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1.  Response to learned threat: an fMRI study in adolescent and adult anxiety 
The American journal of psychiatry  2013;170(10):1195-1204.
Poor threat-safety discrimination reflects prefrontal cortex dysfunction in adult anxiety disorders. While adolescent anxiety disorders are impairing and predict high risk for adult anxiety disorders, no prior study examines neural correlates of threat-safety discrimination in this group. The current study compares prefrontal cortex function in anxious and healthy adolescents and adults following conditioning and extinction, processes requiring threat-safety learning.
Anxious and healthy adolescents and adults (n=114) completed fear conditioning and extinction in the clinic. Conditioned stimuli (CS+) were neutral faces, paired with an aversive scream. Physiological and subjective data were acquired. Several weeks later, 82 participants viewed the CS+ and morphed images resembling the CS+ in a magnetic resonance imaging (MRI) scanner. During scanning, participants made difficult threat-safety discriminations while appraising threat and explicit memory of the CS+.
During conditioning and extinction, anxious groups reported more fear than healthy groups, but patient groups did not differ on physiology. During imaging, both anxious adolescents and adults exhibited lower sub-genual anterior cingulate (sgACC) activation than healthy peers, specifically when appraising threat. In ventromedial prefrontal cortex (vmPFC), relative to their age-matched peer groups, anxious adults exhibited reduced activation when appraising threat, whereas anxious adolescents exhibited a U-shaped pattern of activation, with greater activation to the most extreme CS and CS−.
Two regions of the prefrontal cortex are involved in anxiety disorders. Reduced sgACC engagement is a shared feature in adult and adolescent anxiety disorders, but vmPFC dysfunction is age-specific. The unique U-shaped pattern of vmPFC activation in many anxious adolescents could reflect heightened sensitivity to threat and safety conditions. How variations in the pattern relate to later risk for adult illness remains to be determined.
PMCID: PMC3790858  PMID: 23929092
2.  Enhanced discrimination between threatening and safe contexts in high-anxious individuals 
Biological psychology  2013;93(1):159-166.
Trait anxiety, a stable personality trait associated with increased fear responses to threat, is regarded as a risk factor for the development and maintenance of anxiety disorders. Although the effect of trait anxiety has been examined with regard to explicit threat cues, little is known about the effect of trait anxiety on contextual threat learning. To assess this issue, extreme groups of low and high trait anxiety underwent a contextual fear conditioning protocol using virtual reality. Two virtual office rooms served as the conditioned contexts. One virtual office room (CXT+) was paired with unpredictable electrical stimuli. In the other virtual office room, no electrical stimuli were delivered (CXT−). High-anxious participants tended to show faster acquisition of startle potentiation in the CXT+ versus the CXT− than low-anxious participants. This enhanced contextual fear learning might function as a risk factor for anxiety disorders that are characterized by sustained anxiety.
PMCID: PMC4166521  PMID: 23384512
Trait anxiety; Contextual fear conditioning; Startle reflex; Virtual reality
3.  The role of serotonin in the neurocircuitry of negative affective bias: serotonergic modulation of the dorsal medial prefrontal-amygdala ‘aversive amplification’ circuit 
NeuroImage  2013;78:217-223.
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.
PMCID: PMC3677215  PMID: 23583742
Serotonin; ATD; amygdala; dMPFC; negative bias; aversive amplification
4.  Sustained anxiety increases amygdala–dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults 
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.
Task-independent fMRI data were collected in healthy participants during long-duration periods of shock anticipation and safety. We examined intrinsic functional connectivity.
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.
Inferences regarding anxious pathology should be made with caution because this study was conducted in healthy participants.
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 bio-markers of risk for anxious pathology and target these circuits for therapeutic intervention.
PMCID: PMC4160361  PMID: 24886788
5.  Understanding Placebo and Nocebo Responses for Pain Management 
Placebo analgesia makes individuals experience relief of their pain simply by virtue of the anticipation of a benefit. A reduction of pain can occur also when placebos follow the administration of active and effective painkillers. In fact, studies indicate that placebos mimic the action of active treatments and promote the endogenous release of opioids in both humans and animals. Finally, social support and observational learning also lead to analgesic effects. Thus, different psychological factors and situations induce expectations of analgesia facilitating the activation of the top-down systems for pain control along with the release of endogenous mediators crucially involved in placebo-induced benefits. Recent scientific investigation in the field of brain imaging is opening new avenues to understanding the cognitive mechanisms and neurobiological substrates of expectation-induced pain modulation. Gaining deeper knowledge of top-down mechanisms of pain modulation has enormous implications for personalizing and optimizing pain management.
PMCID: PMC4142751  PMID: 24771206
Keywords Brain Imaging; Cannabinoids; Conditioning; Dopamine; Expectation; Genetics; Interpersonal interactions; Learning; Psychological traits; Opioids; Social observation; Oxytocin
6.  Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression 
Biological psychiatry  2012;72(7):555-561.
Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability and spontaneous gamma oscillations, but it is unknown whether these effects are key to ketamine's mechanism of antidepressant action.
Twenty drug-free MDD patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made ≈3 d before and ≈6.5 h after the infusion while patients passively received tactile stimulation to the right and left index fingers, and also while they rested (eyes-closed). Antidepressant response was assessed by percent change in Montgomery-Åsberg Depression Rating Scale scores.
Patients with robust improvements in depressive symptoms 230 m post-infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical (SS ctx) responses increase post-infusion relative to pretreatment responses in responders but not in treatment non-responders. Spontaneous SS ctx gamma-band activity during rest did not change within the same timeframe following ketamine in either responders or non-responders.
These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later, and, thus, may not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to ketamine's antidepressant effect.
PMCID: PMC3408548  PMID: 22521148
cortical excitability; gamma oscillation; ketamine; major depression; magnetoencephalography; NMDA antagonist
7.  Through the Eyes of Anxiety: Dissecting Threat Bias via Emotional-Binocular Rivalry 
Emotion (Washington, D.C.)  2012;12(5):960-969.
An extensive body of research has demonstrated that anxious individuals abnormally process threat-related content. Yet, the manner in which clinical anxiety affects the selection of threatening signals and their maintenance within consciousness is yet to be explored. The present study used an emotional binocular rivalry (e-BR) procedure, in which pictures of faces depicting either fearful or neutral expressions competed with pictures of a house for conscious perception. We assumed that first- or cumulative-preferred perception of faces with fearful over neutral expression (i.e., initial or sustained threat bias, respectively) stand for preferential selection or maintenance of fear content in awareness, correspondingly. Unmedicated patients with social anxiety disorder (SAD) and panic disorder (PAD) were compared to healthy controls for threat-related perceptual biases in the e-BR. At first perception of face, both SAD and PAD patients showed a greater initial threat bias than healthy controls. In contrast, at cumulative dwell-time of face, patient groups demonstrated a diminished sustained threat bias relative to healthy controls, yet in a different manner. SAD patients showed a sustained threat bias, though it was smaller than in healthy controls. Furthermore, increased levels of reported anxiety among SAD patients were associated with enhanced sustained perception of neutral faces. PAD patients, on the other hand, showed no sustained threat bias and a diminished cumulative perception of fearful faces with increased levels of anxiety traits. These findings indicate that anxiety disorders commonly involve an initially enhanced selection of threat signals into awareness, followed by disorder-specific manifestation of diminished preferred maintenance of threat in awareness.
PMCID: PMC3468657  PMID: 22390706
social anxiety disorder; panic disorder; threat bias; binocular rivalry; information processing
8.  Distinct contributions of human hippocampal theta to spatial cognition and anxiety 
Hippocampus  2012;22(9):1848-1859.
Current views of the hippocampus assign this structure, and its prominent theta rhythms, a key role in both cognition and affect. We studied this duality of function in humans, where no direct evidence exists. Whole-head magnetoencephalographic (MEG) data were recorded to measure theta activity while healthy participants (N = 25) navigated two virtual Morris water mazes, one in which they risked receiving aversive shocks without warning to induce anxiety and one in which they were safe from shocks. Results showed that threat of shock elevated anxiety level and enhanced navigation performance compared to the safe condition. MEG source analyses revealed that improved navigation performance during threat was preferentially associated with increased left septal (posterior) hippocampal theta (specifically 4–8 Hz activity), replicating previous research that emphasizes a predominant role of the septal third of the hippocampus in spatial cognition. Moreover, increased self-reported anxiety during threat was preferentially associated with increased left temporal (anterior) hippocampal theta (specifically 2–6 Hz activity), consistent with this region’s involvement in mediating conditioned and innate fear. Supporting contemporary theory, these findings highlight simultaneous involvement of the human hippocampus in spatial cognition and anxiety, and clarify their distinct correlates.
PMCID: PMC3390451  PMID: 22467298
anxiety; hippocampus; magnetoencephalography; spatial cognition; theta oscillation; virtual navigation
9.  Major Depression Is Not Associated with Blunting of Aversive Responses; Evidence for Enhanced Anxious Anticipation 
PLoS ONE  2013;8(8):e70969.
According to the emotion-context insensitivity (ECI) hypothesis, major depressive disorder (MDD) is associated with a diminished ability to react emotionally to positive stimuli and with blunting of defensive responses to threat. That defensive responses are blunted in MDD seems inconsistent with the conceptualization and diagnostic nosology of MDD. The present study tested the ECI hypothesis in MDD using a threat of shock paradigm. Twenty-eight patients with MDD (35.5±10.4 years) were compared with 28 controls (35.1±7.4 years). Participants were exposed to three conditions: no shock, predictable shock, and unpredictable shock. Startle magnitude was used to assess defensive responses. Inconsistent with the ECI hypothesis, startle potentiation to predictable and unpredictable shock was not reduced in the MDD group. Rather, MDD patients showed elevated startle throughout testing as well as increased contextual anxiety during the placement of the shock electrodes and in the predictable condition. A regression analysis indicated that illness duration and Beck depression inventory scores explained 37% (p<.005) of the variance in patients’ startle reactivity. MDD is not associated with emotional blunting but rather enhanced defensive reactivity during anticipation of harm. These results do not support a strong version of the ECI hypothesis. Understanding the nature of stimuli or situations that lead to blunted or enhanced defensive reactivity will provide better insight into dysfunctional emotional experience in MDD.
PMCID: PMC3738594  PMID: 23951057
10.  Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis? 
Neuropsychopharmacology  2012;37(8):1963-1971.
Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders.
PMCID: PMC3376328  PMID: 22491355
ATD; serotonin; anxiety; startle; depression; biological psychiatry; serotonin; mood/anxiety/stress disorders; psychiatry & behavioral sciences; ATD; anxiety; startle
11.  Describing the interplay between anxiety and cognition: From impaired performance under low cognitive load to reduced anxiety under high load 
Psychophysiology  2012;49(6):842-852.
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.
PMCID: PMC3345059  PMID: 22332819
Brain and cognition  2012;78(3):257-267.
Anxiety is typically considered an impediment to cognition. We propose anxiety-related impairments in cognitive-behavioral performance are the consequences of enhanced stimulus-driven attention. Accordingly, reflexive, habitual behaviors that rely on stimulus-driven mechanisms should be facilitated in an anxious state, while novel, flexible behaviors that compete with the former should be impaired. To test these predictions, healthy adults (N=17) performed a mixed-saccade task, which pits habitual actions (pro-saccades) against atypical ones (anti-saccades), under anxiety-inducing threat of shock and safe conditions. Whole-head magnetoencephalography (MEG) captured oscillatory responses in the preparatory interval preceding target onset and saccade execution. Results showed threat-induced anxiety differentially impacted response times based on the type of saccade initiated, slowing anti-saccades but facilitating erroneous pro-saccades on anti-saccade trials. MEG source analyses revealed that successful suppression of reflexive pro-saccades and correct initiation of anti-saccades during threat was marked by increased theta power in right ventrolateral prefrontal cortical and midbrain regions (superior colliculi) implicated in stimulus-driven attention. Theta activity may delay stimulus-driven processes to enable generation of an anti-saccade. Moreover, compared to safety, threat reduced beta desynchronization in inferior parietal cortices during anti-saccade preparation but increased it during pro-saccade preparation. Differential effects in inferior parietal cortices indicate a greater readiness to execute anti-saccades during safety and to execute pro-saccades during threat. These findings suggest that, in an anxiety state, reduced cognitive-behavioral flexibility may stem from enhanced stimulus-driven attention, which may serve the adaptive function of optimizing threat detection.
PMCID: PMC3448553  PMID: 22289426
anxiety; beta oscillation; magnetoencephalography; saccade; stimulus-driven attention; theta oscillation
13.  The adaptive threat bias in anxiety: amygdala- dorsomedial prefrontal cortex coupling and aversive amplification 
Neuroimage  2011;60(1):523-529.
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.
PMCID: PMC3288162  PMID: 22178453
amygdala; dMPFC; functional connectivity; prelimbic; anxiety; threat bias
14.  The impact of induced anxiety on response inhibition 
Anxiety has wide reaching effects on cognition; evidenced most prominently by the “difficulties concentrating” seen in anxiety disorders, and by adaptive harm-avoidant behaviors adopted under threatening circumstances. Despite having critical implications for daily-living, the precise impact of anxiety on cognition is as yet poorly quantified. Here we attempt to clarify the impact of anxiety on sustained attention and response inhibition via a translational anxiety induction in healthy individuals (N = 22). Specifically, in a within-subjects design, participants completed the Sustained Attention to Response Task (SART) in which subjects withhold responses to infrequent no-go stimuli under threat of unpredictable electrical shock (anxious) and safe (non-anxious) conditions. Different studies have argued that this task measures either (1) attention lapses due to off-task thinking or (2) response inhibition; two cognitive functions which are likely impacted by anxiety. We show that threat of shock significantly reduces errors of commission on the no-go trials relative to the safe condition whilst having no effect on go trials or overall reaction time (RT). We suggest that this is because threat of shock during SART promotes response inhibition. In particular we argue that, by virtue of frequency, subjects acquire a habitual bias toward a go response which impairs no-go performance and that threat of shock improves the ability to withhold these prepotent responses. This improved response inhibition likely falls within the range of adaptive cognitive functions which promote cautious harm avoidance under threatening conditions, although a range of alternative explanations for this effect is discussed.
PMCID: PMC3590569  PMID: 23471118
anxiety; threat; threat of shock; response inhibition; mind-wandering
15.  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.
PMCID: PMC3610083  PMID: 23542914
anxiety; working memory; cognition; startle; electromyography; performance
16.  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.
PMCID: PMC3656338  PMID: 23730279
anxiety; cognition; threat of shock; anxiety disorders; perception; attention; learning and memory; executive function
17.  In the face of fear: Anxiety sensitizes defensive responses to fearful faces 
Psychophysiology  2011;48(12):1745-1752.
Fearful faces readily activate the amygdala. Yet, whether fearful faces evoke fear is unclear. Startle studies show no potentiation of startle by fearful faces, suggesting that such stimuli do not activate defense mechanisms. However, the response to biologically relevant stimuli may be sensitized by anxiety. The present study tested the hypothesis that startle would not be potentiated by fearful faces in a safe context, but that startle would be larger during fearful faces compared to neutral faces in a threat-of-shock context. Subjects viewed fearful and neutral faces in alternating periods of safety and threat of shock. Acoustic startle stimuli were presented in the presence and absence of the faces. Startle was transiently potentiated by fearful faces compared to neutral faces in the threat periods. This suggests that although fearful faces do not prompt behavioral mobilization in an innocuous context, they can do so in an anxiogenic one.
PMCID: PMC3212615  PMID: 21824155
Fear; Anxiety; Startle reflex; Fearful face
18.  Grey matter volume correlates with virtual water maze task performance in boys with androgen excess 
Neuroscience  2011;197:225-232.
Major questions remain about the specific role of testosterone in human spatial navigation. We tested 10 boys (mean age 11.65 years) with an extremely rare disorder of androgen excess (Familial Male Precocious Puberty, FMPP) and 40 healthy boys (mean age 12.81 years) on a virtual version of the Morris Water Maze task. In addition, anatomical magnetic resonance images were collected for all patients and a subsample of the controls (n=21) after task completion. Behaviourally, no significant differences were found between both groups. However, in the MRI analyses, grey matter volume (GMV) was correlated with performance using voxel-based morphometry (VBM). Group differences in correlations of performance with GMV were apparent in medial regions of the prefrontal cortex as well as the middle occipital gyrus and the cuneus. By comparison, similar correlations for both groups were found in the inferior parietal lobule. These data provide novel insight into the relation between testosterone and brain development and suggest that morphological differences in a spatial navigation network covary with performance in spatial ability.
PMCID: PMC3210397  PMID: 21964472
testosterone; spatial navigation; development; familial male precocious puberty; VBM; virtual water maze
19.  Becoming the center of attention in social anxiety disorder: Startle reactivity to a virtual audience during speech anticipation 
A detailed understanding of how individuals diagnosed with social anxiety disorder (SAD) respond physiologically under social-evaluative threat is lacking. We aimed to isolate the specific components of public speaking that trigger fear in vulnerable individuals and best discriminate among SAD and healthy individuals.
Sixteen individuals diagnosed with SAD and 16 healthy individuals were asked to prepare and deliver a short speech in a virtual reality (VR) environment. The VR environment simulated standing center stage before a live audience and allowed us to gradually introduce social cues during speech anticipation. Startle eye-blink responses were elicited periodically by white noise bursts presented during anticipation, speech delivery, and recovery in VR, as well as outside VR during an initial habituation phase.
SAD individuals reported greater distress and state anxiety than healthy individuals across the entire procedure (ps < .005). Analyses of startle reactivity revealed a robust group difference during speech anticipation in VR, specifically as audience members directed their eye gaze and turned their attention toward participants (p < .05, Bonferroni corrected).
The VR environment is sufficiently realistic to provoke fear and anxiety in individuals highly vulnerable to socially threatening situations. SAD individuals showed potentiated startle, indicative of a strong phasic fear response, specifically when they perceived themselves as occupying the focus of others' attention as speech time approached. Potentiated startle under social-evaluative threat indexes SAD-related fear of negative evaluation.
PMCID: PMC3462648  PMID: 21034683
20.  Measuring anxious responses to predictable and unpredictable threat in children and adolescents 
Research has highlighted the need for new methods to assess emotions in children on multiple levels in order to gain better insight into the complex processes of emotional development. The startle reflex is a unique translational tool that has been utilized to study physiological processes during fear and anxiety in rodents and in human subjects. However, it has been challenging to implement developmentally-appropriate startle experiments in children. This paper describes a procedure that uses predictable and unpredictable aversive events to distinguish between phasic fear and sustained anxiety in children and adolescents. We investigated anxious responses, as measured with the startle reflex, in youth (N = 36, mean age[range] = 12.63 [7–17]) across three conditions: no aversive events (N), predictable aversive events (P), and unpredictable aversive events (U). Short-duration cues were presented several times in each condition. Aversive events were signaled by the cues in P, but were presented randomly in U. Participants showed fear-potentiated startle to the threat cue in P. Startle responses were also elevated between cues in U compared to N, suggesting that unpredictable aversive events can evoke a sustained state of anxiety in youth. This latter effect was influenced by sex, being greater in girls compared to boys. These findings indicate the feasibility of this experimental induction of the startle reflex in response to predictable and unpredictable events in children and adolescents, enabling future research on inter-individual differences in fear and anxiety and their development in youth.
PMCID: PMC3110515  PMID: 21440905
fear; anxiety; unpredictability; psychophysiology; startle reflex; sex differences
21.  Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans 
Preclinical evidence implicates several neurotransmitter systems in the extinction of conditioned fear. These results are of great interest, because the reduction of acquired fear associations is critical in therapies for anxiety disorders. We tested whether findings with respect to the N-methyl-D-aspartate (NMDA) and cannabinoid receptor (CB) systems in animals carry over to healthy human subjects. To that end, we administered selected doses of D-cycloserine (partial NMDA receptor agonist, 250 mg), delta-9-tetrahydrocannabinol (THC, CB1 receptor agonist, 10 mg), or placebo prior to the extinction session of a 3-day conditioning protocol. D-cycloserine did not affect within-session extinction, or the retention of extinction in healthy human participants, in contrast with patient data but in line with previous reports in healthy volunteers. During extinction training, Δ9-THC reduced conditioned skin conductance responses, but not fear-potentiated startle. This effect was not retained at the retention test 2 days later, suggesting it was dependent on acute effects of the drug. Our findings implicate that facilitation of the CB1 or NMDA system with the substances used in this study does not affect conditioned fear extinction lastingly in healthy humans. The apparent discrepancy between these findings and the results from (pre-) clinical trials is discussed in terms of room for improvement in these systems in healthy volunteers, and the lack of specificity of THC as a CB1 agonist.
PMCID: PMC3454470  PMID: 22351380
Δ9-THC; d-cycloserine; extinction; fear conditioning; fear-potentiated startle; human
22.  Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test) 
Nature protocols  2012;7(3):527-532.
The threat of predictable and unpredictable aversive events was developed to assess short-duration (fear) and long-duration (anxiety) aversive states in humans. A typical experiment consists of three conditions: a safe condition (neutral (N)), during which participants are safe from aversive stimuli, and two threat conditions—one in which aversive events are administered predictably (P) (i.e., signaled by a threat cue), and one in which aversive stimuli are administered unpredictably (U). During the so-called NPU -threat test, ongoing change in aversive states is measured with the startle reflex. The NPU -threat test has been validated in pharmacological and clinical studies and can be implemented in children and adults. Similar procedures have been applied in animal models, making the NPU -threat test an ideal tool for translational research. The procedure is relatively short (35 min), simple to implement and generates consistent results with large effect sizes.
PMCID: PMC3446242  PMID: 22362158
23.  Anxiety overrides the blocking effects of high perceptual load on amygdala reactivity to threat-related distractors 
Neuropsychologia  2011;49(5):1363-1368.
Amygdala reactivity to threat-related distractor stimuli can be abolished in perceptually-demanding contexts. Premised on the biological imperative to respond swiftly to threat, we demonstrate, however, that when participants are threatened by shock, greater amygdala responses to fearful compared to neutral distractor faces is preserved under conditions of high attentional demand. Lateral prefrontal cortices also showed selective responding to fearful distractor faces under these conditions, suggesting that threat-related distractor stimuli engaged attentional control mechanisms. We conclude that anxiety elicited by looming threat promotes neurocognitive processes that broaden attention and enhance sensitivity to potential danger cues, even when perceptual systems are taxed.
PMCID: PMC3085886  PMID: 21376745
amygdala; anxiety; attention; fearful faces; perceptual load; prefrontal cortices
24.  Development of anxiety: the role of threat appraisal and fear learning 
Depression and anxiety  2010;28(1):5-17.
Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat-related appraisal biases early, which may contribute to chronic disorders in adulthood. The current review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat-sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment.
PMCID: PMC2995000  PMID: 20734364
fear conditioning; generalization; attention; amygdala; ventromedial prefrontal cortex
25.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder 
Psychological medicine  2005;35(6):791-806.
In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).
Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.
Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
PMCID: PMC3233760  PMID: 15997600

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