Shaozheng Qin

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.

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.

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.

Enhanced resting-state connectivity of amygdala in the immediate aftermath of acute psychological stress.

Recent neuroimaging studies investigating responses to stressful stimuli may importantly further our understanding of psychological trauma etiology. However, theory posits that sustained activation of these stress circuits after the stressful event may play an equally important role in the development of stress-related psychopathology. Importantly, such post-stress network changes remain poorly characterized. The amygdala with its connections is crucially positioned in the central stress circuitry that mediates the initial stress response. Hence, we investigated post-stress amygdala-centered connectivity patterns in order to characterize the aftermath of acute, experimentally-induced stress in healthy humans. We recorded resting-state functional MRI in 26 female participants following a period of moderate psychological stress induced by means of aversive (vs. emotionally neutral) movie watching with a self-referencing instruction. Next, we implemented a seedregion analysis calculating the voxel-wise correlation with the anatomically extracted time-series of the amygdala. Various stress measures confirmed successful stress induction. Moreover, we demonstrated enhanced functional coupling of the amygdala with dorsal anterior cingulate cortex, anterior insula, and a dorso-rostral pontine region, which appears to overlap with the anatomical location of the locus coeruleus (LC), when contrasting the stress with the control group. Thus, we show that the aftermath of acute stress is qualified by prolonged activation in an amygdala-connectivity network. This pattern of co-activation may indicate an extended state of hypervigilance that promotes sustained salience and mnemonic processing after stress. Characterization of the post-stress brain state may provide initial insight into the early phases of psychological trauma formation.

Hippocampal-neocortical functional reorganization underlies children's cognitive development.

The importance of the hippocampal system for rapid learning and memory is well recognized, but its contributions to a cardinal feature of childrens cognitive development—the transition from procedure-based to memory-based problem-solving strategies—are unknown. Here we show that the hippocampal system is pivotal to this strategic transition. Longitudinal functional magnetic resonance imaging (fMRI) in 7–9-year-old children revealed that the transition from use of counting to memory-based retrieval parallels increased hippocampal and decreased prefrontal-parietal engagement during arithmetic problem solving. Longitudinal improvements in retrieval-strategy use were predicted by increased hippocampal-neocortical functional connectivity. Beyond childhood, retrieval-strategy use continued to improve through adolescence into adulthood and was associated with decreased activation but more stable interproblem representations in the hippocampus. Our findings provide insights into the dynamic role of the hippocampus in the maturation of memory-based problem solving and establish a critical link between hippocampal-neocortical reorganization and childrens cognitive development.

Amygdala Subregional Structure and Intrinsic Functional Connectivity Predicts Individual Differences in Anxiety During Early Childhood

BACKGROUND Early childhood anxiety has been linked to an increased risk for developing mood and anxiety disorders. Little, however, is known about its effect on the brain during a period in early childhood when anxiety-related traits begin to be reliably identifiable. Even less is known about the neurodevelopmental origins of individual differences in childhood anxiety. METHODS We combined structural and functional magnetic resonance imaging with neuropsychological assessments of anxiety based on daily life experiences to investigate the effects of anxiety on the brain in 76 young children. We then used machine learning algorithms with balanced cross-validation to examine brain-based predictors of individual differences in childhood anxiety. RESULTS Even in children as young as ages 7 to 9, high childhood anxiety is associated with enlarged amygdala volume and this enlargement is localized specifically to the basolateral amygdala. High childhood anxiety is also associated with increased connectivity between the amygdala and distributed brain systems involved in attention, emotion perception, and regulation, and these effects are most prominent in basolateral amygdala. Critically, machine learning algorithms revealed that levels of childhood anxiety could be reliably predicted by amygdala morphometry and intrinsic functional connectivity, with the left basolateral amygdala emerging as the strongest predictor. CONCLUSIONS Individual differences in anxiety can be reliably detected with high predictive value in amygdala-centric emotion circuits at a surprisingly young age. Our study provides important new insights into the neurodevelopmental origins of anxiety and has significant implications for the development of predictive biomarkers to identify children at risk for anxiety disorders.

Stress-induced reduction in reward-related prefrontal cortex function

Acute psychological stress can trigger normal and abnormal motivated behaviors such as reward seeking, habitual behavior, and drug craving. Animal research suggests that such effects may result from actions of catecholamines and glucocorticoids that converge in brain regions that regulate motivated behaviors and incentive processing. At present, however, little is known about the acute effects of stress on these circuits in humans. During functional magnetic resonance imaging (fMRI), twenty-seven healthy young women performed a modified version of the monetary incentive delay (MID) task, which is known to robustly engage ventral striatal and medial prefrontal regions. To induce psychological stress, strongly aversive movie clips (versus neutral movie clips) were shown with the instruction to imagine being an eyewitness. Physiological (cortisol levels, heart rate frequency, and heart rate variability) and subjective measurements confirmed successful induction of moderate levels of acute psychological stress. Brain imaging data revealed that stress induction resulted in a significant decrease in reward-related responses in the medial prefrontal cortex (PFC) without affecting ventral striatal responses. Our results thus show that acute psychological stress induces regionally specific changes in functioning of incentive processing circuits. This regional specificity is in line with animal data showing inverted U-shaped relations between levels of stress-related neuromodulators and functioning of the PFC, a structure that is believed to be critical for coordinating behavior in accordance with higher order internal goals. Our findings thus suggest that stress-related increases in habitual and reward-seeking behaviors may be triggered primarily by an impairment of such PFC-dependent cognitive control mechanisms.

Acute stress modulates genotype effects on amygdala processing in humans

Probing gene–environment interactions that affect neural processing is crucial for understanding individual differences in behavior and disease vulnerability. Here, we tested whether the current environmental context, which affects the acute brain state, modulates genotype effects on brain function in humans. We manipulated the context by inducing acute psychological stress, which increases noradrenergic activity, and probed its effect on tonic activity and phasic responses in the amygdala using two MRI techniques: conventional blood oxygen level–dependent functional MRI and arterial spin labeling. We showed that only carriers of a common functional deletion in ADRA2B, the gene coding for the α2b-adrenoreceptor, displayed increased phasic amygdala responses under stress. Tonic activity, reflecting the perfusion of the amygdala, increased independently of genotype after stress induction. Thus, when tonic activity was heightened by stress, only deletion carriers showed increased amygdala responses. Our results demonstrate that genetic effects on brain operations can be state dependent, such that they only become apparent under specific, often environmentally controlled, conditions.

Immature integration and segregation of emotion-related brain circuitry in young children

The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry.

Understanding Low Reliability of Memories for Neutral Information Encoded under Stress: Alterations in Memory-Related Activation in the Hippocampus and Midbrain

Exposure to an acute stressor can lead to unreliable remembrance of intrinsically neutral information, as exemplified by low reliability of eyewitness memories, which stands in contrast with enhanced memory for the stressful incident itself. Stress-sensitive neuromodulators (e.g., catecholamines) are believed to cause this low reliability by altering neurocognitive processes underlying memory formation. Using event-related functional magnetic resonance imaging, we investigated neural activity during memory formation in 44 young, healthy human participants while incidentally encoding emotionally neutral, complex scenes embedded in either a stressful or neutral context. We recorded event-related pupil dilation responses as an indirect index of phasic noradrenergic activity. Autonomic, endocrine, and psychological measures were acquired to validate stress manipulation. Acute stress during encoding led to a more liberal response bias (more hits and false alarms) when testing memory for the scenes 24 h later. The strength of this bias correlated negatively with pupil dilation responses and positively with stress-induced heart rate increases at encoding. Acute stress, moreover, reduced subsequent memory effects (SMEs; items later remembered vs forgotten) in hippocampus and midbrain, and in pupil dilation responses. The diminished SMEs indicate reduced selectivity and specificity in mnemonic processing during memory formation. This is in line with a model in which stress-induced catecholaminergic hyperactivation alters phasic neuromodulatory signaling in memory-related circuits, resulting in generalized (gist-based) processing at the cost of specificity. Thus, one may speculate that loss of specificity may yield less discrete memory representations at time of encoding, thereby causing a more liberal response bias when probing these memories.