Dynamic changes in large-scale functional network organization during autobiographical memory retrieval.

Autobiographical memory (AM), episodic memory for life events, involves the orchestration of multiple dynamic cognitive processes, including memory access and subsequent elaboration. Previous neuroimaging studies have contrasted memory access and elaboration processes in terms of regional brain activation and connectivity within large, multi-region networks. Although interactions between key memory-related regions such as the hippocampus and prefrontal cortex (PFC) have been shown to play an important role in AM retrieval, it remains unclear how such connectivity between specific, individual regions involved in AM retrieval changes dynamically across the retrieval process and how these changes relate to broader memory networks throughout the whole brain. The present functional magnetic resonance imaging (fMRI) study sought to assess the specific changes in interregional connectivity patterns across the AM retrieval processes to understand network level mechanisms of AM retrieval and further test current theoretical accounts of dynamic AM retrieval processes. We predicted that dynamic connections would reflect two hypothesized memory processes, with initial processes reflecting memory-access related connections between regions such as the anterior hippocampal and ventrolateral PFC regions, and later processes reflecting elaboration-related connections between dorsolateral frontal working memory regions and parietal-occipital visual imagery regions. One week prior to fMRI scanning, fifteen healthy adult participants generated AMs using personally selected cue words. During scanning, participants were cued to retrieve the AMs. We used a moving-window functional connectivity analysis and graph theoretic measures to examine dynamic changes in the strength and centrality of connectivity among regions involved in AM retrieval. Consistent with predictions, early, access-related processing primarily involved a ventral frontal to temporal-parietal network associated with strategic search and initial reactivation of specific episodic memory traces. In addition, neural network connectivity during later retrieval processes was associated with strong connections between occipital-parietal regions and dorsal fronto-parietal regions associated with mental imagery, reliving, and working memory processes. Taken together, these current findings help refine and extend dynamic neural processing models of AM retrieval by providing evidence of the specific connections throughout the brain that change in their synchrony with one another as processing progresses from access of specific event memories to elaborative reliving of the past event.

Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat.

BACKGROUND: Anxiety patients exhibit deficits in cognitive tasks that require prefrontal control of attention, including those that tap working memory (WM). However, it is unclear whether these deficits reflect threat-related processes or symptoms of the disorder. Here, we distinguish between these hypotheses by determining the effect of shock threat versus safety on the neural substrates of WM performance in anxiety patients and healthy controls. METHODS: Patients, diagnosed with generalized and/or social anxiety disorder, and controls performed blocks of an N-back WM task during periods of safety and threat of shock. We recorded blood-oxygen-level dependent (BOLD) activity during the task, and investigated the effect of clinical anxiety (patients vs. controls) and threat on WM load-related BOLD activation. RESULTS: Behaviorally, patients showed an overall impairment in both accuracy and reaction time compared to controls, independent of threat. At the neural level, patients showed less WM load-related activation in the dorsolateral prefrontal cortex, a region critical for cognitive control. In addition, patients showed less WM load-related deactivation in the ventromedial prefrontal cortex and posterior cingulate cortex, which are regions of the default mode network. Most importantly, these effects were not modulated by threat. CONCLUSIONS: This work suggests that the cognitive deficits seen in anxiety patients may represent a key component of clinical anxiety, rather than a consequence of threat.

Induced-anxiety differentially disrupts working memory in generalized anxiety disorder.

BACKGROUND: Anxiety is characterized by a bias towards threatening information, anxious apprehension, and disrupted concentration. Previous research in healthy subjects suggests that working memory (WM) is disrupted by induced anxiety, but that increased task-demand reduces anxiety and WM is preserved. However, it is unknown if patients with generalized anxiety disorder (GAD) can similarly normalize their performance on difficult WM tasks while reducing their anxiety. Increased threat-related bias and impoverished top-down control in trait anxiety suggests that patients may not reap the same cognitive and emotional benefits from demanding tasks that those low in anxiety. Here we examine this possibility using a WM task of varying difficulty. METHODS: GAD patients (N = 30) and healthy controls (N = 30) performed an n-back task (no-load, 1-back, 2-back, and 3-back) while at risk for shock (threat) or safe from shock (safe). Anxiety was measured via startle reflex and self-report. RESULTS: As predicted, healthy controls' performance was impaired under threat during low-load tasks and facilitated during high-load tasks. In contrast, GAD patients' performance was impaired under threat regardless of WM load. Anxiety was reduced as cognitive load increased in both groups. CONCLUSIONS: The divergence of emotion regulation (reduction) and performance (persistent impairment) in the patient but not the control group, suggests that different top-down mechanisms may be operating to reduce anxiety. Continued WM disruption in patients indicates that attentional resources are allocated to emotion regulation instead of goal-directed behavior. Implications for our understanding of cognitive disruption in patients, and related therapeutic interventions are discussed.

Interaction of threat and verbal working memory in adolescents.

Threat induces a state of sustained anxiety that can disrupt cognitive processing, and, reciprocally, cognitive processing can modulate an anxiety response to threat. These effects depend on the level of cognitive engagement, which itself varies as a function of task difficulty. In adults, we recently showed that induced anxiety impaired working memory accuracy at low and medium but not high load. Conversely, increasing the task load reduced the physiological correlates of anxiety (anxiety-potentiated startle). The present work examines such threat-cognition interactions as a function of age. We expected threat to more strongly impact working memory in younger individuals by virtue of putatively restricted cognitive resources and weaker emotion regulation. This was tested by examining the influence of age on the interaction of anxiety and working memory in 25 adolescents (10 to 17 years) and 25 adults (22 to 46 years). Working memory load was manipulated using a verbal n-back task. Anxiety was induced using the threat of an aversive loud scream and measured via eyeblink startle. Findings revealed that, in both age groups, accuracy was lower during threat than safe conditions at low and medium but not high load, and reaction times were faster during threat than safe conditions at high load but did not differ at other loads. Additionally, anxiety-potentiated startle was greater during low and medium than high load. Thus, the interactions of anxiety with working memory appear similar in adolescents and adults. Whether these similarities reflect common neural mechanisms would need to be assessed using functional neuroimaging.

Sustained anxiety increases amygdala-dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults.

BACKGROUND: Neuroimaging research has traditionally explored fear and anxiety in response to discrete threat cues (e.g., during fear conditioning). However, anxiety is a sustained aversive state that can persist in the absence of discrete threats. Little is known about mechanisms that maintain anxiety states over a prolonged period. Here, we used a robust translational paradigm (threat of shock) to induce sustained anxiety. Recent translational work has implicated an amygdala-prefrontal cortex (PFC) circuit in the maintenance of anxiety in rodents. To explore the functional homologues of this circuitry in humans, we used a novel paradigm to examine the impact of sustained anticipatory anxiety on amygdala-PFC intrinsic connectivity. METHODS: Task-independent fMRI data were collected in healthy participants during long-duration periods of shock anticipation and safety. We examined intrinsic functional connectivity. RESULTS: Our study involved 20 healthy participants. During sustained anxiety, amygdala activity was positively coupled with dorsomedial PFC (DMPFC) activity. High trait anxiety was associated with increased amygdala-DMPFC coupling. In addition, induced anxiety was associated with positive coupling between regions involved in defensive responding, and decreased coupling between regions involved in emotional control and the default mode network. LIMITATIONS: Inferences regarding anxious pathology should be made with caution because this study was conducted in healthy participants. CONCLUSION: Findings suggest that anticipatory anxiety increases intrinsic amygdala-DMPFC coupling and that the DMPFC may serve as a functional homologue for the rodent prefrontal regions by sustaining anxiety. Future research may use this defensive neural context to identify biomarkers of risk for anxious pathology and target these circuits for therapeutic intervention.

Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal-amygdala 'aversive amplification' circuit in unmedicated generalized and social anxiety disorders.

BACKGROUND: We have delineated, across four prior studies, the role of positive dorsal medial prefrontal/anterior cingulate cortex (dmPFC/ACC)-amygdala circuit coupling during aversive processing in healthy individuals under stress. This translational circuit, termed the 'aversive amplification circuit', is thought to drive adaptive, harm-avoidant behavior in threatening environments. Here, in a natural progression of this prior work, we confirm that this circuit also plays a role in the pathological manifestation of anxiety disorders. METHODS: Forty-five unmedicated participants (N=22 generalized and social anxiety disorder/N=23 controls) recruited from Washington DC metropolitan area completed a simple emotion identification task during functional magnetic resonance imaging at the National Institutes of Health, Bethesda, MD, USA. FINDINGS: As predicted, a diagnosis by valence interaction was seen in whole-brain amygdala connectivity within the dmPFC/ACC clusters identified in our prior study; driven by significantly greater circuit coupling during fearful versus happy face processing in anxious, but not healthy, participants. Critically, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, providing evidence of a continuous circuit-subjective symptomatology relationship. INTERPRETATION: We track the functional role of a single neural circuit from its involvement in adaptive threat-biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety related circuit across its adaptive and maladaptive stages. Clinically, this may provide a step towards a more mechanistic spectrum-based approach to anxiety disorder diagnosis and may ultimately lead to more targeted treatments.

The impact of anxiety upon cognition: perspectives from human threat of shock studies.

Anxiety disorders constitute a sizeable worldwide health burden with profound social and economic consequences. The symptoms are wide-ranging; from hyperarousal to difficulties with concentrating. This latter effect falls under the broad category of altered cognitive performance which is the focus of this review. Specifically, we examine the interaction between anxiety and cognition focusing on the translational threat of unpredictable shock paradigm; a method previously used to characterize emotional responses and defensive mechanisms that is now emerging as valuable tool for examining the interaction between anxiety and cognition. In particular, we compare the impact of threat of shock on cognition in humans to that of pathological anxiety disorders. We highlight that both threat of shock and anxiety disorders promote mechanisms associated with harm avoidance across multiple levels of cognition (from perception to attention to learning and executive function)-a "hot" cognitive function which can be both adaptive and maladaptive depending upon the circumstances. This mechanism comes at a cost to other functions such as working memory, but leaves some functions, such as planning, unperturbed. We also highlight a number of cognitive effects that differ across anxiety disorders and threat of shock. These discrepant effects are largely seen in "cold" cognitive functions involving control mechanisms and may reveal boundaries between adaptive (e.g., response to threat) and maladaptive (e.g., pathological) anxiety. We conclude by raising a number of unresolved questions regarding the role of anxiety in cognition that may provide fruitful avenues for future research.

The complex interaction between anxiety and cognition: insight from spatial and verbal working memory.

Anxiety can be distracting, disruptive, and incapacitating. Despite problems with empirical replication of this phenomenon, one fruitful avenue of study has emerged from working memory (WM) experiments where a translational method of anxiety induction (risk of shock) has been shown to disrupt spatial and verbal WM performance. Performance declines when resources (e.g., spatial attention, executive function) devoted to goal-directed behaviors are consumed by anxiety. Importantly, it has been shown that anxiety-related impairments in verbal WM depend on task difficulty, suggesting that cognitive load may be an important consideration in the interaction between anxiety and cognition. Here we use both spatial and verbal WM paradigms to probe the effect of cognitive load on anxiety-induced WM impairment across task modality. Subjects performed a series of spatial and verbal n-back tasks of increasing difficulty (1, 2, and 3-back) while they were safe or at risk for shock. Startle reflex was used to probe anxiety. Results demonstrate that induced-anxiety differentially impacts verbal and spatial WM, such that low and medium-load verbal WM is more susceptible to anxiety-related disruption relative to high-load, and spatial WM is disrupted regardless of task difficulty. Anxiety impacts both verbal and spatial processes, as described by correlations between anxiety and performance impairment, albeit the effect on spatial WM is consistent across load. Demanding WM tasks may exert top-down control over higher-order cortical resources engaged by anxious apprehension, however high-load spatial WM may continue to experience additional competition from anxiety-related changes in spatial attention, resulting in impaired performance. By describing this disruption across task modalities, these findings inform current theories of emotion-cognition interactions and may facilitate development of clinical interventions that seek to target cognitive impairments associated with anxiety.

The role of serotonin in the neurocircuitry of negative affective bias: serotonergic modulation of the dorsal medial prefrontal-amygdala 'aversive amplification' circuit.

Serotonergic medications can mitigate the negative affective biases in disorders such as depression or anxiety, but the neural mechanism by which this occurs is largely unknown. In line with recent advances demonstrating that negative affective biases may be driven by specific medial prefrontal-amygdala circuitry, we asked whether serotonin manipulation can alter affective processing within a key dorsal medial prefrontal-amygdala circuit: the putative human homologue of the rodent prelimbic-amygdala circuit or 'aversive amplification' circuit. In a double-blind, placebo-controlled crossover pharmaco-fMRI design, subjects (N=19) performed a forced-choice face identification task with word distractors in an fMRI scanner over two separate sessions. On one session subjects received dietary depletion of the serotonin precursor tryptophan while on the other session they received a balanced placebo control diet. Results showed that dorsal medial prefrontal responding was elevated in response to fearful relative to happy faces under depletion but not placebo. This negative bias under depletion was accompanied by a corresponding increase in positive dorsal medial prefrontal-amygdala functional connectivity. We therefore conclude that serotonin depletion engages a prefrontal-amygdala circuit during the processing of fearful relative to happy face stimuli. This same 'aversive amplification' circuit is also engaged during anxiety induced by shock anticipation. As such, serotonergic projections may inhibit engagement of the 'aversive amplification' circuit and dysfunction in this projection may contribute to the negative affective bias in mood and anxiety disorders. These findings thus provide a promising explanation for the role of serotonin and serotonergic medications in the neurocircuitry of negative affective bias.

Stress increases aversive prediction error signal in the ventral striatum.

From job interviews to the heat of battle, it is evident that people think and learn differently when stressed. In fact, learning under stress may have long-term consequences; stress facilitates aversive conditioning and associations learned during extreme stress may result in debilitating emotional responses in posttraumatic stress disorder. The mechanisms underpinning such stress-related associations, however, are unknown. Computational neuroscience has successfully characterized several mechanisms critical for associative learning under normative conditions. One such mechanism, the detection of a mismatch between expected and observed outcomes within the ventral striatum (i.e., "prediction errors"), is thought to be a critical precursor to the formation of new stimulus-outcome associations. An untested possibility, therefore, is that stress may affect learning via modulation of this mechanism. Here we combine a translational model of stress with a cognitive neuroimaging paradigm to demonstrate that stress significantly increases ventral striatum aversive (but not appetitive) prediction error signal. This provides a unique account of the propensity to form threat-related associations under stress with direct implications for our understanding of both normal stress and stress-related disorders.

Describing the interplay between anxiety and cognition: from impaired performance under low cognitive load to reduced anxiety under high load.

Anxiety impairs the ability to think and concentrate, suggesting that the interaction between emotion and cognition may elucidate the debilitating nature of pathological anxiety. Using a verbal n-back task that parametrically modulated cognitive load, we explored the effect of experimentally induced anxiety on task performance and the startle reflex. Findings suggest there is a crucial inflection point between moderate and high cognitive load, where resources shift from anxious apprehension to focus on task demands. Specifically, we demonstrate that anxiety impairs performance under low load, but is reduced when subjects engage in a difficult task that occupies executive resources. We propose a two-component model of anxiety that describes a cognitive mechanism behind performance impairment and an automatic response that supports sustained anxiety-potentiated startle. Implications for therapeutic interventions and emotional pathology are discussed.

The adaptive threat bias in anxiety: amygdala-dorsomedial prefrontal cortex coupling and aversive amplification.

Functionally, anxiety serves to increase vigilance towards aversive stimuli and improve the ability to detect and avoid danger. We have recently shown, for instance, that anxiety increases the ability to a) detect and b) instigate defensive responses towards aversive and not appetitive face stimuli in healthy individuals. This is arguably the key adaptive function of anxiety, yet the neural circuitry underlying this valence-specific effect is unknown. In the present translational study, we sought evidence for the proposition that dorsomedial regions of the prefrontal (DMPFC) and cingulate cortex constitute the human homologue of the rodent prelimbic and are thus associated with increased amygdala responding during this adaptive threat bias in anxiety. To this end, we applied a novel functional connectivity analysis to healthy subjects (N=20) identifying the emotion of fearful and happy faces in an fMRI scanner under anxious (threat of unpredictable foot shock) and non-anxious (safe) conditions. We showed that anxiety significantly increased positive DMPFC-amygdala connectivity during the processing of fearful faces. This effect was a) valence-specific (it was not seen for happy faces), b) paralleled by faster behavioral response to fearful faces, and c) correlated positively with trait anxiety. As such we provide the first experimental support for an anxiety-mediated, valence-specific, DMPFC-amygdala aversive amplification mechanism in healthy humans. This may be homologous to the rodent prelimbic-amygdala circuit and may, given the relationship with trait anxiety, underlie vulnerability to anxiety disorders. This study thus pinpoints a key neural mechanism in adaptive anxiety and highlights its potential link to maladaptive anxiety.

Neuroimaging support for discrete neural correlates of basic emotions: a voxel-based meta-analysis.

What is the basic structure of emotional experience and how is it represented in the human brain? One highly influential theory, discrete basic emotions, proposes a limited set of basic emotions such as happiness and fear, which are characterized by unique physiological and neural profiles. Although many studies using diverse methods have linked particular brain structures with specific basic emotions, evidence from individual neuroimaging studies and from neuroimaging meta-analyses has been inconclusive regarding whether basic emotions are associated with both consistent and discriminable regional brain activations. We revisited this question, using activation likelihood estimation (ALE), which allows spatially sensitive, voxelwise statistical comparison of results from multiple studies. In addition, we examined substantially more studies than previous meta-analyses. The ALE meta-analysis yielded results consistent with basic emotion theory. Each of the emotions examined (fear, anger, disgust, sadness, and happiness) was characterized by consistent neural correlates across studies, as defined by reliable correlations with regional brain activations. In addition, the activation patterns associated with each emotion were discrete (discriminable from the other emotions in pairwise contrasts) and overlapped substantially with structure-function correspondences identified using other approaches, providing converging evidence that discrete basic emotions have consistent and discriminable neural correlates. Complementing prior studies that have demonstrated neural correlates for the affective dimensions of arousal and valence, the current meta-analysis results indicate that the key elements of basic emotion views are reflected in neural correlates identified by neuroimaging studies.