Brain activation during anticipatory anxiety in social anxiety disorder

Exaggerated anticipatory anxiety during expectation of performance-related situations is an important feature of the psychopathology of social anxiety disorder (SAD). The neural basis of anticipatory anxiety in SAD has not been investigated in controlled studies. The current study used functional magnetic resonance imaging (fMRI) to investigate the neural correlates during the anticipation of public and evaluated speaking vs a control condition in 17 SAD patients and 17 healthy control subjects. FMRI results show increased activation of the insula and decreased activation of the ventral striatum in SAD patients, compared to control subjects during anticipation of a speech vs the control condition. In addition, an activation of the amygdala in SAD patients during the first half of the anticipation phase in the speech condition was observed. Finally, the amount of anticipatory anxiety of SAD patients was negatively correlated to the activation of the ventral striatum. This suggests an association between incentive function, motivation and anticipatory anxiety when SAD patients expect a performance situation.     

Questioning the role of amygdala and insula in an attentional capture by emotional stimuli task

Our senses are constantly monitoring the environment for emotionally salient stimuli that are potentially relevant for survival. Because of our limited cognitive resources, emotionally salient distractors prolong reaction times (RTs) as compared to neutral distractors. In addition, many studies have reported fMRI blood oxygen level‐dependent (BOLD) activation of both the amygdala and the anterior insula for similar valence contrasts. However, a direct correlation of trail‐by‐trial BOLD activity with RTs has not been shown, yet, which would be a crucial piece of evidence to relate the two observations. To investigate the role of the above two regions in the context of emotional distractor effects, we study here the correlation between BOLD activity and RTs for a simple attentional capture by emotional stimuli (ACES) choice reaction time task using a general linear subject‐level model with a parametric RT regressor. We found significant regression coefficients in the anterior insula, supplementary motor cortex, medial precentral regions, sensory‐motor areas and others, but not in the amygdala, despite activation of both insula and amygdala in the traditional valence contrast across trials (i.e., negative vs. neutral pictures). In addition, we found that subjects that exhibit a stronger RT distractor effect across trials also show a stronger BOLD valence contrast in the right anterior insula but not in the amygdala. Our results indicate that the current neuroimaging‐based evidence for the involvement of the amygdala in RT slowing is limited. We advocate that models of emotional capture should incorporate both the amygdala and the anterior insula as separate entities.     

Phasic and sustained brain responses in the amygdala and the bed nucleus of the stria terminalis during threat anticipation

Several lines of evidence suggest that the amygdala and the bed nucleus of the stria terminalis (BNST) are differentially involved in phasic and sustained fear. Even though, results from neuroimaging studies support this distinction, a specific effect of a temporal dissociation with phasic responses to onset versus sustained responses during prolonged states of threat anticipation has not been shown yet. To explore this issue, we investigated brain activation during anticipation of threat in 38 healthy participants by means of functional magnetic resonance imaging. Participants were presented different visual cues indicated the temporally unpredictable occurrence of a subsequent aversive or neutral stimulus. During the onset of aversive versus neutral anticipatory cues, results showed a differential phasic activation of amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (PFC). In contrast, activation in the BNST and other brain regions, including insula, dorsolateral PFC, ACC, cuneus, posterior cingulate cortex, and periaqueductal grey was characterized by a sustained response during the threat versus neutral anticipation period. Analyses of functional connectivity showed phasic amygdala response as positively associated with activation, mainly in sensory cortex areas whereas sustained BNST activation was negatively associated with activation in visual cortex and positively correlated with activation in the insula and thalamus. These findings suggest that the amygdala is responsive to the onset of cues signaling the unpredictable occurrence of a potential threat while the BNST in concert with other areas is involved in sustained anxiety. Furthermore, the amygdala and BNST are characterized by distinctive connectivity patterns during threat anticipation. Hum Brain Mapp 37:1091–1102, 2016. © 2015 Wiley Periodicals, Inc .     

Medial orbitofrontal cortex codes relative rather than absolute value of financial rewards in humans

Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network.     

Postpartum depression and brain response to infants: Differential amygdala response and connectivity

Recent evidence suggests that postpartum depression is associated with reduced amygdala (AMY) response to negative stimuli. However, given the anhedonic features of PPD, it is important to consider mothers’ brain response specifically to positive infant and to other positive stimuli. Mothers with (n = 28) and without (n = 17) clinically determined PPD (n = 28) viewed smiling pictures of infants (Own and Other), and positive non-infant stimuli (Non-Infant). First, we examined group differences in AMY response across conditions. Next, psychophysiological interaction was used to examine group differences in AMY connectivity across conditions. Connectivity estimates were then correlated with measures of maternal mood and anxiety. PPD mothers, compared to non-PPD mothers, showed overall increased AMY response across conditions in the right AMY. Despite this, PPD mothers demonstrated decreased bilateral AMY–right insular cortex (IC) connectivity as compared to non-PPD mothers when they view Own–Other infants. Furthermore, decreasing AMY–IC connectivity was associated with increasing symptoms of depression and anxiety. These differences were evident only for infant stimuli and did not apply to all positively valenced stimuli. Thus, PPD mothers show altered brain response and connectivity in regions strongly implicated in the processing of socially and emotionally relevant stimuli, as well as interoception and the evaluation of subjective emotional experience.     

Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.     

Social status modulates the neural response to unfairness

In human society, which is organized by social hierarchies, resources are usually allocated unequally and based on social status. In this study, we analyze how being endowed with different social statuses in a math competition affects the perception of fairness during asset allocation in a subsequent Ultimatum Game (UG). Behavioral data showed that when participants were in high status, they were more likely to reject unfair UG offers than in low status. This effect of social status correlated with activity in the right anterior insula (rAI) and with the functional connectivity between the rAI and a region in the anterior middle cingulate cortex, indicating that these two brain regions are crucial for integrating contextual factors and social norms during fairness perception. Additionally, there was an interaction between social status and UG offer fairness in the amygdala and thalamus, implicating the role of these regions in the modulation of social status on fairness perception. These results demonstrate the effect of social status on fairness perception and the potential neural underpinnings for this effect.     

Causal Inference Gates Corticostriatal Learning

Attributing outcomes to your own actions or to external causes is essential for appropriately learning which actions lead to reward and which actions do not. Our previous work showed that this type of credit assignment is best explained by a Bayesian reinforcement learning model which posits that beliefs about the causal structure of the environment modulate reward prediction errors (RPEs) during action value updating. In this study, we investigated the brain networks underlying reinforcement learning that are influenced by causal beliefs using functional magnetic resonance imaging while human participants (n = 31; 13 males, 18 females) completed a behavioral task that manipulated beliefs about causal structure. We found evidence that RPEs modulated by causal beliefs are represented in dorsal striatum, while standard (unmodulated) RPEs are represented in ventral striatum. Further analyses revealed that beliefs about causal structure are represented in anterior insula and inferior frontal gyrus. Finally, structural equation modeling revealed effective connectivity from anterior insula to dorsal striatum. Together, these results are consistent with a possible neural architecture in which causal beliefs in anterior insula are integrated with prediction error signals in dorsal striatum to update action values.SIGNIFICANCE STATEMENT Learning which actions lead to reward—a process known as reinforcement learning—is essential for survival. Inferring the causes of observed outcomes—a process known as causal inference—is crucial for appropriately assigning credit to one''s own actions and restricting learning to effective action–outcome contingencies. Previous studies have linked reinforcement learning to the striatum, and causal inference to prefrontal regions, yet how these neural processes interact to guide adaptive behavior remains poorly understood. Here, we found evidence that causal beliefs represented in the prefrontal cortex modulate action value updating in posterior striatum, separately from the unmodulated action value update in ventral striatum posited by standard reinforcement learning models.     

Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI

Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output.     

Attentional modulation of reward processing in the human brain

Although neural signals of reward anticipation have been studied extensively, the functional relationship between reward and attention has remained unclear: Neural signals implicated in reward processing could either reflect attentional biases towards motivationally salient stimuli, or proceed independently of attentional processes. Here, we sought to disentangle reward and attention‐related neural processes by independently modulating reward value and attentional task demands in a functional magnetic resonance imaging study in healthy human participants. During presentation of a visual reward cue that indicated whether monetary reward could be obtained in a subsequent reaction time task, participants either attended to the reward cue or performed an unrelated attention‐demanding task at two different levels of difficulty. In ventral striatum and ventral tegmental area, neural responses were modulated by reward anticipation irrespective of attentional demands, thus indicating attention‐independent processing of reward cues. By contrast, additive effects of reward and attention were observed in visual cortex. Critically, reward‐related activations in right anterior insula strongly depended on attention to the reward cue. Dynamic causal modelling revealed that the attentional modulation of reward processing in insular cortex was mediated by enhanced effective connectivity from ventral striatum to anterior insula. Our results provide evidence for distinct functional roles of the brain regions involved in the processing of reward‐indicating information: While subcortical structures signal the motivational salience of reward cues even when attention is fully engaged elsewhere, reward‐related responses in anterior insula depend on available attentional resources, likely reflecting the conscious evaluation of sensory information with respect to motivational value. Hum Brain Mapp 35:3036–3051, 2014. © 2013 Wiley Periodicals, Inc.     

Fasting biases brain reward systems towards high-calorie foods

Nutritional state (e.g. fasted vs. fed) and different food stimuli (e.g. high-calorie vs. low-calorie, or appetizing vs. bland foods) are both recognized to change activity in brain reward systems. Using functional magnetic resonance imaging, we have studied the interaction between nutritional state and different food stimuli on brain food reward systems. We examined how blood oxygen level-dependent activity within a priori regions of interest varied while viewing pictures of high-calorie and low-calorie foods. Pictures of non-food household objects were included as control stimuli. During scanning, subjects rated the appeal of each picture. Twenty non-obese healthy adults [body mass index 22.1 ± 0.5 kg/m² (mean ± SEM), age range 19–35 years, 10 male] were scanned on two separate mornings between 11:00 and 12:00 h, once after eating a filling breakfast ('fed': 1.6 ± 0.1 h since breakfast), and once after an overnight fast but skipping breakfast ('fasted': 15.9 ± 0.3 h since supper) in a randomized cross-over design. Fasting selectively increased activation to pictures of high-calorie over low-calorie foods in the ventral striatum, amygdala, anterior insula, and medial and lateral orbitofrontal cortex (OFC). Furthermore, fasting enhanced the subjective appeal of high-calorie more than low-calorie foods, and the change in appeal bias towards high-calorie foods was positively correlated with medial and lateral OFC activation. These results demonstrate an interaction between homeostatic and hedonic aspects of feeding behaviour, with fasting biasing brain reward systems towards high-calorie foods.     

Observing cognitive processes in time through functional MRI model comparison

The temporal specificity of functional magnetic resonance imaging (fMRI) is limited by a sluggish and locally variable hemodynamic response trailing the neural activity by seconds. Here, we demonstrate for an attention capture paradigm that it is, never the less, possible to extract information about the relative timing of regional brain activity during cognitive processes on the scale of 100 ms by comparing alternative signal models representing early versus late activation. We demonstrate that model selection is not driven by confounding regional differences in hemodynamic delay. We show, including replication, that the activity in the dorsal anterior insula is an early signal predictive of behavioral performance, while amygdala and ventral anterior insula signals are not. This specific finding provides new insights into how the brain assigns salience to stimuli and emphasizes the role of the dorsal anterior insula in this context. The general analytic approach, named “Cognitive Timing through Model Comparison” (CTMC), offers an exciting and novel method to identify functional brain subunits and their causal interactions.     

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.     

Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference

It has long been theorised that there are two temporally distinctforms of self-reference: extended self-reference linking experiencesacross time, and momentary self-reference centred on the present.To characterise these two aspects of awareness, we used functionalmagnetic resonance imaging (fMRI) to examine monitoring of enduringtraits (’narrative’ focus, NF) or momentary experience(’experiential’ focus, EF) in both novice participantsand those having attended an 8 week course in mindfulness meditation,a program that trains individuals to develop focused attentionon the present. In novices, EF yielded focal reductions in self-referentialcortical midline regions (medial prefrontal cortex, mPFC) associatedwith NF. In trained participants, EF resulted in more markedand pervasive reductions in the mPFC, and increased engagementof a right lateralised network, comprising the lateral PFC andviscerosomatic areas such as the insula, secondary somatosensorycortex and inferior parietal lobule. Functional connectivityanalyses further demonstrated a strong coupling between theright insula and the mPFC in novices that was uncoupled in themindfulness group. These results suggest a fundamental neuraldissociation between two distinct forms of self-awareness thatare habitually integrated but can be dissociated through attentionaltraining: the self across time and in the present moment.     

Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain

The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.     

Frontolimbic responses to emotional face memory: The neural correlates of first impressions

First impressions, especially of emotional faces, may critically impact later evaluation of social interactions. Activity in limbic regions, including the amygdala and ventral striatum, has previously been shown to correlate with identification of emotional content in faces; however, little work has been done describing how these signals may influence emotional face memory. We report an event‐related functional magnetic resonance imaging study in 21 healthy adults where subjects attempted to recognize a neutral face that was previously viewed with a threatening (angry or fearful) or nonthreatening (happy or sad) affect. In a hypothesis‐driven region of interest analysis, we found that neutral faces previously presented with a threatening affect recruited the left amygdala. In contrast, faces previously presented with a nonthreatening affect activated the left ventral striatum. A whole‐brain analysis revealed increased response in the right orbitofrontal cortex to faces previously seen with threatening affect. These effects of prior emotion were independent of task performance, with differences being seen in the amygdala and ventral striatum even if only incorrect trials were considered. The results indicate that a network of frontolimbic regions may provide emotional bias signals during facial recognition. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Pervasive competition between threat and reward in the brain

In the current functional MRI study, we investigated interactions between reward and threat processing. Visual cues at the start of each trial informed participants about the chance of winning monetary reward and/or receiving a mild aversive shock. We tested two competing hypothesis: according to the ‘salience hypothesis’, in the condition involving both reward and threat, enhanced activation would be observed because of increased salience; according to the ‘competition hypothesis’, the processing of reward and threat would trade-off against each other, leading to reduced activation. Analysis of skin conductance data during a delay phase revealed an interaction between reward and threat processing, such that the effect of reward was reduced during threat and the effect of threat was reduced during reward. Analysis of imaging data during the same task phase revealed interactions between reward and threat processing in several regions, including the midbrain/ventral tegmental area, caudate, putamen, bed nucleus of the stria terminalis, anterior insula, middle frontal gyrus and dorsal anterior cingulate cortex. Taken together, our findings reveal conditions during which reward and threat trade-off against each other across multiple sites. Such interactions are suggestive of competitive processes and may reflect the organization of opponent systems in the brain.