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1.  Alcohol affects the emotional modulation of cognitive control: an event-related brain potential study 
Psychopharmacology  2012;222(3):459-476.
Objective
The present study aimed to determine whether alcohol affects the emotional modulation of cognitive control and its underlying neural mechanisms, which is pivotal to an understanding of the socially maladaptive behaviors frequently seen in alcohol-intoxicated individuals.
Method
Event-related potentials (ERPs) were recorded in male participants receiving either a moderate dose of alcohol (0.65 g/kg alcohol; n = 32) or a non-alcoholic placebo beverage (n = 32) while performing an emotional Go/No-Go task that required response execution (Go trials) to pictures of a “target” emotional facial expression (angry, happy, neutral) and response inhibition (No-Go trials) to a different “non-target” expression.
Results
Overall, N200 and P300 amplitudes were more enhanced during No-Go than Go trials. Interestingly, alcohol-intoxicated individuals displayed larger No-Go N200 amplitudes across all emotional conditions than controls, accompanied by decreased task performance (i.e., more errors), particularly in response to angry faces. P300 amplitude in the alcohol group was significantly reduced for both Go and No-Go trials, but only following angry and happy emotional expressions.
Conclusions
These results suggest that alcohol-intoxicated individuals need to effortfully activate more cognitive resources during the early inhibition process in order to regulate a response than controls. Moreover, alcohol affected the emotional modulation of both response inhibition and execution in the later stages of cognitive control. Alcohol dampened emotional responsiveness, which may restrict the availability of attentional resources for cognitive control. Yet, these findings may underlie the lack of control in alcohol-intoxicated individuals when faced with emotionally or socially challenging situations.
doi:10.1007/s00213-012-2664-6
PMCID: PMC3395350  PMID: 22371302
Alcohol; Emotion; Cognitive control; Event-related potentials (ERPs); N200; P300; Go/No-Go
2.  Anterior cingulate cortex and insula response during indirect and direct processing of emotional faces in generalized social anxiety disorder 
Background
Generalized social anxiety disorder (gSAD) is associated with a heightened neural sensitivity to signals that convey threat, as evidenced by exaggerated amygdala and/or insula activation when processing face stimuli that express negative emotions. Less clear in the brain pathophysiology of gSAD are cortical top down control mechanisms that moderate reactivity in these subcortical emotion processing regions. This study evaluated amygdala, insula, and anterior cingulate cortex (ACC) activity in gSAD with a novel “Emotional Faces Shifting Attention Task” (EFSAT), an adaptation of perceptual assessment tasks well-known to elicit amygdala response. In healthy volunteers, the task has been shown to engage the amygdala when attention is directed to emotional faces and the ACC when attention is directed to shapes, away from emotional faces.
Methods
During functional MRI, 29 participants with gSAD and 27 healthy controls viewed images comprising a trio of faces (angry, fear, or happy) alongside a trio of geometric shapes (circles, rectangles, or triangles) within the same field of view. Participants were instructed to match faces or match shapes, effectively directing attention towards or away from emotional information, respectively.
Results
Participants with gSAD exhibited greater insula, but not amygdala, activation compared to controls when attending to emotional faces. In contrast, when attention was directed away from faces, controls exhibited ACC recruitment, which was not evident in gSAD. Across participants, greater ACC activation was associated with less insula activation.
Conclusions
Evidence that individuals with gSAD exhibited exaggerated insula reactivity when attending to emotional faces in EFSAT is consistent with other studies suggesting that the neural basis of gSAD may involve insula hyper-reactivity. Furthermore, greater ACC response in controls than gSAD when sustained goal-directed attention is required to shift attention away from social signals, together with a negative relationship between ACC and bilateral insula activity, indicate the ACC may have served a regulatory role when the focus of attention was directed to shapes amidst emotional faces.
doi:10.1186/2045-5380-3-7
PMCID: PMC3632493  PMID: 23547713
Social anxiety; fMRI; Emotional faces; Threat processing; Brain imaging
3.  Pregabalin effects on neural response to emotional faces 
Pregabalin has shown promise in the treatment of anxiety disorders. Previous functional magnetic resonance imaging (fMRI) studies indicate agents used to treat anxiety, e.g., SSRIs and benzodiazepines, attenuate amygdala, insula, and medial prefrontal cortex (mPFC) activation during emotional processing. Our prior study has shown that during anticipation of an emotional stimulus, pregabalin attenuates amygdala and insula activation but increases medial PFC activation. In this study, we examined whether, similar to SSRIs and benzodiazepines, pregabalin attenuates amygdala, insula, and medial PFC during emotional face processing. Sixteen healthy volunteers underwent a double-blind within-subjects fMRI study investigating effects of placebo, 50 mg, and 200 mg pregabalin on neural activation during an emotional face-matching task. Linear mixed model analysis revealed that pregabalin dose-dependently attenuated left amygdala activation during fearful face-matching and left anterior insula activation during angry face-matching. The 50 mg dose exhibited more robust effects than the 200 mg dose in the right anterior insula and ventral ACC. Thus, pregabalin shares some similarity to SSRIs and benzodiazepines in attenuating anger and fear-related insula and amygdala activation during emotional face processing. However, there is evidence that a subclinical 50 mg dose of pregabalin produced more robust and widespread effects on neural responses in this paradigm than the more clinically relevant 200 mg dose. Taken together, pregabalin has a slightly different effect on brain activation as it relates to anticipation and emotional face processing, which may account for its unique characteristic as an agent for the treatment of anxiety disorders.
doi:10.3389/fnhum.2012.00042
PMCID: PMC3313548  PMID: 22470326
anxiety; anxiolytic; benzodiazepine; emotion; fMRI; pharmaco-imaging; pregabalin
4.  Positive Facial Affect – An fMRI Study on the Involvement of Insula and Amygdala 
PLoS ONE  2013;8(8):e69886.
Imitation of facial expressions engages the putative human mirror neuron system as well as the insula and the amygdala as part of the limbic system. The specific function of the latter two regions during emotional actions is still under debate. The current study investigated brain responses during imitation of positive in comparison to non-emotional facial expressions. Differences in brain activation of the amygdala and insula were additionally examined during observation and execution of facial expressions. Participants imitated, executed and observed happy and non-emotional facial expressions, as well as neutral faces. During imitation, higher right hemispheric activation emerged in the happy compared to the non-emotional condition in the right anterior insula and the right amygdala, in addition to the pre-supplementary motor area, middle temporal gyrus and the inferior frontal gyrus. Region-of-interest analyses revealed that the right insula was more strongly recruited by (i) imitation and execution than by observation of facial expressions, that (ii) the insula was significantly stronger activated by happy than by non-emotional facial expressions during observation and imitation and that (iii) the activation differences in the right amygdala between happy and non-emotional facial expressions were increased during imitation and execution, in comparison to sole observation. We suggest that the insula and the amygdala contribute specifically to the happy emotional connotation of the facial expressions depending on the task. The pattern of the insula activity might reflect increased bodily awareness during active execution compared to passive observation and during visual processing of the happy compared to non-emotional facial expressions. The activation specific for the happy facial expression of the amygdala during motor tasks, but not in the observation condition, might reflect increased autonomic activity or feedback from facial muscles to the amygdala.
doi:10.1371/journal.pone.0069886
PMCID: PMC3749202  PMID: 23990890
5.  High versus Low Level of Response to Alcohol: Evidence of Differential Reactivity to Emotional Stimuli 
Biological psychiatry  2012;72(10):848-855.
Background
The low level of response (LR) or sensitivity to alcohol is genetically influenced and predicts heavy drinking and alcohol problems. Functional magnetic resonance imaging (fMRI) studies using cognitive tasks suggest that subjects with a low LR process cognitive information differently after placebo and alcohol than those with a high LR, but no studies have evaluated if similar LR group differences are seen during an emotional processing task.
Methods
fMRI data were gathered from 116 non-alcoholic subjects (60 women) following oral placebo or ~0.7 ml/kg of ethanol while performing a modified emotional faces processing task. These included 58 low- and high-LR pairs matched on demography and aspects of substance use.
Results
Blood alcohol levels and task performance were similar across LR groups, but low LR subjects consumed ~ 0.8 drinks more per occasion. Thirteen brain regions (mostly the middle and inferior frontal gyri, cingulate, and insula) showed significant LR group or LR by placebo/alcohol condition interactions for emotional (mostly happy) faces relative to non-face trials. Low LR subjects generally showed decreasing BOLD response contrasts across placebo to alcohol, while high LR showed increasing contrasts from placebo to alcohol, even after controlling for drinking quantities and alcohol-related changes in cerebral blood flow.
Conclusions
Thus, LR group fMRI differences are as prominent during an emotional face task as during cognitive paradigms. Low LR individuals processed both types of information in a manner that might contribute to an impaired ability to recognize modest levels of alcohol intoxication in a range of life situations.
doi:10.1016/j.biopsych.2012.04.016
PMCID: PMC3433640  PMID: 22608014
fMRI; alcohol sensitivity; emotional stimuli; fear; Hariri; alcoholism
6.  Modulation of Emotional Appraisal by False Physiological Feedback during fMRI 
PLoS ONE  2007;2(6):e546.
Background
James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined.
Methodology/Principal Findings
We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level.
Conclusions/Significance
Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order “cognitive” representations of bodily arousal state.
doi:10.1371/journal.pone.0000546
PMCID: PMC1890305  PMID: 17579718
7.  Differential Brain Activation to Angry Faces by Elite Warfighters: Neural Processing Evidence for Enhanced Threat Detection 
PLoS ONE  2010;5(4):e10096.
Background
Little is known about the neural basis of elite performers and their optimal performance in extreme environments. The purpose of this study was to examine brain processing differences between elite warfighters and comparison subjects in brain structures that are important for emotion processing and interoception.
Methodology/Principal Findings
Navy Sea, Air, and Land Forces (SEALs) while off duty (n = 11) were compared with n = 23 healthy male volunteers while performing a simple emotion face-processing task during functional magnetic resonance imaging. Irrespective of the target emotion, elite warfighters relative to comparison subjects showed relatively greater right-sided insula, but attenuated left-sided insula, activation. Navy SEALs showed selectively greater activation to angry target faces relative to fearful or happy target faces bilaterally in the insula. This was not accounted for by contrasting positive versus negative emotions. Finally, these individuals also showed slower response latencies to fearful and happy target faces than did comparison subjects.
Conclusions/Significance
These findings support the hypothesis that elite warfighters deploy greater processing resources toward potential threat-related facial expressions and reduced processing resources to non-threat-related facial expressions. Moreover, rather than expending more effort in general, elite warfighters show more focused neural and performance tuning. In other words, greater neural processing resources are directed toward threat stimuli and processing resources are conserved when facing a nonthreat stimulus situation.
doi:10.1371/journal.pone.0010096
PMCID: PMC2854680  PMID: 20418943
8.  The alexithymic brain: the neural pathways linking alexithymia to physical disorders 
Alexithymia is a personality trait characterized by difficulties in identifying and describing feelings and is associated with psychiatric and psychosomatic disorders. The mechanisms underlying the link between emotional dysregulation and psychosomatic disorders are unclear. Recent progress in neuroimaging has provided important information regarding emotional experience in alexithymia. We have conducted three brain imaging studies on alexithymia, which we describe herein. This article considers the role of emotion in the development of physical symptoms and discusses a possible pathway that we have identified in our neuroimaging studies linking alexithymia with psychosomatic disorders. In terms of socio-affective processing, alexithymics demonstrate lower reactivity in brain regions associated with emotion. Many studies have reported reduced activation in limbic areas (e.g., cingulate cortex, anterior insula, amygdala) and the prefrontal cortex when alexithymics attempt to feel other people’s feelings or retrieve their own emotional episodes, compared to nonalexithymics. With respect to primitive emotional reactions such as the response to pain, alexithymics show amplified activity in areas considered to be involved in physical sensation. In addition to greater hormonal arousal responses in alexithymics during visceral pain, increased activity has been reported in the insula, anterior cingulate cortex, and midbrain. Moreover, in complex social situations, alexithymics may not be able to use feelings to guide their behavior appropriately. The Iowa gambling task (IGT) was developed to assess decision-making processes based on emotion-guided evaluation. When alexithymics perform the IGT, they fail to learn an advantageous decision-making strategy and show reduced activity in the medial prefrontal cortex, a key area for successful performance of the IGT, and increased activity in the caudate, a region associated with impulsive choice. The neural machinery in alexithymia is therefore activated more on the physiologic, motor-expressive level and less in the cognitive-experiential domains of the emotional response system. Affects may play an important role in alleviating intrinsic physiologic reactions and adapting to the environment. Deficient development of emotional neural structures may lead to hypersensitivity to bodily sensations and unhealthy behaviors, a possible mechanism linking alexithymia to psychosomatic disorders.
doi:10.1186/1751-0759-7-1
PMCID: PMC3563604  PMID: 23302233
Affect; Alexithymia; Emotional dysregulation; Neuroimaging; Psychosomatic disorders
9.  Effects of acute alcohol intoxication on saccadic conflict and error processing 
Psychopharmacology  2013;230(3):10.1007/s00213-013-3173-y.
Rationale
Flexible behavior optimization relies on cognitive control which includes the ability to suppress automatic responses interfering with relevant goals. Extensive evidence suggests that the anterior cingulate cortex (ACC) is the central node in a predominantly frontal cortical network subserving executive tasks. Neuroimaging studies indicate that the ACC is sensitive to acute intoxication during conflict, but such evidence is limited to tasks using manual responses with arbitrary response contingencies.
Objectives
The present study was designed to examine whether alcohol's effects on top–down cognitive control would generalize to the oculomotor system during inhibition of hardwired saccadic responses.
Methods
Healthy social drinkers (N=22) underwent functional magnetic resonance imaging (fMRI) scanning and eye movement tracking during alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. They performed visually guided prosaccades (PS) towards a target and volitional antisaccades (AS) away from it. To mitigate possible vasoactive effects of alcohol on the BOLD (blood oxygenation level-dependent) signal, resting perfusion was quantified with arterial spin labeling (ASL) and used as a covariate in the BOLD analysis.
Results
Saccadic conflict was subserved by a distributed frontoparietal network. However, alcohol intoxication selectively attenuated activity only in the ACC to volitional AS and erroneous responses.
Conclusions
This study provides converging evidence for the selective ACC vulnerability to alcohol intoxication during conflict across different response modalities and executive tasks, confirming its supramodal, high-level role in cognitive control. Alcohol intoxication may impair top–down regulative functions by attenuating the ACC activity, resulting in behavioral disinhibition and decreased self-control.
doi:10.1007/s00213-013-3173-y
PMCID: PMC3869380  PMID: 23812762
Anterior cingulate cortex; Cognitive control; Antisaccades; Alcohol intoxication; Error-related activity; Arterial spin labeling (ASL)
10.  Acute Alcohol Intoxication Impairs Top-down Regulation of Stroop Incongruity as Revealed by BOLD fMRI 
Human brain mapping  2011;33(2):319-333.
Functional neuroanatomy of executive functions has been delineated in a large number of neuroimaging studies using conflict-inducing tasks. The neural basis of alcohol’s effects on cognitive control is poorly understood despite the evidence of impaired ability to evaluate competing demands and to inhibit maladaptive responses. In order to investigate effects of moderate intoxication, healthy social drinkers participated in both alcohol (0.60 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions while being scanned using blood oxygen level dependent (BOLD) fMRI. A modified 4-color Stroop task combined reading and color naming and used manual responses. Twenty subjects (10 women) were instructed to press a button corresponding to the font color except when a word was written in gray in which case they had to respond to the meaning of the word. Alcohol increased reaction times and a tendency to make more errors on incongruent trials. Behavioral indices of alcohol-induced premature responding correlated with the current drinking levels and impulsivity traits, suggesting an interaction between alcohol effects and personality predispositions. A distributed fronto-parietal cortical network was activated by incongruity. However, moderate alcohol inebriation selectively attenuated anterior cingulate cortex (ACC) activation during both high-conflict trials and erroneous responses, indicating vulnerability of the regulative function subserved by the ACC. By disrupting top-down, strategic processing, alcohol may interfere with goal-directed behavior, resulting in poor self control. The present results support models proposing that alcohol-induced prefrontal impairments diminish inhibitory control and are modulated by dispositional risk factors and levels of alcohol consumption.
doi:10.1002/hbm.21213
PMCID: PMC3754428  PMID: 21391268
cognitive control; anterior cingulate; error-related activity
11.  Subjective and Neural Responses to Intravenous Alcohol in Young Adults with Light and Heavy Drinking Patterns 
Neuropsychopharmacology  2011;37(2):467-477.
Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals' vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. We performed a double-blind, placebo-controlled, randomized crossover alcohol challenge study comparing functional magnetic resonance imaging and subjective response to intravenously administered 6% v/v ethanol to a target blood alcohol concentration of 0.08% or placebo between HDs and social drinkers (SDs). During the imaging, we presented emotional cues in order to measure how emotion modulated the effects of alcohol on the brain's reward circuitry. We found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain's reward system. Our findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol's effects.
doi:10.1038/npp.2011.206
PMCID: PMC3242308  PMID: 21956438
alcohol; fMRI; reward; tolerance; alcoholism; nucleus accumbens; alcohol & alcoholism; neuropharmacology; imaging; clinical or preclinical; biological psychiatry; reward; emotion; FMRI; tolerance
12.  Anterior insular cortex mediates bodily sensibility and social anxiety 
Studies in psychiatry and cognitive neuroscience have reported an important relationship between individual interoceptive accuracy and anxiety level. This indicates that greater attention to one’s bodily state may contribute to the development of intense negative emotions and anxiety disorders. We hypothesized that reactivity in the anterior insular cortex underlies the intensity of interoceptive awareness and anxiety. To elucidate this triadic mechanism, we conducted functional magnetic resonance imaging (fMRI) and mediation analyses to examine the relationship between emotional disposition and activation in the anterior insular cortex while participants evaluated their own emotional and bodily states. Our results indicated that right anterior insular activation was positively correlated with individual levels of social anxiety and neuroticism and negatively correlated with agreeableness and extraversion. The results of the mediation analyses revealed that activity in the right anterior insula mediated the activity of neural correlates of interoceptive sensibility and social fear. Our findings suggest that attention to interoceptive sensation affects personality traits through how we feel emotion subjectively in various situations.
doi:10.1093/scan/nss108
PMCID: PMC3594729  PMID: 22977199
interoception; anxiety; neuroticism; body; emotion
13.  Effects of alcohol on verbal processing: An ERP study 
Background
Behavioral studies suggest that alcohol intoxication impairs speed and accuracy of word recognition and categorization, but alcohol’s effects on the brain during verbal cognitive processing have not been adequately understood. Using event-related potentials (ERP) and a word recognition paradigm, this study investigated the effects of alcohol intoxication on prelexical, semantic, and mnemonic aspects of verbal processing.
Methods
Concurrent measures of ERPs and skin conductance responses (SCRs) were obtained in a word repetition priming task and permitted a comparison of the effects of alcohol on the central and autonomic physiological systems. Social drinkers participated in all four cells of the within-subjects balanced placebo design in which effects of alcohol and instructions as to the beverage content (expectancy) were manipulated. The average peak blood alcohol level was raised to 0.045%.
Results
None of the manipulations affected behavioral performance and expectancy had no effect on any of the measures. In contrast, alcohol ingestion attenuated the temporo-parietal N180 suggesting an impairment in prelexical pattern recognition processes. Alcohol significantly increased the amplitude of N450 and the latency of P580, particularly on trials evoking sympathetic arousal as measured with SCRs.
Conclusions
Although behavioral measures were unaffected, ERPs showed that a moderately low alcohol dose affected verbal processing during both early, prelexical and late, semantic stages. Alcohol significantly increased the difficulty of semantic access and integration as reflected in larger N450 amplitude and longer P580 latency. This effect was particularly prominent on arousal-related trials, suggesting that alcohol impairs processes that modulate cognitive functioning. The lack of an interaction between the factors of repetition and beverage suggests that a moderately low alcohol dose exerts these effects via the semantic and integration systems rather than via memory processes.
PMCID: PMC3746793  PMID: 15084899
Alcohol; Verbal processing; Event-related potentials; N400; Electrodermal activity
14.  Escitalopram effects on insula and amygdala BOLD activation during emotional processing 
Psychopharmacology  2007;196(4):661-672.
Rationale
The amygdala and insular cortex are integral to the processing of emotionally salient stimuli. We have shown in healthy volunteers that an anxiolytic agent, lorazepam, dose-dependently attenuates activation of limbic structures.
Objective
The current study investigated whether administration of a selective serotonin reuptake inhibitor (SSRI), escitalopram, alters the activation of limbic structures. We hypothesized that subchronic (21 days) SSRI treatment attenuates the activation of the amygdala and insula during processing of emotional faces.
Methods
Thirteen healthy volunteers participated in a double-blind, placebo-controlled, cross-over, randomized study. After 21 days of treatment with either escitalopram or placebo, participants underwent functional magnetic resonance imaging (fMRI) during which all subjects completed an emotion face assessment task, which has been shown to elicit amygdala and insula activation.
Results
Subjects activated the bilateral insula and amygdala following treatment with both escitalopram and placebo. In subjects who were adherent to the protocol (as evidenced by sufficiently high urine concentrations of escitalopram), a reduction in amygdala activation was seen in the escitalopram condition compared to placebo.
Conclusion
The current investigation provides further evidence for the mechanism of action of SSRIs through the attenuation of activation in brain regions responsible for emotion processing and provides support for the use of BOLD-fMRI with pharmacological probes to help identify the specific therapeutic effect of these agents in patients with anxiety and mood disorders.
doi:10.1007/s00213-007-1004-8
PMCID: PMC2839135  PMID: 18058090
SSRI; escitalopram; insula; amygdala; fMRI; emotion processing
15.  Mindfulness meditation training alters cortical representations of interoceptive attention 
One component of mindfulness training (MT) is the development of interoceptive attention (IA) to visceral bodily sensations, facilitated through daily practices such as breath monitoring. Using functional magnetic resonance imaging (fMRI), we examined experience-dependent functional plasticity in accessing interoceptive representations by comparing graduates of a Mindfulness-Based Stress Reduction course to a waitlisted control group. IA to respiratory sensations was contrasted against two visual tasks, controlling for attentional requirements non-specific to IA such as maintaining sensation and suppressing distraction. In anatomically partitioned analyses of insula activity, MT predicted greater IA-related activity in anterior dysgranular insula regions, consistent with greater integration of interoceptive sensation with external context. MT also predicted decreased recruitment of the dorsomedial prefrontal cortex (DMPFC) during IA, and altered functional connectivity between the DMPFC and the posterior insula, putative primary interoceptive cortex. Furthermore, meditation practice compliance predicted greater posterior insula and reduced visual pathway recruitment during IA. These findings suggest that interoceptive training modulates task-specific cortical recruitment, analogous to training-related plasticity observed in the external senses. Further, DMPFC modulation of IA networks may be an important mechanism by which MT alters information processing in the brain, increasing the contribution of interoception to perceptual experience.
doi:10.1093/scan/nss066
PMCID: PMC3541492  PMID: 22689216
interoception; fMRI; mindfulness; attention; insula; plasticity
16.  Early neural activation during facial affect processing in adolescents with Autism Spectrum Disorder☆ 
NeuroImage : Clinical  2014;7:203-212.
Impaired social interaction is one of the hallmarks of Autism Spectrum Disorder (ASD). Emotional faces are arguably the most critical visual social stimuli and the ability to perceive, recognize, and interpret emotions is central to social interaction and communication, and subsequently healthy social development. However, our understanding of the neural and cognitive mechanisms underlying emotional face processing in adolescents with ASD is limited. We recruited 48 adolescents, 24 with high functioning ASD and 24 typically developing controls. Participants completed an implicit emotional face processing task in the MEG. We examined spatiotemporal differences in neural activation between the groups during implicit angry and happy face processing. While there were no differences in response latencies between groups across emotions, adolescents with ASD had lower accuracy on the implicit emotional face processing task when the trials included angry faces. MEG data showed atypical neural activity in adolescents with ASD during angry and happy face processing, which included atypical activity in the insula, anterior and posterior cingulate and temporal and orbitofrontal regions. Our findings demonstrate differences in neural activity during happy and angry face processing between adolescents with and without ASD. These differences in activation in social cognitive regions may index the difficulties in face processing and in comprehension of social reward and punishment in the ASD group. Thus, our results suggest that atypical neural activation contributes to impaired affect processing, and thus social cognition, in adolescents with ASD.
Highlights
•The ability to recognize and interpret emotions is central to social interaction.•Deficits in social interactions are hallmarks of autism spectrum disorder (ASD).•Adolescents with and without ASD completed an emotional face task in MEG.•MEG data showed atypical neural activity in ASD to both angry and happy faces.•Insula, cingulate, temporal and orbitofrontal activities were particularly affected in the ASD group.
doi:10.1016/j.nicl.2014.11.009
PMCID: PMC4300004  PMID: 25610782
Implicit face processing; Adolescents; Autism Spectrum Disorder; Magnetoencephalography; Affect processing; Anterior cingulate cortex
17.  Sex Differences in Neural Responses to Stress and Alcohol Context Cues 
Human brain mapping  2010;32(11):1998-2013.
Stress and alcohol context cues are each associated with alcohol-related behaviors, yet neural responses underlying these processes remain unclear. The present study investigated the neural correlates of stress and alcohol context cue experiences and examined sex differences in these responses. Using functional magnetic resonance imaging, brain responses were examined while 43 right-handed, socially drinking, healthy individuals (23 females) engaged in brief guided imagery of personalized stress, alcohol-cue and neutral-relaxing scenarios. Stress and alcohol-cue exposure increased activity in the cortico-limbic-striatal circuit (p<.01, corrected), encompassing the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), left anterior insula, striatum and visuomotor regions (parietal and occipital lobe, and cerebellum). Activity in the right dorsal striatum increased during stress, while bilateral ventral striatum activity was evident during alcohol-cue exposure. Men displayed greater stress-related activations in the mPFC, rostral ACC, posterior insula, amygdala and hippocampus than women, whereas women showed greater alcohol-cue related activity in the superior and middle frontal gyrus (SFG/MFG) than men. Stress-induced anxiety was positively associated with activity in emotion modulation regions, including the medial OFC, ventromedial PFC, left superior-medial PFC and rostral ACC in men, but in women with activation in the SFG/MFG, regions involved in cognitive processing. Alcohol craving was significantly associated with the striatum (encompassing dorsal and ventral) in men, supporting its involvement in alcohol ‘urge’ in healthy men. These results indicate sex differences in neural processing of stress and alcohol-cue experiences, and have implications for sex-specific vulnerabilities to stress- and alcohol-related psychiatric disorders.
doi:10.1002/hbm.21165
PMCID: PMC3236497  PMID: 21162046
Sex differences; Stress; Alcohol cue; Reward; Brain fMRI; Prefrontal Cortex
18.  Subchronic SSRI administration attenuates insula response during affective anticipation 
Context
The anterior cingulate cortex (ACC) and insula are important neural substrates for the integration of cognitive, emotional, and physiological information, as well as the coordination of responses to anticipated stimuli. Increased neural activation within these structures has been observed in individuals with anxiety and depressive disorders. Selective serotonin reuptake inhibitors (SSRIs) are among the most effective and frequently prescribed anxiolytic agents, yet it is not known whether ACC or insula underlie the effects of these drugs. We examined whether subchronic administration of an SSRI to healthy volunteers attenuate activation in ACC or insula during anticipation, an important emotional process underlying anxiety. Support for this hypothesis would help to understand where and by what process SSRIs may exert beneficial effects as anxiolytics and would provide further mechanistic evidence for functional magnetic resonance imaging (fMRI) as a biomarker for the development of anxiolytics.
Participants and Design
15 volunteers participated in a double-blind, placebo-controlled, randomized cross-over study. Participants completed a pleasant and aversive picture cued anticipation task during fMRI after taking either escitalopram (10 mg) or placebo for 21 days.
Main Outcome Measure
Percent BOLD signal change during SSRI administration.
Results
Escitalopram significantly decreased activation in bilateral posterior and middle insula during the anticipation condition irrespective of stimulus valence and in medial prefrontal and ACC during anticipation of aversive versus pleasant images.
Conclusion
Reduced insular and ACC activation during anticipation may be integral to the therapeutic efficacy of SSRIs and provide a mechanistic approach for the use of pharmacofMRI in the identification of novel pharmacotherapeutic agents.
doi:10.1017/S1461145709990149
PMCID: PMC2846821  PMID: 19545475
SSRI; escitalopram; insula; fMRI; anticipation
19.  Alcohol Attenuates Amygdala-Frontal Connectivity During Processing Social Signals in Heavy Social Drinkers: A Preliminary Pharmaco-fMRI Study 
Psychopharmacology  2013;229(1):141-154.
Rationale
Convergent evidence shows that alcohol exerts its effects on social behavior via modulation of amygdala reactivity to affective stimuli. Given that affective processing involves dynamic interactions between the amygdala and the prefrontal cortex (PFC), alcohol's effects are likely to extend beyond regional changes in brain activity to changes that manifest on a broader functional circuit level.
Objective
The current study examines alcohol's effects on functional connectivity (i.e., ‘coupling’) between the amygdala and the PFC during the processing of socio-emotional stimuli using functional magnetic resonance imaging (fMRI).
Methods
In a randomized, double blind, placebo-controlled, within-subjects cross-over design, twelve heavy, social drinkers performed an fMRI task designed to probe amygdala response to socio-emotional stimuli (angry, fearful, and happy faces) following acute ingestion of alcohol or placebo. Functional connectivity between the amygdala and PFC was examined and compared between alcohol and placebo sessions using a conventional generalized psychophysiological interaction (gPPI) analysis.
Results
Relative to placebo, alcohol reduced functional coupling between the amygdala and the right orbitofrontal cortex (OFC) during processing of both angry and fearful faces. Alcohol also reduced functional coupling between the amygdala and left OFC during processing of happy faces.
Conclusions
These preliminary findings suggest that alcohol's effects on social behavior may be mediated by alternations in functional connectivity between the amygdala and OFC during processing of emotional faces.
doi:10.1007/s00213-013-3090-0
PMCID: PMC3740023  PMID: 23584670
alcohol; amygdala; functional connectivity; social threat
20.  Emotional and autonomic consequences of spinal cord injury explored using functional brain imaging 
Brain : a journal of neurology  2005;129(Pt 3):718-728.
In health, emotions are integrated with autonomic bodily responses. Emotional stimuli elicit changes in somatic (including autonomic) bodily states, which feedback to influence the expression of emotional feelings. In patients with spinal cord injury (SCI), this integration of emotion and bodily arousal is partially disrupted, impairing both efferent generation of sympathetic responses and afferent sensory feedback of visceral state via the spinal cord. A number of theoretical accounts of emotion predict emotional deficits in SCI patients, particularly at the level of emotional feelings, yet evidence for such a deficit is equivocal. We used functional MRI (fMRI) and a basic emotional learning paradigm to investigate the expression of emotion-related brain activity consequent upon SC I. We scanned seven SCI patients and seven healthy controls during an aversive fear conditioning task. Subjects viewed randomized presentations of four angry faces. One of the faces (CS + arm) was associated with delivery of electrical shock to the upper arm on 50% of trials. This shock was painful to all subjects. A face of the same gender acted as a ‘safe’ control stimulus (CS − arm). In both control subjects and SCI patients, painful cutaneous stimulation of the arm evoked enhanced activity within components of a central pain matrix, including dorsal anterior cingulate, right insula and medial temporal lobe. However, SCI patients differed from controls in conditioning-related brain activity. SCI patients showed a relative enhancement of activity within dorsal anterior cingulate, periaqueductal grey matter (PAG) and superior temporal gyrus. Conversely, SCI patients showed relative attenuation of activity in subgenual cingulate, ventromedial prefrontal and posterior cingulate cortices to threat of painful arm stimulation (CS + arm > CS − arm). Our findings provide evidence for differences in emotion-related brain activity in SCI patients. We suggest that the observed functional abnormalities including enhanced anterior cingulate and PAG reflect central sensitization of the pain matrix, while decreased subgenual cingulate activity may represent a substrate underlying affective vulnerability in SCI patients consequent upon perturbation of autonomic control and afferent visceral representation. Together these observations may account for motivational and affective sequelae of SCI in some individuals.
doi:10.1093/brain/awh699
PMCID: PMC2633768  PMID: 16330503
autonomic arousal; emotion; functional magnetic resonance; spinal cord injury
21.  Effects of Alcohol Intoxication on Response Conflict in a Flanker Task 
Events evoke seamlessly integrated stimulus evaluation and response preparation processing streams, guided by regulative functions that change behavior flexibly in accord with the internal goals and contextual demands. The neural basis of the effects of alcohol intoxication on these processing streams is poorly understood, despite the evidence of alcohol’s deleterious effects on both attention and motor control. In an attempt to separate and examine relative susceptibility of these two dimensions, we employed a color version of the Eriksen flanker task that manipulated compatibility at the stimulus- and response-processing levels. Functional magnetic resonance imaging (fMRI) was performed in healthy social drinkers as they participated in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. Alcohol increased reaction times to response-level incongruity and decreased accuracy overall. Relative to the no-conflict condition, the observed brain activity was predominantly evoked by response-related conflict in medial prefrontal and lateral prefrontal cortices under placebo, in agreement with extensive evidence of their role in conflict processing. Activity evoked by response incongruity in the medial frontal cortex and insula was insignificant under alcohol, indicating its interference with response inhibition and preparation. Conversely, activity in ventrolateral prefrontal and premotor areas was relatively greater under alcohol than placebo, suggesting their compensatory engagement. This finding is consistent with the compensatory prefrontal activity increase found in studies with chronic alcoholic individuals, indicating functional reorganization with a goal of optimizing response strategy. These results delineate functional differences and selective susceptibility of a prefrontal network subserving response-level conflict processing. Our findings are incompatible with notions that moderate alcohol primarily affects attentional or stimulus-related processing and argue instead that its primary influence is on response inhibition, selection, and execution, with ramifications for the models of behavioral self-control and the inability to refrain from drinking.
doi:10.4172/2155-6105.S3-002
PMCID: PMC3682793  PMID: 23772336
Eriksen flanker; Anterior cingulated; Lateral prefrontal cortex; Compensatory activity
22.  Interoception Drives Increased Rational Decision-Making in Meditators Playing the Ultimatum Game 
Human decision-making is often conceptualized as a competition between cognitive and emotional processes in the brain. Deviations from rational processes are believed to derive from inclusion of emotional factors in decision-making. Here, we investigate whether experienced Buddhist meditators are better equipped to regulate emotional processes compared with controls during economic decision-making in the Ultimatum Game. We show that meditators accept unfair offers on more than half of the trials, whereas controls only accept unfair offers on one-quarter of the trials. By applying fMRI we show that controls recruit the anterior insula during unfair offers. Such responses are powerful predictors of rejecting offers in social interaction. By contrast, meditators display attenuated activity in high-level emotional representations of the anterior insula and increased activity in the low-level interoceptive representations of the posterior insula. In addition we show that a subset of control participants who play rationally (i.e., accepts >85% unfair offers) recruits the dorsolateral prefrontal cortex presumably reflecting increased cognitive demands, whereas rational meditators by contrast display elevated activity in the somatosensory cortex and posterior superior temporal cortex. In summary, when assessing unfairness in the Ultimatum Game, meditators activate a different network of brain areas compared with controls enabling them to uncouple negative emotional reactions from their behavior. These findings highlight the clinically and socially important possibility that sustained training in mindfulness meditation may impact distinct domains of human decision-making.
doi:10.3389/fnins.2011.00049
PMCID: PMC3082218  PMID: 21559066
decision-making; fMRI; mindfulness; posterior insula; anterior insula; social fairness; DLPFC; striatum
23.  Event-Related Theta Power during Lexical-Semantic Retrieval and Decision Conflict is Modulated by Alcohol Intoxication: Anatomically Constrained MEG 
Language processing is commonly characterized by an event-related increase in theta power (4–7 Hz) in scalp EEG. Oscillatory brain dynamics underlying alcohol’s effects on language are poorly understood despite impairments on verbal tasks. To investigate how moderate alcohol intoxication modulates event-related theta activity during visual word processing, healthy social drinkers (N = 22, 11 females) participated in both alcohol (0.6 g/kg ethanol for men, 0.55 g/kg for women) and placebo conditions in a counterbalanced design. They performed a double-duty lexical decision task as they detected real words among non-words. An additional requirement to respond to all real words that also referred to animals induced response conflict. High density whole-head MEG signals and midline scalp EEG data were decomposed for each trial with Morlet wavelets. Each person’s reconstructed cortical surface was used to constrain noise-normalized distributed minimum norm inverse solutions for theta frequencies. Alcohol intoxication increased reaction time and marginally affected accuracy. The overall spatio-temporal pattern is consistent with the left-lateralized fronto-temporal activation observed in language studies applying time-domain analysis. Event-related theta power was sensitive to the two functions manipulated by the task. First, theta estimated to the left-lateralized fronto-temporal areas reflected lexical-semantic retrieval, indicating that this measure is well suited for investigating the neural basis of language functions. While alcohol attenuated theta power overall, it was particularly deleterious to semantic retrieval since it reduced theta to real words but not pseudowords. Second, a highly overlapping prefrontal network comprising lateral prefrontal and anterior cingulate cortex was sensitive to decision conflict and was also affected by intoxication, in agreement with previous studies indicating that executive functions are especially vulnerable to alcohol intoxication.
doi:10.3389/fpsyg.2012.00121
PMCID: PMC3334511  PMID: 22536192
lexical decision; pseudowords; lexical-semantic retrieval; conflict processing; inferior frontal; anterior cingulate; temporal cortex
24.  Withdrawal-Associated Increases and Decreases in Functional Neural Connectivity Associated with Altered Emotional Regulation in Alcoholism 
Neuropsychopharmacology  2012;37(10):2267-2276.
Alcoholic patients who have undergone multiple detoxifications/relapses show altered processing of emotional signals. We performed functional magnetic resonance imaging during performance of implicit and explicit versions of a task in which subjects were presented with morphs of fearful facial emotional expressions. Participants were abstaining, multiply detoxified (MDTx; n=12) or singly detoxified patients (SDTx; n=17), and social drinker controls (n=31). Alcoholic patients were less able than controls to recognize fearful expressions, and showed lower activation in prefrontal areas, including orbitofrontal cortex and insula, which mediate emotional processing. The decrease in activation was greater in MDTx patients who also showed decreased connectivity between insula and prefrontal areas, and between amygdala and globus pallidus. In the explicit condition, the strength of connectivity between insula and areas involved in regulation of emotion (inferior frontal cortex and frontal pole) was negatively correlated with both the number of detoxifications and dependency (measured by the severity of alcohol dependency (SADQ) and control over drinking score (Impaired Control questionnaire, ICQ)). In contrast, increased connectivity was found between insula and the colliculus neuronal cluster, and between amygdala and stria terminalis bed nucleus. In the implicit condition, number of detoxifications and ICQ score correlated positively with connectivity between amygdala and prefrontal cortical areas involved in attentional and executive processes. Repeated episodes of detoxification from alcohol are associated with altered function both in fear perception pathways and in cortical modulation of emotions. Such changes may confer increased sensitivity to emotional stress and impaired social competence, contributing to relapse.
doi:10.1038/npp.2012.77
PMCID: PMC3422491  PMID: 22617355
fMRI; fearful facial expression; detoxification; amygdala; insula; prefrontal cortex; Alcohol & Alcoholism; amygdala; Biological Psychiatry; detoxification; fearful facial expression; fMRI; Imaging; Clinical or Preclinical; insula; Psychiatry & Behavioral Sciences
25.  Pregabalin Influences Insula and Amygdala Activation During Anticipation of Emotional Images 
Neuropsychopharmacology  2011;36(7):1466-1477.
Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.
doi:10.1038/npp.2011.32
PMCID: PMC3096815  PMID: 21430645
pregabalin; neuroimaging; insula; amygdala; anticipation; psychopharmacology; neuropharmacology; psychopharmacology; mood/anxiety/stress disorders; imaging; clinical or preclinical; pregabalin; anxiety; insula; prefrontal cortex; amygdala

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