms were assessed subsequently. RESULTS Participants displaying stronger memory contextualization developed fewer intrusions and PTSD analogue symptoms. Spatial configuration learning was unrelated to memory contextualization and, contrary to prior findings, predicted higher levels of intrusions. LIMITATIONS Due to the analogue design, our findings may not translate directly to clinical populations. Furthermore, due to the correlational design of the study, causal relations remain to be tested. CONCLUSIONS Our results suggest a protective role for the ability to integrate memories in their original visual learning context against the development of PTSD symptoms.