Fear of the unknown: uncertain anticipation reveals amygdala alterations in childhood anxiety disorders.
ABSTRACT: Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an 'uncertain' cue elicited increased amygdala activation, as compared with the same faces following a 'certain' cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs.
Project description:The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.
Project description:Facial expression and eye gaze provide a shared signal about threats. While a fear expression with averted gaze clearly points to the source of threat, direct-gaze fear renders the source of threat ambiguous. Separable routes have been proposed to mediate these processes, with preferential attunement of the magnocellular (M) pathway to clear threat, and of the parvocellular (P) pathway to threat ambiguity. Here we investigated how observers' trait anxiety modulates M- and P-pathway processing of clear and ambiguous threat cues. We scanned subjects (N?=?108) widely ranging in trait anxiety while they viewed fearful or neutral faces with averted or directed gaze, with the luminance and color of face stimuli calibrated to selectively engage M- or P-pathways. Higher anxiety facilitated processing of clear threat projected to M-pathway, but impaired perception of ambiguous threat projected to P-pathway. Increased right amygdala reactivity was associated with higher anxiety for M-biased averted-gaze fear, while increased left amygdala reactivity was associated with higher anxiety for P-biased, direct-gaze fear. This lateralization was more pronounced with higher anxiety. Our findings suggest that trait anxiety differentially affects perception of clear (averted-gaze fear) and ambiguous (direct-gaze fear) facial threat cues via selective engagement of M and P pathways and lateralized amygdala reactivity.
Project description:Anxious individuals have a greater tendency to categorize faces with ambiguous emotional expressions as fearful (Richards et al., 2002). These behavioral findings might reflect anxiety-related biases in stimulus representation within the human amygdala. Here, we used functional magnetic resonance imaging (fMRI) together with a continuous adaptation design to investigate the representation of faces from three expression continua (surprise-fear, sadness-fear, and surprise-sadness) within the amygdala and other brain regions implicated in face processing. Fifty-four healthy adult participants completed a face expression categorization task. Nineteen of these participants also viewed the same expressions presented using type 1 index 1 sequences while fMRI data were acquired. Behavioral analyses revealed an anxiety-related categorization bias in the surprise-fear continuum alone. Here, elevated anxiety was associated with a more rapid transition from surprise to fear responses as a function of percentage fear in the face presented, leading to increased fear categorizations for faces with a mid-way blend of surprise and fear. fMRI analyses revealed that high trait anxious participants also showed greater representational similarity, as indexed by greater adaptation of the Blood Oxygenation Level Dependent (BOLD) signal, between 50/50 surprise/fear expression blends and faces from the fear end of the surprise-fear continuum in both the right amygdala and right fusiform face area (FFA). No equivalent biases were observed for the other expression continua. These findings suggest that anxiety-related biases in the processing of expressions intermediate between surprise and fear may be linked to differential representation of these stimuli in the amygdala and FFA. The absence of anxiety-related biases for the sad-fear continuum might reflect intermediate expressions from the surprise-fear continuum being most ambiguous in threat-relevance.
Project description:Recent studies point to a role of neuropeptide-S (NPS) in the etiology of anxiety disorders. In animal models, NPS and its receptor (NPSR) were shown to be highly expressed in the amygdala, a central structure in the fear circuit, also known to be hyper-responsive in anxiety disorders. Recently, a functional polymorphism in the NPSR gene (rs324981 A/T) has been associated with panic disorder and anxiety sensitivity. However, the role of NPSR gene variation in the modulation of fear-related amygdala responsiveness remains to be clarified. In 79 healthy subjects genotyped for NPSR rs324981, amygdala responses were assessed by means of fMRI. The participants were presented with fear-relevant faces in a robust emotion-processing paradigm frequently used to study amygdala responsiveness. We observed a strong association of NPSR T-alleles with right amygdala responsiveness to fear-relevant faces. The association peak was located in the BLA. Furthermore, responsiveness to aversive stimuli within this BLA cluster predicted a participant's self-reported harm avoidance but not depression level. We conclude that NPSR genotype is associated with increased amygdala responsiveness to fear-relevant stimuli. Thereby, NPSR rs324981 apparently causes an indirect effect on anxiety-related traits and potentially contributes to the pathogenesis of anxiety disorders by shaping fear-related limbic activity.
Project description:Individuals with high trait anxiety form a non-clinical group with a predisposition for an anxiety-related bias in emotional and cognitive processing that is considered by some to be a prerequisite for psychiatric disorders. Anxious individuals tend to experience more worry under uncertainty, and processing uncertain information is an important, but often overlooked factor in anxiety. So, we decided to explore the brain correlates of processing uncertain information in individuals with high trait anxiety using the learn-test paradigm. Behaviorally, the percentages on memory test and the likelihood ratios of identifying novel stimuli under uncertainty were similar to the certain fear condition, but different from the certain neutral condition. The brain results showed that the visual cortex, bilateral fusiform gyrus, and right parahippocampal gyrus were active during the processing of uncertain cues. Moreover, we found that trait anxiety was positively correlated with the BOLD signal of the right parahippocampal gyrus during the processing of uncertain cues. No significant results were found in the amygdala during uncertain cue processing. These results suggest that memory retrieval is associated with uncertain cue processing, which is underpinned by over-activation of the right parahippocampal gyrus, in individuals with high trait anxiety.
Project description:Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach-Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety.
Project description:Uncertainty contributes to stress and anxiety-like behaviors by impairing the ability of participants to objectively estimate threat. Our study used the cue-picture paradigm in conjunction with the event-related potential (ERP) technique to explore the temporal dynamics of anticipation for and response to uncertain threat in healthy individuals. This task used two types of cue. While 'certain' cues precisely forecasted the valence of the subsequent pictures (negative or neutral), the valence of pictures following 'uncertain' cues was not predictable. ERP data showed that, during anticipation, uncertain cues elicited similar Stimulus-Preceding Negativity (SPN) to certain-negative cues, while both of them elicited larger SPN than certain-neutral cues. During affective processing, uncertainty enlarged the mean amplitude of late positive potential (LPP) for both negative and neutral pictures. Behavioral data showed that participants reported more negative mood ratings of uncertain-neutral pictures relative to certain-neutral pictures and overestimated the probability of negative pictures following uncertain cues. Importantly, the enlarged anticipatory activity evoked by uncertain cues relative to that evoked by certain-neutral cues positively modulated the more negative mood ratings of uncertain-neutral pictures relative to certain-neutral pictures. Further, this more negative mood ratings and the general arousal anticipation during anticipatory stage contributed to the covariation bias. These results can provide a novel insight into understanding the neural mechanism and pathological basis of anxiety.
Project description:In the research field of anxiety, previous studies generally focus on emotional responses following threat. A recent model of anxiety proposes that altered anticipation prior to uncertain threat is related with the development of anxiety. Behavioral findings have built the relationship between anxiety and distinct anticipatory processes including attention, estimation of threat, and emotional responses. However, few studies have characterized the brain organization underlying anticipation of uncertain threat and its role in anxiety. In the present study, we used an emotional anticipation paradigm with functional magnetic resonance imaging (fMRI) to examine the aforementioned topics by employing brain activation and general psychophysiological interactions (gPPI) analysis. In the activation analysis, we found that high trait anxious individuals showed significantly increased activation in the thalamus, middle temporal gyrus (MTG), and dorsomedial prefrontal cortex (dmPFC), as well as decreased activation in the precuneus, during anticipation of uncertain threat compared to the certain condition. In the gPPI analysis, the key regions including the amygdala, dmPFC, and precuneus showed altered connections with distributed brain areas including the ventromedial prefrontal cortex (vmPFC), dorsolateral prefrontal cortex (dlPFC), inferior parietal sulcus (IPS), insula, para-hippocampus gyrus (PHA), thalamus, and MTG involved in anticipation of uncertain threat in anxious individuals. Taken together, our findings indicate that during the anticipation of uncertain threat, anxious individuals showed altered activations and functional connectivity in widely distributed brain areas, which may be critical for abnormal perception, estimation, and emotion reactions during the anticipation of uncertain threat.
Project description:Avoidant personality disorder is characterized by pervasive anxiety, fear of criticism, disapproval, and rejection, particularly in anticipation of exposure to social situations. An important but underexplored question concerns whether anxiety in avoidant patients is associated with an impaired ability to engage emotion regulatory strategies in anticipation of and during appraisal of negative social stimuli.We examined the use of an adaptive emotion regulation strategy, cognitive reappraisal, in avoidant patients. In addition to assessing individual differences in state and trait anxiety levels, self-reported affect as well as measures of neural activity were compared between 17 avoidant patients and 21 healthy control participants both in anticipation of and during performance of a reappraisal task.Avoidant patients showed greater state and trait-related anxiety relative to healthy participants. In addition, relative to healthy participants, avoidant patients showed pronounced amygdala hyper-reactivity during reappraisal anticipation, and this hyper-reactivity effect was positively associated with increasing self-reported anxiety levels.Our finding of exaggerated amygdala activity during reappraisal anticipation could reflect anxiety about the impending need to reappraise, anxiety about the certainty of an upcoming negative image, or anxiety relating to anticipated scrutiny of task responses by the experimenters. While we believe that all of these possibilities are consistent with the phenomenology of avoidant personality disorder, future research may clarify this ambiguity.These results suggest that amygdala reactivity in anticipation of receiving negative social information may represent a key component of the neural mechanisms underlying the heightened anxiety present in avoidant patients.
Project description:Social anxiety disorder (SAD) involves abnormalities in social motivation, which may be independent of well-documented differences in fear and arousal systems. Yet, the neurobiology underlying motivational difficulties in SAD is not well understood. The aim of the current study was to spatiotemporally dissociate reward circuitry dysfunction from alterations in fear and arousal-related neural activity during anticipation and notification of social and non-social reward and punishment. During fMRI acquisition, non-depressed adults with social anxiety disorder (SAD; N?=?21) and age-, sex- and IQ-matched control subjects (N?=?22) completed eight runs of an incentive delay task, alternating between social and monetary outcomes and interleaved in alternating order between gain and loss outcomes. Adults with SAD demonstrated significantly reduced neural activity in ventral striatum during the anticipation of positive but not negative social outcomes. No differences between the SAD and control groups were observed during anticipation of monetary gain or loss outcomes or during anticipation of negative social images. However, consistent with previous work, the SAD group demonstrated amygdala hyper-activity upon notification of negative social outcomes. Degraded anticipatory processing in bilateral ventral striatum in SAD was constrained exclusively to anticipation of positive social information and dissociable from the effects of negative social outcomes previously observed in the amygdala. Alterations in anticipation-related neural signals may represent a promising target for treatment that is not addressed by available evidence-based interventions, which focus primarily on fear extinction and habituation processes.